Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][C@H:4]([CH3:16])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1)=[O:6].[H][H]>[Pd].CC1CCCO1>[CH3:17][N:2]([CH3:1])[CH2:3][C@H:4]([CH3:16])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1)=[O:6]
Reactant: [H][H]
Reactant: C[C@@H](CN(C)C)C(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CC1CCCO1
Product: C[C@@H](CN(C)C)C(=O)c1cccc(N)c1
Temperature: 2 °C
Yield: 98 %

Procedure:
(S)-3-(dimethylamino)-2-methyl-1-(3-nitro-phenyl)-propan-1-one (100 g, 0.423 mol), methyl-tetrahydrofuran (400 ml) and Pd/C 5%, anhydrous (4.0 g) are added into a 1 liter autoclave, at room temperature. The suspension is cooled to 0-4° C., then it is hydrogenated at 2 bars of hydrogen gas without exceeding 8° C. The conversion is monitored using HPLC and it is deemed complete when the HPLC area % of the initial product and the reaction intermediates is <0.3. Then catalyst is filtered and the solution can be used as it is in the subsequent step or concentrated under vacuum at 45-50° C. to oily residue. About 86 g of yellow to dark red oil are obtained (about 98% yield, ee≧97%, purity ≧92%).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[CH3:16][C:17]1[NH:21][C:20]2[C:22](=O)[CH2:23][CH2:24][C:19]=2[C:18]=1[C:26]([OH:28])=[O:27]>CN(C=O)C.N1CCCCC1>[CH3:16][C:17]1[NH:21][C:20]2/[C:22](=[C:9]3\[C:10](=[O:15])[NH:11][C:12]4[C:8]\3=[CH:7][C:6]([S:3](=[O:5])(=[O:4])[NH:2][CH3:1])=[CH:14][CH:13]=4)/[CH2:23][CH2:24][C:19]=2[C:18]=1[C:26]([OH:28])=[O:27]
Reactant: Cc1[nH]c2c(c1C(=O)O)CCC2=O
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CNS(=O)(=O)c1ccc2c(c1)/C(=C1\CCc3c1[nH]c(C)c3C(=O)O)C(=O)N2
Temperature: 110 °C
Reaction time: 48 h
Yield: 24.5 %

Procedure:
A mixture of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide (905 mg, 4 mmol) and 2-methyl-6-oxo-1,4,5,6-tetrahydro-cyclopenta[b]pyrrole-3-carboxylic acid (Example B, 716 mg, 4 mmol) in DMF (50 mL) and piperidine (5 mL) was heated at 110° C. with stirring for 48 hours. The solvent was removed and the residue was suspended in methanol-ice-water and acidified with 2N HCl. The solid was collected by filtration and then suspended in DCM. The suspension was washed with 2N aq. NaOH for three times. The combined water layer was backwashed with DCM. The water layer was acidified with 2N HCl and filtered to give a brown solid, which was triturated with MeOH to afford 380 mg of the titled compound as a brown yellow solid. The combined organic layer was dried (Na2SO4) and evaporated to give 130 mg of 3-[2-methyl-4,5-dihydro-1H-cyclopenta[b]pyrrol-(6Z)-ylidene]-2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide (Example 4) as a yellow solid.
Reaction SMILES: [C:1]([O:6][CH2:7]Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[Na+].[I-].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([F:47])=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:41][C@@H:42]([OH:46])[C:43]([OH:45])=[O:44])[NH:26][C:27]([C:29]3[O:33][N:32]=[C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[F:40])[CH:30]=3)=[O:28])=[CH:20][CH:19]=2)[CH:17]=1.CCN(CC)CC>CC(C)=O.CC(O)=O>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([F:47])=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:41][C@@H:42]([OH:46])[C:43]([O:45][CH2:7][O:6][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[O:44])[NH:26][C:27]([C:29]3[O:33][N:32]=[C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[F:40])[CH:30]=3)=[O:28])=[CH:20][CH:19]=2)[CH:17]=1
Reactant: O=C(NN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1cc(-c2ccccc2F)no1
Reactant: CCCC(=O)OCCl
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCCC(=O)OCOC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(-c2ccccc2F)no1
Temperature: 65 °C
Reaction time: 0.42 h
Yield: 30.3 %

Procedure:
Chloromethyl butyrate (11.4 μL, 0.1 mmol) and NaI (13.6 mg, 0.1 mmol) were combined in acetone (0.7 mL, 10 mmol) and heated at 65° C. for 1 hour. The mixture was then cooled to room temperature. A mixture of (R)-3-{N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino}-2-hydroxypropionic acid (16.0 mg, 30 μmol) dissolved in acetone (0.2 mL) and treated with Et3N (8.5 μL, 61 μmol) was added and the resulting mixture was stirred at room temperature for 25 minutes. The mixture was concentrated and the residue was dissolved in AcOH (2.0 mL), filtered and purified by reverse phase preparative HPLC. The desired fractions were combined and freeze dried to yield a yellowish solid. This solid was dissolved in AcOH (1.5 mL), filtered, and purified by reverse phase preparative HPLC. The desired fractions were combined and freeze dried to yield the title compound (5.7 mg, purity 100%) as a TFA salt white solid. MS m/z [M+H]+ calc'd for C31H28ClF2N3O2, 628.16. found 628.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]([NH:18][CH3:19])=[O:17])[CH:13]=[CH:14][CH:15]=2)[C:5]([C:20]#[N:21])=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:3]=1[C:28]#[N:29].Cl.[NH:31]1[CH2:34][CH:33]([OH:35])[CH2:32]1.C(N(CC)CC)C.O>O1CCCC1>[C:20]([C:5]1[C:6]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]([NH:18][CH3:19])=[O:17])[CH:13]=[CH:14][CH:15]=2)=[N:7][C:2]([N:31]2[CH2:34][CH:33]([OH:35])[CH2:32]2)=[C:3]([C:28]#[N:29])[C:4]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)#[N:21]
Reactant: CNC(=O)c1cccc(CSc2nc(Cl)c(C#N)c(-c3ccccc3)c2C#N)c1
Reactant: OC1CNC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CNC(=O)c1cccc(CSc2nc(N3CC(O)C3)c(C#N)c(-c3ccccc3)c2C#N)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
50 mg (0.12 mmol) of 3-{[(6-chloro-3,5-dicyano-4-phenylpyridin-2-yl)sulfanyl]methyl}-N-methylbenzenecarboxamide Example 85A were initially charged in 1 ml of tetrahydrofuran. After addition of 19.6 mg (0.18 mmol) of azetidin-3-ol hydrochloride and 24.2 mg (0.24 mmol) of triethylamine, the mixture was stirred at RT for 30 min. Water was added to the reaction mixture until a clear solution had formed. The solution was purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% trifluoroacetic acid).
Reaction SMILES: [P:1]([O-:9])([O:6][CH2:7][CH3:8])([O:3][CH2:4][CH3:5])=O.Cl[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.[CH:17]1C=CC=CC=1>>[N:14]1[CH:15]=[CH:16][C:11]([CH2:17][P:1](=[O:9])([O:3][CH2:4][CH3:5])[O:6][CH2:7][CH3:8])=[CH:12][CH:13]=1
Reactant: c1ccccc1
Reactant: CCOP(=O)([O-])OCC
Reactant: Clc1ccncc1
Product: CCOP(=O)(Cc1ccncc1)OCC
Temperature: 90 °C

Procedure:
To a suspension of 4-chloropyridine hydrochloride (3.28 g, 20 mmol) in benzene (50 mL) was added 40% NaOH (1.35 mL). The resulting mixture was sonicated for 10 min and filtered. The residue was treated with additional benzene (15 mL), sonicated and filtered. The combined benzene layers were dried (Na2SO4) to give a solution of 4-chloropyridine which was used without further characterization (vida infra). A solution of diethyl phosphate (3.03 g, 22 mmol) in benzene (35 mL) was treated with freshly cut Na (510 mg, 22 mmol). The resulting mixture was refluxed for 30 min (oil temp. 90° C.), cooled to 0° C., then treated added dropwise over 10 min. with the solution of 4-chloropyridine in benzene (prepared as described above). After addition, the resulting mixture was refluxed for 3 h (oil temp. 100° C.) under argon then cooled to rt. The insoluble white precipitate was removed by filtration and rinsed with benzene (20 mL). The combined filtrate was concentrated and dried under high vacuum to give 3.5 g of diethyl pyridin-4-ylmethylphosphonate as a colorless liquid.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10].[ClH:15]>O>[Cl-:15].[C:9]([C:8]1[CH:7]=[C:6]([N+:5]#[N:1])[CH:14]=[CH:13][CH:12]=1)([OH:11])=[O:10]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: Cl
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#[N+]c1cccc(C(=O)O)c1
Product: [Cl-]

Procedure:
Nitromethane (61 g.) was added to a warm (45°-50°) solution of NaOH (61 g.) in water (122 ml.) at such a rate that the temperature was maintained. At the end of the addition the temperature was raised to 55° for 10 minutes and then allowed to fall back to 50°. The mixture was chilled and neutralised to pH 7 with concentrated hydrochloric acid at ≤10°. The precipitated product was redissolved by the addition of aqueous NaOH (12.5 N; 40 ml.) to give a solution of the sodium salt of methazonic acid. A solution of NaNO2 (36.2 g.) in water (300 ml.) was added during approximately 30 minutes to a suspension of 3-aminobenzoic acid (68.6 g.) in concentrated hydrochloric acid (126.3 ml.) and water (200 ml.) at 0°-5°. The mixture was filtered to give a solution of 3-carboxybenzenediazonium chloride.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][CH2:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[C:12]([Cl:20])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>>[C:1]([O:5][C:6](=[O:21])[CH2:7][CH2:8][N:9]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:19])[F:17])=[C:12]([Cl:20])[CH:11]=1)[CH2:23][C:24]([O:26][CH3:27])=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCNc1ccc(C(F)(F)F)c(Cl)c1
Reactant: COC(=O)CBr
Product: COC(=O)CN(CCC(=O)OC(C)(C)C)c1ccc(C(F)(F)F)c(Cl)c1
Yield: 34 %

Procedure:
In analogy to the procedure described for intermediate 40B, 3-(3-chloro-4-trifluoromethyl-phenylamino)-propionic acid tert-butyl ester and methyl bromoacetate gave the title compound in 34% yield as yellow oil. MS: 396.12 (MH+, Cl).
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[N:34]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:32]=[CH:31][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[N:34]=[C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH:32]=[CH:31][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: Brc1nccc(-c2ccccc2)n1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4nccc(-c5ccccc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-4-phenyl-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:40]=[CH:39][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][C:17]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:18][C:12]=3[N:11]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([N:33]4[CH2:37][CH:36]=[CH:35][CH2:34]4)=[O:32])=[CH:27][CH:26]=3)[C:10](=[O:38])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH2:41](N(CC)CC)[CH3:42]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][C:17]([CH2:19][CH2:20][C:21]([O:23][CH2:41][CH3:42])=[O:22])=[CH:18][C:12]=3[N:11]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([N:33]4[CH2:37][CH:36]=[CH:35][CH2:34]4)=[O:32])=[CH:27][CH:26]=3)[C:10](=[O:38])[CH2:9]2)=[O:7])=[CH:39][CH:40]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)CCc1ccc2c(c1)N(Cc1ccc(C(=O)N3CC=CC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc2c(c1)N(Cc1ccc(C(=O)N3CC=CC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2
Reaction time: 8 h

Procedure:
10 mg (0.018 mmol) of 3[4-(4-chlorobenzoyl)-2-oxo-1-[4-(2,5-dihydro-1H-pyrrol-1-ylcarbonyl)benzyl]-2,3,4,5-tetrahydro-1H-benzo[e][1,4]-diazepin-8-propionic acid was dissolved in 2 ml of dichloro-methane. 4 mg (0.02 1 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.005 nil (0.036 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. The solvent was evaporated and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1.[I:21]I>C1COCC1.CCCCCC>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[I:21]
Reactant: Fc1cccc(Br)c1
Reactant: II
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Fc1cccc(Br)c1I
Temperature: -78 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To a solution of diisopropylamine (76 mL, 0.4 mol) in dry THF (664 mL) and n-hexane (220 mL) was added 2.5 M/L n-BuLi (160 mL. 0.4 mol) dropwise at −78° C. during a period of 1 h. The mixture was stirred for 1 h at −78° C. Then a solution of 1-bromo-3-fluoro-benzene (69 g, 0.4 mol) in dry THF (300 mL) at −78° C. was added to the above mixture dropwise. After stirring for an additional 1 h at −78° C., the mixture was added a solution of iodine (101 g, 0.4 mol) in dry THF (400 mL) dropwise at −78° C. The temperature was raised from −78° C. to rt during 2 h. After stirring for 18 h at rt, the mixture was concentrated in vacuo to give crude product (120 g) which was distilled under reduced pressure to afford 1-bromo-3-fluoro-2-iodo-benzene (110 g). 1H NMR (400 MHz, DMSO): 7.24-7.19 (t, 1H), 7.38-7.32 (m, 1H), 7.55-7.53 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][C:26]=1[Cl:27])/[C:20](=[N:22]/O)/[NH2:21].CC(C)N=C=NC(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C.N1C=CC=CC=1.CCOC(C)=O>[Cl:16][C:17]1[CH:18]=[C:19]([C:20]2[N:22]=[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[O:15][N:21]=2)[CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: N/C(=N\O)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCCc1nc(-c2ccc(Cl)c(Cl)c2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.5 %

Procedure:
The 5-(tert-butoxycarbonylamino)pentanoic acid (424 mg, 1.95 mmol) was introduced into a microwave vial charged with DMAP (238 mg, 1.95 mmol) and Intermediate 20A (400 mg, 1.95 mmol). The reactants were dissolved in DMF (5 mL) and the DIC (0.304 mL, 1.95 mmol) was added. The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with 3 mL of pyridine. The vial was capped and the reaction was heated in the microwave at 145° C. for 20 min. The reaction mixture was allowed to cool to rt. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic portion was concentrated under reduced pressure and purified by silica gel chromatography with EtOAc/Hexane to give Intermediate 20B as a white solid (230 mg, 0.595 mmol, 30.5% yield). HPLC/MS (Method D) RT=2.40 min [M+H]+ 385.9.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[NH:6]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@H:7]([C:25](N(OC)C)=[O:26])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:24])[NH:13][S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15].[Li]C1SC=CN=1.Cl.C1C[O:48]CC1>CCCCCC>[NH:6]([C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])[C@H:7]([C:25]([OH:48])=[O:26])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:24])[NH:13][S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:15])=[O:16].[S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C1CCOC1
Reactant: CON(C)C(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li]c1nccs1
Agent: c1cscn1
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a solution of thiazole (2.5 g, 29 mmol) in THF (25 mL) at −78° C. was added n-Budi (1.6 M in hexane, 19 mL) dropwise. The mixture was stirred for 30 minutes. Then a solution of Boc-Arg(Tos)N(Me)OMe, from Example 1, (1.7 g, 3.6 mmol) in THF (50 mL) was added to the lithiothiazole mixture at −78° C. The solution was stirred for 2 hours. 1 M HCl (30 mL) was added to the reaction mixture and warmed to room temperature. The mixture was extracted with EtOAc (100 mL). The organic layer was washed with sat NaCl (30 mL), dried over MgSO4, filtered and evaporated. The crude oily residue was purified by flash column chromatography over SiO2 (50% EtOAc in CH2Cl2) to give Boc-Arg(Tos)-thiazole, shown above, (1.5 g, 84% yield) as a powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[C:20]([C:22](=[O:41])[NH:23][C:24]4[CH:29]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:27]=[C:26]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:25]=4[O:39][CH3:40])[CH:19]=[CH:18][C:17]=3[CH3:42])[CH:15]=2)=[O:10])[CH2:2]1.C=O.[C:45]([BH3-])#N.[Na+]>CO.C(Cl)Cl>[CH3:45][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[C:20]([C:22](=[O:41])[NH:23][C:24]4[CH:29]=[C:28]([C:30]([CH3:31])([CH3:32])[CH3:33])[CH:27]=[C:26]([NH:34][S:35]([CH3:38])(=[O:36])=[O:37])[C:25]=4[O:39][CH3:40])[CH:19]=[CH:18][C:17]=3[CH3:42])[CH:15]=2)=[O:10])[CH2:2]1
Reactant: COc1c(NC(=O)c2ccc(C)c(-n3cc(C(=O)NCC4CCCNC4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(C(=O)NCC4CCCN(C)C4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 25.6 %

Procedure:
To a 0° C. suspension of 106 mg (0.268 mmol) of 1-[5-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-2-methyl-phenyl]-1H-[1,2,3]triazole-4-carboxylic acid (piperidin-3-ylmethyl)-amide in 2 mL of MeOH containing 1% HOAc was added 70 μL of aqueous formaldehyde. The suspension was stirred at 0° C. for five minutes then 18 mg (0.281 mmol) of sodium cyanoborohydride was added and the mixture was warmed to rt. After stirring for ˜1 the reaction mixture was diluted with 40 mL of CH2Cl2 and washed with 25 mL of water. The aqueous wash was extracted with CH2Cl2 (2×25 mL), the combined organic extracts were dried (Na2SO4), filtered and evaporated to afford a yellow solid. Chromatography provided 42 mg of product. mp: 209-211. ESI MS (m/z 612, 100, M+H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.C[Si]([O:17][C:18]#N)(C)C.[Cl-].[Li+].Cl.[O:23]1CCC[CH2:24]1>C(OCC)C.CO>[OH:8][CH:7]([C:6]1[CH:9]=[CH:10][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:4][CH:5]=1)[C:24]([O:17][CH3:18])=[O:23]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: C1CCOC1
Reactant: C[Si](C)(C)OC#N
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C(O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a mixture of 4-(trifluoromethyl)benzaldehyde (500 μL, 3.66 mmol) and trimethylsilyl cyanate (537 μL, 4.03 mmol), lithium chloride (a 0.307 mol/L solution in tetrahydrofuran, 1.2 μL, 0.366 μmol) was added and the mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. The reaction mixture was diluted with diethyl ether (10 mL). To this, a 10% solution of hydrogen chloride in methanol (10 mL) was added at 0° C. and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated, water was added thereto, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3) to give methyl hydroxy-4-(trifluoromethyl)phenylacetate (Compound CH) (587 mg, yield: 68%).
Reaction SMILES: C([O:9][C@@H:10]([C@@H:12]1[C@@H:15]([S:16][CH3:17])[N:14]([C:18]([C:22]([O:24][CH3:25])=[O:23])=[C:19]([CH3:21])[CH3:20])[C:13]1=[O:26])[CH3:11])(=O)C1C=CC=CC=1.[Na].C(O)(=O)C>CO.C(OCC)(=O)C>[OH:9][C@@H:10]([C@@H:12]1[C@@H:15]([S:16][CH3:17])[N:14]([C:18]([C:22]([O:24][CH3:25])=[O:23])=[C:19]([CH3:20])[CH3:21])[C:13]1=[O:26])[CH3:11]
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H]([C@@H](C)OC(=O)c2ccccc2)[C@H]1SC
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H]([C@@H](C)O)[C@H]1SC
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.2 %

Procedure:
91 mg (0.24 mmole) of (3S, 4R)-3-[(R)-1-benzoyloxyethyl]-1-(1-methoxycarbonyl-2-methylprop-1-enyl)-4-methylthioazetidin-2-one were dissolved in 1 ml of methanol. To the resulting solution was added a solution of 7.17 mg (0.31 mmole) of sodium in 0.65 ml of methanol at 0° C., and then the mixture was stirred at room temperature (18°-20° C.) for 5 hours. After completion of the reaction, the mixture was made slightly acidic by the addition of acetic acid, diluted with 20 ml of ethyl acetate and washed with water. After drying the mixture, the solvent was distilled off. The resulting residue was subjected to preparative thin layer chromatography on silica gel developed with a 2:1 by volume mixture of benzene and ethyl acetate to give 50 mg (yield 74.4%) of the pure product as an oil, which was proved by nuclear magnetic resonance spectroscopy to be an approximately 4:1 mixture of the 1'R- and 1'S-isomers.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:8]=[C:9]([C:14](=[O:38])[CH2:15][NH:16][C:17](=O)[CH2:18][CH2:19][C:20]2[N:21](S(N(C)C)(=O)=O)[CH:22]=[C:23]([CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][CH3:28])[N:24]=2)[CH:10]=[CH:11][C:12]=1[F:13].C(=O)(O)[O-].[Na+]>C(#N)C.C(Cl)Cl>[F:6][C:7]1[CH:8]=[C:9]([C:14]2[O:38][C:17]([CH2:18][CH2:19][C:20]3[NH:24][C:23]([CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][CH3:28])=[CH:22][N:21]=3)=[N:16][CH:15]=2)[CH:10]=[CH:11][C:12]=1[F:13]
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(CCC(=O)NCC(=O)c2ccc(F)c(F)c2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCC(C)(C)Cc1cnc(CCc2ncc(-c3ccc(F)c(F)c3)o2)[nH]1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Phosphorus oxychloride (190 mg, 1.2 mmol) was added to a solution of N-[2-(3,4-difluorophenyl)-2-oxoethyl]-3-[1-[(dimethylamino)sulfonyl]-4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]propanamide (for synthesis see example 234) (30 mg, 0.06 mmol) in dry acetonitrile (4 mL) at rt. After stirring at 80° C. overnight, saturated sodium bicarbonate (ca. 3 mL) was added. The aqueous phase was washed with 1:5 ethyl acetate/diethyl ether, basified with 5N aqueous sodium hydroxide and extracted with ethyl acetate. Combined extracts were washed with brine, dried (sodium sulfate) and concentrated to give a residue. The residue was dissolved in methylene chloride to give the title compound, which was acidified with 1M HCl in diethyl ether. Additional diethyl ether and hexane were added, and concentration afforded the HCl salt of the title compound. LC-MS: m/e 360 (M+H).
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([NH2:9])=[N:6][N:5]=2)[CH2:3][CH2:2]1.Br[CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][O:13]1>>[CH:1]1([C:4]2[S:8][C:7](=[NH:9])[N:6]([CH2:11][CH:12]3[CH2:16][CH2:15][CH2:14][O:13]3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: Nc1nnc(C2CC2)s1
Reactant: BrCC1CCCO1
Product: N=c1sc(C2CC2)nn1CC1CCCO1

Procedure:
5-cyclopropyl-1,3,4-thiadiazol-2-amine (ASD) and 2-(bromomethyl)tetrahydrofuran (Acros) were processed using the method described in Example 1C to afford the title compound.