Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4]([Cl:11])[N:3]=1.[CH:12]([NH2:15])([CH3:14])[CH3:13].O>C(OCC)C>[Cl:11][C:4]1[C:5]([C:9]#[N:10])=[C:6]([Cl:8])[N:7]=[C:2]([NH:15][CH:12]([CH3:14])[CH3:13])[N:3]=1
Reactant: N#Cc1c(Cl)nc(Cl)nc1Cl
Reactant: CC(C)N
Solvent: O
Solvent: CCOCC
Product: CC(C)Nc1nc(Cl)c(C#N)c(Cl)n1
Yield: 51.5 %

Procedure:
A stirred solution of 4.2 grams of 2,4,6-trichloro-5-pyrimidinecarbonitrile in 100 ml of diethyl ether was cooled to between -5° and -10°, and a solution of 2.4 grams of isopropylamine in 100 ml of diethyl ether was added dropwise. Upon complete addition, water was added to the reaction mixture, and the ether layer was separated. The ethereal layer was dried over magnesium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure. The residue was recrystallized from methylcyclohexane to give 2.4 grams of 4,6-dichloro-2-isopropylamino-5-pyrimidinecarbonitrile; mp, 179°-181°.
Reaction SMILES: [F:1][CH:2]([C:6](=O)[CH3:7])[C:3](=O)[CH3:4].[C:9]([CH2:11][C:12]([NH2:14])=[O:13])#[N:10].N1CCCCC1>CCO>[NH2:10][CH2:9][C:11]1[C:12](=[O:13])[NH:14][C:3]([CH3:4])=[C:2]([F:1])[C:6]=1[CH3:7]
Reactant: CC(=O)C(F)C(C)=O
Reactant: N#CCC(N)=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(=O)c(CN)c(C)c1F
Temperature: 85 °C

Procedure:
A mixture of 3-fluoro-2,4-pentanedione (247 mg, 2.10 mmol), cyanoacetamide (176 mg, 2.1 mmol, 1 equiv) and piperidine (0.21 mL, 2.1 mmol, 1 equiv) in 3 mL of EtOH was heated at 85° C. for 16 h, resulting in a clear but dark brown solution. The mixture was concentrated in vacuo. The residue was taken up in 2 mL of 1N HCl to give a suspension, which was filtered. The tan solids collected were dried under vacuum to give the desired product as 80 mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.33 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH:14]=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.[BH3-]C#N.[Na+]>CO.COC(OC)OC>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(C=O)C1
Reactant: Nc1cccnc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC(CNc2cccnc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.4 %

Procedure:
To a solution of N-Boc-piperidin-3-yl-formaldehyde 3 (0.89 g, 4.16 mmol) in 3 mL of dry methanol and 3 mL of trimethylorthoformate was added 3-aminopyridine (0.39 g, 1 eq.), and the mixture was stirred at room temperature for 1.5 hours. NaBH3CN (95%, 0.29 g, 1.05 eq.) was introduced in one portion, and the mixture was stirred at room temperature overnight. The mixture was quenched with 10 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3×30 ML). The extracts were combined and washed with aqueous NaHCO3 (sat., 2×10 mL), brine (20 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by flash column chromatography (silica gel, hexane/ethyl acetate) to afford N-(1-Boc-piperidin-3-ylmethyl)-N-(pyridin-3-yl) amine 17 as a white solid (0.91 g, 75%). LRMS 292.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C@H:20]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:21]([NH2:23])=[O:22]>>[NH2:23][C:21](=[O:22])[C@H:20]([NH:19][C:15](=[O:17])[C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: NC(=O)[C@H](N)c1ccccc1
Agent: Cl
Product: NC(=O)[C@H](NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)c1ccccc1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and (αR)-α-amino-benzeneacetamide hydrochloride (1:1) (CAN 63291-39-4) as starting materials, LC-MS (UV peak area/ESI) 100%, 366.1808 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[SH:15][C:16]1[N:17]([CH3:21])[CH:18]=[CH:19][N:20]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:15][C:16]2[N:17]([CH3:21])[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1ccnc1S
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Product: Cn1ccnc1SC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
By a similar manner to Reference Example 35, 1-tert-butoxycarbonyl-4-hydroxypiperidine (1.01 g, 5.0 mmol) was reacted with 2-mercapto-1-methylimidazole (0.68 g, 6.0 mmol) to give the titled compound as pale yellow oily substance (1.04 g, 70%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH:4]([CH2:9][C:10](=O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1.[NH2:18][C:19]1[S:20][CH:21]=[C:22]([C:24]([O:26]C)=[O:25])[N:23]=1>>[CH3:1][CH:2]1[CH2:7][CH2:6][C:5]2[N:18]([C:19]3[S:20][CH:21]=[C:22]([C:24]([OH:26])=[O:25])[N:23]=3)[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][C:4]=2[CH2:3]1
Reactant: COC(=O)c1csc(N)n1
Reactant: CC1CCC(=O)C(CC(=O)c2ccccc2)C1
Product: CC1CCc2c(cc(-c3ccccc3)n2-c2nc(C(=O)O)cs2)C1
Yield: 49 %

Procedure:
Following the general methods as outlined under Intermediate 13, starting from 4-methyl-2-(2-oxo-2-phenylethyl)cyclohexanone and methyl 2-amino-1,3-thiazole-4-carboxylate, the title compound was isolated in 49% yield (93% purity by HPLC). MS(ESI+): 339.5; MS(ESI−): 337.4.
Reaction SMILES: [Br:1]Br.[BrH:3].[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([CH2:13][C:14]([O:16][CH:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[O:15])=[N:5]1>C(O)(=O)C.O>[BrH:1].[Br:3][CH:13]([C:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:4][N:5]=1)[C:14]([O:16][CH:17]1[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]1)=[O:15]
Reactant: BrBr
Reactant: CN1CCC(OC(=O)Cc2noc3ccccc23)CC1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CN1CCC(OC(=O)C(Br)c2noc3ccccc23)CC1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 87.3 %

Procedure:
A solution of bromine (1.48 g) in glacial acetic acid (3 ml) was added dropwise with stirring to a solution of 1-methyl-4-piperidyl 1,2-benzisoxazole-3-acetate hydrobromide (3.0 g) in glacial acetic acid (6 ml). After the reaction mixture was stirred for 40 minutes at 60° C., it was diluted with water (100 ml) and extracted with two 100-ml portions of chloroform. The chloroform solution was dried over anhydrous sodium sulfate and evaporated to give crude 1-methyl-4-piperidyl 2-bromo-2-(1,2-benzisoxazol-3-yl)acetate hydrobromide (3.2 g). The hydrobromide thus obtained was dissolved in chloroform (15 ml) and thereto was added heptamethyleneimine (4.5 ml). The resulting mixture was stirred overnight at room temperature and evaporated in vacuo to give a residue, to which water (50 ml) was added. The resulting mixture was extracted with two 100-ml portions of toluene. The toluene layer was extracted with 5% hydrochloric acid (70 ml). The aqueous layer was made alkaline with aqueous ammonia solution and extracted with toluene. The toluene layer was dried over anhydrous sodium sulfate and evaporated in vacuo to give an oily residue (2.25 g). The residue and oxalic acid (0.74 g) were dissolved in ethanol (10 ml). The solution was concentrated in vacuo to about a half volume. To the residue was added diethyl ether until it became turbid. The crystals precipitated were collected by filtration and recrystallized from ethanol-diethyl ether to give 1-methyl-4-piperidyl 2-heptamethyleneimino-2-(1,2-benzisoxazol-3-yl)acetate oxalate (2.41 g), m.p. 170°-173° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[H-].[Na+].[OH:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>O1CCOCC1.CN(C=O)C>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([O:30][CH2:31][CH2:32][N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: OCCN1CCOCC1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(OCCN4CCOCC4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium hydride and N-(2-hydroxyethyl)morpholine in dioxane and DMF. ES-MS m/e (%): 500 (M+H+, 100).
Reaction SMILES: [H-].[Na+].[NH2:3]/[C:4](/[C:11]([F:14])([F:13])[F:12])=[CH:5]\[C:6]([O:8]CC)=O.[CH2:15]([N:18]=[C:19]=[S:20])[CH:16]=[CH2:17]>CN(C=O)C>[CH2:15]([N:18]1[C:6](=[O:8])[CH:5]=[C:4]([C:11]([F:12])([F:13])[F:14])[N:3]=[C:19]1[SH:20])[CH:16]=[CH2:17]
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: C=CCN=C=S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(S)nc(C(F)(F)F)cc1=O
Reaction time: 0.33 h
Yield: 89 %

Procedure:
Sodium hydride (60% in oil, 2.71 q, 60.0 mmol) was added to DMF (40 ml) solution of ethyl 3-amino-4,4,4-trifluorocrotonate spending 30 minutes under ice-cooling, followed by stirring for 20 minutes. Next, allyl isothiocyanate (5.3 ml, 54.0 mmol) was added under ice-cooling, followed by overnight stirring while gradually returning to room temperature. After completion of the reaction, the reaction solution was concentrated under a reduced pressure, water (40 ml) and 2 N hydrochloric acid (1.25 ml) were added to the thus obtained residue. The thus precipitated solid was isolated by filtration, washed with water and hexane and then thoroughly dried to obtain light yellow solid of 3-allyl-2-mercapto-6-trifluoromethyl-4(3H)-pyrimidinone (12.7 g, 89%).
Reaction SMILES: S[C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=2[N:6]=1.CN(C=O)C.S(Cl)([Cl:21])=O>>[Cl:21][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=2[N:6]=1
Reactant: O=[N+]([O-])c1ccc2oc(S)nc2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2oc(Cl)nc2c1
Temperature: 65 °C

Procedure:
Subsequently, the crude 2-mercapto-5-nitrobenzoxazole (10 g, 51 mmol), previously prepared, was dissolved in thionyl chloride (100 mL). DMF (60 μL) was added and the reaction mixture was heated at 65° C. for 45 min. After cooling, the solvent was removed under reduced pressure and to the residue, toluene was added twice (2×20 mL) and each time subsequently evaporated in vacuo to remove volatiles via azeotrope. The resultant crude product was dissolved in ethyl acetate (400 mL), washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated to give compound 29, 2-chloro-5-nitrobenzoxazole, as (8.2 g, crude).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O.CC(O)=O.[Rh]>[C:21]([N:1]1[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH:3]([C:10]([OH:12])=[O:11])[CH2:2]1)([O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:22]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: [Rh]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)C2CCCCC12
Reaction time: 30 h
Yield: 34.2 %

Procedure:
A solution of 25 g (155 mmol) of indole-3-carboxylic acid in 1500 mL H2O and 150 mL HOAc was charged with 25 g of 5% Rh/Al2O3 and the mixture hydrogenated at 60 psi for 30 hr at 60° C. The mixture was filtered through Celite® and evaporated in vacuo to a dark oil which was treated with benzylchloroformate (26.35 g; 155 mmol) under basic conditions substantially according to the procedures of Example 1,A. The crude product crystallized out of hot CH2Cl2 /hexanes to yield 16.06 g (53 mmol; 49%) of N-Cbz-3-perhydroindolylcarboxylic acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH:4][S:18]([CH3:17])(=[O:20])=[O:19]
Reactant: Cc1ccc(N)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NS(C)(=O)=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
A solution of 2-chloro-4-methylaniline (5.00 g) and triethylamine (3.57 g) in dichloromethane (100 ml) was cooled to 0° C. Methanesulphonyl chloride (4.04 g) was added dropwise and the mixture stirred at ambient temperature overnight. The mixture was then washed with 2N aqueous hydrochloric acid solution (50 ml) and the solvent removed by evaporation. The residue was dissolved in ethyl acetate (75 ml) extracted with 2N aqueous sodium hydroxide solution (2×50 ml). The aqueous phase was acidified with 2N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×75 ml). This was subsequently dried (MgSO4) and the solvent evaporated. Thus was obtained N-(2-chloro-4-methylphenyl)methanesulphonamide (2.5 g, 32%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6](Cl)=[O:7].[CH2:15]([N:22]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH2:15]([N:22]1[CH2:26][CH2:25][C@H:24]([O:27][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:11]([N+:12]([O-:14])=[O:13])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Reactant: O[C@H]1CCN(Cc2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(C(=O)O[C@H]2CCN(Cc3ccccc3)C2)ccc1[N+](=O)[O-]
Reaction time: 18 h
Yield: 77.6 %

Procedure:
A solution of 3-methoxy-4-nitro-benzoyl chloride (608 mg, 2.82 mmol) in 10 mL of CH2Cl2 was added to stirred solution of 500 mg (2.82 mmol) of (3S)-1-benzyl-pyrrolidin-3-ol and 1 mL of pyridine in 15 mL CH2Cl2 at room temperature. After stirring for 18 h, the reaction mixture was diluted with 20 mL of saturated aqueous NaHCO3 and extracted with CH2Cl2 (2×10 mL). The combined extracts were washed with 20 mL of brine, dried over MgSO4, filtered, and concentrated in vacuo to furnish 780 mg (71%) of the desired ester as a yellow oil, which solidified after drying under high vacuum. The resulting solid was further purified by trituration with 1:1 ether-hexane. 1H-NMR (400 MHz, CDCl3) δ 7.83 (d, J=7.83 Hz, 1H), 7.74 (s, 1H), 7.68 (d, J=7.83 Hz, 1H), 7.2-7.4 (m, 5H), 5.44 (br.m, 1H), 4.02 (s, 2H), 3.69 (dd, J=30 Hz, J=13 Hz, 1H), 2.8-3.0 (m, 2H), 2.5-2.6 (m, 1H), 2.3-2.45 (m, 1H); 2.0-2.1 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH2:15][CH:16]([F:18])[F:17].[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:24](Cl)=[O:25]>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:15][CH:16]([F:18])[F:17])[C:24](=[O:25])[C:23]1[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=[C:21]([C:20]([F:19])([F:34])[F:35])[CH:22]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: FC(F)CNc1cnccc1-c1ccccc1Cl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N(CC(F)F)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(2-chloro-phenyl)-pyridin-3-yl]-(2,2-difluoro-ethyl)-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of n-heptane:EtOAc (100:0 to 70:30) for the chromatographic purification. Light brown solid (0.053 g; 11%). MS (ESI): m/z=509.07 [M+H]+.
Reaction SMILES: I.[NH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:8]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[C:15](=[O:27])[O:14][N:13]=2)=[N:9][O:10][N:11]=1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[O:27]=[C:15]1[O:14][N:13]=[C:12]([C:8]2[C:7]([NH:6][CH2:5][CH2:4][CH2:3][NH:2][S:36]([CH3:35])(=[O:38])=[O:37])=[N:11][O:10][N:9]=2)[N:16]1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1
Reactant: NCCCNc1nonc1-c1noc(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Agent: I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NCCCNc1nonc1-c1noc(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-{4-[(3-aminopropyl)amino]-1,2,5-oxadiazol-3-yl}-4-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5(4H)-one hydroiodide (from Example 15, Step F; 25 mg, 50 μmol) in dichloromethane (1 mL) was treated with triethylamine (17 μL, 0.12 mmol) and methanesulfonyl chloride (6 μL, 70 μmol) and stirred at 25° C. for 2 h. The reaction mixture was concentrated to give the intermediate, N-{3-[(4-{5-oxo-4-[3-(trifluoromethyl)phenyl]-4,5-dihydro-1,2,4-oxadiazol-3-yl}-1,2,5-oxadiazol-3-yl)amino]propyl}methanesulfonamide, as a crude residue which was used without further purification. A solution of the crude intermediate in methanol (1 mL) was treated with 2 N NaOH (0.25 mL, 0.5 mmol) and stirred at 25° C. for 30 min. The reaction mixture was treated with acetic acid (50 μL, 0.9 mmol), filtered and purified by preparative LCMS to give the desired product (13 mg, 65%) as a solid. LCMS for C14H18F3N6O4S (M+H)+: m/z=423.1. 1H NMR (400 MHz, DMSO-d6): δ 11.6 (s, 1H), 9.11 (s, 1H), 7.37 (dd, J=8.0, 8.0 Hz, 1H), 7.20 (d, J=7.8 Hz, 1H), 7.07-7.01 (m, 2H), 6.96 (d, J=8.0 Hz, 1H), 6.20 (t, J=5.9 Hz, 1H), 3.27-3.22 (m, 2H), 2.99-2.94 (m, 2H), 2.87 (s, 3H), 1.78-1.71 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH:11](O)[O:10][C:9]1=[O:14])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[NH2:27][C@H:28]([C:31]([O:33][CH3:34])=[O:32])[CH2:29][SH:30].Cl.O>CCO>[CH3:34][O:33][C:31]([CH:28]1[CH2:29][S:30][CH:11]([CH2:12][C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])([C:9]([OH:10])=[O:14])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:27]1)=[O:32]
Reactant: CC(C)(C)OC(=O)NC1(c2ccccc2)CC(O)OC1=O
Reactant: COC(=O)[C@@H](N)CS
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)C1CSC(CC(NC(=O)OC(C)(C)C)(C(=O)O)c2ccccc2)N1
Reaction time: 8 h
Yield: 89.3 %

Procedure:
To a solution of compound 14 (5.6 g, 19.1 mmol) in EtOH (80 mL) was added 1 M aq. NaHCO3 solution (19.1 mL, 19.1 mmol), followed by the addition of L-Cys-OMe.HCl (3.3 g 19.1 mmol). The pH value of the resulting mixture was adjusted to 6.5 with 1 M NaHCO3 solution. After stirring overnight, the mixture was poured into water, extracted with ethyl acetate, and the combined organic phases were dried over Na2SO4 and concentrated to afford product 15 (7 g, 51.1%). MS (M+1): 411. This product was used in the next step without further purification.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][C@H:12]([C:14]([OH:16])=O)[C@H:11]([CH2:17][CH3:18])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH:19]([C:21]1[N:22]=[C:23]2[CH:29]=[CH:28][N:27]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:24]2=[N:25][CH:26]=1)[NH2:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.[Si](O[C@H]1C[C@H](C(NNC2N=C3C=CN(S(C4C=CC(C)=CC=4)(=O)=O)C3=NC=2)=O)[C@H](CC)C1)(C(C)(C)C)(C)C>[Si:1]([O:8][CH:9]1[CH2:13][CH:12]([C:14]([NH:20][NH:19][C:21]2[N:22]=[C:23]3[CH:29]=[CH:28][N:27]([S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[C:24]3=[N:25][CH:26]=2)=[O:16])[CH:11]([CH2:17][CH3:18])[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Reactant: CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1C(=O)O
Agent: CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1C(=O)NNc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCC1CC(O[Si](C)(C)C(C)(C)C)CC1C(=O)NNc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a scalemic mixture enriched in (1S,2R,4R)-4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentanecarboxylic acid (1.62 g, 5.96 mmol) in DCM (60 mL) was added 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (Example #1, Step D, 1.86 g, 6.13 mmol), HATU (2.38 g, 6.26 mmol) and TEA (3.32 mL, 23.8 mmol). The reaction mixture was stirred at ambient temperature for about 1 h. The reaction mixture was diluted with DCM (200 mL), washed with water (50 mL) and brine (50 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The residue was purified using silica gel chromatography eluting with 0-30% EtOAc in DCM to give a scalemic mixture enriched in (1S,2R,4R)-4-(tert-butyldimethylsilyloxy)-2-ethyl-N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)cyclopentanecarbohydrazide (2.64 g, 79%) as a brown solid: LC/MS (Table 1, Method b) Rt=3.20 min; MS m/z: 558 (M+H)+.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]([C:12]1[CH:13]=[C:14]([C:23](=O)[CH3:24])[CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])([CH3:11])[CH3:10].[CH3:26][N:27]([CH3:35])[N:28]1[C:32](=[O:33])[CH2:31][S:30][C:29]1=[S:34].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH3:11][C:9]([C:12]1[CH:13]=[C:14]([CH2:23][CH:24]=[C:31]2[S:30][C:29](=[S:34])[N:28]([N:27]([CH3:35])[CH3:26])[C:32]2=[O:33])[CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])([CH3:8])[CH3:10]
Reactant: CN(C)N1C(=O)CSC1=S
Reactant: CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CN(C)N1C(=O)C(=CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)SC1=S

Procedure:
To 675 ml of toluene were added 20.9 g of 1-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]ethanone, 13.3 g of N-dimethylaminorhodanine 6.5 g of ammonium acetate and about 20 ml of acetic acid. The mixture was heated at reflux temperature and any aqueous layer generated was collected in a Dean-Stark trap. Over the following 52 hours an additional 39 g of ammonium acetate and about 100 ml of acetic acid were added in increments and a total of 89.2 ml of aqueous phase was drawn off. Following workup by conventional techniques, 17.1 g of the desired subtitled intermediate was recovered.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].[Cl:16][CH2:17][C:18](Cl)=[O:19]>O1CCOCC1>[Cl:16][CH2:17][C:18]([N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:19]
Reactant: O=C(Cl)CCl
Reactant: CCOCCNc1ncccc1[N+](=O)[O-]
Solvent: C1COCCO1
Product: CCOCCN(C(=O)CCl)c1ncccc1[N+](=O)[O-]
Reaction time: 4 h
Yield: 100 %

Procedure:
To a stirred solution of 42.24 parts of N-(2-ethoxyethyl)-3-nitro-2-pyridinamine in 309 parts of 1,4-dioxane were added 49.7 parts of 2-chloroacetyl chloride. The reaction mixture was stirred for 4 hours at reflux temperature. The whole was evaporated and the residue was taken up in methylbenzene. The organic layer was evaporated again, yielding 57.5 parts (100%) of 2-chloro-N-(2-ethoxyethyl)-N-(3-nitro-2-pyridinyl)acetamide as a residue (int. 1).