Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13][CH:14]([CH3:16])[CH3:15])=[N:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2.[CH2:17]([O:24][C:25]1[C:30]([CH2:31]Cl)=[C:29]([CH3:33])[CH:28]=[C:27]([CH3:34])[N:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1COCC1>O1CCOCC1>[CH2:17]([O:24][C:25]1[C:30]([CH2:31][N:9]2[CH2:8][CH2:7][C:6]3[C:11](=[C:2]([Cl:1])[C:3]([O:13][CH:14]([CH3:16])[CH3:15])=[N:4][CH:5]=3)[C:10]2=[O:12])=[C:29]([CH3:33])[CH:28]=[C:27]([CH3:34])[N:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cc(C)c(CCl)c(OCc2ccccc2)n1
Reactant: CC(C)Oc1ncc2c(c1Cl)C(=O)NCC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Cc1cc(C)c(CN2CCc3cnc(OC(C)C)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Temperature: 100 °C
Yield: 18.9 %

Procedure:
To a mixture of 8-chloro-7-(propan-2-yloxy)-3,4-dihydro-2,6-naphthyridin-1(2H)-one (112e, 60.0 mg, 0.250 mmol) and 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (Cpd Z, 78 mg, 0.3 mmol) in 1,4-dioxane (3 mL) was added KHMDS in THF (1.0 M, 1.24 mL, 1.24 mmol). The reaction mixture was heated at 100° C. for 1 hour, then cooled to room temperature. The reaction mixture was concentrated, H2O (10 mL) was added, and the aqueous layer extracted with EtOAc (3×10 mL). The combined organic layers were concentrated under vacuum and the residue purified by preparative HPLC to give 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-7-(propan-2-yloxy)-3,4-dihydro-2,6-naphthyridin-1(2H)-one (112f, 22 mg, 19% yield) as a white solid.
Reaction SMILES: [N:1]1[N:2]([CH2:6][C:7]([OH:9])=O)[N:3]=[CH:4][CH:5]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:37]=[CH:38][CH:39]=1)[CH2:14][C@H:15]1[CH2:19][NH:18][C@H:17]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[O:21])[CH2:16]1>>[N:3]1[N:2]([CH2:6][C:7]([N:18]2[CH2:19][C@H:15]([CH2:14][C:13]3[CH:37]=[CH:38][CH:39]=[C:11]([Cl:10])[CH:12]=3)[CH2:16][C@H:17]2[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[CH:25][CH:24]=2)=[O:21])=[O:9])[N:1]=[CH:5][CH:4]=1
Reactant: O=C(O)Cn1nccn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2cccc(Cl)c2)CN1
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2cccc(Cl)c2)CN1C(=O)Cn1nccn1

Procedure:
Proceeding as in Example 1, but substituting 2-(2H-1,2,3-triazol-2-yl)acetic acid and (2S,4R)-4-(3-chlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 268, (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(3-chlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:19]([OH:21])=O)[CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(N[C@H](C(O)=O)CC1SC=CC=1)=O)C1C=CC=CC=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[C:58]([NH2:62])([CH3:61])([CH3:60])[CH3:59]>C1COCC1>[C:58]([NH:62][C:19](=[O:21])[C@H:12]([CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])([CH3:61])([CH3:60])[CH3:59]
Reactant: CC(C)(C)N
Reactant: O=C(NC(Cc1cccs1)C(=O)O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: O=C(N[C@@H](Cc1cccs1)C(=O)O)OCc1ccccc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)[C@H](Cc1cccs1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.29 h
Yield: 97 %

Procedure:
Into a 500 ml flask was placed 8.06 g of the subtitled compound of Example A, N-(Benzyloxycarbonyl)-3-(2-thienyl)-L-alanine, in 130 ml of THF. The compound was cooled to 0° C. N-Methylmorpholine (4.23 ml) was added, followed by isobutylchloroformate (4.04 ml) over two minutes. The mixture was stirred for 15-20 minutes, and 3.74 ml of t-butylamine was added. The bath was removed, and the mixture was stirred at room temperature for two hours. The mixture was concentrated on rotovap, and the residue was taken up in ethyl acetate. The residue was washed successively with H2O, HCl, and saturated NaHCO3 solution. The organics were separated and dried with Na2SO4, filtered, and concentrated to an oil. The oil was dissolved in 100 ml hot hexane and cooled in a refrigerator overnight to give a solid. The hexane was decanted, followed by drying to yield a solid of 9.25 g N-(carbobenzyloxy)-3-(2-thienyl)-L-alanine-tert-butylamide (97% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=CC=CC=1.Cl.ClCC[NH2:12].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][CH2:2][CH2:7][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:19]([NH2:12])(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Clc1ccccc1
Reactant: NCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: NS(=O)(=O)c1ccccc1CCCl

Procedure:
580 g. of monochlorobenzene were added to an aqueous solution of 116 g. (1 mole) of 2-chloroethylamine hydrochloride in 450 g. of water and 177 g. (1 mole) of benzenesulfonylchloride, and then the mixture was stirred at 10° ± 3°C. for 3 hours while adjusting pH to 6.5 to 8.5 with 138 g. (1 mole) of potassium carbonate. After completion of the reaction, the reaction solution was treated in the same manner as described in Example 3 to obtain 2-chloroethylbenzenesulfonamide in 94 % of yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1(C(OC)=O)[C:12](=[O:13])[CH2:11][CH2:10][N:9]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:8]1)=[O:5])[CH3:2].[Cl-].[Li+].O>CN(C)C=O>[O:13]=[C:12]1[CH2:11][CH2:10][N:9]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:8][CH:7]1[CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)CN1CCC(=O)C(CC(=O)OCC)(C(=O)OC)C1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CN(CC(=O)OCC)CCC1=O
Yield: 48.6 %

Procedure:
Ethyl 3-ethoxycarbonylmethyl-3-methoxycarbonyl-4-oxo-1-piperidineacetate (1.0 g) and 140 mg of lithium chloride were dissolved in 10 ml of N,N-dimethylformamide and the solution was refluxed for 48 hours. Then, 10 ml of water was added to the reaction liquid, and the mixture was extracted with 100 ml of ethyl acetate. The resulting extract was dried over sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: chloroform) to give 400 mg of diethyl 4-oxo-1,3-piperidinediacetate as an oily substance.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH2:20])=[CH:15][CH:14]=1.OO.C(=O)(O)[O-:34].[Na+]>CO.O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]=[N:20][OH:34])=[CH:17][CH:18]=1)[CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reactant: O=C([O-])O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: O
Product: ON=Cc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reaction time: 3 h
Yield: 63 %

Procedure:
To a stirred solution of N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (200 mg, 0.50 mmol) in MeOH (5 mL) was added solid sodium tungstate dihydrate (332 mg, 1.0 mmol) followed by a 35 wt % aqueous solution of hydrogen peroxide (2.9 mL, 30 mmol). The resulting suspension was stirred 3 h, then saturated aqueous sodium bicarbonate (5 mL) was added. The phases were separated and the aqueous layer was extracted with CH2Cl2 (3×10 mL), then the combined organic extracts were washed once with brine (10 mL), dried (MgSO4), and concentrated in vacuo. Purification of the crude material by flash chromatography (silica gel, 75:1:1 CH2Cl2MeOH/NH4OH) afforded the title compound (130 mg, 63%) as a white solid. 1H NMR (CDCl3) δ 1.63–1.66 (m, 1H), 1.97–2.07 (m, 2H), 2.25–2.27 (m, 1H), 2.66–2.72 (m, 1H), 2.80–2.85 (m, 1H), 3.65 (d, 1H, J=14 Hz), 3.71 (d, 1H, J=14 Hz), 5.03 (d, 1H, J=16 Hz), 4.14 (dd, 1H, J=9, 7 Hz), 4.21 (d, 1H, J=16 Hz), 7.11–7.19 (m, 3H), 7.41–7.48 (m, 6H), 7.65 (br d, 1H, J=5 Hz), 8.18 (s, 1H), 8.67 (dd, 1H, J=5, 1 Hz); 13C NMR (CDCl3) δ 22.2, 23.9, 30.2, 49.5, 55.0, 61.2, 112.1, 119.4, 122.7, 123.3, 127.8, 130.1, 133.0, 136.2, 138.7, 141.4, 147.8, 150.0, 156.2, 157.7. ES-MS m/z 412 (M+H). Anal. Calcd. for C25H25N5O.0.4H2O.0.3CH2Cl2: C, 68.41; H, 5.99; N, 15.77. Found: C, 68.57; H, 5.86; N, 15.48.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:15]([CH3:16])=[C:14]([Cl:17])[CH:13]=[CH:12][C:11]=1[S:18]([Cl:21])(=[O:20])=[O:19].O>ClC(Cl)C(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:1][CH2:16][C:15]1[C:10]([Cl:9])=[C:11]([S:18]([Cl:21])(=[O:20])=[O:19])[CH:12]=[CH:13][C:14]=1[Cl:17]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1c(Cl)ccc(S(=O)(=O)Cl)c1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)C(Cl)Cl
Solvent: O
Product: O=S(=O)(Cl)c1ccc(Cl)c(CCl)c1Cl
Temperature: 120 °C
Yield: 11.6 %

Procedure:
10 g (0.075 mol) of N-chlorosuccinimide and 30 mg of benzoyl peroxide are added to a solution of 6.5 g (0.025 mol) of 2,4-dichloro-3-methylbenzenesulfonyl chloride in 30 ml of 1,1,2,2-tetrachloroethane at room temperature and under a nitrogen atmosphere. The reaction mixture is heated at 120° C. for 3 hours, cooled to room temperature, poured into water and then extracted with dichloromethane. The organic phase is washed with water, with saturated sodium bicarbonate solution and finally with water until the washings are neutral. It is then dried over magnesium sulfate and concentrated under reduced pressure. Recrystallization from hexane gives 0.85 g of the expected product in the form of white crystals (yield=11.5%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[OH:13].[C:14]([O-:17])([O-])=O.[K+].[K+].C([O-])([O-])=O.[Cs+].[Cs+].CN([CH:29]=[O:30])C>CC(C)=O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][C:7](=[O:12])[CH:6]=[C:5]([O:13][CH2:11][CH2:2][CH2:3][O:17][CH:14]3[CH2:9][CH2:4][CH2:5][CH2:29][O:30]3)[C:4]=2[CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Reactant: O=c1cc(O)c2cc(Br)ccc2o1
Agent: [Cs+]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1cc(OCCCOC2CCCCO2)c2cc(Br)ccc2o1
Temperature: 55 °C
Yield: 62 %

Procedure:
6-Bromo-4-hydroxycoumarin (1.19 mmol, 0.287 g), K2CO3 (3.57 mmol, 0.493 g) and 2-3-(bromopropoxy)tetrahydro-2H-pyran (1.19 mmol, 0.264 g) is suspended in 10 mL of acetone, and is heated to 55° C. for 24 hrs at which time the reaction is not complete. Cs2CO3 (1.54 mmol, 0.5 g) and 5 mL of DMF are added and the reaction is heated for an additional 2 hrs. Twenty-five percent of the crude THP protected material is purified by HPLC to afford the title compound (70.8 mg, 62%); 1H NMR (CDCl3, 300 MHz) δ 7.91 (1H, d, J=2.25 Hz), 7.82 (1H, dd, J=2.5, 9 Hz), 7.39 (1H, d, J=9 Hz), 5.98 (1H, s), 4.59 (1H, m), 4.31 (2H, t, J=6 Hz), 3.83 (1H, m), 3.72 (1H, m), 3.55 (2H, m), 2.09 (2H, m), 1.65 (2H, m), 1.45 (4H, m); MS (ESI, Pos.) calcd for C17H19BrO5 m/z [M+H]=383.0, found 383.1.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([Br:18])[N:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(N(CC)CC)C>O1CCOCC1>[Br:18][C:4]1[CH:5]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:7]=[C:2]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:3]=1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(Br)c2)cc1
Reactant: C1CNCCN1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Nc1ccc(S(=O)(=O)c2cc(Br)nc(N3CCNCC3)c2)cc1
Temperature: 40 °C
Reaction time: 72 h
Yield: 82.7 %

Procedure:
0.275 g (0.0007 mol) of 4-(2,6-dibromopyridine-4-sulphonyl)-phenylamine was dissolved in 10 ml of dioxane and treated with 0.066 g (0.00077 mol) of piperazine and 1 ml of triethylamine. The mixture was stirred at 40° C. for 72 hrs. and the solvent was then removed. The residue was partitioned in ethyl acetate and water and the organic phase was extracted with sat. sodium chloride solution and dried over MgSO4 and filtered. After removal of the solvent the residue was chromatographed on silica gel with dichloromethane/methanol 9:1 and there was obtained 0.23 g (82%) of 4-(2-bromo-6-piperazin-1-ylpyridin-4-sulphonyl) -phenylamine as yellowish crystals; m.p.: 173-175° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[Cl:16]N1C(=O)CCC1=O.CN(C)C=O>O>[NH2:1][C:2]1[C:3]([Cl:16])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1cc2cccc(N)c2[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(Cl)c(N)c2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
A mixture of ethyl 7-amino-1H-indole-2-carboxylate (2.30 g), N-chlorosuccinimide (1.40 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature overnight. To the reaction mixture was added water, and the resulting crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (1.59 g, yield 63%) was obtained as pale-yellow crystals from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). melting point 217-218° C. (decomposition).
Reaction SMILES: C([NH:4][C@@H:5]1[C:11](=[O:12])[O:10][C:8](=[O:9])[CH:7]([CH3:13])[CH2:6]1)(O)=O.CN(C)CCCN.C([NH:24][C@H:25]([C:41]([O:43]C(=O)[C@H](CCCCNC(OCC1C=CC=CC=1)=O)NC(O)=O)=[O:42])[CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])(O)=[O:22]>ClCCCl>[CH3:13][CH:7]([C:8]([OH:9])=[O:22])[CH2:6][C@@H:5]([C:11]([OH:10])=[O:12])[NH2:4].[CH2:34]([O:33][C:31]([NH:30][CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]([C:41]([OH:43])=[O:42])[NH2:24])=[O:32])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC1C[C@H](NC(=O)O)C(=O)OC1=O
Reactant: O=C(O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)O
Agent: CN(C)CCCN
Solvent: ClCCCl
Product: CC(C[C@H](N)C(=O)O)C(=O)O
Product: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To 1,2-dichloroethane (20 ml) was added N-carboxy-γ-methyl-L-glutamic acid anhydride (5.00 g, 26.72 mmol), and the mixture was cooled to 0° C. N,N-Dimethyl-1,3-propanediamine (66.80 μl, 0.534 mmol) was added as an initiator, and the mixture was stirred at 25° C. for 1 day and cooled again to 0° C. 1,2-Dichloroethane (20 ml) was added, Nα-carboxy-Nε-benzyloxycarbonyl-L-lysine anhydride (4.09 g, 13.36 mmol) was added, and the mixture was stirred at 25° C. for 1 day to give a γ-methyl-L-glutamic acid-Nε-benzyloxycarbonyl-L-lysine block copolymer. The weight average molecular weight, Mw, of the copolymer was measured by Measurement Method 1 described below. In addition, the composition of the copolymer was measured by Measurement method 2 described below.
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][C:19]3[N:23]([C:24]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:22]=[N:21][N:20]=3)[C:10](=[O:43])[CH:9]([N:44]3C(=O)C4=CC=CC=C4C3=O)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>O1CCCC1>[NH2:44][CH:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:18][C:19]2[N:23]([C:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:22]=[N:21][N:20]=2)[C:10]1=[O:43]
Reactant: O=C1C(N2C(=O)c3ccccc3C2=O)N=C(c2ccccc2)c2ccccc2N1Cc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: NC1N=C(c2ccccc2)c2ccccc2N(Cc2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)C1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 51.3 %

Procedure:
To a solution of (3RS)-1,3-dihydro-5-phenyl-3-phthalimido-1-[(1-trityl-1H-tetrazol -5-yl)methyl]-2H-1,4-benzodiazepin-2-one (128 g) in tetrahydrofuran (2.56 l) was added hydrazine monohydrate (10.43 ml ) at room temperature. The mixture was stirred at 60° C. for 4 hours and the resultant precipitate was filtered off. The filtrate and the washings were evaporated in vacuo and the residue was dissolved in dichloromethane. After the insoluble material was filtered off, the solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate and washed with 1N-sodium hydroxide solution and subsequently with water. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was evaporated in vacuo to about 300 ml. The residue was stirred at room temperature. The resulting precipitates were collected by filtration to give (3RS)-3-amino-1,3-dihydro-5-phenyl-1-[(1-trityl-1H-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (53.6 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(CC)CC)C.[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[O:21]=[C:15]1[CH:14]([N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:36]([NH:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:37])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3c(CNC(=O)Nc4ccccc4)cccc3C2=O)C(=O)N1
Temperature: 4 °C
Reaction time: 5 h
Yield: 84.9 %

Procedure:
A suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and triethylamine (0.3 g, 2.7 mmol) in THF (30 mL) was cooled to 4° C. Phenyl isocyanate (0.3 g, 2.7 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The mixture was concentrated, and the residue was stirred with 1N HCl (30 mL). The solid was collected and slurried with ethanol (10 mL) to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-phenyl-urea (0.7 g, 89%) as a white solid: mp 328-330° C.; 1H NMR (DMSO-d6) δ 2.00-2.04 (m, 1H), 2.36-2.64 (m, 2H), 2.86-2.98 (m, 1H), 4.37-4.58 (m, 4H, 2CH2), 5.12-5.19 (dd, J=5.0 and 13.2 Hz, 1H, CH), 6.71 (t, J=5.7 Hz, 1H, NH), 6.89 (t, J=7.3 Hz, 1H, Ar), 7.21 (t, J=7.6 Hz, 2H, Ar), 7.38 (d, J=7.6 Hz, 2H, Ar), 7.48-7.65 (m, 3H, Ar), 8.61 (s, 1H, NH), 11.03 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.57, 31.18, 39.67, 46.20, 51.58, 117.80, 121.20, 121.54, 128.29, 128.62, 130.33, 131.64, 135.59, 139.90, 140.29, 155.22, 168.09, 171.01, 172.84; Anal. calcd. for C21H20N4O4: C, 64.28; H, 5.14; N, 14.28. Found: C, 64.36; H, 4.96; N, 14.17.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13]>C1(C)C=CC=CC=1>[N:1]1([CH2:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: COC(=O)c1cccc(CBr)c1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of piperidine (25 ml) and 3-(bromomethyl)benzoic acid, methyl ester (20 g) in toluene (600 ml) was stirred at room temperature for 4 h. The white precipitate was removed by filtration and the filtrate was distilled to give the title compound as a colourless oil (17.56 g) b.p. 110° (10-1 mm). TLC silica; ether; Rf 0.7.
Reaction SMILES: [CH2:1]([O:14][C:15]1[CH:33]=[CH:32][C:18]([CH2:19][NH:20][C:21]2[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH-].[K+].C(O)C.O.C(O)(=O)C>O>[CH2:1]([O:14][C:15]1[CH:33]=[CH:32][C:18]([CH2:19][NH:20][C:21]2[CH:31]=[CH:30][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCCOc1ccc(CNc2ccc(C(=O)OCC)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCCCCCCCCCCOc1ccc(CNc2ccc(C(=O)O)cc2)cc1

Procedure:
A mixture of 7.0 g. of ethyl p-[(p-tridecyloxybenzyl)amino]benzoate (prepared as described in Example 22), 7.0 g. of potassium hydroxide and 150 ml. of ethanol-water (9:1) is refluxed for 3.5 hours. The solution is acidified while hot, diluted with water, filtered and the solid washed with water to give white crystals, m.p. 110°-113° C. and 145°-150° C. The solid is heated with 200 ml. of glacial acetic acid and the solution chilled and filtered to give crystals, m.p. 110°-112° C. and 155°-160° C. The filtrate is diluted with water to give white crystals (pure by TLC) m.p. 108°-122° C. and 150°-155° C. The first crop of crystals is slurried in 75 ml. of acetone, filtered and the filtrate chilled and filtered. The filtrate is diluted with water to give white crystals (pure by TLC). The two crops pure by TLC are combined, dried in vacuo to give white crystals, m.p. 110°-112° C. and 155°-160° C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cu](C#N)[C:20]#[N:21]>>[C:20]([C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])#[N:21]
Reactant: N#C[Cu]C#N
Reactant: CCCCCCCCCCCCc1ccsc1Br
Product: CCCCCCCCCCCCc1ccsc1C#N
Yield: 34 %

Procedure:
A reaction between 2-bromo-3-dodecylthiophene (Compound-1, 81.0 mmol) and excess copper cyanide (CuCN) produced 2-cyano-3-dodecylthiophene (Compound-2, 34% yield), which was heated and reacted with excess (approximately 2.5 equivalents) dithiophosphoric acid O,O′-diethylether in tetrahydrofuran (THF) solution for about 12 hours. The obtained 2-thioamino-3-dodecylthiophene (Compound-3, 45% yield) and 1.2 equivalents of bromooctanone were reacted to obtain 2-thiazole(3′-dodecyl)-3-dodecylthiophene (Compound-4, 32% yield), which was in turn reacted with N-bromosuccinimide (NBS) to obtain the thiophene-thioazol derivative (Compound-5, 82% yield). An NMR analysis result of the resultant product was as follows:
Reaction SMILES: [C:1]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:2][C:3]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])([C:5]([O:7][CH2:8][CH3:9])=[O:6])O.[H][H]>C(O)C>[CH2:2]([C:1]([O:17][CH2:18][CH3:19])=[O:16])[CH:3]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CC(O)(CC(=O)OCC)C(=O)OCC
Reactant: [H][H]
Solvent: CCO
Product: CCOC(=O)CC(CC(=O)OCC)C(=O)OCC
Yield: 54 %

Procedure:
400 ml of triethyl citrate were hydrogenated at 175° C. and 10 bar together with 1100 ml of ethanol and 60 g of catalyst B (4-mm pellets) until the take-up of hydrogen had ceased. The reaction product was freed from ethanol and distilled under reduced pressure, giving 231.8 g (54%) of triethyl 1,2,3-propanetricarboxylate.
Reaction SMILES: [O:1]=[S:2]1(=[O:26])[C:7]2[CH:8]=[C:9]([O:12][C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=3)[C:16]([NH:18][NH2:19])=[O:17])[CH:10]=[CH:11][C:6]=2[N:5]2[CH2:23][CH2:24][CH2:25][C:4]2=[N:3]1.[C:27](N1C=CN=C1)(N1C=CN=C1)=[O:28].CCN(CC)CC.Cl>C1COCC1.CN(C=O)C>[O:26]=[S:2]1(=[O:1])[C:7]2[CH:8]=[C:9]([O:12][C:13]3[CH:14]=[C:15]([C:16]4[O:17][C:27](=[O:28])[NH:19][N:18]=4)[CH:20]=[CH:21][CH:22]=3)[CH:10]=[CH:11][C:6]=2[N:5]2[CH2:23][CH2:24][CH2:25][C:4]2=[N:3]1
Reactant: NNC(=O)c1cccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=c1[nH]nc(-c2cccc(Oc3ccc4c(c3)S(=O)(=O)N=C3CCCN34)c2)o1

Procedure:
A suspension of 150 mg (0.40 mmol) of the product obtained in Step B, 85 mg (0.52 mmol) of 1,1′-carbonyldiimidazole and 95 μl (0.68 mmol) of Et3N in a mixture of THF (3.7 ml) and DMF (3.7 ml) is refluxed for 3 hours. The mixture is allowed to return to ambient temperature and is acidified with 1N HCl. A white precipitate forms, which is filtered off to yield the title product.