Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].C(N(CC)CC)C.Cl.[NH2:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([NH:26][C:27]3[CH:32]=[C:31]([O:33][C:34]([O:36][CH3:37])=[O:35])[C:30]([CH3:38])=[CH:29][C:28]=3[F:39])=[N:21][CH:22]=[N:23]2)=[CH:18][CH:17]=1>C(Cl)Cl>[F:39][C:28]1[CH:29]=[C:30]([CH3:38])[C:31]([O:33][C:34]([O:36][CH3:37])=[O:35])=[CH:32][C:27]=1[NH:26][C:20]1[C:19]2[C:24](=[CH:25][C:16]([NH:15][C:4](=[O:5])[CH2:3][O:2][CH3:1])=[CH:17][CH:18]=2)[N:23]=[CH:22][N:21]=1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(N)ccc23)c(F)cc1C
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)Nc1ccc2c(Nc3cc(OC(=O)OC)c(C)cc3F)ncnc2c1
Reaction time: 1 h
Yield: 54.8 %

Procedure:
Methoxyacetyl chloride (119 mg, 1.1 mmol) followed by triethylamine (232 mg, 2.3 mmol) were added to a suspension of 7-amino-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)quinazoline hydrochloride (415 mg, 1.1 mmol) in methylene chloride (10 ml) and the mixture stirred for 1 hour. The solvent was removed by evaporation and the residue partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The resulting solid was purified by column chromatography eluting with methylene chloride/acetonitrile 50/50 followed by methylene chloride/acetonitrile/methanol 50/45/5 to give 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-methoxyacetamidoquinazoline (250 mg, 60%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:4]=1N.N(OC(C)(C)C)=O.[I:21]I>C(Cl)Cl>[I:21][C:4]1[CH:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:8]=[CH:9][C:3]=1[O:2][CH3:1]
Reactant: II
Reactant: COc1ccc(C(F)(F)F)cc1N
Agent: CC(C)(C)ON=O
Solvent: ClCCl
Product: COc1ccc(C(F)(F)F)cc1I
Temperature: 70 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 2-methoxy-5-(trifluoromethyl)aniline (500 mg, 2.62 mmol) in CH2Cl2 (10 mL) was added t-butyl nitrite (467 μL, 3.93 mmol). The reaction was stirred for 5 min prior to addition of iodine (1.3 g, 5.24 mmol), and then heated at 70° C. for 2 h. The reaction was cooled, diluted with CH2Cl2 (10 mL), washed with sat. Na2S2O3 (10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (hexanes) to afford 2-iodo-1-methoxy-4-(trifluoromethyl)benzene as a light yellow solid. 1H NMR (CDCl3, 500 MHz): δ 8.05 (d, J=2 Hz, 1 H), 7.61 (dd, J=8.7, 1.8 Hz, 1 H), 6.89 (d, J=8.7 Hz, 1 H), 3.97 (s, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[NH:15][N:14]=[N:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:16]O>S(Cl)(Cl)=O>[CH3:16][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[CH:10][C:2]=1[F:1]
Reactant: CO
Reactant: O=C(O)c1ccc(-c2nnn[nH]2)cc1F
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(-c2nnn[nH]2)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
To a solution of 2-fluoro-4-(1H-tetrazol-5-yl)-benzoic acid (100 mg, 0.48 mmol) in methanol (5 ml), thionyl chloride (0.5 ml) was added at 0° C. and the reaction mixture was stirred at 25° C. for 12 h. The solvents were distilled off in vacuo, and the residue was purified by chromatography over silica gel (5% methanol/dichloromethane) to afford the title compound as a yellow solid (58%). MS (Turbo Spray): m/z=222.0 (M+H).
Reaction SMILES: CO[C:3](=[O:14])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[NH2:5].[CH3:15][NH2:16]>C(O)C>[CH3:15][NH:16][C:3](=[O:14])[C@H:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1)[NH2:5]
Reactant: CN
Reactant: COC(=O)[C@@H](N)Cc1ccc(N)cc1
Solvent: CCO
Product: CNC(=O)[C@@H](N)Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
To a stirred solution of p-aminophenylalanine methyl ester (1.7 g, 8.8 mmol) in ethanol (150 ml) was added methylamine in ethanol (33%/8M) (100 ml). After stirring at room temperature for 24 hours the reaction mixture was reduced under pressure to yield the title compound as a brown solid (1.7 g, 100%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]1(OB(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OB(O)Oc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2ccccc2)nc1
Temperature: 50 °C
Yield: 88.3 %

Procedure:
2,5-dibromopyridine (7.11 g, 30 mmol), toluene (130 mL), phenylboric acid (4.57 g, 37.5 mmol), and tetrakis(triphenylphosphine)palladium(0) (1.73 g, 1.5 mmol) were weighed into a reaction container, and the reactants were dissolved, while being stirred at 50° C. under a nitrogen gas flow. A 2 M aqueous sodium carbonate solution (30 mL) was added to the solution, and the mixture was stirred at 80° C. for 6 hours. The organic layer of the obtained reaction solution was recovered, and washed with an aqueous sodium carbonate solution and a saturated saline solution. The organic layer was dried with sodium sulfate, filtered, and then distilled off. The residue was purified by silica gel column chromatography (hexane/toluene), and the solvent was distilled off to obtain 5-bromo-2-phenylpyridine (6.21 g, 26.5 mmol).
Reaction SMILES: [K+].F[C:3]1[CH:8]=[C:7]([C:9]2[C:14]3[CH:15]=[C:16]([C:32]([O-:34])=[O:33])[N:17]([CH2:18][CH2:19][O:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=4)[C:13]=3[CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:5][N:4]=1.[CH2:35]([CH2:37][NH2:38])[OH:36]>N1C=CC=CC=1>[OH:36][CH2:35][CH2:37][NH:38][C:3]1[CH:8]=[C:7]([C:9]2[C:14]3[CH:15]=[C:16]([C:32]([OH:34])=[O:33])[N:17]([CH2:18][CH2:19][O:20][C:21]4[CH:22]=[CH:23][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:25][CH:26]=4)[C:13]=3[CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:5][N:4]=1
Reactant: NCCO
Reactant: O=C([O-])c1cc2c(-c3ccnc(F)c3)nccc2n1CCOc1ccc(OC(F)(F)F)cc1
Agent: [K+]
Solvent: c1ccncc1
Product: O=C(O)c1cc2c(-c3ccnc(NCCO)c3)nccc2n1CCOc1ccc(OC(F)(F)F)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
4-(2-Fluoropyridin-4-yl)-1-{2-[4-(trifluoromethoxy)phenoxy]ethyl}-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid potassium salt (25 mg, 0.050 mmole) was taken up in pyridine (0.3 mL) in a screw cap vial. To this was added ethanolamine (0.015 mL, 0.250 mmole). The vial was capped then heated to 120° C. After stirring overnight ethanolamine (0.015 mL, 0.250 mmole) was added and heating continued. After stirring overnight the mixture was cooled to RT and concentrated. The crude material was taken up in DMSO and acidified with TFA. The resulting solution was purified by preparative reversed-phase HPLC (30×100 mm Phenomenex AXIA-Gemini-NX, 5%-95% CH3CN/water containing 0.1% TFA over 18 min at 50 mL/min) to give the title compound (16 mg, 52%) as a yellow solid. 1H NMR (499 MHz, DMSO): δ 8.58 (d, J=5.9 Hz, 1 H); 8.04 (d, J=6.7 Hz, 1 H); 7.95 (d, J=6.0 Hz, 1 H); 7.73 (s, 1 H); 7.66 (s, 1 H); 7.43 (d, J=6.6 Hz, 1 H); 7.23 (d, J=8.6 Hz, 2 H); 6.90 (d, J=8.8 Hz, 2 H); 5.13-5.04 (m, 2H); 4.39-4.35 (m, 2 H); 3.68 (m, 2 H); 3.49 (bs, 2 H). HRMS (ESI) calc (M+H)+=503.1537. found 503.1529.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[S:18](=[O:20])(=[O:19])[N:17](CC[Si](C)(C)C)[C:16](=[O:27])[CH2:15]2)=[C:10]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[S:18](=[O:20])(=[O:19])[NH:17][C:16](=[O:27])[CH2:15]2)=[C:10]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(Cc3ccccc3)cc2OCc2ccccc2)S1(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=C1CN(c2ccc(Cc3ccccc3)cc2OCc2ccccc2)S(=O)(=O)N1
Temperature: 50 °C

Procedure:
A mixture of 5-(4-benzyl-2-benzyloxyphenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (1.1 g, 2.16 mmol) and TBAF (1.0 M solution in THF, 4.0 mL, 4 mmol) is heated at 50° C. for 18 h. After THF is removed under reduced vacuum, KHCO3 solution (0.50 M, 10 mL) is added, followed by water (10-15 mL). The residue is allowed to coat the glassware and the water is decanted. The residue is washed with water (2×), and ether (1×). The residue is treated with 1N HCl solution and is extracted with EtOAc. The organic layer is then washed with water, dried with MgSO4 and concentrated to give the title compound as an orange oil.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-])=O)[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][N:17]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:18]=3)[S:13][C:6]=12.[BH4-].[Na+]>CO.Cl[Ni]Cl>[F:1][C:2]1[CH:30]=[C:29]([NH2:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][N:17]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:25])([CH3:24])[CH3:26])[CH:18]=3)[S:13][C:6]=12
Reactant: C[Si](C)(C)CCOCn1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[Si](C)(C)CCOCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Reaction time: 1 h
Yield: 93.5 %

Procedure:
To a solution of 7-(2-fluoro-4-nitrophenoxy)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)thieno[3,2-b]pyridine (103) (WO 2006010264) (400 mg, 0.82 mmol) in MeOH (10 mL) at 0° C. was added NiCl2×6H2O (650 mg, 2.5 eq, 2.73 mmol) and NaBH4 (165 mg, 4 eq, 4.4 mmol). The reaction mixture was allowed to stir for 1 hr, concentrated to dryness and the resultant solid was dissolved in 2 M HCl. This solution was then made basic with concentrated aqueous ammonium hydroxide and extracted with DCM. The DCM extract was dried over anhydrous sodium sulfate, filtered and evaporated to give 3-fluoro-4-(2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)benzenamine (104) (350 mg, 100% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH2:6][CH2:5]1.Cl[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>C(Cl)(Cl)Cl>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[NH:1][CH2:2][CH2:3][N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH2:8][CH2:9]1
Reactant: Clc1ccccn1
Reactant: COc1ccccc1N1CCN(CCN)CC1
Solvent: ClC(Cl)Cl
Product: COc1ccccc1N1CCN(CCNc2ccccn2)CC1
Temperature: 25 °C

Procedure:
23.5 g of 1-(2-aminoethyl)-4-(2-methoxyphenyl)piperazine [Hexachemie-Reuil Malmaison-France] and 4.85 mL of 2-chloropyridine were stirred at 160° C. in a closed reaction vessel for 10.5 hours. The reaction mixture was cooled to room temperature, dissolved in 320 mL of chloroform and washed with 1N sodium hydroxide (3×320 mL), followed by water (2×400 mL). The organic layer was dried (sodium sulfate) and evaporated to dryness under reduced pressure. The crude product was purified by column flash chromatography eluting with an ethyl acetate-3N NH3 in methanol 100:2 mixture affording, after evaporation of the collected fractions, 5 g of the title compound as an oil. A sample was crystallized from ethyl acetate to give a solid melting at 89-94° C.
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@@H:18]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].[Li]N([Si](C)(C)C)[Si](C)(C)C.[O:33]1CCCC1>>[C:11]([O-:33])(=[O:12])[C:6]1[CH:7]=[CH:20][CH:19]=[CH:18][CH:5]=1.[CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@@H:18]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15]
Reactant: C1CCOC1
Agent: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Product: O=C([O-])c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of hydrocodone freebase (0.596 g, 1.99 mmol) in tetrahydrofuran (25 mL) was added 1 M LiN(SiMe3)2 in tetrahydrofuran (5.98 mL). The resulting orange suspension was stirred at ambient temperatures for 30 min. after which benzoate-succinic ester (1.25 g, 5.98 mmol) was added. The resulting mixture was stirred overnight at ambient temperatures and was quenched after 18 h by the addition of 100 mL saturated ammonium chloride solution which was allowed to stir for another 2 h. Ethyl acetate (100 mL) was added to the mixture and washed with saturated ammonium chloride solution (3×100 mL) and water (1×100 mL). Organic extracts were dried over anhydrous MgSO4, solvent was removed and residue was taken up in 2-isopropanol (50 mL). Water was added until a solid formed. The resulting mixture was chilled, filtered and dried to obtain benzoate-hydrocodone freebase (0.333 g, 0.826 mmol, 42% yield) as a dark brown solid. This synthesis is depicted in FIG. 13A.
Reaction SMILES: [OH-].[Na+].Cl[CH2:4][CH2:5][CH2:6][OH:7].[CH3:8][C:9]1[N:13]=[C:12]([SH:14])[NH:11][N:10]=1>O>[CH3:8][C:9]1[N:13]=[C:12]([S:14][CH2:4][CH2:5][CH2:6][OH:7])[NH:11][N:10]=1
Reactant: Cc1n[nH]c(S)n1
Reactant: OCCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1n[nH]c(SCCCO)n1

Procedure:
To a solution of sodium hydroxide (0.4 g.) in water (5 ml.) was added 3-chloropropan-1-ol (0.83 ml.) and 3-methyl-5-mercapto-1,2,4-triazole (1.1 g.) and the mixture was heated at 100° for 1.5 hours. The solvent was evaporated and the residue was extracted twice with EtOAc/EtOH 50:50 v/v (20 ml.). The extracts were combined and evaporated to dryness. The residual solid was recrystallised from EtOAc to give 3-methyl-5-(3-hydroxypropylthio)-1,2,4-triazole (0.4 g.) which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH2:21])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=1)=[O:6].C[O:23][C:24](=[O:39])[C:25]([CH3:38])([CH3:37])[CH2:26][C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([CH:34]=O)=[C:29]([CH3:36])[CH:28]=1>>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5]([C:4]2[CH:18]=[CH:19][C:20]3[N:21]=[C:34]([C:30]4[C:29]([CH3:36])=[CH:28][C:27]([CH2:26][C:25]([CH3:37])([CH3:38])[C:24]([OH:39])=[O:23])=[CH:32][C:31]=4[CH3:33])[NH:1][C:2]=3[CH:3]=2)=[O:6])=[CH:9][CH:10]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)C(C)(C)Cc1cc(C)c(C=O)c(C)c1
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(N)c(N)c2)cc1
Product: Cc1cc(CC(C)(C)C(=O)O)cc(C)c1-c1nc2ccc(C(=O)Nc3ccc(C(C)(C)C)cc3)cc2[nH]1

Procedure:
The title compound was prepared from 3,4-diamino-N-(4-tert-butylphenyl)-benzamide and 3-(4-formyl-3,5-dimethylphenyl)-2,2-dimethylpropionic acid methyl ester analogous to Example 6-26. 1H NMR (Methanol-d4, 400 MHz): δ 8.26 (s, 1H), 7.93 (d, 1H), 7.72 (m, 1H), 7.65 (m, 2H), 7.44 (m, 2H), 7.05 (s, 2H), 2.89 (s, 2H), 2.15 (s, 6H), 1.35 (s, 9H), 1.2 (s, 6H). MS (m/z) 498.2 (M+1); Retention time: 1.47 min (Method 10).
Reaction SMILES: [NH2:1][C@H:2]([C:12]([NH:14][C@H:15]([C:28]([NH:30][C@H:31]([C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])[CH2:32][CH:33]([CH3:35])[CH3:34])=[O:29])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:19][CH:18]=1)=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C1C=CC2N(O)N=NC=2C=1.[NH:56](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:57]([C:67](O)=[O:68])[CH2:58][CH2:59][C:60](=[O:66])[O:61][C:62]([CH3:65])([CH3:64])[CH3:63].CCN=C=NCCCN(C)C.Cl.C(O)(=O)C(CC(O)=O)S.C1CCN2C(=NCCC2)CC1.S(O)(C)(=O)=O>[Cl-].[Na+].O.C(Cl)(Cl)Cl>[NH2:56][C@H:57]([C:67]([NH:1][C@H:2]([C:12]([NH:14][C@H:15]([C:28]([NH:30][C@H:31]([C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])[CH2:32][CH:33]([CH3:35])[CH3:34])=[O:29])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[CH:21][CH:22]=1)=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:68])[CH2:58][CH2:59][C:60](=[O:66])[O:61][C:62]([CH3:64])([CH3:65])[CH3:63]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@@H](N)CCC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@@H](N)CCC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the chloroform solution (30 ml) of H-Glu(OtBu)-Tyr(tBu)-Leu-OBzl was added HOBt (68 mg, 0.50 mmol), Fmoc-Glu(OtBu)-OH (468 mg, 1.10 mmol) and EDC.HCl (232 mg, 1.21 mmol) were added under ice-cooling, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was evaporated under reduced pressure until the mixture became 15 mL, to the concentrated solution were added under ice-cooling thiomalic acid (450 mg, 3.00 mmol) and DBU (1.34 mL, 9.00 mmol), and the mixture was stirred at room temperature for 3 hr. After completion of the reaction, to this solution was added dropwise under ice-cooling a mixture of MsOH (0.17 mL, 2.70 mmol) and chloroform (1.7 mL), chloroform (15 mL) and 20% brine (30 ml) was added to give an organic layer and an aqueous layer. Then, the aforementioned pH=9.0 washing was performed three times. The obtained organic layer was washed three times with 10% aqueous sodium carbonate solution (30 ml) and twice with 20% brine (30 ml) with stirring at room temperature, and the organic layer and the aqueous layer were partitioned. The obtained organic layer was dried over sodium sulfate and filtered. The filtrate was recovered, and the solvent in the recovered filtrate was evaporated under reduced pressure. To the obtained residue was added hexane (10 ml), and the precipitate was recovered by filtration. The recovered precipitate was dried to give H-Glu(OtBu)-Glu(OtBu)-Tyr(tBu)-Leu-OBzl (787 mg, 0.97 mmol). The yield of the finally obtained C-protected peptide was calculated from H-Leu-OBzl.TsOH salt (1.00 mmol), which is the starting material of Example 5(i), to find 97%.
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[CH3:31][N:32]1[CH2:36][CH2:35][CH2:34][CH:33]1[CH2:37][CH2:38][NH2:39]>>[CH3:31][N:32]1[CH2:36][CH2:35][CH2:34][CH:33]1[CH2:37][CH2:38][NH:39][C:8](=[O:30])[NH:9][C:10]1[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=2[F:26])[C:11]=1[C:27]([NH2:28])=[O:29]
Reactant: CN1CCCC1CCN
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCC3CCCN3C)c2C(N)=O)c(F)c1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 2-(1-methyl-pyrrolidin-2-yl)-ethylamine by the procedure analogous to Example 1. MS (APCI, m/z): 472 [M+H]+.
Reaction SMILES: [ClH:1].C([S:5][CH2:6][CH:7]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=1)[C:8]([NH:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[C:14]([OH:16])=[O:15])=[O:9])(=O)C.[OH-].[Na+].Cl>CO>[ClH:1].[SH:5][CH2:6][CH:7]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=1)[C:8]([NH:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[C:14]([OH:16])=[O:15])=[O:9]
Reactant: CC(=O)SCC(Cc1ccc(N(C)C)cc1)C(=O)Nc1cc(C)cc(C(=O)O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(NC(=O)C(CS)Cc2ccc(N(C)C)cc2)cc(C(=O)O)c1
Reaction time: 1 h
Yield: 49.3 %

Procedure:
3-[[2-Acetylthiomethyl-3-(4-dimethylaminophenyl)-propionyl]amino]5-methylbenzoic acid hydrochloride (compound of Example 59) (1.9 g) is dissolved in 50% aqueous methanol (30 ml), and the mixture is adjusted to pH 12.0 with 10% aqueous sodium hydroxide solution under nitrogen. After reacting at room temperature for one hour, the reaction mixture is adjusted to pH 4.5 with 10% hydrochloric acid and methanol is distilled off under reduced pressure. The residue is purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected, and acetonitrile is distilled off under reduced pressure and the residue is extracted with ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate, and ethyl acetate is distilled off under reduced pressure. To the residue is added 35% ethanolic hydrochloric acid (0.5 ml), and the mixture is cooled and thereto is added diethyl ether (50 ml). The pricipitated white powder is separated by filtration to give the title compound (0.85 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH:12]1[C:17](=[O:22])[N:18]([O:20][CH3:21])[CH3:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:25](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH3:25])[CH2:13][CH:12]1[C:17](=[O:22])[N:18]([O:20][CH3:21])[CH3:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CON(C)C(=O)C1CNCCN1C(=O)OCc1ccccc1
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: CON(C)C(=O)C1CN(C)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96 %

Procedure:
To (RS)-2-(methoxy-methyl-carbamoyl)-piperazine-1-carboxylic acid benzyl ester, D52 (3 g, 10 mmol) in 1,2-dichloroethane (50 ml) was added formaldehyde (0.85 ml of 37% w/w solution in water, 11 mmol) and the mixture stirred at ambient temperature for 0.75 h. Sodium triacetoxyborohydride (2.55 g, 12 mmol) was added portionwise over 0.25 h, and the resulting mixture stirred at ambient temperature for 18 h. The reaction was partitioned between dichloromethane (300 ml) and 1M sodium hydroxide (100 ml). The aqueous was re-extracted with dichloromethane (250 ml) and the combined extracts dried (Na2SO4) and the solvent removed in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate-hexane mixtures to afford the title product (3 g, 96%) as a gum.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH3:9])=[O:3].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[C:17]([N:19]1[C:28]2[C:23](=[CH:24][C:25]([C:29]3[CH:34]([CH3:35])[S:33][C:32](=[O:36])[NH:31][N:30]=3)=[CH:26][CH:27]=2)[C:22]([CH3:38])([CH3:37])[CH2:21][CH2:20]1)=[O:18].N1C=CC=CC=1>ClCCl>[CH2:8]([N:7]([CH2:6][CH2:5][O:4][C:2]([N:31]1[N:30]=[C:29]([C:25]2[CH:24]=[C:23]3[C:28](=[CH:27][CH:26]=2)[N:19]([C:17](=[O:18])[C:16]2[CH:39]=[CH:40][C:41]([O:42][CH3:43])=[C:14]([O:13][CH3:12])[CH:15]=2)[CH2:20][CH2:21][C:22]3([CH3:37])[CH3:38])[CH:34]([CH3:35])[S:33][C:32]1=[O:36])=[O:3])[CH2:10][CH3:11])[CH3:9]
Reactant: CCN(CC)CCOC(=O)Cl
Reactant: COc1ccc(C(=O)N2CCC(C)(C)c3cc(C4=NNC(=O)SC4C)ccc32)cc1OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN(CC)CCOC(=O)N1N=C(c2ccc3c(c2)C(C)(C)CCN3C(=O)c2ccc(OC)c(OC)c2)C(C)SC1=O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
6 g of 2-(N,N-diethylamino)ethyl chloroformate dissolved in 50 ml of dichloromethane are added dropwise with stirring to a solution of 10 g of 3,6-dihydro-5-[1,2,3,4-tetrahydro-1-(3,4-dimethoxybenzoyl)-4,4-dimethyl-6-quinolyl]-6-methyl-2H-1,3,4-thiadiazin-2-one ("B") and 9.8 ml of pyridine in 100 ml of dichloromethane and the mixture is subsequently stirred at 20° C. for one hour. The solvent is removed and the mixture is worked up in the conventional manner to give 3-[2-(N,N-diethylamino)ethoxycarbonyl]-5-[1,2,3,4-tetrahydro-1-(3,4-dimethoxybenzoyl)-4,4-dimethyl-6-quinolyl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; Rf (THF) 0.65.