Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[C:11](=S)[NH:10][C@@H:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[Br:20])[CH2:8][C:6]=2[N:7]=1.[NH2:22][O:23][CH2:24][C@@H:25]1[CH2:29][C@@H:28]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:27][N:26]1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>[Hg](OC(C)=O)OC(C)=O.C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2=[C:6]([CH2:8][C@H:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[Br:20])[NH:10]/[C:11]/2=[N:22]\[O:23][CH2:24][C@@H:25]2[CH2:29][C@@H:28]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:27][N:26]2[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[N:7]=1
Reactant: Cc1nc(N)nc2c1C(=S)N[C@@H](c1ccc(F)cc1Br)C2
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CON
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: Cc1ccccc1
Product: Cc1nc(N)nc2c1/C(=N/OC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C)N[C@@H](c1ccc(F)cc1Br)C2
Temperature: 100 °C
Yield: 58.8 %

Procedure:
A mixture of (R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-5(6H)-thione (183 mg, 0.5 mmol), (2S,4R)-tert-butyl 2-(aminooxymethyl)-4-(tert-butyldimethylsilyloxy)pyrrolidine-1-carboxylate (692 mg, 2.0 mmol), Hg(OAc)2 (320 mg, 1.0 mmol) and toluene (2 mL) was heated at 100° C. for 2 h. Cooled to r.t., filtered through celite and purified to afford (2S,4R)-tert-butyl 2-(((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5-(6H)-ylidene)aminooxy)methyl)-4-(tert-butyldimethylsilyloxy)pyrrolidine-1-carboxylate (200 mg, 50%) as off white solid. MS (ES) [M+H] calculated for C30H45BrFN6O4Si, 679.24; found 679.20.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:27]=1[CH2:28]Br.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC3C=CC(F)=CC=3F)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:28][C:27]3[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:26]=3[F:25])[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: CC(C)(C)OC(=O)N1CCc2nn(Cc3ccc(F)cc3F)c(-c3ccc(Cl)cc3)c2CC1
Product: Fc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)c(F)c1
Yield: 40.1 %

Procedure:
The title compound (0.030 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 2,4-difluorobenzyl bromide (0.3 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-(2,4-difluoro-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C20H18ClF2N3, 373.12; found, m/z 374.1 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.52-7.49 (br m, 4H), 7.27-7.24 (br m, 1H), 7.01-6.99 (br m, 2H), 5.52 (s, 2H), 3.51-3.49 (br m, 2H), 3.43-3.40 (br m, 2H), 3.34-3.31 (br m, 2H), 3.11-3.09 (br m, 2H).
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=1>C(OCC)(=O)C.[Fe]>[F:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1ccc(F)cc1OCc1ccccc1
Temperature: 76 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
To a mixture of iron powder (90.36 g, 1.62 mol) and acetic acid (10%, 400 mL) at 80° C. was added a solution of the title compound of Step A (40 g, 0.162 mol) in ethyl acetate (200 mL) dropwise with vigorous stirring. The reaction mixture was stirred further at 76° C. for 1 h. After the reaction was complete, the hot reaction mixture was filtered through Celite® (200 g) and the filter cake was washed with ethyl acetate (1000 mL). The filtrate was washed with water (3×200 mL), sodium bicarbonate solution (5%, 3×200 mL), dried (MgSO4) and concentrated to give the crude product. The product was purified by flash chromatography to give 24.76 g of the title compound of Step B. 1H NMR (CDCl3, 400 MHz): δ7.41 (m,5H), 6.60 (m,3H), 5.04 (s,2H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br.BrCC1[CH:51]=[CH:50][N:49]=[CH:48][C:47]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:51]=[CH:50][N:49]=[CH:48][C:47]=3[Cl:52])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: Clc1cnccc1CBr
Agent: Br
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3ccncc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 4-(bromomethyl)-3-chloropyridine hydrobromide and isolated as yellow gum. MS (m/e): 408.3 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH2:17][CH2:18][CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:42])=[O:41])=[CH:36][CH:35]=1
Reactant: CCOC(=O)C(CCCCN)(CCCc1cccnc1)C(=O)OCC
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CCCCNS(=O)(=O)c1ccc(Cl)cc1)(CCCc1cccnc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 15.0 g (42.8 mmol) of diethyl [4-aminobutyl][3-(3-pyridyl)propyl]-malonate in 115 ml methylene chloride is cooled to 0° and 0.1 g 4-dimethylaminopyridine is added followed by 8.4 ml (60 mmol) triethylamine and 10.12 g (46.5 mmol) p-chlorophenylsulfonyl chloride. The solution is stirred at room temperature for 48 h and then washed with saturated aqueous sodium bicarbonate solution. The organic phase is dried (MgSO4), filtered and evaporated to give diethyl [4-(p-chlorophenylsulfonamido)butyl][3-(3-pyridyl)propyl]-malonate as an oil.
Reaction SMILES: [CH:1]1([C:7]2([CH2:15][NH2:16])[O:12][CH2:11][C:10]([CH3:14])([CH3:13])[CH2:9][O:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([CH3:28])[CH3:27])[C:21]=1[N:29]=[C:30]=[O:31])[CH3:19]>CCCCCC.C(OC(=O)C)C>[CH3:19][CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([CH3:27])[CH3:28])[C:21]=1[NH:29][C:30]([NH:16][CH2:15][C:7]1([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[O:12][CH2:11][C:10]([CH3:13])([CH3:14])[CH2:9][O:8]1)=[O:31])[CH3:17]
Reactant: CC1(C)COC(CN)(C2CCCCC2)OC1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NCC1(C2CCCCC2)OCC(C)(C)CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.9 %

Procedure:
To a stirred solution of (2-cyclohexyl-5,5-dimethyl-1,3-dioxan-2-yl)methylamine (2.27 g 0.100 mole) in 40 ml of n-hexane/ethylacetate (5:1) is added dropwise at room temperature 2,6-bis(1-methylethyl)phenylisocyanate (1.94 g 0.105 mole). The reaction mixture is stirred at room temperature for two hours. Precipitated solid is filtered, washed with n-pentane/ether (1:1) and dried, yielding 3.85 g of N-[2,6-bis(1-methylethyl)phenyl]-N'-(2-cyclohexyl-5,5-dimethyl-1,3-dioxan-2-yl)methylurea.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])[O:12][CH2:11][C:10]1[N:5]2[C@H:6]([CH3:24])[C:7](=[O:23])[NH:8][N:9]=1.CC1(C)C(C)(C)OB([C:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH:34]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[C:42]([O:41][C:39]([N:36]1[CH2:35][CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[O:12][CH2:11][C:10]2[N:5]3[C@H:6]([CH3:24])[C:7](=[O:23])[NH:8][N:9]=2)[CH2:38][CH2:37]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c(Br)cc3N21
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c(C4=CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Temperature: 90 °C
Yield: 63.3 %

Procedure:
A mixture of (R)-6-bromo-7-(2-fluoro-phenyl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (2.0 g, 5.13 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2.38 g, 7.69 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.84 g, 1.03 mmol) and K2CO3 (1.42 g, 10.25 mmol) in dioxane (21 mL) and water (7 mL) was heated at 90° C. overnight. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 10-50% EtOAc in petroleum ether) to give 4-[(R)-7-(2-fluoro-phenyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.6 g, 61%) as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ 8.64 (brs, 1H), 7.36-7.20 (m, 3H), 7.19-7.05 (m, 2H), 6.99 (s, 1H), 6.81 (s, 1H), 5.49 (brs, 1H), 4.79 (q, J=6.4 Hz, 1H), 4.72-4.57 (m, 2H), 3.88 (brs, 2H), 3.35 (m, 2H), 2.06 (brs, 2H), 1.60-1.57 (m, 3H), 1.47 (s, 9H).
Reaction SMILES: [C:1]([NH:3][C:4]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)#[N:2].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[S:29])=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][NH:12][C:4]([NH:3][C:1]#[N:2])=[N:5][C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)=[S:29])=[CH:23][CH:22]=1
Reactant: N#CNC(=Nc1ccncc1)NCCCCCCO
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: N#CNC(=Nc1ccncc1)NCCCCCCOC(=S)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
N-Cyano-N′-(6-hydroxyhexyl)-N″-4-pyridylguanidine (0.5 g), 4-chlorophenyl isothiocyanate (0.4 g) and diisopropylethylamine (0.32 ml) was mixed in a two-necked flask with a three-way-tap and a septum. The air was exchanged with argon through the three-way-tap. Dry pyridine (10 ml) was added through the septum. The reaction mixture was stirred for 5 days at room temperature.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].CCN(CC)CC.Cl[C:18](Cl)([O:20]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[N:5]=[C:18]=[O:20])[CH3:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCc1ccccc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccccc1N=C=O

Procedure:
The compound was prepared substantially in accordance with the procedure detailed in Example 27A, using 2-ethylaniline (1.5 ml, 12.2 mmol), Et3N (4.3 ml, 30.4 mmol) and triphosgene (1.2 g, 4.0 mmol) in 45 ml of CH2Cl2.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([F:15])([F:14])[F:13])=[C:9]([C:16](Cl)=[O:17])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:22]=[C:23]([NH2:31])[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1.C(N(CC)C(C)C)(C)C.Cl.C([O-])(O)=O.[Na+]>ClCCl>[F:19][C:20]([F:32])([F:33])[C:21]1[CH:22]=[C:23]([NH:31][C:16]([C:9]2[CH:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:11][C:10]=2[C:12]([F:15])([F:14])[F:13])=[O:17])[CH:24]=[C:25]([C:27]([F:28])([F:30])[F:29])[CH:26]=1
Reactant: O=C(Cl)c1cc(-c2ccccc2)oc1C(F)(F)F
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.1 %

Procedure:
An excess of 5-phenyl-2-trifluoromethyl-furan-3-carbonyl chloride (1 g, 3.6 mmol) was added to a solution of 3,5-bis-trifluoromethyl-phenylamine (0.758 g, 3.3 mmol) and N,N-diisopropylethylamine (0.58 mL) in dichloromethane (50 mL). After stirring at room temperature for 1 day, the reaction underwent an aqueous acidic (dilute HCl, 2×30 mL) and basic (dilute NaHCO3, 2×30 mL) workup followed by washing with brine (saturated NaCl, 2×30 mL), drying over MgSO4, and concentration. The crude compound was purified by passing through a silica gel plug eluting with ethyl acetate/hexanes (2:1) to afford the title compound (1.42 g, 92% yield). ES-MS negative Q1 (m/z) 466.
Reaction SMILES: Cl[C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:6])=[O:5].[CH3:15]C1C(C(F)(F)F)=CC=CC=1C(O)=O.ClC1C(C(F)(F)F)=CC=CC=1C(O)=O>>[CH3:15][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:6])=[O:5]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Reactant: Cc1c(C(=O)O)cccc1C(F)(F)F
Agent: O=C(O)c1cccc(C(F)(F)F)c1Cl
Product: Cc1c(C(=O)Cl)cccc1C(F)(F)F

Procedure:
The title compound was prepared in a manner analogous to Intermediate 12 substituting 2-methyl-3-(trifluoromethyl)benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:4]=1.C(O)(=O)C.S(=O)(=O)(O)O.[Br:24]N1C(C)(C)C(=O)N(Br)C1=O>O>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:8]=[C:7]([Br:24])[CH:6]=[C:5]([C:9]([F:10])([F:11])[F:12])[CH:4]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: FC(F)(F)c1cccc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 40 °C
Reaction time: 4.5 h
Yield: 94 %

Procedure:
A vigorously stirred solution of 1,3-bis(trifluoromethyl)benzene (107 g) in a mixture of glacial acetic acid (22 mL) and concentrated sulfuric acid (142 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (77.25 g) at 25° C. The exothermic reaction raised the temperature to approximately 40° C. After aging at 45° C. for 4.5 h, the mixture was cooled to approximately 0° C. and poured into cold water (250 mL). After washing with 5N NaOH (75 mL) the organic layer contained 137 g of the desired 3,5-bis(trifluoromethyl)-1-bromobenzene by assay (94% yield). This product was used in the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[N:11]([C@@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=O)[C:10](=[O:20])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[NH2:21][C:22]1[S:23][CH:24]=[CH:25][N:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[O:1]=[C:2]1[N:11]([C@@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH:21][C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[O:15])[C:10](=[O:20])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: CC(C)C[C@@H](C(=O)O)n1c(=O)[nH]c2ccccc2c1=O
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)Nc1nccs1)n1c(=O)[nH]c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of Compound 1 (187 mg, 0.7 mmol), 2-aminothiazole (70 mg, 0.7 mmol), HBTU (303 mg, 0.8 mmol) and 0.2 mL of Et3N in DMF (5 mL) was stirred at room temperature for 2 hours to provide the title compound, which purified by HPLC. 1H NMR (400 MHz, CD3OD) δ: 8.03 (dd, J=1.2, 8.0 Hz, 1H), 7.70-7.63 (m, 1H), 7.42 (d, J=4.0 Hz, 1H), 7.27-7.17 (m, 2H), 7.15 (d, J=4.0 Hz, 1H), 5.76 (dd, J=4.8, 9.2 Hz, 1H), 2.29-2.20 (m, 1H), 2.11-2.01 (m, 1H), 1.61-1.49 (m, 1H), 1.01 (d, J=6.8 Hz, 3H), 0.94 (d, J=6.8 Hz, 3H). [M+H] calc'd for C17H18N4O3S, 359; found, 359.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: CC(C)(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COC(=O)C(C)(C)C)CC1
Temperature: 60 °C

Procedure:
To 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butylester (480 mg, 2.1 mmol) dissolved in dry DMF (10 ml) was added NaH (120 mg, 3.0 mmol, 55-65% in mineral oil) and the mixture was warmed to 60° C. for 2 h. The mixture was allowed to cool to rt and then pivaloyl chloride (0.1.6 ml, 1.3 mmol) was added. The reaction was allowed to stir over night and then poured into water and the mixture was extracted with ether. The combined organic phases were washed with brine, dried (Na2SO4), filtered, concentrated under reduced pressure and the oily residue was purified by Flash column chromatography (SiO2; heptane/EtOAc 70:30) to yield 4-(2,2-dimethylpropionyloxymethyl)piperidine-1-carboxylic acid t-butyl ester as an oil. Deprotection of 4-(2,2-dimethylpropionyloxymethyl)piperidine-1-carboxylic acid t-butyl ester was conducted using the method (CH2Cl2:TFA; 1:1) to yield the title compound as an oil (85 mg, 0.43 mmol, 33 %). This crude was used without further purification.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@@H:10]([C:14](O)=[O:15])[CH:11]([CH3:13])[CH3:12])=[CH:5][CH:4]=1.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1>[CH3:12][CH:11]([CH3:13])[C@@H:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:17])[F:18])=[CH:4][CH:5]=1)[CH2:14][OH:15]
Reactant: CC(C)[C@@H](Nc1ccc(C(F)(F)F)cc1)C(=O)O
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)[C@H](CO)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
N-[4-(Trifluoromethyl)phenyl]-D-valine (2.15 g, 8.23 mmol) obtained in Step 1 of Example 1 was dissolved in tetrahydrofuran (50 ml), and triethylamine (1.71 mL, 12.3 mmol) and ethyl chloroformate (0.94 mL, 9.88 mmol) were added under cooling. The precipitated salt was filtered off, sodium borohydride (0.62 g, 16.4 mmol) and ice were added, and the mixture was stirred overnight at room temperature. The solvent was evaporated and, after work-up according to a conventional method, the residue was purified by silica gel column chromatography (30% mixed solvent of ethyl acetate/hexane) to give the title compound (0.95 g, 3.84 mmol, 47%).
Reaction SMILES: [BH4-].[Na+].CO.[C:5]([C:9]1[S:13][C:12]([N:14]2[C:18](=[O:19])[C:17]([CH3:20])=[C:16]([CH3:21])[C:15]2=[O:22])=[N:11][N:10]=1)([CH3:8])([CH3:7])[CH3:6]>C(O)(=O)C>[C:5]([C:9]1[S:13][C:12]([N:14]2[C:15](=[O:22])[C:16]([CH3:21])=[C:17]([CH3:20])[CH:18]2[OH:19])=[N:11][N:10]=1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC1=C(C)C(=O)N(c2nnc(C(C)(C)C)s2)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC1=C(C)C(O)N(c2nnc(C(C)(C)C)s2)C1=O
Reaction time: 3 h
Yield: 77.3 %

Procedure:
Sodium borohydride (0.07 g) was added at room temperature to a methanol solution (100 ml) of N-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-2,3-dimethylmaleinimide (0.95 g), and the mixture was stirred for 3 hours. After the reaction, glacial acetic acid (0.5 ml) was added and the solvent was evaporated under reduced pressure. Water (30 ml) was added to the residue, and potassium carbonate was added to make the mixture alkaline. It was extracted with dichloromethane (50 ml×2). The extractants were dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting crude crystals were washed with a small amount of diethyl ether to give the desired N-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-3,4-dimethyl-2-hydroxy-5-oxo-2,5-dihydropyrrole (0.74 g). mp. 179°-182° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C@H:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[NH:5][C:6](=[O:21])[C@H:7]([CH2:19][OH:20])[NH:8]C(OCC1C=CC=CC=1)=O.[ClH:31].[H][H]>CO>[ClH:31].[CH3:1][O:2][C:3](=[O:30])[C@H:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[NH:5][C:6](=[O:21])[C@H:7]([CH2:19][OH:20])[NH2:8]
Reactant: [H][H]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)CO

Procedure:
To a mixture consisting of 4.16 g. of N-benzyloxycarbonyl-L-seryl-L-tyrosine methyl ester [for the preparation of this compound see J. Am. Chem. Soc., 76, 5076 (1954)], 30 ml. of methanol, and 416 mg. of 5% palladium-on-barium sulfate is added 8.7 ml. of methanol containing 400 mg. of hydrogen chloride, and hydrogen is passed over the stirred mixture for 75 minutes. The mixture is then filtered to remove the catalyst, and the filtrate is evaporated to dryness under reduced pressure to give a solid residue of L-seryl-L-tyrosine methyl ester hydrochloride, which is suitable for use without further purification.
Reaction SMILES: [C:1]1([S:7][CH2:8][C:9]([NH:11][NH:12][C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[O:18][C:17]3[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:16]2=3)=[O:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:36].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[C:1]1([S:7]([CH2:8][C:9]([NH:11][NH:12][C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[O:18][C:17]3[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:16]2=3)=[O:14])=[O:10])=[O:36])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(CSc1ccccc1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CS(=O)c1ccccc1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
To a stirred solution of 1.0 g (2.19 mmole) of the title product of Example 2 in 30 ml of cold (ca.0° ) dichloromethane was added 0.463 g (2.19 mmole) of 81% m-chloroperoxybenzoic acid. After about ninety minutes, 5 ml of saturated aqueous sodium thiosulfate was added. The mixture was washed sequentially with three portions of saturated aqueous sodium bicarbonate and three portions of water. The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to give tht title compound.