Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1C=C(C=CC=1O)C=O)C1C=CC=CC=1.[Cl:18][C:19]1[C:26]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:25]([OH:35])[CH:24]=[CH:23][C:20]=1[CH:21]=[O:22]>>[Cl:18][C:19]1[C:26]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:25]([O:35][CH2:1][O:8][CH3:9])[CH:24]=[CH:23][C:20]=1[CH:21]=[O:22]
Reactant: O=Cc1ccc(O)c(OCc2ccccc2)c1
Reactant: O=Cc1ccc(O)c(OCc2ccccc2)c1Cl
Product: COCOc1ccc(C=O)c(Cl)c1OCc1ccccc1

Procedure:
Proceeding as in example 63, but replacing for 3-benzyloxy-4-hydroxybenzaldehyde an equivalent quantity of 2-chloro-3-benzyloxy-4-hydroxybenzaldehyde obtained as described in example 85, 2-chloro-3-benzyloxy-4-methoxymethoxybenzaldehyde was obtained, m.p. 66°-67° C. (from petroleum ether, b.p. 30°-70° C.).
Reaction SMILES: [C:1]([C:4]1[C:12]2[CH2:11][CH2:10][N:9]([C:13](=[O:15])[CH3:14])[CH2:8][C:7]=2[S:6][C:5]=1[CH2:16][CH2:17]Cl)(=[O:3])[CH3:2].Cl.[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][O:27][C:23]=2[CH:22]=1>>[C:1]([C:4]1[C:12]2[CH2:11][CH2:10][N:9]([C:13](=[O:15])[CH3:14])[CH2:8][C:7]=2[S:6][C:5]=1[CH2:16][CH2:17][N:31]1[CH2:30][CH2:29][CH:28]([C:25]2[C:24]3[CH:34]=[CH:35][C:21]([F:20])=[CH:22][C:23]=3[O:27][N:26]=2)[CH2:33][CH2:32]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)c1c(CCCl)sc2c1CCN(C(C)=O)C2
Agent: Cl
Product: CC(=O)c1c(CCN2CCC(c3noc4cc(F)ccc34)CC2)sc2c1CCN(C(C)=O)C2

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 1.5 g of 3,6-diacetyl-2-(2-chloroethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine and 1.3 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 3,6-diacetyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine as an oil.
Reaction SMILES: [C:1]1([C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:10][CH:9]=2)=O)[S:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:24][OH:25]>N1C=CC=CC=1>[S:5]1[CH:4]=[CH:3][CH:2]=[C:1]1[C:6](=[N:24][OH:25])[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:10][CH:9]=1
Reactant: NO
Reactant: O=C(O)COc1ccc(C(=O)c2cccs2)c2ccccc12
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)COc1ccc(C(=NO)c2cccs2)c2ccccc12
Yield: 95 %

Procedure:
5 g [4-(2-thenoyl)-1-naphthyloxy]-acetic acid are dissolved in 50 ml pyridine. 1.5 g hydroxylamine hydrochloride are introduced in solution and the mixture maintained at reflux temperature for 12 hours. The solvent is then removed under reduced pressure, the residue washed with a dilute aqueous hydrochloric acid solution; the oxime obtained with a 95% yield, which is a mixture of two stereoisomers, melts at 215° C.
Reaction SMILES: Cl[N:2]1[C:6](=O)CC[C:3]1=O.[CH3:9][O:10][C:11]1[C:19]2[O:18][C:17]([S:20]([OH:22])=[O:21])=[CH:16][C:15]=2[CH:14]=[CH:13][CH:12]=1.[Li].Cl.CNC>ClCCl.O1CCCC1.C(N(CC)CC)C>[CH3:3][N:2]([CH3:6])[S:20]([C:17]1[O:18][C:19]2[C:11]([O:10][CH3:9])=[CH:12][CH:13]=[CH:14][C:15]=2[CH:16]=1)(=[O:22])=[O:21]
Reactant: COc1cccc2cc(S(=O)O)oc12
Reactant: O=C1CCC(=O)N1Cl
Agent: CNC
Agent: Cl
Agent: [Li]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc2cc(S(=O)(=O)N(C)C)oc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
N-Chlorosuccinimide (1 g) was added portionwise to 7-methoxybenzofuran-2-sulfinic acid, lithium salt (1.47 g) in dichloromethane (15 ml) at 0-5° C. under an inert atmosphere. The reaction was stirred at this temperature for 15 minutes and then warmed to ambient temperature and stirred for a further 15 minutes. The mixture was then flushed through a pad of celite, washing well with dichloromethane. The solvent was removed in vacuo to give a tan solid as the crude intermediate. This intermediate was added to a stirred solution of dimethylamine hydrochloride (0.67 g) and triethylamine (2.2 ml) in tetrahydrofuran (20 ml) at 0-5° C. under an inert atmosphere. The reaction was stirred at this temperature for 1 h and then warmed to room temperature and stirred for a further 48 h. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (2×40 ml) and water (50 ml). The combined organic phases were washed with 1M hydrochloric acid (2×20 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was washed with hexane (40 ml) to give the title compound as a tan solid (0.88 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([NH:11][C@@H:12]2[C@@H:17]3[CH2:18][C@@H:14]([CH:15]=[CH:16]3)[C@@H:13]2[C:19]([NH2:21])=[O:20])[C:5]([Cl:22])=[CH:4][N:3]=1>O1CCCC1.C(O)(=O)C.O.[Fe]>[NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:11][C@@H:12]2[C@@H:17]3[CH2:18][C@@H:14]([CH:15]=[CH:16]3)[C@@H:13]2[C:19]([NH2:21])=[O:20])[C:5]([Cl:22])=[CH:4][N:3]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2[N+](=O)[O-])[C@H]2C=C[C@@H]1C2
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Temperature: 30 °C
Reaction time: 4 h
Yield: 87.4 %

Procedure:
(1S,2S,3R,4R)-3-(2-Amino-5-chloro-3-nitro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (100 mg, 0.3 mmol) was dissolved in a mixture of tetrahydrofuran (1 mL) and acetic acid (1.6 mL). Powdered iron (121 mg, 2.162 mmol) was added and the mixture was stirred at 30° C. for four hours. Two drops of water was added and suspended solids were removed by filtration. The solid was washed with ethyl acetate (5 mL) and the combined filtrates were portioned between ethyl acetate and saturated sodium bicarbonate solution. The organics were extracted with ethyl acetate (3×25 mL), were dried (sodium sulfate) and were concentrated. Purification was effected via ISCO chromatography (12 g silica cartridge: gradient elution—0 to 15% MeOH:DCM) to afford 77 mg (80%) of the title compound as a tan solid. 1H NMR (d-chloroform): 7.49 (s, 1H), 6.18-6.20 (m, 4H), 6.09 (m, 1H), 4.51 (d, J=11 Hz, 1H), 4.09 (br s, 2H), 3.79 (d, J=9 Hz, 1H), 2.97 (s, 1H), 2.64 (s, 1H), 2.53 (d, J=8 Hz, 1H), 2.32 (d, J=9 Hz, 1H), 2.06 (s, 1H), 1.66 (d, J=9 Hz, 1H). MS: 294.99 (M+H). HPLC retention time: 1.62 minutes (G Method).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)=[O:4].C(=O)(O)[O-].[Na+].[CH2:21]([O:28][CH2:29][C:30](Cl)=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[O:15])[C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:30](=[O:31])[CH2:29][O:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:12][CH:13]=1)=[O:4]
Reactant: O=C(Cl)COCc1ccccc1
Reactant: COC(=O)COC(=O)c1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)COC(=O)c1ccc(NC(=O)COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a mixture of 4-amino-benzoic acid methoxycarbonylmethyl ester 6 (10 grams, 47.84 mmol) and sodium bicarbonate (8 grams, 95.23 mmol) in ethyl acetate (50 mL) at 0° C. is added benzyloxy acetyl chloride (12 grams, 65.04 mmol) drop wise. The reaction mixture is stirred at room temperature for 10 hours. The solids are filtered off, and the ethyl acetate layer is washed with 5% sodium bicarbonate solution (2×25 mL), water (2×25 mL), dried over sodium sulfate, and distilled to give crude 7, which can be purified via crystallized with a suitable solvent.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:43])[CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14](=[O:42])[CH:15]=[C:16]([C:20]3[CH:25]=[C:24]([O:26]CC4C=CC=CC=4)[CH:23]=[C:22]([O:34]CC4C=CC=CC=4)[CH:21]=3)[O:17]2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([NH:5][CH2:6][CH:7]([OH:43])[CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14](=[O:42])[CH:15]=[C:16]([C:20]3[CH:21]=[C:22]([OH:34])[CH:23]=[C:24]([OH:26])[CH:25]=3)[O:17]2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)NCC(O)COc1ccc2c(=O)cc(-c3cc(OCc4ccccc4)cc(OCc4ccccc4)c3)oc2c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)NCC(O)COc1ccc2c(=O)cc(-c3cc(O)cc(O)c3)oc2c1

Procedure:
To a suspension of 7-(3-tert-butylamino-2-hydroxy-propoxy)-3′,5′-dibenzyloxy-flavone, 34 (1.0 g, 1.73 mmol) in dry methanol (60 mL) was added 40 mg 10% Pd/C. The reaction mixture was shaken in Parr hydrogenation assembly under hydrogen gas atmosphere at 60 lbs for 4 h after replacement of the air by nitrogen. The Pd/C was filtered and methanol evaporated on rotavapor under reduced pressure to provide 48. Yield 660 mg (96%); mp 153° C. (decomposes); MS (FAB) 400 (M++1); IR (KBr) 3401, 1618; 1H NMR (200 MHz, DMSO-d6) δ 7.98 (d, J=8.8 Hz, 1IH), 7.30 (s, 1H), 7.13 (d, J=8.8 Hz, 1H), 6.90 (d, J=1.2 Hz, 2H), 6.7 (s, 1H), 6.52 (s, 1H), 4.27-4.23 (m, 3H), 3.18-2.99 (m, 2H), 1.32 (s, 9H). Analysis Calcd for C22H25NO6: C, 66.15; H, 6.31; N, 3.51. Found: C, 66.19; H, 6.47; N, 3.43.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([NH:16][C:17](=[O:34])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1)[CH:10]=2)=[O:5])C.O.[OH-].[Li+]>O1CCCC1CO.O>[F:33][C:30]([F:31])([F:32])[C:27]1[CH:28]=[CH:29][C:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]([NH:16][C:11]2[CH:10]=[C:9]3[C:14]([CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]3)=[CH:13][CH:12]=2)=[O:34])=[N:25][CH:26]=1
Reactant: CCOC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cn3)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: OCC1CCCO1
Product: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cn3)ccc2c1

Procedure:
7-[2-(5-Trifluoromethyl-pyridin-2-yl)-benzoylamino]-quinoline-3-carboxylic acid ethyl ester (180 mg, 0.387 mmol) was dissolved in 5 ml of a 3:1:1 mixture of tetrahydrofuran-methanol-water, and lithium hydroxide monohydrate (50 mg, 1.16 mmol) was added. After 18 h at reflux, the volatiles were removed under vacuum and water was added to the mixture, which was acidified with 1N HCl, extracted with ethyl acetate. The combined organic layers were dried (magnesium sulfate), filtered and concentrated under vacuum to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][N:12]=[C:11](C)[C:10]=1C#N.S(=O)(=O)(O)O.N([O-])=O.[Na+].[CH3:26][C:27](=[O:31])[O:28]CC>>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][N:12]=[C:11]([CH3:10])[C:26]=1[C:27]([OH:28])=[O:31]
Reactant: Cc1ccc(-c2snc(C)c2C#N)c(F)c1
Reactant: CCOC(C)=O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1ccc(-c2snc(C)c2C(=O)O)c(F)c1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
Into a 25-mL round-bottom flask, was placed 5-(2-fluoro-4-methylphenyl)-3-methyl-1,2-thiazole-4-carbonitrile (200 mg, 0.86 mmol, 1.00 equiv). This was followed by the addition of sulfuric acid (conc.) (10 mL). The mixture was stirred for 1 h at 120° C. To this was added NaNO2 (aq) (201 mg) at 0-5° C. The resulting solution was stirred for 30 min at 50° C. The resulting solution was diluted with 50 mL of EA. The organic phase was washed with 1×20 mL of 2N HCl and 1×20 mL brine. The mixture was dried over anhydrous sodium sulfate and concentrated. This resulted in 180 mg (crude) of 5-(2-fluoro-4-methylphenyl)-3-methyl-1,2-thiazole-4-carboxylic acid as a yellow oil.
Reaction SMILES: [N:1]([C:4]1[N:5]=[N:6][C:7]([N:10]=[N+:11]=[N-])=[N:8][N:9]=1)=[N+:2]=[N-].CC1C=C(C)N(C2N=NC(N3C(C)=CC(C)=N3)=NN=2)N=1.NN.O>>[NH:1]([C:4]1[N:5]=[N:6][C:7]([NH:10][NH2:11])=[N:8][N:9]=1)[NH2:2]
Reactant: [N-]=[N+]=Nc1nnc(N=[N+]=[N-])nn1
Agent: Cc1cc(C)n(-c2nnc(-n3nc(C)cc3C)nn2)n1
Agent: NN
Solvent: O
Product: NNc1nnc(NN)nn1

Procedure:
The invention also includes a method for preparing 3,6-di(azido)-1,2,4,5-tetrazine. The method involves reacting 3,6-bis(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine with NH2NH2.H2O to form 3,6-di(hydrazino)-1,2,4,5-tetrazine (DHT), then reacting the 3,6-di(hydrazino)-1,2,4,5-tetrazine with an aqueous hydrochloric acid solution of NaNO2, thereby forming a crude reaction product comprising 3,6-di(azido)-1,2,4,5-tetrazine and solid impurities, and extracting the 3,6-di(azido)-1,2,4,5-tetrazine away from the impurities in the crude reaction product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH2:9]2)[CH2:2]1.Br[CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:25]([N:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([CH2:7][N:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:12][CH2:13]2)[CH2:2]1)[CH3:26]
Reactant: CCBr
Reactant: O=C(OCc1ccccc1)N1CCN(C[C@@H]2CCCNC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN1CCC[C@@H](CN2CCN(C(=O)OCc3ccccc3)CC2)C1
Temperature: 25 °C

Procedure:
Benzyl 4-[(3R)-piperidin-3-ylmethyl]piperazine-1-carboxylate (1.8 g), bromoethane (1.3 ml) and potassium carbonate (3.9 g) was refluxed in acetone (50 ml) for seven hours. The reaction mixture was allowed to cool to room temperature then filtered. The filtrate was concentrated in vacuo and the resulting oil separated between dichloromethane (100 ml) and water (100 ml). The dichloromethane layer was separated, dried over magnesium sulphate, filtered then concentrated in vacuo onto silica gel (5 g). The resulting powder was subjected to chromatography on silica gel (50 g) using a gradient of 100% dichloromethane through to 20% methanolic ammonia in dichloromethane to give the title compound (352 mg).
Reaction SMILES: N[C@H](C(N[C@H](C(N1CCC[C@H]1C(NCC)=O)=O)CCCNC(=N)N)=O)CSC(C)(C)C.Cl.[NH2:33][C@@H:34]([C:39]([NH:41][C@H:42]([C:49]([NH:51][C@H:52]([C:60]([N:62]1[CH2:71][CH2:70][CH2:69][C@H:63]1[C:64]([NH:66][CH2:67][CH3:68])=[O:65])=[O:61])[CH2:53][CH2:54][CH2:55][NH:56][C:57](=[NH:59])[NH2:58])=[O:50])[CH2:43][S:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37].C([O-])(=O)C.[NH:76]([C:102]([O:104][CH2:105][C:106]1[CH:111]=[CH:110][CH:109]=[CH:108][CH:107]=1)=[O:103])[C@H:77]([C:80]([NH:82][C@H:83]([C:99](O)=[O:100])[CH2:84][C:85]1[CH:90]=[CH:89][C:88]([O:91][CH2:92][C:93]2[CH:98]=[CH:97][CH:96]=[CH:95][CH:94]=2)=[CH:87][CH:86]=1)=[O:81])[CH2:78][OH:79].C(N1CCOCC1)C.C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C=O.C1C=CC2N(O)N=NC=2C=1>[NH:76]([C:102]([O:104][CH2:105][C:106]1[CH:111]=[CH:110][CH:109]=[CH:108][CH:107]=1)=[O:103])[C@H:77]([C:80]([NH:82][C@H:83]([C:99]([NH:33][C@@H:34]([C:39]([NH:41][C@H:42]([C:49]([NH:51][C@H:52]([C:60]([N:62]1[CH2:71][CH2:70][CH2:69][C@H:63]1[C:64]([NH:66][CH2:67][CH3:68])=[O:65])=[O:61])[CH2:53][CH2:54][CH2:55][NH:56][C:57](=[NH:58])[NH2:59])=[O:50])[CH2:43][S:44][C:45]([CH3:47])([CH3:46])[CH3:48])=[O:40])[CH2:35][CH:36]([CH3:37])[CH3:38])=[O:100])[CH2:84][C:85]1[CH:90]=[CH:89][C:88]([O:91][CH2:92][C:93]2[CH:98]=[CH:97][CH:96]=[CH:95][CH:94]=2)=[CH:87][CH:86]=1)=[O:81])[CH2:78][OH:79]
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CSC(C)(C)C)NC(=O)[C@H](N)CC(C)C
Reactant: O=C(N[C@@H](CO)C(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(=O)[O-]
Agent: CCN1CCOCC1
Solvent: CN(C)C=O
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CSC(C)(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Yield: 86.8 %

Procedure:
In analogy to Example 8(b) 3.6 g (6.8 mmols) of H-Cys(But)-Arg-Pro-NH-C2H5 . 2 HCl were reacted with 3 g of Z-D-Leu-OTcp and worked up. The oily residue (6.1 g of contaminated Z-D-Leu-Cys(But)-Arg-Pro-NH--C2H5) was hydrogenated catalytically in analogy to Example 8(b). Yield: 2.5 g (57%). The compound was strongly contaminated and purified over Sephadex LH 20 in analogy to Example 1(a). Yield: 1.734 g (40%) of H-D-Leu-Cys(But)-Arg-Pro-NH-C2H5 -diacetate. The 1.734 g (2.7 mmols) of H-D-Leu-Cys(But)-Arg-Pro-NH-C2H5 -acetate were reacted in analogy to Example 8(b) with 1.33 g of Z-Ser-Tyr(Bzl)-OH, 0.71 ml of N-ethyl morpholine, 3.65 mg of HOBt and 595 mg of DCC in 5 ml of dimethylformamide and worked up. The substance obtained (2.45 g of Z-Ser-Tyr(Bzl)-D-Leu-Cys(But)-Arg-Pro-NH-C2H5) was hydrogenated catalytically in analogy to Example 8(b) and purified over Sephadex LH 20.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C:10](=[O:14])[C@@H:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[Cl:35][C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([Cl:44])[CH:43]=1)[CH2:39]O.N>C1COCC1.C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([O:14][CH2:39][C:38]2[CH:37]=[C:36]([Cl:35])[CH:43]=[C:42]([Cl:44])[CH:41]=2)[C@@H:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cc(Cl)cc(Cl)c1
Reactant: O=C1OCCN(Cc2ccccc2)[C@H]1c1ccccc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: N
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Clc1cc(Cl)cc(CO[C@H]2OCCN(Cc3ccccc3)[C@H]2c2ccccc2)c1
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
A solution of 5.11 g (19.1 mmole) of N-benzyl-3-(S) -phenylmorpholine-2-one (from Example 14) in 100 mL of dry THF was cooled to -75° C. under nitrogen and was treated dropwise with 20.5 mL (20.5 mmole) of a 1M solution of lithium tri(sec-butyl)borohydride (L-Selectride®) in THF. After stirring the solution at -75° C. for 30 min, a solution of 3,5-dichlorobenzyl alcohol, trifluoromethanesulfonate ester in toluene (from Example 44, Step A) was added by cannula so that the internal temperature was maintained below -60° C. The resulting solution was stirred between -38° C. and -50° C. for 9 hr, and was then treated with 14 mL of aqueous ammonia and stored at -20° C. for 12 hours. The solution was then poured into a mixture of 50 mL of ethyl acetate and 100 mL of water, and the layers were separated. The aqueous phase was extracted with 2×100 mL of ethyl acetate, each extract was washed with brine, the combined organic layers were dried over sodium sulfate, the mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on 235 g of silica eluting with 1.5 L of 100:2 hexanes:ethyl acetate, then 1.5 L of 100:3 hexanes:ethyl acetate and then 1.9 L of 100:5 hexanes:ethyl acetate to give 4.4 g (54%) of an oil, which by 1H NMR is a 8:1 mixture of cis:trans morpholines.
Reaction SMILES: C(O[C:4](=[O:15])[C:5]([N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[CH:6][N:7](C)C)C.[NH:16]([C:18]1[CH:23]=[C:22]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[N:21]=[CH:20][N:19]=1)N.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)(=O)C>[N:10]1([C:5]2[C:4](=[O:15])[N:16]([C:18]3[CH:23]=[C:22]([N:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]4)[N:21]=[CH:20][N:19]=3)[NH:7][CH:6]=2)[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: CCOC(=O)C(=CN(C)C)n1ccnc1
Reactant: NNc1cc(N2CCCCC2)ncn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Product: O=c1c(-n2ccnc2)c[nH]n1-c1cc(N2CCCCC2)ncn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5.5 g (26.3 mmol) of the compound from Example 42A and 6.1 g (31.5 mmol) of the compound from Example 8A are dissolved in 55 ml ethyl acetate and 1.2 g (10.5 mmol) p-toluenesulfonic acid are added. The mixture is heated to the reflux and is stirred at this temperature for 16 h. After cooling to RT, the precipitate is filtered off and washed with ethyl acetate. The solid is dissolved in 50 ml water and the solution is adjusted to pH 7 with 1 N hydrochloric acid. The precipitate is filtered off, washed with water and diisopropyl ether and finally dried over phosphorus pentoxide.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:39])[O:6][CH:7]1[CH:11]2[O:12][Si](C(C)(C)C)(C(C)(C)C)[O:14][CH2:15][CH:10]2[O:9][CH:8]1[N:24]1[C:28]2[N:29]=[C:30]([N:33]=[CH:34][N:35]([CH3:37])[CH3:36])[N:31]=[CH:32][C:27]=2[S:26][C:25]1=[O:38])([CH3:3])[CH3:2].N1C(=O)CC[C@H]1C(O)=O>CO>[CH:1]([O:4][C:5](=[O:39])[O:6][CH:7]1[CH:11]([OH:12])[CH:10]([CH2:15][OH:14])[O:9][CH:8]1[N:24]1[C:28]2[N:29]=[C:30]([N:33]=[CH:34][N:35]([CH3:37])[CH3:36])[N:31]=[CH:32][C:27]=2[S:26][C:25]1=[O:38])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)OC1C2O[Si](C(C)(C)C)(C(C)(C)C)OCC2OC1n1c(=O)sc2cnc(N=CN(C)C)nc21
Agent: O=C1CC[C@@H](C(=O)O)N1
Solvent: CO
Product: CC(C)OC(=O)OC1C(O)C(CO)OC1n1c(=O)sc2cnc(N=CN(C)C)nc21
Reaction time: 0.08 h
Yield: 94.6 %

Procedure:
Carbonic acid 2,2-di-tert-butyl-6-[5-(dimethylamino-methyleneamino)-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-furo[3,2-d][1,3,2]dioxasilin-7-yl ester isopropyl ester (1.70 g, 2.92 mmol) (14) was dissolved in anhydrous MeOH (10.0 mL) and HF/Pyr (245 uL) was added. The clear colorless reaction suddenly thickened with a white precipitate within 5 min. The reaction was stirred 15 min then conc in vacuo. The solids were triturated with EtOAc then dried at 40° C. 16 h to obtain 1.22 g (95%) of 15 as a flocculent snow white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.72 (1H, s), 8.64 (1H, s), 6.11 (1H, d, J=9.1 Hz), 5.84 (1H, d, J=4.1 Hz), 5.57 (1H, dd, J1=1.2 Hz, J2=3.9 Hz), 4.66-4.74 (2H, m), 4.24-4.28 (2H, m), 4.24-4.28 (1H, m), 3.97-4.01 (1H, m), 3.56-3.73 (2H, m), 3.14 (3H, s), 3.04 (3H, s), 1.18 (3H, dd, J1=0.0 Hz, J2=0.0 Hz), 1.20 (3H, d, J=6.2 Hz), 1.17 (3H, d, J=6.2 Hz); [M+H]+ @ m/z 442.5.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH3:20])[C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([O:18]C)=[O:17])=[N:14][CH:15]=1)=[O:8])(=O)C.C(SCC(C)C(NC1N=CC=CC=1C(OC)=O)=O)(=O)C>>[SH:4][CH2:5][CH:6]([CH3:20])[C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([OH:18])=[O:17])=[N:14][CH:15]=1)=[O:8]
Reactant: COC(=O)c1ccc(NC(=O)C(C)CSC(C)=O)cn1
Agent: COC(=O)c1cccnc1NC(=O)C(C)CSC(C)=O
Product: CC(CS)C(=O)Nc1ccc(C(=O)O)nc1

Procedure:
Following the procedure of Example 3, but substituting an equivalent amount of methyl 5-(2-acetylthiomethyl-propionamido)-picolinate, obtained as disclosed in Example 21, for methyl 2-(2-acetylthiomethyl-propionamido)-nicotinate, 5-(2-mercaptomethyl-propionamido)-picolinic acid is obtained; m.p. 175°-177° C., from acetone.
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[OH:34][C:35]([C@@H:38]1[CH2:42][CH2:41][NH:40][CH2:39]1)([CH3:37])[CH3:36]>>[OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:40]4[CH2:41][CH2:42][C@@H:38]([C:35]([OH:34])([CH3:37])[CH3:36])[CH2:39]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: CC(C)(O)[C@@H]1CCNC1
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CC[C@@H](C(C)(C)O)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and (R)-3-(1-hydroxy-1-methyl-ethyl)-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.40 (s, 1H), 4.14 (s, 1H), 3.74 (m, 1H), 3.65 (m, 1H), 3.36 (m, 2H), 3.28 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.15 (m, 6H), 1.03 (m, 1H), 0.83 (d, 3H), 0.74 (m, 1H). m/z: 460 [M+H]
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([C:2]2[CH:8]=[C:7]([CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:6]=[CH:5][C:3]=2[NH2:4])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)Cc1ccc(N)c(Br)c1
Reactant: OB(O)c1ccccc1
Product: CS(=O)(=O)Cc1ccc(N)c(-c2ccccc2)c1

Procedure:
2-bromo-4-(methylsulfonylmethyl)aniline and benzene boronic acid can be combined to form 2-phenyl-4-(methylsulfonylmethyl)aniline,