Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:34])[CH2:10][C:11]1([C:28]2[S:29][C:30](Br)=[CH:31][CH:32]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:14]([C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12]1.C(N(CC)CC)C.[C:42]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)#[CH:43]>CN(C)C=O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:34])[CH2:10][C:11]1([C:28]2[S:29][C:30]([C:43]#[C:42][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:31][CH:32]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:14]([C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12]1
Reactant: C#Cc1ccccc1
Reactant: O=C(CC1(c2ccc(Br)s2)CCN(C(=O)c2ccccc2)CCS1(=O)=O)NOC1CCCCO1
Agent: I[Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CC1(c2ccc(C#Cc3ccccc3)s2)CCN(C(=O)c2ccccc2)CCS1(=O)=O)NOC1CCCCO1
Temperature: 60 °C
Reaction time: 2 h
Yield: 110.9 %

Procedure:
To a mixture of N-(2-tetrahydropyranyloxy)-2-[7-(5-bromo-2-thienyl)-4-benzoyl-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (200 mg), palladium(II) acetate (1.57 mg), triphenylphosphine (7.34 mg), copper(II) iodide (6.7 mg) and triethylamine (106 mg) in dimethylformamide was added ethynylbenzene (46.5 mg) at room temperature under nitrogen. After stirring for 2 hours at 60° C., the mixture was diluted with ethyl acetate, washed with 3% aqueous sodium bicarbonate and brine, dried over sodium sulfate and filtered. The obtained filtrate was concentrated and purified by column chromatography on silica gel (eluent: 0-2% methanol in chloroform) to give N-(2-tetrahydropyranyloxy)-2-[7-(5-(2-phenylethynyl)-2-thienyl)-4-benzoyl-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (230 mg) as yellow amorphous solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19]COC)=[C:15]([O:23][CH3:24])[CH:14]=3)=[C:10]([S:25][CH3:26])[C:9]=2[CH:27]=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].O>ClCCl>[CH3:24][O:23][C:15]1[CH:14]=[C:13]([C:11]2[O:12][C:8]3[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][O:2][CH3:1])=[CH:27][C:9]=3[C:10]=2[S:25][CH3:26])[CH:18]=[CH:17][C:16]=1[OH:19]
Reactant: COCCc1ccc2oc(-c3ccc(OCOC)c(OC)c3)c(SC)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCc1ccc2oc(-c3ccc(O)c(OC)c3)c(SC)c2c1
Reaction time: 0.67 h

Procedure:
The solution containing 590 mg of 5-(2-methoxy-ethyl)-2-(3-methoxy-4-methoxymethoxy-phenyl)-3-methylsulfanyl-benzofuran (14a; 1.52 mM) dissolved in 8 ml of dichloromethane was cooled to 0□. 4.0 ml of trifluoroacetic acid was added thereto and stirred for 40 mins at 0□. 7.5 g of solid sodium hydrogen carbonate and 60 ml of water were added thereto slowly at 0□. The reaction mixture was extracted with dichloromethane. The organic solvent layer was dried with magnesium sulfuric acid, filtrated and the filtrate was concentrated with vaccuo.
Reaction SMILES: C([O:4][C:5]1[C:10]2[CH:11]=[CH:12][O:13][C:9]=2[CH:8]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C>[OH:4][C:5]1[C:10]2[CH:11]=[CH:12][O:13][C:9]=2[CH:8]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=1
Reactant: CCOC(=O)c1cc(OC(C)=O)c2ccoc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cc(O)c2ccoc2c1
Yield: 95.5 %

Procedure:
To a solution of the compound obtained in the above (1) (24.7 g) in ethanol (150 mL) was added potassium carbonate (42.0 g), and the mixture was heated to reflux for 30 minutes. The reaction mixture was ice-cooled, and then acidified by 10% hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was triturated with n-hexane-dichloromethane (5:1) to give ethyl 4-hydroxy-1-benzofuran-6-carboxylate [REx(7-1)] (19.6 g) as a pale yellow powder.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[N:15]=[CH:14][C:13]([C:16]4[N:17]=[C:18]([C:21]5([C:27]6[CH:35]=[CH:34][C:30]([C:31]([OH:33])=O)=[CH:29][CH:28]=6)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[S:19][CH:20]=4)=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[C:36]1([NH2:43])[C:37]([NH2:42])=[CH:38][CH:39]=[CH:40][CH:41]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[NH:43][C:31](=[O:33])[C:30]1[CH:29]=[CH:28][C:27]([C:21]2([C:18]3[S:19][CH:20]=[C:16]([C:13]4[CH:14]=[N:15][C:10]([N:7]5[CH2:8][CH2:9][N:4]([CH:1]6[CH2:2][CH2:3]6)[CH2:5][CH2:6]5)=[CH:11][CH:12]=4)[N:17]=3)[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[CH:35][CH:34]=1
Reactant: O=C(O)c1ccc(C2(c3nc(-c4ccc(N5CCN(C6CC6)CC5)nc4)cs3)CCOCC2)cc1
Reactant: Nc1ccccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1ccc(C2(c3nc(-c4ccc(N5CCN(C6CC6)CC5)nc4)cs3)CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(4-{4-[6-(4-cyclopropyl-piperazin-1-yl)-pyridin-3-yl]-thiazol-2-yl}-tetrahydro-pyran-4-yl)-benzoic acid (60 mg, 0.122 mmol), benzene-1,2-diamine (26 mg, 2.0 eq), HATU (56 mg, 1.2 eq), and DIPEA (0.042 mL, 2.1 eq) were dissolved in DMF and stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was extracted with EtOAc and water. The organic phase was dried with MgSO4 and evaporated. The solid was purified by reverse phase chromatography to afford title compound. MS found for C33H36N6O2S as (M+H)+ 581.56. 1H NMR (400 MHz, dmso-d6): δ: 9.24 (s, 1H), 8.35 (s, 1H), 7.68 (d, J=6.2 Hz, 1H), 7.60 (d, J=8.2 Hz, 2H), 7.51 (s, 1H), 7.23 (d, J=8.4 Hz, 2H), 6.79 (d, J=7.2 Hz, 1H), 6.62-6.51 (m, 2H), 6.41 (d, J=7.4 Hz, 1H), 6.22 (t, J=5.2 Hz, 1H), 4.51 (s, 2H), 3.45-3.38 (m, 2H), 3.32-3.25 (m, 2H), 3.18-3.11 (m, 4H), 2.38-2.22 (m, 6H), 2.15-2.05 (m, 2H), 1.31-1.23 (m, 1H), 0.12-0.1 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][N:6]([C:17](=[O:31])[C@@H:18]([NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:19]([CH3:21])[CH3:20])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][N:6]([C:17](=[O:31])[C@@H:18]([NH:22][C:23](=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH:19]([CH3:21])[CH3:20])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1)[CH3:2]
Reactant: CCOC(=O)CN(Cc1cccc([N+](=O)[O-])c1)C(=O)[C@@H](NC(=O)c1ccccc1)C(C)C
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CN(Cc1cccc(N)c1)C(=O)[C@@H](NC(=O)c1ccccc1)C(C)C
Yield: 98.6 %

Procedure:
A mixture of compound 734 (1.5 g, 3.4 mmol) and 10% Pd/C (150 mg) in MeOH (35 mL) was placed under H2 (1 atm) and stirred until the reduction was complete. The H2 was replaced with nitrogen and the reaction filtered. The filtrate was concentrated to provide 1.38 g of compound 735. ##STR114##
Reaction SMILES: [Na].[NH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:18][C:19](=[O:22])[NH:20][OH:21])[CH:9]=[CH:10]2)[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].[N:28]1([CH2:34][CH2:35]Br)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[NH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:18][C:19](=[O:22])[NH:20][O:21][CH2:35][CH2:34][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:9]=[CH:10]2)[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: BrCCN1CCCCC1
Reactant: CCOC(=O)c1c2ccc(CC(=O)NO)ccc-2c(C(=O)OCC)c1N
Agent: [Na]
Product: CCOC(=O)c1c2ccc(CC(=O)NOCCN3CCCCC3)ccc-2c(C(=O)OCC)c1N
Yield: 7 %

Procedure:
In an analogous manner to that described in Example 1, from diethyl 2-amino-6-[(hydroxycarbamoyl)-methyl]-azulene-1,3-dicarboxylate sodium and 2-piperidinoethyl bromide the title compound of m.p. 163-165° C. is obtained in 7% yield.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:9]2[O:20][CH2:21][CH3:22])=O)C.CC(C)=O.C(=O)=O.CC(C[AlH]CC(C)C)C>ClCCl.C1(C)C=CC=CC=1.CO>[CH2:21]([O:20][C:9]1[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([CH2:4][OH:3])[CH:7]=2)[N:12]=[CH:11][C:10]=1[S:16]([CH3:19])(=[O:18])=[O:17])[CH3:22]
Reactant: CCOC(=O)c1ccc2ncc(S(C)(=O)=O)c(OCC)c2c1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C=O
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CC(C)=O
Product: CCOc1c(S(C)(=O)=O)cnc2ccc(CO)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-ethoxy-3-methanesulfonyl-quinoline-6-carboxylic acid ethyl ester (example 74a) in anhydrous dichloromethane (500 mL) was cooled to −78 degrees by acetone and dry-ice bath. DIBAL-H in toluene (1M, 50.8 mL, 50.8 m mol) was added dropwise into the above solution. The solution was allowed to react at −78 degrees for 4 hours. Then methanol was added to the reaction mixture. The resulted reaction mixture was stirred at −78 degrees for another 30 min, and then warmed to room temperature slowly. After the reaction, the solvent was evaporated; dichloromethane was added to the residue. After filtering out the insoluble, filtrate was collected, and concentrated to give (4-ethoxy-3-methanesulfonyl-quinolin-6-yl)-methanol which was used in the next step reaction without further purification. LC-MS m/e 282 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[F:16][C:17]([F:29])([F:28])[S:18]([C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>>[F:28][C:17]([F:16])([F:29])[S:18]([C:21]1[CH:22]=[CH:23][C:24]([NH:25][C:11](=[O:12])[C:6]2[C:7](=[C:2]([Cl:1])[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]=2[Cl:13])[C:8]([OH:10])=[O:9])=[CH:26][CH:27]=1)(=[O:19])=[O:20]
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Product: O=C(O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C(=O)Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Reaction time: 2 h
Yield: 54.8 %

Procedure:
14 g (0.05 mol) of tetrachlorophthalic anhydride and 11 g (0.05 mol) of 4-trifluoromethylsulphonylaniline were heated to 200° C. and the mixture was kept at this temperature for 2 hours. It was then cooled and the reaction product was precipitated by adding ice-water. The product was then filtered off, washed with 50 ml of methanol and then stirred with 10% strength sodium hydroxide solution until it had dissolved. The impurities were filtered off and aqueous dilute hydrochloric acid was added to the filtrate. The crystals thereby obtained were filtered off and dried at 50° C. 14 g (that is to say 56% of theory) of N-(4-trifluoromethylsulphonylphenyl)-tetrachlorophthalamic acid of melting point 92°-97° C. were obtained.
Reaction SMILES: COCOC1C=C([C@@H](N2CC[C@H](OCOC)C2)CO)C=CC=1.[CH3:23][O:24][CH2:25][O:26][C:27]1[CH:28]=[C:29]([C@H:33](O)[CH2:34][N:35]2[CH2:39][CH2:38][C@H:37]([O:40][CH2:41][O:42][CH3:43])[CH2:36]2)[CH:30]=[CH:31][CH:32]=1.[CH3:45][NH:46][C:47]1[CH:56]=[CH:55][C:50]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][CH:48]=1>>[CH3:23][O:24][CH2:25][O:26][C:27]1[CH:28]=[C:29]([C@H:33]([N:46]([C:47]2[CH:56]=[CH:55][C:50]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][CH:48]=2)[CH3:45])[CH2:34][N:35]2[CH2:39][CH2:38][C@H:37]([O:40][CH2:41][O:42][CH3:43])[CH2:36]2)[CH:30]=[CH:31][CH:32]=1
Reactant: COCOc1cccc([C@H](O)CN2CC[C@H](OCOC)C2)c1
Reactant: CNc1ccc(C(=O)OC)cc1
Agent: COCOc1cccc([C@H](CO)N2CC[C@H](OCOC)C2)c1
Product: COCOc1cccc([C@@H](CN2CC[C@H](OCOC)C2)N(C)c2ccc(C(=O)OC)cc2)c1
Yield: 60 %

Procedure:
This was prepared from the mixture of 2-(R)-(3-methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)ethanol and 1-(S)-(3-methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)ethanol and methyl 4-methylaminobenzoate in 60% yield according to a procedure similar to that described in Example 1 (i).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[N:9]=[C:8]([Cl:10])[C:7]([Cl:11])=[C:6](NN)[C:5]=1Cl.O>C(O)(C)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:11])=[C:8]([Cl:10])[N:9]=1
Reactant: NNc1c(Cl)c(Cl)nc(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Clc1ccc(Cl)c(Cl)n1
Reaction time: 2 h

Procedure:
To a 10 milliliter solution of 5 Normal sodium hydroxide was added a mixture of 5 grams of tetrachloro-4-hydrazinopyridine in 25 milliliters of isopropanol. The mixture was heated at its boiling point with rapid stirring for 2 hours. The mixture was mixed with 100 milliliters of water and the organic material extracted with methylene chloride. The organic phase was water washed and subjected to sublimation. The 2,5,6-trichloropyridine product was recovered in a yield of 1.85 grams (~ 51 percent of theoretical).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:34](=[O:35])[N:13]3[C:14]([C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=4)=[O:22])=[C:15]([Cl:20])[CH:16]([CH3:19])[S:17](=O)[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C.Cl.C(OCC)(=O)C>CN(C)C=O.O>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:34](=[O:35])[N:13]3[C:14]([C:21]([O:23][CH2:24][C:25]4[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=4)=[O:22])=[C:15]([Cl:20])[CH:16]([CH3:19])[S:17][C@H:12]23)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1C(Cl)=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1=O
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)Cl
Product: CC1S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C1Cl
Reaction time: 3 h
Yield: 78.7 %

Procedure:
Nmr: δd 6-DMSO : 1.36d(8.0Hz)3H, 3.62s2H, 3.93q(8.0Hz)1H, 4.90d(5.0Hz)1H, 5.40s2H, 5.87dd(5.0;8.0Hz)1H, 7.2-8.4m1OH. (II) To a solution of p-nitrobenzyl 7-phenylacetamido-2-methyl-3-chloro-3cephem-4-carboxylate-1-oxide (38 mg) in dimethylformamide (2 ml) one adds stannous chloride dihydrate (44 mg) and acetyl chloride (0.2 ml), stirs for 3hours under ice cooling, adds 5% hydrochloric acid, extracts with ethyl acetate, washes with water, dries, and chromatographs on silica gel to give p-nitrobenzyl 7-phenylacetamido-2-methyl-3-chloro-3cephem-4-carboxylate (29 mg).
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]1[C:19](=[O:43])[CH2:20][NH:21][C:22](=[O:42])[NH:23][C:24]1[CH:25]=[C:26]([CH:30]([CH3:41])[C:31]([O:33]CC2C=CC=CC=2)=[O:32])[CH:27]=[CH:28][CH:29]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]1[C:19](=[O:43])[CH2:20][NH:21][C:22](=[O:42])[NH:23][C:24]1[CH:25]=[C:26]([CH:30]([CH3:41])[C:31]([OH:33])=[O:32])[CH:27]=[CH:28][CH:29]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C(=O)OCc1ccccc1)c1cccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3)CC[C@H]2C(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C(=O)O)c1cccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3)CC[C@H]2C(=O)OC(C)(C)C)c1
Yield: 67.2 %

Procedure:
The operation is carried out as in Example 84, but starting from 0.88 g of benzyl 2-{3-{3-[2-((2S,5R)-2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}phenyl}propionate (B form) in solution in 50 cm3 of ethyl acetate and 0.22 g of 10% palladium on charcoal. After treatment, 0.5 g of 2-{3-{3-[2-((2S,5R)-2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}phenyl}propionic acid (B form), melting at 120° C., [α]D20 =+49.8°±0.8° (c=0.53; methanol), is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[CH:8][CH:7]=[CH:6]2.[CH:14]([N:17]1[CH2:20][CH:19]([OH:21])[CH2:18]1)([CH3:16])[CH3:15].[OH-].[K+].[ClH:24]>>[ClH:24].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][CH2:20][CH:19]([OH:21])[CH2:18][NH:17][CH:14]([CH3:16])[CH3:15])=[CH:8][CH:7]=[CH:6]2
Reactant: COc1ccc2c(O)cccc2c1
Reactant: CC(C)N1CC(O)C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: COc1ccc2c(OCC(O)CNC(C)C)cccc2c1
Temperature: 140 °C
Yield: 57.5 %

Procedure:
A mixture of 9.5 parts of 6-methoxy-1-naphthol, 5.8 parts of 1-(iso-propyl)-3-azetidinol and 0.3 part of potassium hydroxide was heated under nitrogen gas at 140° C. for 8 hours with agitation. The reaction mixture was treated in the same manner as in Example 1, and when the resulting hydrochloride was recrystallized from iso-propyl alcohol, there was obtained 17.7 parts of 1-(6'-methoxy-1-naphthoxy)-3-(iso-propylamino)-2-propanol hydrochloride melting at 165° - 167° C. The yield was 57.5%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:5]=[CH:4][C:3]=1[C:13]1[NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([NH2:24])=[O:23])[C:15]=2[N:14]=1.C(N(CC)CC)C.[CH3:32][C:33]([CH3:35])=O.C([BH3-])#N.[Na+]>CO>[F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH:33]([CH3:35])[CH3:32])[CH:5]=[CH:4][C:3]=1[C:13]1[NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([NH2:24])=[O:23])[C:15]=2[N:14]=1
Reactant: CC(C)=O
Reactant: NC(=O)c1cccc2[nH]c(-c3ccc(C4CCCN4)cc3F)nc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)N1CCCC1c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of EXAMPLE 50F (80 mg) in methanol (3 mL) was added triethylamine (67 mL) and acetone (35 mL). This solution was stirred at ambient temperature for 1 hour, treated with sodium cyanoborohydride (30 mg), stirred at 50° C. for 18 hours and concentrated. The concentrate was purified by HPLC (Zorbax, C-18, 250×2.54 column, mobile phase A: 0.1% TFA in water; B: 0.1% TFA in CH3CN; 0-100% gradient). 1H NMR (CD3OD) δ 1.33 (d, J=6.71 Hz, 3H), 1.35 (d, J=6.71 Hz, 3H), 2.25-2.34 (m, 3H), 2.58-2.64 (m, 1H), 3.47-3.61 (m, 2H), 3.67-3.74 (m, 1H), 4.72-4.79 (m, 1H), 7.45 (t, J=7.78 Hz, 1H), 7.63 (d, J=8.24 Hz, 1H), 7.66 (d, J=11.90 Hz, 1H), 7.86 (d, J=8.24 Hz, 1H), 8.00 (d, J=7.32 Hz, 1H), 8.48 (t, J=7.78 Hz, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[N:9]=[CH:10][N:11]2[CH:15]=[CH:14][S:13][C:12]=12)=[O:7].[CH2:16]([Sn:20](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[N:9]=[CH:10][N:11]2[CH:15]=[C:14]([Sn:20]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16][CH2:17][CH2:18][CH3:19])[S:13][C:12]=12)=[O:7]
Reactant: O=C(c1cccs1)c1ncn2ccsc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3cccs3)c2s1

Procedure:
The title compound (923 mg) was prepared in substantially the same manner as in step c) of Synthesis Example 1, except that 550 mg of 7-(thiophen-2-yl)carbonylimidazo[5,1-b]thiazole, 0.701 ml of tri-n-butylstannyl chloride, and 3.6 ml of a 1.0 N lithium bis(trimethylsilyl)amide/THF solution were used as the starting materials.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[CH2:22][CH2:21][C:14]3[N:15]=[C:16]([S:19][CH3:20])[N:17]=[CH:18][C:13]=3[CH2:12]2)[CH:5]=1.[OH-].[Na+]>O1CCOCC1>[CH3:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:23])=[O:2])=[CH:5][C:6]=1[N:11]1[CH2:22][CH2:21][C:14]2[N:15]=[C:16]([S:19][CH3:20])[N:17]=[CH:18][C:13]=2[CH2:12]1
Reactant: COC(=O)c1ccc(C)c(N2CCc3nc(SC)ncc3C2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CSc1ncc2c(n1)CCN(c1cc(C(=O)O)ccc1C)C2
Temperature: 100 °C
Yield: 85.3 %

Procedure:
A solution of methyl-4-methyl-3-[2-(methylsulfanyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-yl]benzoate (82 mg, 0.249 mmol) in 1,4-dioxane (5 ml) was treated with 1.0 N NaOH (aq.) (0.748 ml, 0.748 mmol) and the reaction mixture was heated at 100° C. for 15 hours. The solvent was removed in vacuo and the residue was taken up in water. The aqueous mixture was washed with EtOAc and acidified to pH˜2-3 with 1.0 N HCl (aq.). The white, amorphous precipitate which formed was collected, washed with water, and dried to give the title compound (67 mg, 87%).
Reaction SMILES: [CH3:1][CH2:2][NH:3][C:4]([C@H:6]1[N:10]([C:11]([C@@H:13]([NH:21][C:22]([C@@H:24]([NH:29][C:30]([C@H:32]([NH:37][C:38]([C@@H:40]([NH:49][C:50]([C@@H:52]([NH:55][C:56]([C@@H:58]([NH:69][C:70]([C@@H:72]([NH:79][C:80]([C@H:82]2[NH:87][C:85](=[O:86])[CH2:84][CH2:83]2)=[O:81])[CH2:73][C:74]2[N:78]=[CH:77][NH:76][CH:75]=2)=[O:71])[CH2:59][C:60]2[C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][C:63]=3[NH:62][CH:61]=2)=[O:57])[CH2:53][OH:54])=[O:51])[CH2:41][C:42]2[CH:43]=[CH:44][C:45]([OH:48])=[CH:46][CH:47]=2)=[O:39])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:31])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:23])[CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH2:20])=[NH:19])=[O:12])[CH2:9][CH2:8][CH2:7]1)=[O:5].CS(C)=[O:90]>>[CH3:1][CH2:2][NH:3][C:4]([C@H:6]1[N:10]([C:11]([C@@H:13]([NH:21][C:22]([C@@H:24]([NH:29][C:30]([C@H:32]([NH:37][C:38]([C@@H:40]([NH:49][C:50]([C@@H:52]([NH:55][C:56]([C@@H:58]([NH:69][C:70]([C@@H:72]([NH:79][C:80]([C@H:82]2[NH:87][C:85](=[O:86])[CH2:84][CH2:83]2)=[O:81])[CH2:73][C:74]2[N:78]=[CH:77][NH:76][CH:75]=2)=[O:71])[CH2:59][C:60]2[C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][C:63]=3[NH:62][CH:61]=2)=[O:57])[CH2:53][OH:54])=[O:51])[CH2:41][C:42]2[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=2)=[O:39])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:31])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:23])[CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH2:20])=[NH:19])=[O:12])[CH2:9][CH2:8][CH2:7]1)=[O:5].[CH3:84][C:85]([OH:86])=[O:90]
Reactant: CS(C)=O
Agent: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCC(=O)N1
Product: CC(=O)O

Procedure:
Solutions of 40% leuprolide acetate (w/w) in DMSO were prepared, loaded into reservoirs, stored for two months at 80° C. and analyzed as described above. Results, shown in FIGS. 1 (RP-HPLC) and 2 (SEC) show that 81.1% leuprolide was recovered, with only 14.6% chemical degradation and 5.1% physical aggregation.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:18][CH:17]([N:19](C(OC(C)(C)C)=O)[CH2:20][CH:21]([OH:45])[CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][S:31]([C:34]4[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:36][CH:35]=4)(=[O:33])=[O:32])=[CH:26][CH:25]=3)[CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:16][CH:17]([NH:19][CH2:20][CH:21]([OH:45])[CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][S:31]([C:34]4[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:36][CH:35]=4)(=[O:32])=[O:33])=[CH:26][CH:25]=3)[CH2:18]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(S(=O)(=O)Oc2ccc(OCC(O)CN(C(=O)OC(C)(C)C)C3CN(S(=O)(=O)c4ccc(OCCCC)cc4)C3)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1ccc(S(=O)(=O)Oc2ccc(OCC(O)CNC3CN(S(=O)(=O)c4ccc(OCCCC)cc4)C3)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.6 %

Procedure:
To a solution of 4-butoxy-benzenesulfonic acid 4-(3-{[1-(4-butoxybenzene-sulfonyl)azetidin-3-yl]-tert-butoxycarbonyl-amino}-2-hydroxy-propoxy)-phenylester (0.12 g, 0.15 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid (0.12 ml, 1.5 mmol). The mixture was stirred at room temperature for 4 h, and then quenched with saturated sodium carbonate solution and extracted with dichloromethane. The organic solution was washed with brine, dried over sodium sufate, and evaporated to give 0.10 g of a white solid; MS (ES) m/z 663.1 (MH+); HRMS (ES) Calcd. for C32H43N2O9S2 (MH+): 663.2410, Found: 663.2401.