Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:6][C:7](=[O:19])/[CH:8]=[CH:9]/[C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[CH:15][NH:16]2)=[CH:12][CH:11]=1)[CH2:4][CH3:5].Br[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[O:32][CH3:33]>CN(C)C=O>[CH2:3]([NH:6][C:7](/[CH:8]=[CH:9]/[C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[CH:15][N:16]2[CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=2[O:32][CH3:33])=[CH:12][CH:11]=1)=[O:19])[CH2:4][CH3:5]
Reactant: CCCNC(=O)/C=C/c1ccc2cc[nH]c2c1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCNC(=O)/C=C/c1ccc2ccn(Cc3ccc(C(=O)OC)cc3OC)c2c1
Reaction time: 1 h
Yield: 62.9 %

Procedure:
Sodium hydride (0.12 g of a 60% dispersion in mineral oil) was added to a stirred solution of E-N-propylindole-6-acrylamide (0.7 g) in N,N-dimethylformamide (35 ml) cooled by an ice bath. After approximately 1 hr, a solution of methyl 4-bromomethyl-3-methoxybenzoate (0.79 g) (see Example 1, part 1) in N,N-dimethylformamide (2 ml) was added, the cooling bath removed and the mixture stirred for 1 hr. The mixture was poured into ice and extracted with ethyl acetate. The extracts were washed with brine, dried (MgSO4) and evaporated. The residue was crystallized from a mixture of ethyl acetate and hexane to give methyl E-4-[6-[2-(propylcarbamoyl)vinyl]indol-1-ylmethyl]-3-methoxybenzoate (0.78 g) as a white solid. The mother liquor was evaporated and the residue was purified by flash chromatography, eluting with 1:1 ethyl acetate:hexane, to give a further quantity of the product (0.23 g, 84% combined yield); partial NMR (250 MHz, DMSO-d6): 0.87(t, 3H, CH2CH2CH3), 1.45(m, 2H, CH2CH2CH3), 3.12(m, 2H, CH2CH2CH3) 3.83(s, 3H, OCH3), 3.96(s, 3H, OCH3), 5.46(s, 2H, NCH2Ar), 7.98(br t, 1H, NHCO).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].CC1(C)C(C)(C)OB([C:30]2[N:31]=[CH:32][C:33]([NH2:36])=[N:34][CH:35]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O>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.COCCOC>[NH2:36][C:33]1[N:34]=[CH:35][C:30]([C:2]2[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=2)[C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[O:6])=[N:31][CH:32]=1
Reactant: CC1(C)OB(c2cnc(N)cn2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(Br)c1
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: COCCOC
Solvent: O
Product: Nc1cnc(-c2cccc(C(=O)Nc3ccc(OC(F)(F)F)cc3)c2)cn1

Procedure:
3-Bromo-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 3.1, 50 mg, 0.139 mmol), 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-amine (0.180 mmol), 2 M Na2CO3 (0.104 mL, 0.208 mmol), (Ph3P)4Pd (8 mg, 6.94 μmol), water (0.8 mL) and DME (2.4 mL) were added to a vial, which was sealed and subjected to MW irradiation at 150° C. for 10 min. The RM was filtered through a PL-Thiol MP SPE cartridge (StratoSpheres™, 6 mL) and the cartridge was washed with MeOH (10 mL). The combined filtrates were evaporated to dryness under reduced pressure and the crude product was purified by preparative HPLC to afford the title compound. UPLC-MS (Condition 6) tR=1.84 min, m/z=375.3 [M+H]+.
Reaction SMILES: I[CH2:2][CH3:3].[F:4][CH2:5][CH2:6][O:7][C:8]1[C:16]([O:17][CH2:18][CH2:19][F:20])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)C>[F:4][CH2:5][CH2:6][O:7][C:8]1[C:16]([O:17][CH2:18][CH2:19][F:20])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([O:12][CH2:2][CH3:3])=[O:11]
Reactant: CCI
Reactant: O=C(O)c1cccc(OCCF)c1OCCF
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: CCOC(=O)c1cccc(OCCF)c1OCCF
Temperature: 25 °C
Yield: 89.3 %

Procedure:
Under a dry nitrogen atmosphere 0.91 gram (0.0058 mole) of iodoethane was added dropwise to a stirred mixture of 1.2 gram (0.0049 mole) of 2,3-di(2-fluoroethoxy)benzoic acid (Compound 105) and 1.4 grams (0.0097 mole) of potassium carbonate in 40 ml of acetone. The reaction mixture was heated at reflux for 24 hours and then was allowed to cool to room temperature. The solvent was evaporated under reduced pressure leaving a residue. This residue was dissolved in diethyl ether, and the solution was washed with water followed by an aqueous, saturated sodium chloride solution. The washed organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 1.2 gram of ethyl 2,3-di(2-fluoroethoxy)benzoate as an oil, Compound 107 of Table 1.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[OH:26][NH:27][C:28](=N)[CH2:29][CH2:30][CH3:31]>>[CH:23]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:26][N:27]=[C:28]([CH2:29][CH2:30][CH3:31])[N:2]=3)[CH2:8][CH2:7]2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: CCCC(=N)NO
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Product: CCCc1noc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and N-hydroxy-butyramidine following a procedure analogous to that described in Example 1. LC (method 6): tR=1.15 min; Mass spectrum (ESI+): m/z=422 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[CH:17]=[N:16][N:15]([CH3:18])[C:14]=3[C:19]([OH:21])=O)=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[O:29]1[CH2:33][CH2:32][CH2:31][C@@H:30]1[CH2:34][NH2:35]>>[CH3:18][N:15]1[C:14]([C:19](=[O:21])[NH:35][CH2:34][C@H:30]2[CH2:31][CH2:32][CH2:33][O:29]2)=[C:13]([NH:12][C:10]([C:8]2[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[N:9]=2)=[O:11])[CH:17]=[N:16]1
Reactant: NC[C@H]1CCCO1
Reactant: Cn1ncc(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)c1C(=O)O
Product: Cn1ncc(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)c1C(=O)NC[C@H]1CCCO1

Procedure:
The product was obtained starting from 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-2-methyl-2H-pyrazole-3-carboxylic acid (30 mg, 79 μmol; example 236, step 3) and (R)-(tetrahydrofuran-2-yl)methanamine (15 μl, 142 μmol) according to the method described in example 64, step 6 after purification by preparative HPLC using an acetonitrile/water gradient as yellow solid (35 mg, 96%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[N:16]=2)[CH:13]=1)([O-])=O.[Cl-].[NH4+]>CO.[C].[Pd].[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[N:16]=2)[CH:13]=1
Reactant: O=C(Nc1cn2cc(Oc3cccc([N+](=O)[O-])c3)ccc2n1)C1CC1
Agent: [Pd]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.5 %

Procedure:
To a solution of N-[6-(3-nitrophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (622 mg, 1.84 mmol) in methanol (10 mL) was added palladium carbon (50% water-containing product, 50 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (20 mL), and ammonium chloride (300 mg, 5.61 mmol) and zinc (360 mg, 5.51 mmol) were added. The mixture was stirred under refluxing conditions for 2 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, ethyl acetate) to give the title compound (275 mg, 49%) as a white solid.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH2:13][C@H:14]([C:30](=[O:48])[NH:31][CH2:32][CH2:33][C:34]3[N:35]([CH2:39][C:40]4[CH:45]=[CH:44][C:43]([C:46]#[N:47])=[CH:42][CH:41]=4)[CH:36]=[N:37][CH:38]=3)[CH:15](C(OC(C)(C)C)=O)[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]=2[N:10]=[CH:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:46]([C:43]1[CH:42]=[CH:41][C:40]([CH2:39][N:35]2[C:34]([CH2:33][CH2:32][NH:31][C:30]([C@H:14]3[CH2:13][C:12]4[NH:8][CH:9]=[N:10][C:11]=4[N:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:15]3)=[O:48])=[CH:38][N:37]=[CH:36]2)=[CH:45][CH:44]=1)#[N:47]
Reactant: CC(C)(C)OC(=O)C1[C@@H](C(=O)NCCc2cncn2Cc2ccc(C#N)cc2)Cc2c(ncn2C(=O)OC(C)(C)C)N1c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(Cn2cncc2CCNC(=O)[C@H]2Cc3[nH]cnc3N(c3ccccc3)C2)cc1
Reaction time: 0.75 h

Procedure:
To a solution of 6(S)-{2-[3-(4-cyano-benzyl)-3H-imidazol-4yl]ethylcarbamoyl}-4-phenyl-6,7-dihydro-4H-imidazo [4,5-]pyridine-1,5-dicarboxylic acid di-tert-butyl ester (0.58 g) in CH2Cl2 (10 ml) was added TFA (5 ml) and the solution was stirred 45 min. The solvents were removed in vacuo and the crude product was purified by preparative HPLC to obtain diastereomer A and diastereomer B as the title compounds.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH2:4]([O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)[CH3:5].[OH-].[Na+]>O.C(O)C>[CH2:4]([O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[N:2][OH:3])=[CH:9][CH:8]=1)[CH3:5]
Reactant: NO
Reactant: CCOc1ccc(C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1ccc(C=NO)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85.8 %

Procedure:
A solution of 34.8 g of hydroxylamine hydrochloride in 50 ml of water was added in one portion to a solution of 37.5 g of 4-ethoxybenzaldehyde in 100 ml of ethanol in a 500-ml Erlenmeyer flask equipped with a magnetic stirrer. The reaction mixture was stirred for approximately 5 minutes, until clear. A room-temperature solution of 15.2 g of sodium hydroxide in 20 ml of water was added in several portions during 15 minutes. The reaction mixture was stirred for 5 minutes and then heated to boiling. After the cloudy reaction mixture had cooled to room temperature, water was added and product separated from solution as an oil. The mixture was extracted four times with 50-ml portions of chloroform. The chloroform extracts were combined, washed twice with 75-ml portions of saturated aqueous sodium chloride solution and dried over sodium sulfate. The dry chloroform solution was filtered, the filtrate was evaporated, and the residue crystallized with a slight amount of cooling. The crude solid was recrystallized from cyclohexane to give 35.4 g of 4-ethoxybenzaldoxime, m.p. 81°-86°. The ir spectrum was consistent with the assigned structure.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.CS(O)(=O)=O.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:38][CH2:37][N:36]([CH2:39][C@H:40]([OH:45])[C:41]([F:44])([F:43])[F:42])[CH2:35][CH2:34]2)=[CH:29][C:28]=1[O:46][CH3:47].FC(F)(F)C(O)=O>COCC(O)C>[F:44][C:41]([F:42])([F:43])[C@@H:40]([OH:45])[CH2:39][N:36]1[CH2:35][CH2:34][CH:33]([C:30]2[CH:31]=[CH:32][C:27]([NH:26][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=5[O:19][CH3:20])[N:6]4[N:5]=3)=[C:28]([O:46][CH3:47])[CH:29]=2)[CH2:38][CH2:37]1
Reactant: COc1cc(C2CCN(C[C@H](O)C(F)(F)F)CC2)ccc1N
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Agent: CS(=O)(=O)O
Solvent: COCC(C)O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C2CCN(C[C@H](O)C(F)(F)F)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Temperature: 135 °C
Reaction time: 48 h
Yield: 18 %

Procedure:
2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (50.00 mg, 0.174 mmol), methanesulfonic acid (0.034 mL, 0.52 mmol) and (S)-3-[4-(4-amino-3-methoxy-phenyl)-piperidin-1-yl]-1,1,1-trifluoro-propan-2-ol (109 mg, 0.342 mmol) were combined in 1-methoxy-2-propanol (1.02 mL) in a capped tube and the reaction was stirred at 135° C. for 48 h. The product was isolated by reverse phase preparative hplc (Gilson) followed by neutralization of the trifluoroacetic acid salt to afford (S)-1,1,1-trifluoro-3-(4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-propan-2-ol as a brown solid (17 mg, 18%). MP: 77-94° C.; 1H-NMR (CDCl3) δ 8.69 (s, 1H), 8.30 (d, J=8.1 Hz, 1H), 7.99 (d, J=7.6 Hz, 1H), 7.44 (m, 2H), 7.14 (m, 1H), 7.08 (d, J=8.4 Hz, 1H), 7.02 (4.4 Hz, 1H), 6.83 (d, J=4.5 Hz, 1H), 6.71 (m, 2H), 4.08 (m, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.02 (m, 2H), 2.67 (m, 2H), 2.52 (m, 2H), 2.23 (m, 1H), 1.77 (m, 3H); LC/MS (ESI+): 542.3 (M+H).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:32](=[O:33])[N:14]2[CH:15]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)=[O:21])[C:16](=C)[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=[O:36])C>>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:32](=[O:33])[N:14]2[C:15]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)=[O:21])=[C:16]([OH:36])[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: C=C1CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc(OC)cc1
Product: COc1ccc(COC(=O)C2=C(O)CS[C@@H]3C(NC(=O)COc4ccccc4)C(=O)N23)cc1
Temperature: 0 °C

Procedure:
A solution of 2.5 g. of p-methoxybenzyl 7-phenoxyacetamido-3-methylenecepham-4-carboxylate in 350 ml. of ethyl acetate was cooled in an acetone-dry ice bath. Ozone was bubbled through the cold solution for 8 minutes and then oxygen was passed through the ozonized reaction mixture to expel excess ozone. The intermediate ozonide was decomposed by adding to the reaction mixture 25 g. of sodium bisulfite with stirring at a temperature of about 0° C. The reaction solution was decanted and was washed successively with water, 5% hydrochloric acid and a saturated solution of sodium chloride. The washed mixture was dried and evaporated to yield the reaction product, p-methoxybenzyl 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylate as an amorphous solid.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.[NH2:7][CH2:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[C:17]3[C:22](=[N:23][CH:24]=2)[N:21]([C:25]([NH2:27])=[O:26])[CH2:20][CH2:19][CH2:18]3)[CH:12]=[N:13][CH:14]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH:1]1([C:4]([NH:7][CH2:8][C:9]2[CH:10]=[C:11]([C:15]3[CH:16]=[C:17]4[C:22](=[N:23][CH:24]=3)[N:21]([C:25]([NH2:27])=[O:26])[CH2:20][CH2:19][CH2:18]4)[CH:12]=[N:13][CH:14]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: NCc1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1
Reactant: O=C(O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)N1CCCc2cc(-c3cncc(CNC(=O)C4CC4)c3)cnc21
Reaction time: 8 h

Procedure:
To the cyclopropanecarboxylic acid (16 mg, 0.18 mmol) is added a solution of 6-(5-aminomethyl-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (40 mg, 0.14 mmol) in DMF (1 mL) followed by HATU (100 mg, 0.26 mmol) in DMF (1 mL) followed by triethylamine (51 mg, 0.50 mmol). The mixture is stirred overnight. The mixture is concentrated in vacuo, dissolved in 2 mL of DMF, filtered and purified by reverse phase HPLC to afford the titled product.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[Br:8][C:9]1[C:10]([NH:16][C:17](=[O:29])[C:18]([NH:21][C:22](=O)OC(C)(C)C)([CH3:20])[CH3:19])=[N:11][CH:12]=[C:13]([Br:15])[N:14]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].[O:37]1[CH2:42][CH2:41][CH:40]([CH2:43]C=O)[CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CO.ClCCCl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[Br:8][C:9]1[C:10]([NH:16][C:17](=[O:29])[C:18]([CH3:19])([NH:21][CH2:22][CH2:43][CH:40]2[CH2:41][CH2:42][O:37][CH2:38][CH2:39]2)[CH3:20])=[N:11][CH:12]=[C:13]([Br:15])[N:14]=1
Reactant: O=CCC1CCOCC1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)Nc1ncc(Br)nc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)(NCCC1CCOCC1)C(=O)Nc1ncc(Br)nc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.3 %

Procedure:
TFA (3.66 mL, 47.5 mmol) was added to a stirred mixture of tert-butyl 1-(3,5-dibromopyrazin-2-ylamino)-2-methyl-1-oxopropan-2-ylcarbamate (1.04 g, 2.374 mmol) in dichloromethane (20 mL). The resulting clear yellow solution was stirred at room temperature for 3 h. All volatiles were removed under reduced pressure and the residue dried under high vacuum to give a yellow semi-solid. MS (ESI) m/z 339.1 [M+1]+. Sodium sulfate (1.686 g, 11.87 mmol) was added followed by 2-(tetrahydro-2H-pyran-4-yl)acetaldehyde (0.396 g, 3.09 mmol) and 1,2-dichloroethane (20 mL). The resulting mixture was stirred vigorously and heated at 80° C. under a reflux condenser under nitrogen for 2.5 h. More 2-(tetrahydro-2H-pyran-4-yl)acetaldehyde (0.100 g, 0.780 mmol) and sodium sulfate (1.00 g, 7.04 mmol) were added and heating at 80° C. continued for another 2 h. The resulting yellow solution was removed by pipette from the solid sodium sulfate into a dry 250 mL round bottom flask equipped with a stirbar. The resulting mixture was stirred vigorously and cooled to 0° C. under nitrogen. Sodium triacetoxyborohydride (0.553 g, 2.61 mmol) was added slowly. The resulting mixture was stirred vigorously at 0° C. under nitrogen for 30 min. The cold bath was removed and the resulting mixture stirred at room temperature under nitrogen for 2 h. The mixture was cooled to 0° C. and more sodium triacetoxyborohydride (0.250 g, 1.180 mmol) was added. The cold bath was removed and the resulting mixture stirred at room temperature under nitrogen for 1.5 h. More sodium triacetoxyborohydride (0.055 g, 0.260 mmol) was added. The resulting mixture was stirred vigorously at room temperature under nitrogen for 1 h and then stirred overnight at 0° C. The resulting mixture was diluted with methanol and the volatiles removed under reduced pressure. The residue was taken up in methanol, filtered and purified using reverse-phase preparatory HPLC (10-40% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min). Fractions containing the desired product were combined and the solvent removed under reduced pressure. The residue was dried under vacuum to give the desired product (0.890 g, 1.978 mmol, 67% yield) as a slightly yellow foam-solid. MS (ESI) m/z 451.3 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9]C(CBr)=CC=1.BrCCCC(F)(F)F.[CH3:21][C:22]1[N:23]=[C:24]([N:32]2[C:36](=[O:37])[NH:35][N:34]=[CH:33]2)[S:25][C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[CH3:21][C:22]1[N:23]=[C:24]([N:32]2[C:36](=[O:37])[N:35]([CH2:9][CH2:10][CH2:3][C:2]([F:1])([F:11])[F:12])[N:34]=[CH:33]2)[S:25][C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: FC(F)(F)CCCBr
Product: CCOC(=O)c1sc(-n2cnn(CCCC(F)(F)F)c2=O)nc1C
Yield: 32 %

Procedure:
Following the procedure as described in Example 19, making variation as required to replace 4-(trifluoromethyl)benzyl bromide with 4-bromo-1,1,1-trifluorobutane to react with ethyl 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate, the title compound was obtained as a white solid in 32% yield: 1H NMR (300 MHz, CDCl3) δ 8.28 (s, 1H), 4.29 (q, J=7.1 Hz, 2H), 3.92 (t, J=6.6 Hz, 2H), 2.64 (s, 3H), 2.99-1.96 (m, 4H), 1.35 (t, J=7.1 Hz, 3H); MS (ES+) m/z 365.3 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:9]=[CH:8][N:7](S(C2C=CC(C)=CC=2)(=O)=O)[CH:6]=1)=[O:4].[CH3:20][O:21][CH2:22][CH2:23][OH:24].[Br-].[Li+].[OH-].[Na+]>[Cl-].[Na+].O>[CH3:20][O:21][CH2:22][CH2:23][O:24][CH2:2][C:3]([C:5]1[CH:9]=[CH:8][NH:7][CH:6]=1)=[O:4]
Reactant: COCCO
Reactant: Cc1ccc(S(=O)(=O)n2ccc(C(=O)CCl)c2)cc1
Agent: [Br-]
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Product: COCCOCC(=O)c1cc[nH]c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 29 %

Procedure:
In a 100 cm3 three neck flask fitted with a thermometer, a condenser with a bubbler and an argon inlet, 2.35 g of 3-chloroacetyl-l-tosyl pyrrole 3 (8 mmoles) was introduced together with 50 cm3 of 2-methoxy ethanol. 3 g of lithium bromide was added and the solution was set under reflux and argon flux during 24 hours. After cooling, 20 cm3 of 5 N aqueous solution of sodium hydroxide was added and the mixture was maintained under stirring at ambient temperature during 24 hours. 20 cm3 of brine was added and after decantation, the aqueous layer was extracted with ethyl acetate. The combine organic layer was washed with brine, dried and evaporated. The crude product (1.4 g) was dissolved in a little amount of methanol and separated on a silica gel column (150 g; 60-200 μm; eluting with 1-29-70 acetic acid-ethyl acetate-heptane) to give 0.42 g of purified product 4 (M=183, yield: 29%). NMR: (CDCl3) ppm 7.5 1H; 6.7 1H; 6.6 1H; 4.5 s 2H; 3.6 4H; 3.3 s 3H.
Reaction SMILES: C(OC([O-])=O)(=O)OC(C)(C)C.Cl.[Cl:13][C:14]1[CH:15]=[C:16]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]1[CH:21]([C:27]3([C:31](OCC)=[O:32])[CH2:30][CH2:29][CH2:28]3)[NH:20][CH2:19][CH2:18][C:17]2=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.ClC(OCC)=O.[OH-].[NH4+:56]>O1CCOCC1.O.[OH-].[Na+].O1CCCC1.CN1CCOCC1>[ClH:13].[Cl:13][C:14]1[CH:15]=[C:16]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]1[CH:21]([C:27]3([C:31]([NH2:56])=[O:32])[CH2:28][CH2:29][CH2:30]3)[NH:20][CH2:19][CH2:18][C:17]2=1
Reactant: CCOC(=O)C1(C2NCCc3c2[nH]c2ccc(Cl)cc32)CCC1
Reactant: [NH4+]
Agent: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CN1CCOCC1
Product: NC(=O)C1(C2NCCc3c2[nH]c2ccc(Cl)cc32)CCC1
Temperature: -10 °C

Procedure:
0.8 g of tert-butyl pyrocarbonate is added at 0° C. to a solution of 1 g of the compound of Example 1 in 20 ml of dioxane, 20 ml of water and 10 ml of 1M sodium hydroxide solution. After reaction for 4 hours, the reaction mixture is diluted by the addition of water and acidified with a 5% citric acid solution. After extraction with ethyl acetate, drying the organic phases, and concentration under reduced pressure, the residue obtained is diluted with 50 ml of tetrahydrofuran and 0.5 ml of N-methylmorpholine. After cooling the mixture to −10° C., 0.3 ml of ethyl chloroformate are added, followed by 0.2 ml of a 28% ammonium hydroxide solution. After reaction for 12 hours, the solvent is distilled off. The residue is then taken up in a water/dichloromethane mixture. After decanting, drying and concentrating under reduced pressure, the residue is treated with a solution of ethanol and ethereal hydrogen chloride, enabling the desired product to be obtained in the form of the hydrochloride.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.OC[CH2:27][C@:28]1([CH2:42][O:43][CH3:44])[CH2:32][N:31]([C@@H:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH3:34])[C:30](=[O:41])[CH2:29]1>ClCCl>[Br:5][CH2:1][CH2:27][C@:28]1([CH2:42][O:43][CH3:44])[CH2:32][N:31]([C@@H:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH3:34])[C:30](=[O:41])[CH2:29]1
Reactant: COC[C@]1(CCO)CC(=O)N([C@H](C)c2ccccc2)C1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC[C@]1(CCBr)CC(=O)N([C@H](C)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.1 %

Procedure:
Carbon tetrabromide (3.58 g, 10.8 mmol) and triphenylphosphine (2.83 g, 10.8 mmol) were sequentially added to a solution of (4R)-4-(2-hydroxyethyl)-4-methoxymethyl-1-[(1R)-1-phenylethyl]pyrrolidin-2-one (2.85 g, 10.3 mmol) in dichloromethane (30 mL) in a nitrogen atmosphere at 0° C., and the mixture was stirred for 10 minutes. The mixture was heated to room temperature and stirred for 24 hours, and then the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane→hexane:ethyl acetate=2:1→1:1→1:2) to give 2.07 g (59%) of the title compound as a colorless oil.