Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:14](O)(=[O:18])[C@H:15]([CH3:17])[OH:16].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[OH:16][CH:15]([CH3:17])[C:14]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)=[O:18]
Reactant: C[C@H](O)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC(O)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl piperazine-1-carboxylate (0.367 g), L-(+)-lactic acid (0.213 g), and HBTU (0.822 g) was stirred at rt overnight. Diluted with DCM, the mixture was washed with water (2×), brine, and dried (Na2SO4). Filtration and concentration gave 1-tert-butyl 4-(2-hydroxypropanoyl)piperazine-1-carboxylate as viscous oil, which was treated with trifluoroacetic acid in dichloromethane. After concentration, the residue was reacted with 4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine in the presence of diisopropylethylamine (10 eq) following General Procedure E of amine alkylation to give 269. LCMS: M+H+=520.3
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16](I)=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[Cl:37]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16]([Cl:37])=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CCc1nc(I)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A cooled (−78° C.) solution of 3-ethyl-1-iodo-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (300 mg; 0.546 mmol) in anhydrous THF (4 ml) was treated dropwise with a solution of 1.6M n-BuLi in hexanes (0.34 ml; 0.546 mmol). The resulting solution was additionally stirred at −78° C. for 10 min., and was then treated dropwise with a solution of hexachloroethane (517 mg; 2.184 mmol; 4 eq.) in anhydrous THF (1 ml). The reaction mixture was further stirred at −78° C. for 1 h. The mixture was then quenched with water (0.2 ml), diluted with ether (30 ml), and was allowed to warm-up to rt. The organic layer was dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. The crude was purified by FC (DCM/MeOH=100/3) to give the pure product 1-chloro-3-ethyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow solid (143 mg; 57%). LC-MS: tR=1.02 min.; [M+H]+=458.49 g/mol.
Reaction SMILES: O[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][C:6]=1[Br:16].C(N(S(F)(F)[F:23])CC)C>ClCCl>[F:23][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][C:6]=1[Br:16]
Reactant: OCCOc1ccc(OC(F)(F)F)cc1Br
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: FCCOc1ccc(OC(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.9 %

Procedure:
To a cooled (-78° C.) suspension of 2-(2-hydroxyethoxy)-5-(trifluoromethoxy)bromobenzene (Description 30; 8.9 g, 30 mmol). in dichoromethane (80 ml) was added diethylaminosulphur trifluoride (3.88 ml, 31.5 mmol). The solution was stirred at ambient temperature for 2 h., then quenched by the dropwise addition of water (100 ml). The organic layer was separated, washed with brine (100 ml), dried (MgSO4), and evaporated in vacuo. Purification in silica, eluting with 15%-20% ethyl acetate in hexane gave the title compound as a clear oil (1.9 g, 15%). 1H NMR (360 MHz, CDCl3) δ4.23 (1H, m), 4.31 (1H, m), 4.37 (1H, m), 4.86 (1H, m), 6.90 (1H, m), 7.15 (1H, m), and 7.47 (1H, t, J 0.7 Hz).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1.C(OC([N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1)=O)(C)(C)C.O>C(OCC)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:24]2([OH:27])[CH2:25][CH2:26][NH:21][CH2:22][CH2:23]2)=[N:8][CH:9]=1
Reactant: Clc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: OC1(c2ccc(Cl)cn2)CCNCC1
Reaction time: 0.5 h

Procedure:
Butyllithium (15% in hexane; 7.6 ml) was added dropwise to a solution of 2-bromo-5-chloropyridine (2.0 g) in diethyl ether (50 ml) at −78° C. and, after one hour, a solution of N-tert-butoxycarbonyl-4-piperidinone (2.1 g) in diethyl ether (10 ml) was added dropwise. After 30 minutes, water was cautiously added, and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was treated by method G. This resulted in the product with the molecular weight of 212.68 (C10H13ClN2O); MS(ESI): 213 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[CH3:19][NH2:20]>C1COCC1.O>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:10]=[C:9]([CH2:11][NH:20][CH3:19])[S:8][C:6]=2[N:7]=1
Reactant: CN
Reactant: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2s1
Solvent: O
Solvent: C1CCOC1
Product: CNCc1nc2c(N3CCOCC3)nc(Cl)nc2s1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Also, to a solution of 5-chloro-7-morpholinothiazolo[5,4-d]pyrimidine-2-carbaldehyde 44 in 50 mL THF was added 20 mL of 40% methylamine in water. The reaction mixture was stirred at room temperature under N2 for 24 hours. The solvents were removed in vacuo and the residue was dissolved in 50 mL MeOH and 50 mL THF and the NaBH4 added portion-wise. This reaction mixture was stirred at room temperature under N2 for 24 hours and complete reaction was confirmed by LCMS. The solvents were removed in vacuo and the crude product purified by flash chromatography (EtOAc/EtOH) to give of 1-(5-chloro-7-morpholinothiazolo[5,4-d]pyrimidin-2-yl)-N-methylmethanamine 61.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[NH4+:14].[OH-]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([S:8]([NH2:14])(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(Br)cc1S(=O)(=O)Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(Br)cc1S(N)(=O)=O
Reaction time: 2 h

Procedure:
To 5-bromo-2-methoxybenzenesulfonyl chloride (45g; 157.6 mmol, from Lancaster Chemical) at 0° C. in THF, was added concentrated NH4OH (42.5 mL) and the reaction mixture was brought to r.t. for 2 h. The reaction mixture was diluted with EtOAc, extracted with NaHCO3 (2×), brine, and the organic phase was dried over MgSO4. The solvent was removed to give the title compound.
Reaction SMILES: [CH2:1]([SH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H-].[Na+].Cl[C:17]1[S:21][C:20]([C:22]([OH:24])=[O:23])=[CH:19][CH:18]=1.Cl>C1(C)C=CC=CC=1.O>[CH2:1]([S:13][C:17]1[S:21][C:20]([C:22]([OH:24])=[O:23])=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: CCCCCCCCCCCCS
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCSc1ccc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 40.5 g (0.2 mole) of 1-dodecanethiol (laurylmercaptan) in 19.2 g (0.4 mole) of sodium hydride (50% in oil) in 1 liter of toluene is refluxed with stirring for 1 hour then cooled to room temperature. To the mixture 32.5 g (0.2 mole) of 5-chloro-2-thiophenecarboxylic acid is added and the mixture is refluxed with stirring for 24 hours after which the mixture is cooled to room temperature and acidified with 5% aqueous hydrochloric acid. Water is added, and the toluene layer is separated, dried over sodium sulfate and evaporated to give 5-(dodecylthio)-2-thiophenecarboxylic acid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[C:13]1([S:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:13]1([S:19]([N:22]2[CH2:27][CH2:26][N:25]([CH2:2][C:3]3[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=3)[CH2:24][CH2:23]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=S(=O)(c1ccccc1)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(CN2CCN(S(=O)(=O)c3ccccc3)CC2)cc1

Procedure:
A mixture of 11.5 g. (50 mmole) methyl 4-bromomethylbenzoate, 11.3 g. (50 mmole) 1-benzenesulphonylpiperazine, 6.91 g. (50 mmole) powdered potassium carbonate and 100 ml. butan-2-one is maintained at reflux temperature for 20 hours, then suction filtered while hot and the filtrate evaporated. After cooling, the product is filtered off with suction and recrystallised from methanol to give 11.6 g. (62% of theory) of the desired product; m.p. 145°-146° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[F:42])[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=5[F:42])[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Fc1ccccc1Cc1cccc(Br)n1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Cc5ccccc5F)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 41, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-(2-fluoro-benzyl)-pyridine.
Reaction SMILES: C(N1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])(OCC)=O.Cl.[NH2:18][C@H:19]([C:27]([NH2:29])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:7]1(=[O:16])[N:18]([C@@H:19]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]([NH2:29])=[O:28])[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]12
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Product: NC(=O)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O

Procedure:
By following the procedure of Example 19 but employing N-carbethoxyphthalimide and (S)-phenylalaninamide hydrochloride, there is obtained (S)-2-phthalimido-3-phenylpropionamide which can be recrystallized from ethanol to afford white crystals: mp 211°-215° C.; 1H NMR (DMSO-d6) δ 7.92 (s, 5 H, Ph), 7.72, 7.33 (2 s, 2 H), 7.2-7.0 (m, 4 H, Ar), 4.92 (dd, 1H, J=12,4.5 Hz), 3.52 (dd, 1 H, J=4.3, 13.9), 3.35 (dd, 1 H, J=12, 13.9); 13C NMR (DMSO-d6) δ 169.6, 167.4, 137.7, 134.3, 131.2, 128.5, 128.1, 126.3, 122.9, 54.2, 33.7.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH:15][C:16](=[O:18])[CH3:17])[CH:3]1[OH:19])=[N:10][O:11][N:12]=3.N1C=CC=CC=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(OCC)(=O)C>[CH3:1][C:2]1([CH3:20])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH:15][C:16](=[O:18])[CH3:17])[CH:3]1[O:19][C:27](=[O:29])[CH3:28])=[N:10][O:11][N:12]=3
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)NC1c2cc3nonc3cc2OC(C)(C)C1O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)NC1c2cc3nonc3cc2OC(C)(C)C1OC(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 26 %

Procedure:
A mixture of 100 mg (0.36 m mol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-acetylamino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole, 2 ml of pyridine and 34 μl (0.36 m mol) of acetic anhydride was stirred at the room temperature for 24 hours. After the completion of the reaction, the mixture was diluted with ethyl acetate, washed with water and saturated anhydrous NaCl solution and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was recrystallized from chloroform to obtain 58 mg (yield: 26%) of the intended compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[N:13]=[C:12]([CH2:14]O)[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:23])CC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[N:13]=[C:12]([CH2:14][F:23])[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1nccc(CO)n1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nccc(CF)n1
Reaction time: 0.17 h
Yield: 31.7 %

Procedure:
A solution of (4-hydroxymethylpyrimidin-2-yl)carbamic acid tert-butyl ester (450 mg, 2.0 mmol) in DCM (10 mL) at 0° C. was treated with DAST (396 μL, 3.0 mmol) and stirred for 10 minutes. The reaction mixture was partitioned between DCM and sodium bicarbonate (sat. aq.). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (50% ethyl acetate in cyclohexane) to afford the title compound as a white solid (144 mg, 32% yield). 1H NMR (300 MHz, CDCl3): δ 8.64 (d, J=5.1 Hz, 1H), 7.53 (s, 1H), 7.15-7.12 (m, 1H), 5.45-5.44 (m, 1H), 5.33-5.32 (m, 1H), 1.54 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[C:5]2[C:6]3[CH:12]([CH2:13][CH2:14][NH2:15])[CH2:11][CH2:10][C:7]=3[CH:8]=[CH:9][N:4]2[N:3]=1.C(N(CC)CC)C.[CH:24]1([C:27](Cl)=[O:28])[CH2:26][CH2:25]1>O1CCCC1.C(=O)([O-])O.[Na+]>[CH3:1][C:2]1[CH:16]=[C:5]2[C:6]3[CH:12]([CH2:13][CH2:14][NH:15][C:27]([CH:24]4[CH2:26][CH2:25]4)=[O:28])[CH2:11][CH2:10][C:7]=3[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: Cc1cc2c3c(ccn2n1)CCC3CCN
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc2c3c(ccn2n1)CCC3CCNC(=O)C1CC1
Reaction time: 0.25 h
Yield: 74.1 %

Procedure:
To a mixture of 2-(2-methyl-8,9-dihydro-7H-cyclopenta[c]pyrazolo[1,5-a]pyridin-9-yl)ethanamine (69.7 mg, 0.324 mmol) and triethylamine (90.3 μL, 0.648 mmol) in tetrahydrofuran (3 mL) was added cyclopropanecarbonyl chloride (35.3 μL, 0.389 mmol) under ice-cooling, and the mixture was stirred for 15 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (68.0 mg, yield 74%).
Reaction SMILES: [CH2:1](Cl)[O:2][CH3:3].[I:5][C:6]1[CH:11]=[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])[N:9]=[C:8]([O:16][CH3:17])[C:7]=1[CH2:18][OH:19].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[I:5][C:6]1[CH:11]=[C:10]([Si:12]([CH3:14])([CH3:13])[CH3:15])[N:9]=[C:8]([O:16][CH3:17])[C:7]=1[CH2:18][O:19][CH2:1][O:2][CH3:3]
Reactant: COc1nc([Si](C)(C)C)cc(I)c1CO
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOCc1c(I)cc([Si](C)(C)C)nc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
MOMCl (2.0 mL, 26.7 mmol) was added dropwise to a 0° C. solution of 2a (3 g, 8.9 mmol) and iPr2EtN (4.6 mL, 26.7 mmol) in dry CH2Cl2 (35 mL). The resulting mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with 5% aq. NaHCO3 solution and the product was extracted with CH2Cl2. The combined organic phases were washed with brine, dried over MgSO4 and concentrated under reduced pressure to give 3.0 g (88% yield) of the crude product 3a as an orange oil. The crude product was sufficiently pure for the subsequent reaction. 1H NMR (300 MHz, CDCl3) δ0.27 (s, 9H), 3.46 (s, 3H), 3.98 (s, 3H), 4.71 (s, 2H), 4.75 (s, 2H), 7.51 (s, 1H); 13C NMR (75 MHz, CDCl3) δ−2.08, 53.79, 55.53, 67.85, 96.39, 113.84, 122.6, 132.98, 161.43, 166.37; IR (film, NaCl, cm−1) 2946, 1528, 1340, 1042, 840; LRMS (70 eV, EI) m/z (rel int %) 381 (M+), 366, 336, 320, 306, 169, 128, 84 (100), 73. HRMS m/z calcd for C12H20NO3SiI (M+) 381.0257, found 381.0241.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[Br:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([N+:18]([O-])=O)=[CH:12][C:11]=1[F:21]>C(O)C.O>[Br:9][C:10]1[C:11]([F:21])=[CH:12][C:13]([NH2:18])=[C:14]([O:16][CH3:17])[CH:15]=1
Reactant: COc1cc(Br)c(F)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc(Br)c(F)cc1N
Yield: 40.3 %

Procedure:
Sodium hydrosulfite (14.7 g, 84.4 mmol) was added to a solution of 1-bromo-2-fluoro-5-methoxy-4-nitrobenzene (9.28 g, 37.12 mmol) in ethanol (180 mL) and water (130 mL) at 80° C. in three portions. After 5 hours the organic solvent was removed and the solid in aqueous layer was collected by filtration. The solid was further washed with heptane/ethyl acetate (3:2, 400 mL). The filtrate was evaporated to give 4-bromo-5-fluoro-2-methoxyaniline (3.29 g, 40%). 1H NMR (DMSO-d6) δ 3.75 (s, 3H), 5.22 (s, 2H), 6.56 (d, J=10.68 Hz, 2H), 6.94 (d, J=6.57 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]([CH3:26])([CH3:25])[C:3]([NH:5][C:6]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:7]=1)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[C:57](O)=[O:58]>C(Cl)Cl.CCOC(C)=O>[CH2:18]([N:8]1[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:10][C:6]([NH:5][C:3]([C:2]([NH:1][C:57]([C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][N:51]=2)=[O:58])([CH3:26])[CH3:25])=[O:4])=[N:7]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccccn1
Reactant: CC(C)(N)C(=O)Nc1nc(-c2ccc(F)cc2)n(Cc2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(NC(=O)c1ccccn1)C(=O)Nc1nc(-c2ccc(F)cc2)n(Cc2ccccc2)n1
Reaction time: 24 h

Procedure:
2-Amino-N-[1-benzyl-5-(4-fluoro-phenyl)-1H-[1,2,4]triazol-3-yl]-2-methyl-propionamide (137 mg, 0.388 mmol), HATU (295 mg, 0.776 mmol), and picolinic acid (72 mg, 0.582 mmol) were stirred in DCM (6 mL). TEA (108 uL, 0.776 mmol) was added to the reaction mixture and it was stirred for 1 day. It was diluted with EtOAc (65 mL) and extracted with water (15 mL), followed by saturated NaHCO3 (15 mL). The organic layer was dried with a brine wash (10 mL) followed by Na2SO4. The solvents were removed in vacuo and the residue was purified by reverse phase HPLC (C18, 45-100% MeOH/H2O+5 mM NH4OH) followed by silica gel chromatography (0-30% ACN/DCM) to afford the title compound as a white solid: 1H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm 1.73 (s, 6H) 5.35 (s, 2H) 7.07-7.22 (m, 4H) 7.26-7.39 (m, 3H) 7.49 (ddd, J=7.61, 4.77, 1.14 Hz, 1H) 7.52-7.61 (m, 2H) 7.90 (td, J=7.74, 1.71 Hz, 1H) 8.19 (dt, J=7.77, 1.04 Hz, 1H) 8.47 (br. s., 1H) 8.58 (ddd, J=4.77, 1.61, 0.95 Hz, 1H) 9.45 (br. s., 1H); Rt (method A)=1.22 min, (M+H)+ 459.0.
Reaction SMILES: C[O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[CH2:22]([C:24]1[S:28][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:26][C:25]=1[CH2:35][CH2:36]O)[CH3:23]>>[NH2:5][C@@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:36][CH2:35][C:25]2[N:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[S:28][C:24]=2[CH2:22][CH3:23])=[CH:18][CH:19]=1)[C:3]([OH:2])=[O:21]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: CCc1sc(-c2ccccc2)nc1CCO
Product: CCc1sc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Yield: 94 %

Procedure:
Intermediate 57 was prepared as described above for the preparation of intermediate 52. From 575 mg of N-(Boc)-L-Tyrosine methyl ester and 500 mg of Intermediate 9B was prepared 940 mg of BOC-protected intermediate methyl ester (94% yield; 1H NMR (DMSO-d6, 300 MHz) δ7.93 (m, 2H), 7.47-7.41 (m, 3H), 7.04 (d, 2H, J=8.4), 6.86 (d, 2H, J=8.6), 4.96 (d, 1H, J=4.56 (m, 1H), 4.34 (t, 2H, J=6.8), 3.73 (s, 3H), 3.23 (t, 2H, J=6.9), 3.04 (m, 2H), 2.90 (q, 2H, J=7.5), 1.44 (s, 9H), 1.37 (t, 3H, J=7.5)); From 900 mg of protected intermediate was prepared 900 mg of intermediate 57 as a solid. 1H NMR (DMSO-d6, 300 MHz) δ8.16 (br s, 2H), 7.85 (m, 2H), 7.5-7.43 (m, 3H), 7.14 (d, 2H, J=8.6), 6.90 (d, 2H, J=8.6), 4.27 (t, 2H, J=6.5), 4.12 (m, 1H), 3.12 (t, 2H, J=6.5), 3.0 (m, 2H), 2.86 (q, 2H, J=7.5), 1.26 (t, 3H, J=7.5).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[S:9][C:10]([NH2:13])=[CH:11][N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O[CH:17]=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>N1C=CC=CC=1.O>[N:1]1([CH2:7][C:8]2[S:9][C:10]([NH:13][CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:11][N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Nc1cnc(CN2CCOCC2)s1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)C(=CNc1cnc(CN2CCOCC2)s1)C(=O)OCC
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of 2-(morpholin-4-ylmethyl)-1,3-thiazol-5-amine (Preparation 27, 1.13 g) in pyridine (10 mL) at 45° C. is added diethyl ethoxymethylenemalonate (2.26 mL). The mixture is stirred overnight, diluted with water (100 mL), and extracted with EtOAc (3×75 mL). The organic layer is dried (MgSO4) and the solvent removed. The residue is purified by column chromatography (eluent 50% EtOAc/hexane) to afford 1.51 g (86%) of the title compound as a brown oil. Physical characteristics: 1H NMR (CDCl3) δ1.27-1.37, 2.58, 3.72, 3.73, 4.20-4.30, 8.10, 11.02; IR (diffuse reflectance) 1687, 1637, 1596, 1416, 1337, 1301, 1274, 1268, 1243, 1234, 1114, 1094, 1011, 867, 801 cm−1; HRMS (FAB) m/z 370.1420 (C16H23N3O5S+H). Anal. Found: C, 51.80; H, 6.32; N, 11.26.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[OH:15][C:16]1[C:21]([CH2:22][CH2:23][CH3:24])=[C:20]([SH:25])[CH:19]=[CH:18][C:17]=1[C:26](=[O:28])[CH3:27]>CC(C)=O>[C:26]([C:17]1[CH:18]=[CH:19][C:20]([S:25][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])=[C:21]([CH2:22][CH2:23][CH3:24])[C:16]=1[OH:15])(=[O:28])[CH3:27]
Reactant: CCCc1c(S)ccc(C(C)=O)c1O
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(SCCCCBr)ccc(C(C)=O)c1O
Yield: 52.5 %

Procedure:
To a refluxing mixture of 1.4-dibromobutane (32.9 g), anhydrous potassium carbonate (5.25 g) and potassium iodide (1 g) in acetone (100 ml) was added dropwise a solution of 2'-hydroxy-4'-mercapto-3'-propylacetophenone (8.00 g) in acetone (20 ml) during an hour and refluxed for 2 hours. The mixture was filtered off and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography, eluting with benzene, to give the title compound (6.90 g, 52.6 %) as yellow oil.