Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]3[O:18][CH2:19][C:20](=[O:22])[NH:21][C:16]=3[N:15]=[C:14]([CH3:23])[N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:31][C:32]([NH2:34])=[O:33]>C(C(C)=O)C>[NH2:34][C:32]([CH2:31][N:21]1[C:20](=[O:22])[CH2:19][O:18][C:17]2[C:12]([N:9]3[CH2:10][CH2:11][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]3)=[N:13][C:14]([CH3:23])=[N:15][C:16]1=2)=[O:33]
Reactant: NC(=O)CCl
Reactant: CCOC(=O)N1CCN(c2nc(C)nc3c2OCC(=O)N3)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)N1CCN(c2nc(C)nc3c2OCC(=O)N3CC(N)=O)CC1
Reaction time: 8 h
Yield: 57.5 %

Procedure:
A suspension containing 0.96 g of 4-(4-ethoxycarbonyl-1-piperazinyl)-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one (Example 1), 25 ml of methyl ethyl ketone, 0.5 g of anhydrous potassium carbonate and 0.31 g of chloroacetamide is boiled under stirring for 8 hours, filtered as hot, washed with methyl ethyl ketone and this filtrate is set aside. The precipitate is washed with water, then with ether and dried to give 0.65 g of the product, m.p.: 225°-227° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.N12CCC(CC1)CN2>CS(C)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: C1CN2CCC1CN2
Solvent: CS(C)=O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCOCC3)c(F)cc2c1=O
Temperature: 140 °C
Yield: 68.5 %

Procedure:
A mixture of 2.83 g (0.01 mol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.9 g (0.01 mol) of morpholine and 2.3 g of diazabicyclo [2.2.2]octane (0.02 mol) in 35 ml of dimethyl sulphoxide is heated to 140° C. for 5 hours. The solvent is distilled off in vacuo, 50 ml of water are added to the residue, the mixture is acidified with semiconcentrated hydrochloric acid, and, when the mixture is cold, the product is filtered off under suction, washed with water, dried in vacuo and recrystallised from glycol monomethyl ether. 2.4 g of 1-cyclopropyl-6,8-difluoro-7-(morpholin-4-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid having a decomposition temperature of 257°-260° C. are obtained.
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Br.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1([CH:24]2[C:33]3[C:28](=[CH:29][C:30]([O:35][CH3:36])=[C:31]([OH:34])[CH:32]=3)[CH2:27][CH2:26][N:25]2[CH3:37])[CH2:23][CH2:22]1.C(N(CC)CC)C>CCOCC>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1([CH:24]2[C:33]3[C:28](=[CH:29][C:30]([O:35][CH3:36])=[C:31]([O:34][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:32]=3)[CH2:27][CH2:26][N:25]2[CH3:37])[CH2:23][CH2:22]1
Reactant: CCCCCCCCCC(=O)Cl
Reactant: COc1cc2c(cc1O)C(C1(c3ccccc3Cl)CC1)N(C)CC2
Agent: Br
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCCCCCC(=O)Oc1cc2c(cc1OC)CCN(C)C2C1(c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Decanoyl chloride (0.45 g) was added to a mixture of (+)-1-[1-(2-chlorophenyl)cyclopropyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrobromide (1 g, prepared in a similar manner to that described in Example 77), triethylamine (0.7 g) and ether (30 ml). The mixture was stirred at ambient temperature for 24 hours, then washed with water, 10% aqueous sodium hydroxide solution, and brine. The organic layer was dried over magnesium sulphate, filtered and concentrated to yield a gum which was purified by chromatography on a silica gel column using a 1:3 mixture of ether and light petroleum as eluant. The relevant fractions were concentrated in vacuo to yield (+)-1-[1-(2-chlorophenyl)cyclopropyl]-7-decanoyloxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (0.95 g) as a gum; having specific optical rotation αD of +21.47°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:10]2=[O:20])=[CH:5][CH:4]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH2:30][CH:31]1[O:33][CH2:32]1.[ClH:34]>C(O)(C)C>[ClH:34].[OH:33][CH:31]([CH2:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[O:22][CH3:21])[CH2:32][N:17]1[CH2:18][CH2:19][CH:14]([N:11]2[CH2:12][CH2:13][N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:10]2=[O:20])[CH2:15][CH2:16]1
Reactant: COc1ccc(N2CCN(C3CCNCC3)C2=O)cc1
Reactant: COc1ccccc1OCC1CO1
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(N2CCN(C3CCN(CC(O)COc4ccccc4OC)CC3)C2=O)cc1

Procedure:
A mixture of 17.9 g of 1-(4-methoxy-phenyl)-3-(4-piperidyl)-2-imidazolidinone and 11.7 g of 1-(2-methoxyphenyloxy)-2,3-epoxypropane in 200 ml of isopropyl alcohol is refluxed for 6 hours. The mixture is thereafter acidified with 5 N methanolic hydrochloric acid and concentrated under reduced pressure. The residue is freed from moisture still adhering to it by treatment with toluene. Recrystallisation of the residue from methanol with the addition of activated charcoal yields the 1-{1-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]-4-piperidyl}-3-(4-methoxy-phenyl)-imidazolidin-2-one-hydrochloride as a white crystalline substance with a melting point of 214°-215° C. The 1-(4-methoxy-phenyl)-3-(4-piperidyl)-2-imidazolidinone used as starting material can be prepared as follows: A mixture of 61.5 g of 4-methoxy-aniline and 51.3 g of 2-bromoethylamine-hydrobromide in 125 ml of methyl ethyl ketone is refluxed for 5 hours with stirring. The viscous suspension is thereafter evaporated to dryness under reduced pressure. The residue is suspended in 150 ml of isopropanol and then collected by filtration. The filter cake is washed with three 50 ml portions of isopropanol and with two 50 ml portions of diethyl ether. The crystalline product is made alkaline with a concentrated aqueous ammonia solution and extracted with five 50 ml portions of chloroform. The extracts are dried over sodium sulphate and concentrated under reduced pressure. The oily residue crystallises after trituration to give the 1-(4-methoxyphenyl)-ethylenediamine with a melting point of 64° C.
Reaction SMILES: C([O:3][P:4]([CH2:9][O:10][C@:11]1([CH3:26])[C@@H:15]([OH:16])[C@@H:14]([OH:17])[C@H:13]([N:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[N:20][C:19]2=[O:25])[O:12]1)(=[O:8])[O:5]CC)C.N1C(C)=CC=CC=1C.C[Si](I)(C)C>C(#N)C>[NH2:24][C:21]1[CH:22]=[CH:23][N:18]([C@@H:13]2[O:12][C@:11]([CH3:26])([O:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5])[C@@H:15]([OH:16])[C@H:14]2[OH:17])[C:19](=[O:25])[N:20]=1
Reactant: CCOP(=O)(CO[C@@]1(C)O[C@@H](n2ccc(N)nc2=O)[C@H](O)[C@@H]1O)OCC
Agent: C[Si](C)(C)I
Solvent: Cc1cccc(C)n1
Solvent: CC#N
Product: C[C@]1(OCP(=O)(O)O)O[C@@H](n2ccc(N)nc2=O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a solution of compound 30.5 (112 mg, 0.29 mmol) in acetonitrile (10 mL) was added 2,6-lutidine (0.20 mL, 1.7 mmol) and then trimethylsilyl iodide (0.41 mL, 2.8 mmol). The mixture was stirred at room temperature for 1 h. After the reaction was done, 0.30 mL of 2,6-lutidine was added to the mixture and the mixture was concentrated under reduced pressure. The residue was then put into solution with water (3 mL) and treated with sodium hydroxide 1N to pH=10. The solution was then acidify to pH=3 using acetic acid and subjected to a reverse phase (YMC-Pack ODS-A) to give compound 30.6 (69 mg, 72% yield). 1H NMR (300 MHz, D2O): δ 1.39 (s, 3H), 3.54 (m, 2H), 3.99 (d, 1H, J=4.6), 4.63 (m, 1H), 6.09 (d, 1H, J=7.0), 6.14 (d, 1H, J=7.0), 8.0 (d, 1H, J=7.6). LRMS (ESI) MH+ C10H16N3O8P requires 338.2. Found 337.8.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([CH2:14][NH2:15])[OH:13]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:15][CH2:14][CH2:12][OH:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: NCCO
Product: O=S(=O)(NCCO)c1ccc(F)cc1

Procedure:
The title compound was prepared according to the procedure of Intermediate 33 from 3.97 g (20 mmol) of 4-fluorobenzenesulfonyl chloride and 3.11 g (50 mmol) of ethanolamine, yielding 3.0 g of a white solid; m.p. 77-78° C.; MS (ES) m/z 219.8 (MH+); HRMS (EI) Calcd. for C8H10FNO3S (M+): 219.0366, Found: 219.0369.
Reaction SMILES: [C:1]([C:3]1[N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=2)#[N:2].[Br:22]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:22][CH2:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[O:13][CH3:14])[N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3]([C:1]#[N:2])=[CH:11]2
Reactant: COc1cc2c(cc1C)cc(C#N)n2C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc2c(cc1CBr)cc(C#N)n2C(=O)OC(C)(C)C
Yield: 100.1 %

Procedure:
To a stirred solution of 174 mg of tert-butyl 2-cyano-6-methoxy-5-methyl-1H-indole-1-carboxylate (0.61 mmol) in carbon tetrachloride (2.5 mL) was added 108 mg of N-bromosuccinimide (0.61 mmol) and 11 mg of AIBN (0.065 mmol). The mixture was refluxed for 1 h, then cooled and concentrated and filtered through short silica gel plug using hexane-ethyl acetate 10:1 to give 223 mg of crude tert-butyl 5-(bromomethyl)-2-cyano-6-methoxy-1H-indole-1-carboxylate that was used in the next step without further purification.
Reaction SMILES: C([N:8]1[CH2:15][C@H:14]([F:16])[CH2:13][C@H:9]1[C:10](O)=O)(OC(C)(C)C)=O.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([NH2:28])[CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[CH:26]=[CH:25][C:24]2[NH:27][C:10]([C@@H:9]3[CH2:13][C@@H:14]([F:16])[CH2:15][NH:8]3)=[N:28][C:23]=2[CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)O
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Product: CC(C)(C)c1ccc2[nH]c([C@@H]3C[C@@H](F)CN3)nc2c1

Procedure:
The title compound was prepared according to Method 4 using N-Boc-trans-4-fluoro-L-proline and 4-tert-butyl-1,2-diaminobenzene. The final residue was washed with ethyl acetate and diluted with water, basified with saturated lithium hydroxide solution (pH=8), extracted with ethyl acetate and dried over anhydrous Na2SO4 and concentrated under reduced pressure.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[C:5]([N:10]1[CH2:15][CH2:14][C:13](=O)[CH:12]([CH2:17][CH3:18])[CH2:11]1)([O:7][CH2:8][CH3:9])=[O:6].C([BH3-])#N.[Na+]>CO>[C:5]([N:10]1[CH2:15][CH2:14][CH:13]([NH:4][CH:1]2[CH2:3][CH2:2]2)[CH:12]([CH2:17][CH3:18])[CH2:11]1)([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)N1CCC(=O)C(CC)C1
Reactant: NC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)N1CCC(NC2CC2)C(CC)C1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Cyclopropylamine (14.25 g, 250 mmol) was added to the stirred solution of 1-carbethoxy-3-ethyl-4-piperidone (10 g, 50 mmol) in methanol (100 ml) and stirring was continued for 12 hr at ambient temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (3.9 g, 62 mmol) was added to it. Cooling was removed after 10 min. and stirring was continued for 12 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1 M sodium hydroxide solution (pH ˜10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to afford crude 1-carbethoxy-4-cyclopropylamino-3-ethyl piperidine. The obtained crude 1-carbethoxy-4-cyclopropylamino-3-ethylpiperidine was suspended in 7 M NaOH solution (30 ml), stirred at 130° C. for 160 hr, cooled and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to afford 4-cyclopropylamino-3-ethyl-piperidine. Yield 5.7 g (67%), C10H20N2, m/z 169, (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[C:8]([O:11][CH2:12][CH2:13][C@@H:14]([C:16]([OH:18])=[O:17])[NH2:15])(=[O:10])[CH3:9].C(OC(=O)C[C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])C.Cl>C(O)C.O>[F:26][C:25]([F:28])([F:27])[C:24]([NH:15][C@H:14]([C:16]([OH:18])=[O:17])[CH2:13][CH2:12][O:11][C:8](=[O:10])[CH3:9])=[O:29]
Reactant: CC(=O)OCC[C@H](N)C(=O)O
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(=O)OCC[C@H](NC(=O)C(F)(F)F)C(=O)O
Reaction time: 14 h
Yield: 45.1 %

Procedure:
7.6 g (55 mol) of potassium carbonate are added to a suspension of 9.9 g (50 mmol) of O-acetyl-L-homoserine hydrochloride and 7.8 g (55 mmol) of trifluoroacetylacetic acid ethyl ester in 200 ml of ethanol, and stirring is carried out for 14 hours. 10.8 g (110 mmol) of 37% hydrochloric acid and 200 ml of water are then added. The product obtained after removal of the ethanol by distillation is filtered off with suction, washed with water and dried. 5.8 g (45%) of N-trifluoroacetyl-O-acetyl-L-homo-serine are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:19]=[CH:20][N:21]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([C:8]([O:10]C)=[O:9])[CH:7]=1.[OH-].[Na+].O.Cl>O1CCCC1>[Cl:1][C:2]1[C:3]2[N:4]([CH:19]=[CH:20][N:21]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([C:8]([OH:10])=[O:9])[CH:7]=1
Reactant: COC(=O)c1cc(Cl)c2nccn2c1-c1cccc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(Cl)c2nccn2c1-c1cccc(F)c1
Temperature: 20 °C
Reaction time: 6 h
Yield: 102.6 %

Procedure:
A solution of methyl 8-chloro-5-(3-fluorophenyl)imidazo[1,2-a]pyridine-6-carboxylate (0.18 g, 0.57 mmol) in tetrahydrofuran (3 mL) was treated with 1 M sodium hydroxide in water (1.7 mL, 1.7 mmol) and stirred at 20° C. for 6 hours. The reaction mixture was concentrated, diluted with water, cooled to 0° C., and treated with 1 M hydrogen chloride in water (2.3 mL, 2.3 mmol) dropwise. The resultant suspension was filtered to give the desired product (0.17 g, quantitative) that was used without further purification. LCMS calculated for C14H9ClFN2O2 (M+H)+: m/z=291.0. found: 290.9.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:20][C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=O)=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1(N=C=NC2CCCCC2)CCCCC1.ClCCl.[NH2:62][C@H:63]([C:76]([O:78][CH2:79][C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1)=[O:77])[CH2:64][CH2:65][C:66]([O:68][CH2:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)=[O:67]>O1CCOCC1>[C:1]([O:18][CH:19]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:20][C:21]([NH:23][CH2:24][CH2:25][C:26]([NH:62][C@H:63]([C:76]([O:78][CH2:79][C:80]1[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=1)=[O:77])[CH2:64][CH2:65][C:66]([O:68][CH2:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)=[O:67])=[O:28])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)NCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)NCCC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 0.25 h
Yield: 46.6 %

Procedure:
N-(3-hexadecanoyloxyoctadecanoyl)-β-alanine (1.47 g) prepared by the method of Preparation B-5 and N,N'-dicyclohexylcarbodiimide (412 mg) were added to a mixed solution of dichloromethane (20 ml) and dioxane (20 ml). The resulting mixture was stirred for 15 minutes. Then, a solution of dibenzyl L-glutamate (650 mg) in dioxane (10 ml) was added thereto over a period of 30 minutes. The mixture was stirred for 2 hours at room temperature and allowed to stand overnight. The precipitated N,N'-dicyclohexylurea was removed off by filtration, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethanol to afford crystals of dibenzyl N-[N-(3-hexadecanoyloxyoctadecanoyl)-β-alanyl]-L-glutamate (850 mg).
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][NH:14][CH2:13][CH2:12]2.Br[C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([NH:27][C:28](=[O:34])[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[C:22]([Cl:35])[CH:21]=1>C1(C)C=CC=CC=1>[Cl:35][C:22]1[CH:21]=[C:20]([N:14]2[CH2:13][CH2:12][C:11]3[C:16](=[CH:17][CH:18]=[C:9]([Cl:8])[CH:10]=3)[CH2:15]2)[CH:25]=[C:24]([CH3:26])[C:23]=1[NH:27][C:28](=[O:34])[CH2:29][C:30]([CH3:32])([CH3:31])[CH3:33]
Reactant: Cc1cc(Br)cc(Cl)c1NC(=O)CC(C)(C)C
Reactant: Clc1ccc2c(c1)CCNC2
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCc3cc(Cl)ccc3C2)cc(Cl)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and (2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene (10 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (197 mg, 1.75 mmol), 6-chloro-1,2,3,4-tetrahydroisoquinoline hydrochloride salt (133 mg, 0.65 mmol), and N-(4-bromo-2-chloro-6-methylphenyl)-3,3-dimethylbutanamide (200 mg, 0.63 mmol) were then added, and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to room temperature, concentrated, and purified by thin layer chromatography (dichloromethane:methanol 5%) to afford the title compound as a solid.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]1[CH:33]=[CH:32][C:9]2[N:10]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:24]=3[O:30][CH3:31])(=[O:22])=[O:21])[C:11](=[O:19])[N:12]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:8]=2[CH:7]=1)[CH3:4].Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:36]>O.C1COCC1>[CH2:3]([O:5][C:6]1[CH:33]=[CH:32][C:9]2[N:10]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:35]([O:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[O:36])=[CH:25][C:24]=3[O:30][CH3:31])(=[O:21])=[O:22])[C:11](=[O:19])[N:12]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:8]=2[CH:7]=1)[CH3:4]
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(N)cc1OC
Reactant: O=C(Cl)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(NC(=O)Oc2ccccc2)cc1OC
Reaction time: 5 h

Procedure:
0.29 g of NaOH pellets in 2 ml of water was added at 5° C., with stirring, to a solution of 1.1 g of 5-ethoxy-1,3-dihydro-1-(2-methoxy-4-aminobenzenesulfonyl)-3-cyclo-hexyl-2H-benzimidazol-2-one, obtained in Example 5 step B), in 25 ml of THF. 1 ml of phenyl chloroformate was then added with continued stirring. The reaction mixture was then stirred for 5 hours, the temperature being allowed to rise to 20° C. The mixture was then concentrated under vacuum, the residue was taken up with water, extracted with ether and washed with water and the organic phase was dried over sodium sulfate and concentrated under vacuum. 1 g of the expected product was obtained by crystallization from iso ether. M.p.=197° C.
Reaction SMILES: C(N(CC)[C:4](=[O:30])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][CH:13]=[C:12]2[CH2:16][C@H:17]([NH:19][CH2:20][C@H:21]([OH:29])[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[CH3:18])C.[OH-:33].[K+]>O.C(O)C>[OH:29][C@H:21]([C:22]1[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=1)[CH2:20][NH:19][C@H:17]([CH3:18])[CH2:16][C:12]1[C:11]2[C:15](=[C:7]([O:6][CH2:5][C:4]([OH:33])=[O:30])[CH:8]=[CH:9][CH:10]=2)[NH:14][CH:13]=1
Reactant: [OH-]
Reactant: CCN(CC)C(=O)COc1cccc2c(C[C@@H](C)NC[C@H](O)c3ccc(O)cc3)c[nH]c12
Agent: [K+]
Solvent: O
Solvent: CCO
Product: C[C@H](Cc1c[nH]c2c(OCC(=O)O)cccc12)NC[C@H](O)c1ccc(O)cc1
Yield: 67.4 %

Procedure:
A solution of N,N-diethyl-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxyphenyl)ethylamino]propyl}-1H-indol-7-yloxy) acetamide (12 mg, 0.027 mmol) and potassium hydroxide (60 mg, 1.1 mmol) in water (0.5 mL) and ethanol (0.5 mL) is stirred at 60° C. for 6 hours. After cooling, the mixture is concentrated and acidified by addition of water (30 mL) and acetic acid. The resultant is purified by reversed phase column chromatography (COSMOSIL 75C18-OPN (Nacalai Tesque) (octadecyl-silica gel, particle diameter: 75 μm, hereinafter, the same), water→water/methanol=10/ 1) to give the desired (3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxyphenyl)ethylamino]propyl}-1H-indol-7-yloxy)acetic acid (7 mg, yield: 68%).
Reaction SMILES: [OH-].[Na+].[C:3]([C:8]1[CH:25]=[CH:24][C:11]([CH2:12][N:13]2[CH:17]=[CH:16][CH:15]=[C:14]2[CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)=[CH:10][CH:9]=1)([O:5]CC)=[O:4]>O.C(O)C>[C:3]([C:8]1[CH:9]=[CH:10][C:11]([CH2:12][N:13]2[CH:17]=[CH:16][CH:15]=[C:14]2[CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)=[CH:24][CH:25]=1)([OH:5])=[O:4]
Reactant: CCOC(=O)c1ccc(Cn2cccc2Cn2ccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(Cn2cccc2Cn2ccnc2)cc1
Yield: 35.5 %

Procedure:
A solution of sodium hydroxide (0.20 g) in water (20 ml) was added to a solution of 1-(4-carbethoxybenzyl)-2-(imidazol-1-ylmethyl) pyrrole (1.55 g) in ethanol (20 ml) and the mixture was heated under reflux for 8 hours. The solution was evaporated and the residue was taken up in water (25 ml). The solution was acidified with acetic acid and continuously extracted with chloroform to give a solid which was crystallised from isopropanol to give 1-(4-carboxybenzyl)-2-(imidazol-1-ylmethyl)pyrrole (0.50 g), m.p. 190°-191° (d).
Reaction SMILES: C(O[C:4]1[C:8]([O:9][CH2:10][CH3:11])=[N:7][S:6](=[O:12])[N:5]=1)C.[NH2:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[C:16]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[N:15]=1>O1CCCC1.CO>[CH2:10]([O:9][C:8]1[C:4]([N:31]2[CH2:32][CH2:33][N:28]([C:16]3[N:15]=[C:14]([NH2:13])[C:23]4[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=4)[N:17]=3)[CH2:29][CH2:30]2)=[N:5][S:6](=[O:12])[N:7]=1)[CH3:11]
Reactant: CCOC1=NS(=O)N=C1OCC
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Solvent: CO
Solvent: C1CCOC1
Product: CCOC1=NS(=O)N=C1N1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1.9 g (10 mMoles) of 3,4-diethoxy-1,2,5-thiadiazole-1-oxide are added to 2.9 g (10 mMoles) of 4-amino-6,7-dimethoxy-2-piperazinoquinazoline dissolved in 50 ml of tetrahydrofuran and 10 ml of methanol, followed by stirring for 5 hours at room temperature. The solid accumulating is separated off and recrystallized from 15 ml of dimethyl formamide and 10 ml of ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11]O)=[NH:10])=[CH:4][CH:3]=1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[C:14]#[CH:15].CCO.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH2:18]([O:17][C:13]([C:14]1[N:10]=[C:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[NH:11][CH:15]=1)=[O:16])[CH3:19]
Reactant: N=C(Cc1ccc(Br)cc1)NO
Reactant: C#CC(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)c1c[nH]c(Cc2ccc(Br)cc2)n1
Temperature: 190 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
2-(4-bromophenyl)-N-hydroxyacetamidine (5.0 g, 21.8 mmol) and ethyl propiolate (2.4 mL, 24.0 mmol) were dissolved in EtOH (100 mL, 2 mol). The mixture was heated to reflux for 7 hours, cooled and then concentrated. The residue was then dissolved in diphenyl ether (75 mL, 470 mmol), heated at 190° C. for 2 hours, cooled, combined with 400 mL of hexanes, and allowed to sit overnight. The solvent was decanted and the precipitant was dissolved in DCM and purified by column chromatography (0-10% MeOH in DCM) to yield 2-(4-bromobenzyl)-1H-imidazole-4-carboxylic acid ethyl ester (3.3 g).