Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C@@H:20]([OH:31])[CH2:21][C@@H:22]([CH3:30])[C:23]([NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])(C)(C)C.[CH2:39]([C@H:46]([CH2:50][C:51]([N:53]([CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[CH3:54])=[O:52])C(O)=O)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH2:39]([C@H:46]([CH2:50][C:51]([N:53]([CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[CH3:54])=[O:52])[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C@@H:20]([OH:31])[CH2:21][C@@H:22]([CH3:30])[C:23]([NH:25][CH2:26][CH:27]([CH3:28])[CH3:29])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CC(C)CNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C
Reactant: CN(Cc1ccccc1)C(=O)C[C@@H](Cc1ccccc1)C(=O)O
Product: CC(C)CNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H](CC(=O)N(C)Cc1ccccc1)Cc1ccccc1
Yield: 53.3 %

Procedure:
The procedure described in Example 6(b) was repeated, but using 300 mg (0.543 mmole) of (2R, 4S, 5S)-5-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-4-hydroxy-N-isobutyl-2-methylhexanamide [prepared as described in Example 17(a)] and 170 mg (0.543 mmole) of 2(R)-benzyl-3-(N-benzyl-N-methylaminocarbonyl)propionic acid, to afford 216 mg of the title compound as a colorless powder, melting at 118°-120° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:9]([OH:11])=O)=[C:5]([CH2:7][CH3:8])[N:6]=1.CN(C)C=O.C(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([C:9]([Cl:19])=[O:11])=[C:5]([CH2:7][CH3:8])[N:6]=1
Reactant: CCc1nc(C)sc1C(=O)O
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCc1nc(C)sc1C(=O)Cl

Procedure:
In a similar apparatus to Example 1, 18.8 g (0.11 mole) of 2-methyl-4ethylthiazole-5carboxylic acid were suspended in 150 ml of toluene, followed by the addition of 0.1 g of N,N-dimethylformamide. Under heating and reflux, phosgene was blown at a rate of 1.5 l/hr for 4 hours (0.27 mole). After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain 20.3 g of 2-methyl-4-ethylthiazole-5-carboxylic acid chloride. Its purity and yield were 98.0% and 97.5%, respectively.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH3:9])[C:6]=1[O:7][CH3:8].[Cl:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[C:13]([O:18][CH3:19])[C:12]=1[C@H:20]([C:22]1[C:30]2[C:25](=[N:26][CH:27]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:29]=2)[NH:24][CH:23]=1)[CH3:21].C(=O)([O-])[O-].[K+].[K+].ClCCl>O1CCOCC1>[Cl:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[C:13]([O:18][CH3:19])[C:12]=1[C@H:20]([C:22]1[C:30]2[C:25](=[N:26][CH:27]=[C:28]([C:2]3[CH:3]=[N:4][N:5]([CH3:9])[C:6]=3[O:7][CH3:8])[CH:29]=2)[NH:24][CH:23]=1)[CH3:21]
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: COc1c(Br)cnn1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3cnn(C)c3OC)cc12
Temperature: 100 °C

Procedure:
A solution of 4-bromo-5-methoxy-1-methyl-1H-pyrazole (0.0133 g, 0.0697 mmol), 3-[(1S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)ethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (0.020 g, 0.046 mmol), potassium carbonate (0.0193 g, 0.139 mmol) 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride, dichloromethane (3.79 mg, 0.00464 mmol) in previously degassed 4:1 dioxane:water (1.0 mL) was evacuated and charged with N2 (2×) and heated under microwave conditions [Biotage, 100° C., 30 min, high absorption]. This was further purified by Gilson HPLC. The combined fractions were concentrated in vacuo resulting in the title compound an off-white solid. 1H NMR (400 MHz, CD3OD): δ=1.80 (d, J=7.3 Hz, 3H), 3.63 (s, 3H), 3.67 (br. s., 2H), 3.72 (s, 3H), 5.07-5.16 (m, 1H), 6.91 (dd, J=4.2, 9.0 Hz, 1H), 7.10 (dd, J=8.8, 8.8 Hz, 1H), 7.34 (d, J=1.3 Hz, 1H), 7.52 (s, 2H), 7.67 (s, 1H). MS (ES+): m/z 415.09, 417.07 [MH+]. HPLC: tR=3.95 min (polar—5 min, ZQ3)
Reaction SMILES: Cl[O-].[Na+].[CH2:4]=[C:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1.[CH:18](=[N:25][OH:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[C:19]1([C:18]2[CH2:4][C:5]3([CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]3)[O:26][N:25]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ON=Cc1ccccc1
Reactant: C=C1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC2(CC(c3ccccc3)=NO2)C1
Reaction time: 2 h
Yield: 73.2 %

Procedure:
A 10% aqueous sodium hypochlorite solution (2.88 mL, 4.66 mmol) was added dropwise to a solution of tert-butyl 3-methylenepiperidine-1-carboxylate (230 mg, 1.166 mmol) and benzaldehyde oxime (282 mg, 2.332 mmol) in CH2Cl2 (5 mL) at 0° C. After 2 h at 0° C., the mixture was diluted CH2Cl2 (50 mL) and washed with water (10 mL). The aqueous phase was extracted with CH2Cl2 (3×20 mL). The combined organic extracts were washed with brine (10 mL), dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 0 to 15% ethyl acetate in hexanes, gave the expected product as a colorless oil (270 mg, 73% yield). LCMS: (M+Na)+=339.12. 1H NMR (400 MHz, chloroform-d) δ ppm 7.55-7.79 (2H, m), 7.31-7.47 (3H, m), 3.57-3.93 (2H, m), 2.90-3.29 (4H, m), 1.78-2.04 (2H, m), 1.51-1.65 (2H, m), 1.46 (9H, s).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[NH:13][CH:12]=[N:11]2)=[CH:6][CH:5]=1.[CH3:16][Si:17]([CH3:24])([CH3:23])[CH2:18][CH2:19][O:20][CH2:21]Cl>CN(C=O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14](=[O:15])[N:13]([CH2:21][O:20][CH2:19][CH2:18][Si:17]([CH3:24])([CH3:23])[CH3:16])[CH:12]=[N:11]2)=[CH:8][CH:9]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=c1[nH]cnn1-c1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cnn(-c2ccc(Br)cc2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To dry NaH (67.8 mg, 2.83 mmol) under an Argon atmosphere was added a solution of compound 84b (532 mg, 1.88 mmol) in anhydrous DMF (5 mL) slowly over 2 min. The mixture was stirred at rt for 1 h and then cooled to 0° C. 2-(Trimethylsilyl)ethoxymethyl chloride (0.612 mL, 3.391 mmol) was added dropwise over 2 min. After stirring at rt for 1 h, the mixture was quenched carefully with 1 mL of saturated aqueous NH4Cl and poured into brine (75 mL). The mixture was extracted with EtOAc (3×25 mL) and the combined extracts were washed with water (2×25 mL) and brine (25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a faintly yellow crystalline solid. The solid was purified by flash column chromatography on silica gel (0-40% EtOAc-heptane) to give compound 84c as a white solid. Mass spectrum (LCMS, ESI pos.): Calcd. for C14H20BrN3O2Si, 392.1/394.1 (M+Na). found 392.2/394.1.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]3[C@H:19]([C:22]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=4Br)[CH2:20][CH2:21][C@@H:14]23)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1COCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:48][O:49][C:50]1[CH:55]=[CH:54][C:53]([CH2:56][CH2:57][C:58]([O:60][CH3:61])=[O:59])=[CH:52][C:51]=1B1OC(C)(C)C(C)(C)O1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].O>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]3[C@H:19]([C:22]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=4[C:55]4[C:50]([O:49][CH3:48])=[CH:51][CH:52]=[C:53]([CH2:56][CH2:57][C:58]([O:60][CH3:61])=[O:59])[CH:54]=4)[CH2:20][CH2:21][C@@H:14]23)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C1O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]2CC[C@@H](c3cc(C(F)(F)F)ccc3Br)N12
Reactant: COC(=O)CCc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2[C@@H]2CC[C@H]3[C@@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)OC(=O)N23)c1
Temperature: 62 °C
Yield: 90.9 %

Procedure:
To Intermediate B2 (30 mg, 0.044 mmol) was added THF (2 mL), water (0.1 mL), tribasic potassium phosphate (45.3 mg, 0.213 mmol), methyl 3-[4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (51.3 mg, 0.16 mmol) (Intermediate H), palladium(II) acetate (1.2 mg, 5.34 mmol), and 1,1′-bis(di-tert-butylphosphino)ferrocene (2.53 mg, 5.34 mmol). The system was flushed with nitrogen gas and was heated at 62° C. overnight. The reaction was diluted with ethyl acetate:hexanes (1:2, 10 mL) and was partitioned with water (10 mL). The organic was dried over sodium sulfate, filtered and concentrated. The crude product was purified by reverse phase HPLC to yield methyl 3-[2′-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-6-methoxy-4′-(trifluoromethyl)biphenyl-3-yl]propanoate (27 mg, 0.04 mmol). 1H NMR indicated that this compound exists as a pair of rotamers at 1.2:1 ratio. 1H NMR (500 MHz, CDCl3) δ7.87 (s, 1H), 7.81 (s, 2H), 7.75 (s, 1H, major rotamer), 7.73 (s, 1H, minor rotamer) 7.6 (m, 1H) 6.8-7.3 (m, 4H), 6.06 (d, J=7.9 Hz, 1H, major rotamer), 6.06 (d, J=7.9 Hz, 1H, major rotamer), 6.01 (d, 1H, minor rotamer), 5.12 (m, 1H, major rotamer), 4.98 (m, 1H, minor rotamer), 4.1 (m, 1H), 3.84 (s, 3H, major rotamer), 3.68 (s, 3H), 3.67 (s, 3H) 3.62 (s, 3H, minor rotamer), 2.9 (m, 2H), 2.6 (m, 2H), 0.9-1.7 (m, 4H). MS ESI calc'd. for C32H27F9NO5 [M+H]+ 676.2. found 676.4. RTA (95% HS): 296 nM
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:12]([O:16][C:17](=[O:28])[NH:18][CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][C:23]([NH2:27])=[CH:22][N:21]=1)([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1>C(Cl)Cl>[C:12]([O:16][C:17](=[O:28])[NH:18][CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][C:23]([NH:27][S:8]([C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=2)(=[O:10])=[O:9])=[CH:22][N:21]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Reactant: Cc1cc(N)cnc1CNC(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(NS(=O)(=O)c2cccnc2Cl)cnc1CNC(=O)OC(C)(C)C
Yield: 111.8 %

Procedure:
The title compound (1.98 g) was prepared from 2-chloropyridine-3-sulfonyl chloride (910 mg, 4.29 mmol), tert-butyl(5-amino-3-methylpyridin-2-yl)methylcarbamate (IntC12) (1.12 g, 4.72 mmol) and pyridine (1.04 mL, 12.9 mmol) in DCM (25 mL) at rt using the methods of (IntC1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[CH:5]([CH2:7][OH:8])[NH2:6].[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:20](O)=[O:21])=[CH:14]2>>[CH3:2][O:3][C:4](=[O:9])[CH:5]([NH:6][C:20]([C:15]1[NH:16][C:17]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:10])=[CH:19][CH:18]=2)=[O:21])[CH2:7][OH:8]
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: COC(=O)C(N)CO
Agent: Cl
Product: COC(=O)C(CO)NC(=O)c1cc2cc(Cl)ccc2[nH]1

Procedure:
D,L-Serine methyl ester hydrochloride (2.1 mmol) and 5-chloro-1H-indole-2-carboxylic acid (2.0 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, washed with acid first then with saturated NaHCO3) and the product purified by chromatography on silica gel eluted with 10, 20, 40 and 60% ethyl acetate in hexanes: Yield 565 mg, 95%; HPLC (60/40) 3.46 minutes (98%); mp 153-155 ° C.; TSPMS 297/299 (MH+, 100/40%);
Reaction SMILES: [C:1]([C:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([CH2:9][C:10](OC)=[O:11])[CH2:4][C:5]([O:7][CH3:8])=[O:6])#[N:2].[H][H]>CO.[Ni]>[CH3:8][O:7][C:5](=[O:6])[CH2:4][C:3]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][C:10](=[O:11])[NH:2][CH2:1]1
Reactant: [H][H]
Reactant: COC(=O)CC(C#N)(CC(=O)OC)C(=O)OC(C)(C)C
Agent: [Ni]
Solvent: CO
Product: COC(=O)CC1(C(=O)OC(C)(C)C)CNC(=O)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.8 %

Procedure:
To a solution in methanol (70 mL) of the compound (5.00 g) obtained in step (1) above, a Raney nickel catalyst (about 7.5 g) was added. The mixture was stirred at 70° C. for 8 hours in a hydrogen atmosphere with 0.4 megapascals (MPa). After being cooled to room temperature, the reaction mixture was filtered through Celite (registered trademark) and the filtrate was concentrated under reduced pressure. To the resulting residue, diethyl ether (50 mL) and hexane (10 mL) were added and the mixture was stirred at room temperature for 15 minutes. The resulting precipitate was recovered by filtration to give tert-butyl 3-(2-methoxy-2-oxoethyl)-5-oxopyrrolidine-3-carboxylate as a colorless solid (1.75 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.[S:16]1[C:20]([C:21]2[O:22][CH:23]=[C:24]([CH2:26]Cl)[N:25]=2)=[CH:19][C:18]2[CH:28]=[CH:29][CH:30]=[CH:31][C:17]1=2>>[S:16]1[C:20]([C:21]2[O:22][CH:23]=[C:24]([CH2:26][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)=[CH:4][CH:3]=3)[N:25]=2)=[CH:19][C:18]2[CH:28]=[CH:29][CH:30]=[CH:31][C:17]1=2
Reactant: ClCc1coc(-c2cc3ccccc3s2)n1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: c1ccc2sc(-c3nc(COc4ccc(CCCn5ccnc5)cc4)co3)cc2c1
Yield: 68 %

Procedure:
In substantially the same manner as in Working Example 48, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 2-(2-benzo[b]thienyl)-4-chloromethyloxazole to give 2-(2-benzo[b]thienyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 68%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 149-150° C.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)(=[O:5])=[O:4])[CH3:2].[CH2:11]([N:14]([CH2:18][CH3:19])[C:15](Cl)=[O:16])[CH:12]=[CH2:13].C(N(CC)CC)C>O1CCCC1>[CH2:11]([N:14]([CH2:18][CH3:19])[C:15]([N:8]1[CH:9]=[N:10][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[N:7]1)=[O:16])[CH:12]=[CH2:13]
Reactant: C=CCN(CC)C(=O)Cl
Reactant: CCS(=O)(=O)c1nc[nH]n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN(CC)C(=O)n1cnc(S(=O)(=O)CC)n1

Procedure:
A mixture of 6.45 g. 3-ethylsulphonyl-1,2,4-triazole, 5.9 g. N-allyl-N-ethylcarbamoyl chloride, 6.5 ml. dry triethylamine and 80 ml. dry tetrahydrofuran was refluxed under anhydrous conditions for 6 hours. The reaction mixture was worked up as described in Example 1 to produce a solid residue which was recrystallized from benzene/petroleum ether, b.p. 40° - 60° C. to give 1-(N-allyl-N-ethylcarbamoyl)-3-ethylsulphonyl-1,2,4-triazole, m.p. 41° - 43° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15]([SH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CS(C)=O>[CH2:15]([S:22][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cccc(Cl)n1
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cccc(SCc2ccccc2)n1
Temperature: 25 °C
Yield: 87 %

Procedure:
2-Chloro-6-methylpyridine (1.30 g), potassium carbonate (2.12 g) and benzylmercaptan (1.8 mL) were stirred in dimethyl sulfoxide (10 mL) at 150° C. for 3 hr. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=15:1) to give the title compound as a pale-red oil (yield 1.90 g, 87%).
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[C:6]([C:18]2[CH:26]=[CH:25][C:21]3[O:22][CH2:23][O:24][C:20]=3[CH:19]=2)[CH:5]=1.[OH-].[Na+]>O1CCOCC1>[O:22]1[C:21]2[CH:25]=[CH:26][C:18]([C:6]3[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH2:11][C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:7]=3)[C:3]([OH:27])=[O:2])=[CH:19][C:20]=2[O:24][CH2:23]1
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(-c2ccc3c(c2)OCO3)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1cc(OCc2ccccc2)cc(-c2ccc3c(c2)OCO3)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
3-Benzo[1,3]dioxol-5-yl-5-benzyloxy-benzoic acid methyl ester (14.2 g) was dissolved in 1,4-dioxane (200 mL) and then 1 M aq. NaOH (40 mL) was added. The mixture was stirred at room temperature overnight. The solvents were removed under reduced pressure and the residue was diluted with water (200 mL). It was then made acidic by addition of 10% HCl (aq.) solution and the precipitated material was collected by filtration. The solid was washed with water and dried to yield 13.2 g (97% yield) of the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[CH:13]=[C:14]([C:16]([OH:18])=O)[CH:15]=[C:5]2[C:4]1=[O:19])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:32][C:33]1[NH:37][N:36]=[N:35][N:34]=1>CN(C)C=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[CH:13]=[C:14]([C:16]([NH:32][C:33]3[NH:37][N:36]=[N:35][N:34]=3)=[O:18])[CH:15]=[C:5]2[C:4]1=[O:19])[CH3:2]
Reactant: Nc1nnn[nH]1
Reactant: CCn1c(=O)c2cc(C(=O)O)cn2c2ccccc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCn1c(=O)c2cc(C(=O)Nc3nnn[nH]3)cn2c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
A mixture of 1.2 g (4.7 mmole) of 4,5-dihydro-5-ethyl-4-oxo-pyrrolo-[1,2-a]-quinoxaline-2-carboxylic acid (prepared by the process of French application No. 2,387,230), 0.81 g (5.0 mmole) of carbonyldiimidazole and 25 ml of anhydrous dimethylformamide was stirred until a clear solution was obtained and 0.425 g (5.0 mmole) of anhydrous 5-amino-tetrazole were added thereto. The mixture was stirred at room temperature for 30 minutes and was then filtered. The recovered product was washed with ethyl acetate and dried over P2O5 under vacuum to obtain 1.4 g of 4,5-dihydro-5-ethyl-4-oxo-N-(1H-tetrazol-5-yl)-pyrrolo-[1,2-a]-quinoxaline-2-carboxamide in the form of white crystals melting at 315°-318° C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[N+:2]=[N-:3].Cl.[CH3:17][O:18][C:19](=[O:40])[C@H:20]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([C:32]2[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:39])=[O:31])=[CH:25][CH:24]=1)[NH2:21]>>[CH3:17][O:18][C:19](=[O:40])[C@H:20]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30]([C:32]2[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:39])=[O:31])=[CH:27][CH:28]=1)[NH:21][C:13]([C:8]1([CH2:7][CH2:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])[CH2:9][CH2:10][CH2:11][CH2:12]1)=[O:15]
Reactant: [N-]=[N+]=NCCCCC1(C(=O)O)CCCC1
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)C1(CCCCN=[N+]=[N-])CCCC1

Procedure:
4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[I-(4-azidobutyl)cyclopentyl]-carbonyl]-L-phenylalanine methyl ester was prepared from 1-[4-(azido)butyl]cyclopentane carboxylic acid and of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester hydrochloride salt using the procedure described in example 46 to give a 99% yield of a white solid, mp 195-199° C. HR MS (C27H31Cl2N5O4): Obs mass, 560.1833. Calcd mass, 560.1831 (M+H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[O:12][CH:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[NH:16]1[CH2:17][CH2:18][CH:13]([O:12][N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(ON2C(=O)c3ccccc3C2=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2ccccc2C(=O)N1OC1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
tert-Butyl 4-(1,3-dioxoisoindolin-2-yloxy)piperidine-1-carboxylate (3.81 g, 11.0 mmol) was added to trifluoroacetic acid (80 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction was concentrated in vacuo and the residue was triturated with diethyl ether (100 ml). The resulting solid was washed with diethyl ether (20 ml×3) to give 2-(piperidin-4-yloxy)isoindoline-1,3-dione trifluoroacetic acid (3.50 g, 90%) as a white solid: LCMS: 247 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH3:40])([C:36]([F:39])([F:38])[F:37])[C:10]([NH:12][NH:13][C:14]([C:16]1[C:21]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:20][C:19]([C:30]([F:33])([F:32])[F:31])=[C:18]([O:34][CH3:35])[N:17]=1)=[O:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1.CCOC(C)=O>[CH2:1]([O:8][C:9]([C:10]1[O:15][C:14]([C:16]2[C:21]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[CH:20][C:19]([C:30]([F:33])([F:31])[F:32])=[C:18]([O:34][CH3:35])[N:17]=2)=[N:13][N:12]=1)([CH3:40])[C:36]([F:37])([F:38])[F:39])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1nc(C(=O)NNC(=O)C(C)(OCc2ccccc2)C(F)(F)F)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1nc(-c2nnc(C(C)(OCc3ccccc3)C(F)(F)F)o2)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F

Procedure:
A stirring suspension of tert-butyl 2-(2-(2-(benzyloxy)-3,3,3-trifluoro-2-methylpropanoyl)hydrazine carbonyl)-6-methoxy-5-(trifluoromethyl)pyridin-3-ylcarbamate (step 1) (1 g, 1.723 mmol) in dry THF (20 ml) was treated with Burgess reagent (3 equiv.) and heated at reflux under N2 for 1 h 45 min. The RM was reduced in vacuo to approximate volume of 5 ml and diluted with EtOAc (150 ml). The mixture was washed with 2M NaOH, 0.5M HCl, water, brine and dried (MgSO4) and concentrated in vacuo. The crude product was triturated with MeOH to afford the title compound. LC-MS Rt=1.59 min [M+H]+ 563.5 Method High pH_v003.
Reaction SMILES: [CH:1]([NH:4][C:5]1[NH:10][C:9]2[CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=[CH:14][C:8]=2[S:7](=[O:20])(=[O:19])[N:6]=1)([CH3:3])[CH3:2].[BrH:21].OO>O>[Br:21][C:13]1[C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][C:9]2[NH:10][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[N:6][S:7](=[O:19])(=[O:20])[C:8]=2[CH:14]=1
Reactant: Br
Reactant: CC(C)NC1=NS(=O)(=O)c2ccc(C(F)(F)F)cc2N1
Agent: OO
Solvent: O
Product: CC(C)NC1=NS(=O)(=O)c2cc(Br)c(C(F)(F)F)cc2N1
Temperature: 70 °C
Yield: 5.7 %

Procedure:
A solution of 3-isopropylamino-6-trifluoromethyl-4H-1,2,4-benzothiadiazine 1,1-dioxide (307 mg; 1 mmol) in water (5 ml) was added 40% hydrobromic acid (0.44 ml; 3 mmol). The solution was then heated to 70° C. and 30% hydrogen peroxide (0.33 g; 3 mmol) was added. After 30 min the reaction mixture was cooled and extracted with ethyl acetate (20 ml) and purified by column chromatograpy (ethyl acetate:ethanol 9:1). Concentration of the appropiate fractions produced the title compound (22 mg); 1H-NMR (DMSO-d6) ppm; 7.60 (s, 1H), 7.10 (s, 1H), 6.65 (s, 1H), 3.95 (m, 1H) 1.11 (d, 6H).