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: CC(C)N
Reactant: N#Cc1c(Cl)nc(Cl)nc1Cl
Solvent: CCOCC
Solvent: O
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: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:41][CH2:42][CH:43]([C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([O:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:46]=1)[OH:44]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@H:13]([C:14]([NH:41][CH2:42][CH:43]([OH:44])[C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([O:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:46]=1)=[O:15])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: NCC(O)c1cccc(Oc2ccccc2)c1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NCC(O)c1cccc(Oc2ccccc2)c1
Yield: 21.1 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (96 mg, 0.16 mmol) and 2-amino-1-(3-phenoxyphenyl)-1-ethanol (45 mg, 0.20 mmol) according to Method C with HPLC purification to give the title compound (25 mg) as a diasteromeric mixture. 1H-NMR (400 MHz, CD3OD) d 7.59 (d, J=1.7 Hz, 1H), 6.87 (dd, J=1.2 Hz, J=8.3 Hz, 1H), 4.66 (m, 3H), 4.55 (t, J=7.0 Hz, 1H), 4.23 (m, 1H), 3.02 (m, 2H), 3.52 (m, 1H), 2.90 (m, 1H), 2.69 (m, 1H), 1.34 (s, 9H); HRMS m/z 741.2925 (calc. of monoisotopic mass for C40H43N3O11 gives 741.2898).
Reaction SMILES: Br.[CH:2]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([NH2:19])[S:17][CH:18]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.Cl>N1C=CC=CC=1>[CH:2]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([NH:19][S:26]([C:23]4[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=4)(=[O:28])=[O:27])[S:17][CH:18]=3)=[CH:10][CH:9]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Nc1nc(-c2ccc(C3CCCCC3)cc2)cs1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3ccc(C4CCCCC4)cc3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.2 %

Procedure:
A mixture of 0.5 g of 4-(4-cyclohexyl-phenyl)-thiazol-2-ylamine hydrobromide with 0.31 g of p-toluenesulfonyl chloride was stirred for 3 hours with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic phase was dried with magnesium sulphate and concentrated. The residue was dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. The product separated in amorphous form upon neutralization with concentrated hydrochloric acid. After chromatography on 70 g of Kieselgel 60 with ethyl acetate/hexane (1:2) the product-containing fractions were concentrated. Recrystallization from 50% ethanol yielded 0.22 g of N-[4-(4-cyclohexyl-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.ClC(Cl)(Cl)[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[CH:26]=[N:25][CH:24]=[CH:23]2)=[O:16].C1CCN2C(=NCCC2)CC1>>[CH:26]1[C:27]2[C:22](=[CH:21][CH:20]=[CH:19][C:18]=2[NH:17][C:15]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:4][CH:5]=2)=[O:16])[CH:23]=[CH:24][N:25]=1
Reactant: O=C(Nc1cccc2ccncc12)C(Cl)(Cl)Cl
Reactant: NCc1ccc(C(F)(F)F)cc1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cccc2ccncc12

Procedure:
The title compound was prepared using 4-(trifluoromethyl)benzylamine, the product from Example 57D, DBU and the procedure described in Example 1B. MS (ESI+) m/z 346 (M+H)+; 1H NMR (DMSO-d6) δ 9.58 (s, 1H), 9.10 (s, 1H), 8.49 (d, 1H), 8.12 (d, 1H), 7.81-7.54 (m, 7H), 7.20 (t, 1H), 4.47 (d, 2H); Anal. Calcd for C18H14F3N3O.0.2H2O: C, 61.96; H, 4.16; N, 12.04. Found: C, 62.06; H, 4.23; N, 11.91.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C@@H:6]1[CH2:21][C@@:14]2([C:18](=[O:19])[NH:17][C:16](=[O:20])[NH:15]2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:22])[CH:12]=2)[O:7]1)=[O:5])[CH3:2].Br[CH2:24][CH2:25][CH2:26][Cl:27].[H-].[Na+]>CN(C)C=O.O>[CH2:1]([NH:3][C:4]([C@@H:6]1[CH2:21][C@@:14]2([C:18](=[O:19])[N:17]([CH2:24][CH2:25][CH2:26][Cl:27])[C:16](=[O:20])[NH:15]2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:22])[CH:12]=2)[O:7]1)=[O:5])[CH3:2]
Reactant: CCNC(=O)[C@@H]1C[C@]2(NC(=O)NC2=O)c2cc(F)ccc2O1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=O)[C@@H]1C[C@]2(NC(=O)N(CCCCl)C2=O)c2cc(F)ccc2O1
Reaction time: 15 h
Yield: 73.5 %

Procedure:
To a solution of (2S,4S)-N-ethyl-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carboxamide (21.0 g, 68.4 mmol) in N,N-dimethylformamide (100 ml, 1.29 mmol) was added 1-bromo-3-chloropropane (21.5 g, 137 mmol). After adding 60% NaH (2.75 g, 68.8 mmol) over 30 minutes at 15°-20° C., the mixture was stirred for 15 hours at 15°-25° C. The reaction mixture was poured into iced water (500 ml), extracted with AcOEt (1000 ml×3), dried over MgSO4. The solvent was distilled off, the residue was chromatographed on silica gel, eluted with CH2Cl2 -CH2Cl2 /MeOH (9/1), and recrystallized from AcOEt to give the desired compound (19.3 g, 73.8%) as colorless prism crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[C:6]([NH:8][C:9]1[C:10]([Cl:15])=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:7])([O-])=O.O.[OH-].[Na+]>C(O)C>[NH2:1][C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[C:6]([NH:8][C:9]1[C:10]([Cl:15])=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:7]
Reactant: O=C(Nc1cccnc1Cl)c1ccccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ccccc1C(=O)Nc1cccnc1Cl

Procedure:
Stannous chloride (60.0 g, 320 mmol) was added in the solution of 2-nitro-N-(2-chloro-pyridin-3-yl)-benzamide (14.0 g) in absolute ethanol (200 mL). After being refluxed for 4 hours the solution was diluted with 160 ml conc. HCI and left in the refrigerator to crystallize. Obtained product was isolated by filtration. Isolated substance was dissolved in 100 ml boiling water and made alkaline with 30% NaOH (pH 8.5). Obtained precipitate was isolated by filtration and dried. Yield 7.0 g, mp 172-175° C.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[CH2:27]([C:34]1[CH:49]=[CH:48][C:37]([O:38][CH:39](C)[CH2:40][CH2:41][CH2:42][CH2:43][C:44](O)=[O:45])=[CH:36][CH:35]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH2:27]([C:34]1[CH:49]=[CH:48][C:37]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([C:1]2[C:6](=[O:7])[O:5][CH2:4][C:2]=2[OH:3])=[O:45])=[CH:36][CH:35]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: O=C1COC(=O)C1
Reactant: CCCCCCCc1ccc(OC(C)CCCCC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCCc1ccc(OCCCCCC(=O)C2=C(O)COC2=O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 49.2 %

Procedure:
To a stirring solution of 1.1 g (10.98 mmol) of tetronic acid in 25 mL of dimethylformamide is added 1.53 mL (10.98 mmol) of triethylamine and 400 mg of 4-dimethylaminopyridine at 0° C. Next, 2.28 g (11.98 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 3.38 g (10.98 mmol) of 6-(4-heptylphenoxy)heptanoic acid are added and the reaction mixture is stirred for 3 days at room temperature. The reaction mixture is acidified with 1.0N HCl and extracted with three 200 mL portions of ether. The combined organic layers are dried over MgSO4 and concentrated in vacuo. Trituration of the crude product in ethyl acetate/hexane affords 2.1 g (50%) of 3-[6-(4-heptylphenoxy)-1-oxohexyl]-4-hydroxy-2(5H)-furanone.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH:13]([C:28]([O:30][CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:23])[CH3:22])=[C:16]([O:24][C:25](=[O:27])[CH3:26])[CH:15]=2)/[C:8](O)=[O:9])[N:6]=1.[C:44]1([CH:50]([O:57][C:58]([C:60]2[N:61]3[C@H:64]([S:65][CH2:66][C:67]=2[CH2:68][S:69][C:70]2[N:75]4[N:76]=[C:77]([C:79]([O:81][CH:82]([C:89]5[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=5)[C:83]5[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=5)=[O:80])[N:78]=[C:74]4[N:73]=[C:72]([CH3:95])[CH:71]=2)[C@H:63]([NH2:96])[C:62]3=[O:97])=[O:59])[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:44]1([CH:50]([O:57][C:58]([C:60]2[N:61]3[C@H:64]([S:65][CH2:66][C:67]=2[CH2:68][S:69][C:70]2[N:75]4[N:76]=[C:77]([C:79]([O:81][CH:82]([C:89]5[CH:90]=[CH:91][CH:92]=[CH:93][CH:94]=5)[C:83]5[CH:84]=[CH:85][CH:86]=[CH:87][CH:88]=5)=[O:80])[N:78]=[C:74]4[N:73]=[C:72]([CH3:95])[CH:71]=2)[C@H:63]([NH:96][C:8](=[O:9])/[C:7](/[C:5]2[N:6]=[C:2]([NH2:1])[S:3][CH:4]=2)=[N:11]\[O:12][CH:13]([C:28]([O:30][CH:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:29])[C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:23])[CH3:22])=[C:16]([O:24][C:25](=[O:27])[CH3:26])[CH:15]=2)[C:62]3=[O:97])=[O:59])[C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CC(=O)Oc1ccc(C(O/N=C(\C(=O)O)c2csc(N)n2)C(=O)OC(c2ccccc2)c2ccccc2)cc1OC(C)=O
Reactant: Cc1cc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](N)[C@H]3SC2)n2nc(C(=O)OC(c3ccccc3)c3ccccc3)nc2n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C(O/N=C(\C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CSc4cc(C)nc5nc(C(=O)OC(c6ccccc6)c6ccccc6)nn45)CS[C@H]23)c2csc(N)n2)C(=O)OC(c2ccccc2)c2ccccc2)cc1OC(C)=O
Temperature: 25 °C
Yield: 72.1 %

Procedure:
To an ice-cooled solution containing the product obtained in Step 1 (3.0 g) and (6R,7R)-7-amino-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester (3.75 g) in dichloromethane (100 ml) was added dicyclohexylcarbodiimide (1.54 g), and the mixture was stirred at room temperature. After filtering off the insoluble matters, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, giving 4.8 g of the objective compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:5]=[C:6]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[NH:10][CH:9]=2)[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].Cl[CH2:50][CH2:51][NH+:52]([CH3:54])[CH3:53].O>CN(C)C=O>[CH3:53][N:52]([CH3:54])[CH2:51][CH2:50][O:1][C:2]1[CH:3]=[C:4]([NH:37][S:38]([CH3:41])(=[O:39])=[O:40])[CH:5]=[C:6]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[NH:10][CH:9]=2)[CH:7]=1
Reactant: C[NH+](C)CCCl
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cc(O)cc(NS(C)(=O)=O)c5)c34)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cc(NS(C)(=O)=O)cc(OCCN(C)C)c5)c34)n(-c3ccccc3)c(=O)c12
Temperature: 50 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
(S)—N-(3-Hydroxy-5-(4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)methanesulfonamide (6 mg, 0.01 mmol) was dissolved in 120 μl N,N-dimethylformamide. Sodium carbonate (8 mg, 0.07 mmol) and 2-chloro-N,N-dimethylethanaminium chloride (4 mg, 0.03 mmol) were added and the mixture was stirred at 50° C. overnight. The reaction was poured into water and extracted twice with ethyl acetate. The organics were combined and washed with brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified using SP1® Purification System (0% to 100%, dichloromethane-dichloromethane/2-propanol 85:15) to give 4 mg (56% yield) of the title compound.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH:7]([CH3:11])[C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[C:14]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)([OH:16])=[O:15].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][CH:7]1[O:6][C:5]2[CH:12]=[CH:13][C:2]([C:21]3[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=3)[C:14]([OH:16])=[O:15])=[CH:3][C:4]=2[NH:9][C:8]1=[O:10]
Reactant: CC1Oc2ccc(Br)cc2NC1=O
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1Oc2ccc(-c3cccc(C(=O)O)c3)cc2NC1=O
Temperature: 80 °C

Procedure:
To a 20 mL screw cap vial was added 6-bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one 19 (100 mg, 0.5 mmol), 3-carboxy phenylboronic acid (91 mg, 0.55 mmol), Pd(PPh3)4 (17 mg, 0.015 mmol), and aqueous Na2CO3 (2M, 0.62 mL, 1.25 mmol) in DMF (4 mL). The reaction was heated at 80° C. overnight then cooled and filtered. The filtrate was purified by preparative HPLC-MS (15-60% MeCN in water). The appropriate fractions were combined and concentrated in vacuo to give a white solid: 1H NMR (DMSO-d6, 400 MHz): δ=13.11 (br. s., 1H), 10.72 (s, 1H), 8.09 (t, J=1.6 Hz, 1H), 7.91 (dt, J=7.6, 1.4 Hz, 1H), 7.80-7.85 (m, 1H), 7.54-7.62 (m, 1H), 7.27 (dd, J=8.3, 2.3 Hz, 1H), 7.20 (d, J=2.0 Hz, 1H), 7.07 (d, J=8.3 Hz, 1H), 4.69-4.77 (m, 1H), 1.45 ppm (d, J=6.8 Hz, 3H). ESI-MS: m/z 284.2 (M+H)+.
Reaction SMILES: [C:1]([C:3](=[C:7]([S:10][CH3:11])SC)[C:4]([NH2:6])=[O:5])#[N:2].[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[Cl:20])[NH2:16]>CCO>[C:1]([C:3](=[C:7]([NH:16][C:15]1[CH:17]=[CH:18][C:19]([Cl:20])=[C:13]([Cl:12])[CH:14]=1)[S:10][CH3:11])[C:4]([NH2:6])=[O:5])#[N:2]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CSC(SC)=C(C#N)C(N)=O
Solvent: CCO
Product: CSC(Nc1ccc(Cl)c(Cl)c1)=C(C#N)C(N)=O

Procedure:
Dissolved 0.500 g 2-cyano-3,3-bis(methylthio)acrylamide in 15 mL EtOH and added 172 mg (1.0 eq.) 3,4-dichloroaniline. Stirred reaction at 75° C. until starting amide was absent by HPLC. Once complete (18 hrs), reaction was brought to room temperature and filtered to obtain 2-cyano-3-((3,4-dichlorophenyl)amino)-3-(methylthio)acrylamide as a light yellow powder as product. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:28]([CH3:30])[CH3:29]>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH:28]([CH3:30])[CH3:29])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 90 °C
Yield: 65.3 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (30 mg, 0.12 mmol), potassium carbonate (32 mg, 0.23 mmol) and 2-iodopropane (17 μL, 0.17 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 90° C. for 2 hours. The reaction was cooled, diluted with dichloromethane, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography using a hexanes/ethyl acetate/dichloromethane (3.5:0.5:4) afforded 24 mg (68%) of 3-(2-pyridyl)-5-(3-cyano-5-isopropoxyphenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.86 (d, 1H), 8.23 (d, 1H), 8.12 (s, 1H), 7.98 (s, 1H), 7.91 (m, 1H), 7.49 (m, 1H), 7.36 (s, 1H), 4.71 (m, 1H), 1.41 (m, 6H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[O:15][CH2:14][C@@:13]([NH:24][C:25]([NH:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[S:26])([C:16]2[CH:21]=[C:20]([Br:22])[CH:19]=[CH:18][C:17]=2[F:23])[C@H:12]([CH2:36]O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl>[CH2:1]([O:8][CH2:9][C@@H:10]1[O:15][CH2:14][C@:13]2([C:16]3[CH:21]=[C:20]([Br:22])[CH:19]=[CH:18][C:17]=3[F:23])[N:24]=[C:25]([NH:27][C:28](=[O:35])[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[S:26][CH2:36][C@@H:12]2[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC(=S)N[C@@]1(c2cc(Br)ccc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NC1=N[C@@]2(c3cc(Br)ccc3F)CO[C@@H](COCc3ccccc3)C[C@H]2CS1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of N-{[(3S,4R,6R)-6-[(benzyloxy)methyl]-3-(5-bromo-2-fluorophenyl)-4-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]carbamothioyl}benzamide (C31) (9.49 g, 16.2 mmol) and pyridine (4.94 mL, 61.4 mmol) in dichloromethane (278 mL) was cooled to −50° C. Trifluoromethanesulfonic anhydride (5.44 mL, 32.3 mmol) was added drop-wise to the solution and the mixture was gradually warmed to 0° C. After 2 hours, the reaction mixture was partitioned between dichloromethane (1 L) and water (500 mL). The organic layer was washed with dichloromethane (2×250 mL) and the combined organics were then washed with brine (500 mL). The resulting organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to yield an orange oily residue. Purification via silica gel chromatography (Gradient: 0% to 60% ethyl acetate in heptane) afforded the product as an orange solid. Yield: 5.53 g, 60%. LCMS m/z 571.2 [M+H+]. 1H NMR (400 MHz, CD3OD) characteristic peaks: δ 8.12 (d, J=7.4 Hz, 2H), 7.43-5.58 (m, 5H), 7.12-7.32 (m, 6H), 4.51-4.60 (m, 2H), 4.10-4.13 (m, 1H), 3.87-3.91 (m, 1H), 3.55-3.63 (m, 2H), 3.18-3.21 (m, 1H), 2.94 (dd, J=13.2, 4.0 Hz, 1H), 2.74 (dd, J=13.1, 2.9 Hz, 1H), 1.90-1.99 (m, 1H), 1.67-1.72 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=1[O:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13](=[O:29])[CH2:14][NH:15][C:16]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[NH:20][N:19]=2)=[O:17])[CH2:9][CH2:8]1)([O-])=O>CO.C1COCC1.[Pd]>[NH2:1][C:4]1[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=1[O:6][CH:7]1[CH2:8][CH2:9][N:10]([C:13](=[O:29])[CH2:14][NH:15][C:16]([C:18]2[CH:22]=[C:21]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:20][N:19]=2)=[O:17])[CH2:11][CH2:12]1
Reactant: O=C(NCC(=O)N1CCC(Oc2ccccc2[N+](=O)[O-])CC1)c1cc(-c2ccccc2)[nH]n1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccccc1OC1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)[nH]n2)CC1
Reaction time: 0.5 h
Yield: 37.2 %

Procedure:
To a stirred solution of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-nitro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide (0.07 g, 0.00016 mole) in a mixture of methanol (5 mL) and THF (5 mL) was added 10% Pd/C (0.01 g). The resulting mixture was stirred under an atmosphere of hydrogen for 30 minutes. The mixture was then filtered through celite, and the celite was washed with methanol. The combined organic layers were concentrated under reduced pressure. The resulting residue was re-crystallized from a hexane/chloroform mixture to afford 0.025 g (39%) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-amino-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 420.2 (M+1)+, 96.9%, 1H NMR (DMSO-d6): δ 8.1 (bs, 1H), 7.8 (d, 2H), 7.5-7.3 (m, 3H), 7.1 (m, 1H), 6.85 (d, 1H), 6.7 (m, 2H), 6.5 (m, 1H), 4.7 (s, 2H), 4.6 (s, 1H), 4.2 (s, 2H), 3.9 (m, 2H), 2.0 (m, 2H), 1.8 (m, 2H), 1.4 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][C:34](O)=[O:35].CCN=C=NCCCN(C)C>>[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][C:34]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:35]
Reactant: O=C(O)Cc1ccccn1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)Cc4ccccn4)c3)c2c1
Yield: 10.6 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (200 mg, 0.56 mmol) with 2-pyridylacetic acid hydrochloride (0.12 g, 0.71 mmol) and EDCI (0.17 g, 0.89 mmol) furnished 22 mg (10% yield) of the title compound. 1H NMR (DMSOd6) δ 13.4 (br s, 1H), 10.4 (s, 1H), 8.6 (s, 1H), 8.5 (dd, 1H), 8.2 (br s, 1H), 8.1 (s, 1H), 7.9 (d, 1H), 7.75 (m, 2H), 7.6 (d, 1H), 7.45 (m, 2H), 7.35–7.2 (m, 2H), 3.8 (s, 2H); ES-MS (m/z) 372 [M+H]+.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=1[C:24]([F:27])([F:26])[F:25])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.ClC1C=CC([CH2:35][C:36]#[N:37])=CC=1.Cl>CN(C=O)C>[CH2:7]([O:14][C:15]1[C:16]([C:24]([F:25])([F:26])[F:27])=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[C:19]([CH2:35][C:36]#[N:37])[CH:20]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Reactant: N#CCc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCc1cc(OCc2ccccc2)c(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
Potassium tert-butoxide (3.94 g, 35.4 mmol) was dissolved in anhydrous DMF (15 ml) and a mixture of 2-benzyloxy-5-nitro-trifluoromethylbenzene (3.5 g, 16.1 mmol) and 4-chlorophenylacetonitrile (2.96 g, 17.7 mmol) in DMF (20 ml) was added over 30 minutes keeping the temperature at −15° C. The mixture was stirred at −10° C. for 1 hour, then poured into 1M hydrochloric acid (150 ml) and the product extracted with dichloromethane (2×100 ml). The organic extracts were dried (MgSO4) and purified by silica column chromatography eluting with dichloromethane/hexane (1/1) to give 5-benzyloxy-2-nitro-4-(trifluoromethyl)phenylacetonitrile (5.2 g, 77%).