Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2].[H-].[Na+].[O:13]=[C:14]1[C:26]2[C:21](=[N:22][C:23](C#N)=[C:24](C#N)[N:25]=2)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]1=2.CO.[CH3:33][N:34](C=O)C>>[C:7]([O:6][C:4](=[O:5])[CH:3]([C:33]#[N:34])[C:1]1[N:2]=[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14](=[O:13])[C:26]2=[N:25][C:24]=1[C:23]#[N:22])([CH3:10])([CH3:9])[CH3:8]
Reactant: CN(C)C=O
Reactant: N#Cc1nc2c(nc1C#N)-c1ccccc1C2=O
Reactant: CC(C)(C)OC(=O)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)C(C#N)c1nc2c(nc1C#N)C(=O)c1ccccc1-2
Reaction time: 0.25 h

Procedure:
tert-Butyl cyanoacetate (292 mg, 2.07 mmol) was dissolved, under inert atmosphere, in dry DMF (4 ml) and NaH (60% dispersion in mineral oil, 90 mg, 2.24 mmol) was added portionwise. After 15 min, a solution of 1 (400 mg, 1.72 mmol) in dry DMF (3 ml) was added dropwise. After 16 h MeOH was added, the solvents were evaporated and the crude purified by flash chromatography (EtOAc:MeOH 9:1) affording cyano-(2-cyano-9-oxo-9H-indeno[1,2-b]pyrazin-3-yl)-acetic acid tert-butyl ester as dark red solid.
Reaction SMILES: Cl.[NH2:2][OH:3].[N+:4]([C:7]1[CH:18]=[CH:17][C:16]2[CH2:15][CH:14]3[C:19](=O)[CH:11]([CH2:12][CH2:13]3)[CH2:10][C:9]=2[CH:8]=1)([O-:6])=[O:5].C([O-])(=O)C.[Na+].C(O)C>O>[N+:4]([C:7]1[CH:18]=[CH:17][C:16]2[CH2:15][CH:14]3[C:19](=[N:2][OH:3])[CH:11]([CH2:12][CH2:13]3)[CH2:10][C:9]=2[CH:8]=1)([O-:6])=[O:5]
Reactant: NO
Reactant: O=C1C2CCC1Cc1cc([N+](=O)[O-])ccc1C2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)CC1CCC(C2)C1=NO
Temperature: 25 °C

Procedure:
Hydroxylamine hydrochloride (9.72 g) was added to a stirred solution of 5-nitro-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-one* (10.82 g) and sodium acetate (19.08 g) in a mixture of absolute ethanol (50 rat) and water (50 mL). The reaction was warmed to reflux for 18 hours cooled to room temperature and diluted with water (200 mL). The product was filtered off, dried under high vacuum to afford the title compound as a white powder (10.73 g) m/z 247 (M+H+). *J. Org. Chem. 1982, 47, 4329–4334
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=O)[CH2:13][CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH2:16]([NH2:19])[C:17]#[CH:18]>C(#N)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:11][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][C:4]=2[C:5]2[CH2:14][CH2:13][C:12](=[N:19][CH2:16][C:17]#[CH:18])[C:6]1=2
Reactant: Cn1c2c(c3cc(O)ccc31)CCC2=O
Reactant: C#CCN
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CC#N
Product: C#CCN=C1CCc2c1n(C)c1ccc(O)cc21
Reaction time: 16 h

Procedure:
To a stirred suspension of 7-hydroxy-4-methyl-1,4-dihydrocyclopent[b]indol-3(2H)-one (5.5 g) in acetonitrile (100 ml) was added propargyl amine (3.0 g), the solution was stirred at room temperature under a nitrogen atmosphere while titanium (IV) isopropoxide (15.6 g) was added in a dropwise manner. The mixture was stirred for 16 hours before quenching with ice water. The mixture was filtered, the solids were washed with CH2Cl2, the layers were separated and the organic portion was dried (Na2SO4). After concentration, the crude product was purified via flash chromatography eluting with hexane/acetone (2: 1) to give 4-methyl-3-(2-propynyl)imino-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5](S(C1C=CC(C)=CC=1)(=O)=O)[CH2:6][C:7]([F:26])([F:25])[CH2:8][CH2:9][N:10](S(C1C=CC(C)=CC=1)(=O)=O)[CH2:11][CH2:12][CH2:13][NH2:14].Br>CC(C)=O>[F:25][C:7]([F:26])([CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH2:14])[CH2:6][NH:5][CH2:4][CH2:3][CH2:2][NH2:1]
Reactant: Cc1ccc(S(=O)(=O)N(CCCN)CCC(F)(F)CN(CCCN)S(=O)(=O)c2ccc(C)cc2)cc1
Agent: Br
Solvent: CC(C)=O
Product: NCCCNCCC(F)(F)CNCCCN
Temperature: 25 °C

Procedure:
The compound 1,12-diamino-6,6-difluoro-4,9-di-p-toluenesulfonyl-4,9-diaza-dodecane (2.7 g, 4.36 mM) and 47% aqueous HBr are refluxed (bath temperature: 110° C.) for 17 hours. After cooling to room temperature, the solution is carefully extracted with ether (three times) and finally with chloroform. Evaporation of the aqueous phase, followed by stripping with isopropanol (twice) and ethanol (twice) produces a solid residue which is digested with acetone, collected, and washed with acetone (three times), ethanol (three times) and finally with ether: white crystals, 1.8 g (74%). This material is recrystallized by dissolving in hot (80° C.) aqueous ethanol (100 mL, H2O: ethanol 1:9), filtering through paper, and adding additional ethanol (10-20 mL) to yield the desired 6,6-difluoro-1,12-diamino-4,9-diaza-dodecane as the tetrahydrobromide salt: white crystals 1.2 g, (49%).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9](Cl)(=[O:11])=[O:10].[NH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]1>N1C=CC=CC=1>[CH3:13][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][O:22][S:9]([C:2]2[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=2[CH3:13])(=[O:11])=[O:10])[CH2:16][CH2:15]1)(=[O:11])=[O:10]
Reactant: OCCC1CCNCC1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: c1ccncc1
Product: Cc1cc(C)c(S(=O)(=O)OCCC2CCN(S(=O)(=O)c3c(C)cc(C)cc3C)CC2)c(C)c1
Temperature: 0 °C
Reaction time: 44 h

Procedure:
2-Mesitylenesulfonyl chloride (24.78 g, 0.113 mol) in pyridine (60 ml) was added all at once to 4-piperidineethanol (5.58 g, 43.2 mmol) in pyridine (25 ml) at −16° C.; the temperature rose to −11° C. The flask was stored in the refrigerator at 5.5° C. for 44 hours under argon. The reaction mixture was poured into ice (1 kg) and after 3 hours, 16.00 g (75%) of (2) as a yellow solid was filtered off: mp 93.5-94° C.; NMR (CDCl3/TMS) δ1.4-2.1 (m, 7H), 2.27 (s, 6H), 2.44-2.96 (m+s, 14H), 3.37-3.69 (m, 2H), 3.97 (t, 2H, J=5), 6.90 and 6.93 (2s, 4H). Anal. calcd. for C25H35NO5S2: C, 60.82, H, 7.15, N, 2.84. Found: C, 60.90, H, 7.13, N, 2.85.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:54]([O:56][CH2:57][CH2:58]O)[CH3:55]>C(Cl)Cl>[ClH:13].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:55][CH2:54][O:56][CH2:57][CH3:58])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: CCOCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOCCOc1cc2ncnc(Nc3ccc(Cl)cc3F)c2cc1OC
Product: Cl
Temperature: 0 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
Diethyl azodicarboxylate (123 μl, 0.88 mmol) was added portionwise to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (250 mg, 0.8 mmol), (prepared as described for the starting material in Example 4), triphenylphosphine (228 mg, 0.96 mmol) and 2-ethoxyethanol (71 μl, 0.8 mmol) in methylene chloride (20 ml) cooled at 0° C. The mixture was then allowed to warm to ambient temperature and stirred for 18 hours. The resulting precipitate was removed by filtration and the solvent removed from the filtrate by evaporation. The residue was purified by chromatography eluting with methylene chloride/methanol (96/4). The resulting purified oil was dissolved in acetone and treated with water (80 μl) then ethereal hydrogen chloride. The resulting granular solid was collected by filtration to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-ethoxyethoxy)quinazoline hydrochloride (96 mg, 31%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][NH:8][CH:9]([C:13](C)(C)[O:14][SiH2]C(C)(C)C)[CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[CH:23](N(C(C)C)CC)(C)C.CI>CN(C=O)C>[C:1]([O:5][C:6](=[O:22])[CH2:7][N:8]([CH:9]([CH2:13][OH:14])[CH:10]([CH3:11])[CH3:12])[CH3:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)C(NCC(=O)OC(C)(C)C)C(C)(C)O[SiH2]C(C)(C)C
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)C(CO)N(C)CC(=O)OC(C)(C)C

Procedure:
{[1-(tert-Butyl-dimethyl-silanyloxymethyl)-2-methyl-propyl]-amino}-acetic acid tert-butyl ester (1.9 g, 6.1 mmol) and diisopropylethylamine (4.2 mL, 24 mmol) were dissolved in DMF (15 mL). A solution of MeI (0.45 mL, 7.3 mmol) in DMF (100 mL) was slowly added over 15 min. The reaction was stirred for 2½ h. The solvent was removed in vacuo. The residue product was dissolved in EtOAc (100 mL) and the solution was washed with water (20 mL). The organic phase was dried over magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was dissolved in acetonitrile (45 mL) and Et3N 3HF (2 mL, 12.3 mmol) was added. The reaction was stirred for 16 h. The solvent was removed in vacuo. The crude product was dissolved in EtOAc (100 mL) and washed with saturated sodium bicarbonate solution (25 mL) and saturated sodium chloride solution (25 mL). The organic phase was dried over magnesium sulfate and the solution was slowly filtered through 5 g of silica gel. The filtrate was evaporated in vacuo. Yield: 1.1 g, 78%.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[O:13][CH3:14].[N-:15]=[N+:16]=[N-:17].[Na+].O>CN(C=O)C>[N:15]([C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[O:13][CH3:14])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1nc(Br)cc(Br)c1OC
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc(Br)cc(N=[N+]=[N-])c1OC
Temperature: 60 °C
Reaction time: 48 h
Yield: 57.7 %

Procedure:
Methyl 4,6-dibromo-3-methoxypyridine-2-carboxylate (0.980 g, 3.02 mmol) was dissolved in a minimum amount of DMF. Slowly sodium azide (0.216 g, 3.32 mmol) was added followed by H2O to form a homogeneous solution. The reaction mixture was heated to 60° C. and stirred for 2 days. Reaction mixture added to a flask filled with ice water and extracted with ethyl acetate (3×50 mL). Extracts were combined and back washed with H2O, dried (MgSO4) and concentrated to give 0.500 g of an orange oil. 1H NMR(CDCl3): δ 3.90 (s, 3H); 3.95 (s, 3H); 7.20 (s, 1H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:37]([C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)(=[O:39])[CH3:38].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:43]2[CH:44]=[CH:45][C:40]([C:37](=[O:39])[CH3:38])=[CH:41][CH:42]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 88.5 %

Procedure:
To a mixture of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (prepared as in Example 43, 0.5 g, 0.96 mmol), 4-acetylphenylboronic acid (394 mg, 2.4 mmol) and dichlorobis(triphenylphosphine)palladium (II) (67 mg, 0.1 mmol) in dioxane (8 mL) was added an aqueous sodium carbonate solution (2 M, 1.2 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (200 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 30% ethyl acetate/hexanes) afforded 1-{4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-phenyl}-ethanone (400 mg, 89%) as a white solid: LC/MS m/e calcd for C28H26N2O3S [M+H]+ 471.60, observed 471.0.
Reaction SMILES: [SH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[C:11]1([C:17]#[C:18][C:19]([OH:21])=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[NH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([S:1][C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=2)[CH:17]=[CH:18][C:19]([OH:21])=[O:20])=[CH:3]1
Reactant: Sc1c[nH]c2ccccc12
Reactant: O=C(O)C#Cc1ccccc1
Product: O=C(O)C=Cc1cccc(Sc2c[nH]c3ccccc23)c1

Procedure:
-- By the same method as described in Example 1, 0.2 mole each of 3-mercaptoindole and phenylpropiolic acid gives 20.0 g of product after recrystallization from acetone-water, mp 165°-167° C.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]1([C:26]2[CH:33]=[CH:32][C:29]([CH2:30][Br:31])=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C(C)=CC=CC=1>[Br-:31].[C:20]1([C:26]2[CH:27]=[CH:28][C:29]([CH2:30][P+:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:32][CH:33]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: BrCc1ccc(-c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: [Br-]
Product: c1ccc(-c2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc2)cc1
Yield: 90.5 %

Procedure:
Triphenylphosphine (1.34 g) was added to a stirred solution of 4-phenylbenzyl bromide (1.26 g) in xylene (20 mL). The mixture was refluxed for 19 hr to a give white solid. The solid was washed with toluene and hexane to afford the titled compound (2.35 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][C:6]1[C:15]2[N:14]=[C:13]([CH3:16])[C:12](=[O:17])[NH:11][C:10]=2[N:9]=[CH:8][CH:7]=1.[C:21]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([NH:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:4]([O:5][C:6]2[C:15]3[N:14]=[C:13]([CH3:16])[C:12](=[O:17])[NH:11][C:10]=3[N:9]=[CH:8][CH:7]=2)[CH:3]=1)=[O:29])([CH3:24])([CH3:22])[CH3:23]
Reactant: Cc1nc2c(Oc3cccc(N)c3)ccnc2[nH]c1=O
Reactant: CC(C)(C)c1cccc(C(=O)Cl)c1
Product: Cc1nc2c(Oc3cccc(NC(=O)c4cccc(C(C)(C)C)c4)c3)ccnc2[nH]c1=O

Procedure:
Method G1 was used with 8-(3-aminophenoxy)-2-methylpyrido[2,3-b]pyrazin-3(4H)-one and 3-tertbutylbenzoyl chloride to afford the title compound as a slightly yellow solid (77 mg, 97%).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:9]([OH:11])=[O:10])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[Ba:12].[OH-].[Ba+2].[OH-].C(OC(=O)C(NC(=O)C)C(OCC)=O)C>O>[C:1]([NH:4][CH:5]([C:9]([O-:11])=[O:10])[C:6]([O-:8])=[O:7])(=[O:3])[CH3:2].[Ba+2:12]
Reactant: CC(=O)NC(C(=O)O)C(=O)O
Reactant: [Ba]
Agent: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Product: CC(=O)NC(C(=O)[O-])C(=O)[O-]
Temperature: 25 °C

Procedure:
Preparation of Barium acetamidomalonic acid--To 14.5 g (46.0 mmol) of barium hydroxide in 750 ml of water is added 10.0 g (46 mmol) of acetamidomalonic acid diethyl ester. The solution is refluxed for one hour and suction filtered while still hot. The filtrate is allowed to cool to room temperature to give barium acetamidomalonate in quantitative yield as white crystals. IR (KBr) 3366.8, 1654, 1640, 1599, 1578,1530, 1427, 1344 cm-1. Elemental analysis for BaC5H
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:16]=2)[N:13]=[C:12]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])[CH2:11]1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([S:42]([CH3:41])(=[O:44])=[O:43])[CH2:23][CH2:22]3)[CH:16]=2)[N:13]=[C:12]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])[CH2:11]1
Reactant: Fc1ccc(C2CC(C(F)(F)C(F)(F)F)=NN2c2cccc(N3CCNCC3)c2)c(F)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2cccc(N3N=C(C(F)(F)C(F)(F)F)CC3c3ccc(F)cc3F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.4 %

Procedure:
5-(2,4-Difluoro-phenyl)-1-[3-(piperazin-1-yl)-phenyl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (20.0 mg, 0.04 mmol) prepared in Example 216, triethylamine (28.0 uL, 0.20 mmol) and methanesulfonyl chloride (5.0 uL, 0.06 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 18 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 10.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8](=[NH:34])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C@H:19]2[N:23]3[C:24](=[O:33])[C:25]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:26][N:27]=[C:22]3[CH2:21][CH2:20]2)=[O:18])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC(C1C=CC(CNC([C@H]2N3C(=O)C(N(CC)CC)=CN=C3CC2)=O)=CC=1)=N)(C)(C)C.[F:71][C:72]([F:85])([F:84])[O:73][C:74]1[CH:79]=[CH:78]C(S(Cl)(=O)=O)=[CH:76][CH:75]=1>>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8](=[NH:34])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C@H:19]2[N:23]3[C:24](=[O:33])[C:25]([NH:28][S:29]([C:32]4[CH:78]=[CH:79][C:74]([O:73][C:72]([F:85])([F:84])[F:71])=[CH:75][CH:76]=4)(=[O:31])=[O:30])=[CH:26][N:27]=[C:22]3[CH2:21][CH2:20]2)=[O:18])=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NS(C)(=O)=O)c(=O)n32)cc1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Agent: CCN(CC)c1cnc2n(c1=O)[C@H](C(=O)NCc1ccc(C(=N)NC(=O)OC(C)(C)C)cc1)CC2
Product: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NS(=O)(=O)c4ccc(OC(F)(F)F)cc4)c(=O)n32)cc1
Yield: 41.6 %

Procedure:
Following a procedure similar to that for the preparation of 16a, intermediate 3a (50 mg, 0.117 mmol) and 4-(trifluoromethoxy)benzene sulfonyl chloride (39.6 mg, 0.152 mmol) yielded 31.7 mg (41.6%) of 33a. MS (ESI) 651.0 (M+H+).
Reaction SMILES: [CH:1]12[C@@H:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]1[S:4][CH:3]=[CH:2]2.B(O[O-])=[O:13].O.[Na+].O>O1CCCC1>[OH:13][C@H:2]1[CH:1]2[CH:5]([C@@H:6]2[C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:4][CH2:3]1
Reactant: CCOC(=O)[C@@H]1C2C=CSC21
Reactant: O=BO[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1C2SC[C@@H](O)C21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl (6S)-4-thiabicyclo[3.1.0]hex-2-ene-6-carboxylate (22.2 g, 131 mmol) in 136 mL of tetrahydrofuran under nitrogen at 0° C. is added borane-THF complex (98 mL, 98 mmol) over 15-20 minutes. After stirring at 0° C. for 30 minutes, the reaction is allowed to warm to 15° C. and stir until complete by HPLC (1.5-2 hours). The reaction is cooled to 0° C. and transferred over 10-15 minutes to 111 mL of a pre-cooled (0° C.) 1 N pH 7 buffer solution while maintaining the temperature at 0° C. To the mixture is added sodium perborate monohydrate (15.6 g, 157 mmol) as a solid in five portions such that the temperature is maintained below 20° C. The solution is allowed to warm to room temperature and stir for 1 hour followed by the addition of 222 mL of water. After stirring for 2 hours, the peroxides are quenched by adding sodium thiosulfate pentahydrate (9.7 g) dissolved in 24 mL of water followed by stirring for 10 minutes. The mixture is extracted with ethyl acetate (2×222 mL). The combined organic extracts are washed with saturated aqueous sodium bicarbonate (1×222 mL) followed by brine (1×222 mL) and concentration in vacuo to dryness. The crude product is dissolved in 1,2-dichloroethane (1 mL per 1 g of crude oil) and loaded onto a silica gel column (4 g of silica gel per 1 g of crude oil slurried and packed in 15% ethyl acetate-heptane). The column is eluted with 15% ethyl acetate-heptane until product is visible by TLC, at which time the solvent is switched to 50% ethyl acetate-heptane. All fractions containing the title product are combined and concentrated in vacuo to an oil. Overall yield is in the 55-65% range.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:16][CH3:17])[C:5]([NH:10][C@@H:11]([CH2:14][CH3:15])[CH2:12][OH:13])=[N:6][C:7]=1[CH2:8][CH3:9].[H-].[Na+].I[CH2:21][CH3:22]>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]([CH2:16][CH3:17])[C:5]([NH:10][C@H:11]([CH2:12][O:13][CH2:21][CH3:22])[CH2:14][CH3:15])=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1nc(N[C@@H](CC)CO)c(CC)nc1Br
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC[C@H](CC)Nc1nc(CC)c(Br)nc1CC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49.5 %

Procedure:
A dry 50 mL round bottom flask was charged with a solution of (2S)-2-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]butan-1-ol (356 mg, 1.18 mmol) in DMF (12 mL). NaH (70.8 mg, 1.77 mmol) was added to the homogeneous solution. Effervescence was observed and the solution turned cloudy. Iodoethane (0.189 mL, 2.36 mmol) was added at once. The now yellow solution was stirred at ambient temperature for 20 minutes. The same quantities of NaH and iodoethane were added to the reaction mixture two more times in the same manner. The reaction was quenched with water and extracted twice with ethyl acetate. The organics were combined, dried with Na2SO4, filtered and concentrated to give 510 mg of a crude yellow oil. This material was purified by Biotage MPLC (90 g column, using 5% ethyl acetate in heptane) to give 193 mg (50%) of 5-bromo-N-[(1S)-1-(ethoxymethyl)propyl]-3,6-diethylpyrazin-2-amine as a yellow oil. Rf 0.16 (5% ethyl acetate in heptane).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]([F:31])([F:30])[C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[CH:25]=O)[N:18]=1.[C:32]1([C:38]2[N:39]=[C:40]([C:43]3([CH2:49][NH2:50])[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)[S:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClC(Cl)C>[C:32]1([C:38]2[N:39]=[C:40]([C:43]3([CH2:49][NH:50][CH2:25][C:24]4[CH:27]=[CH:28][CH:29]=[C:22]([C:19]5[N:18]=[C:17]([C:16]([F:31])([F:30])[F:15])[O:21][N:20]=5)[CH:23]=4)[CH2:44][CH2:45][O:46][CH2:47][CH2:48]3)[S:41][CH:42]=2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=Cc1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCC1(c2nc(-c3ccccc3)cs2)CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: FC(F)(F)c1nc(-c2cccc(CNCC3(c4nc(-c5ccccc5)cs4)CCOCC3)c2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.6 %

Procedure:
Sodium triacetoxy borohydride (200 mg, 0.9 mmol) was added to a solution of 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzaldehyde (140 mg, 0.6 mmol) and (4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine (170 mg, 0.6 mmol) in dry dichloroethane (20 mL) at 0° C. under nitrogen atmosphere and stirred at room temperature for 8 h. The reaction mixture was carefully quenched with 10% NaHCO3 solution and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluent 20-25% EtOAc in petroleum ether) to get 1-(4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)-N-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzyl)methanamine (65 mg, yield 22%): 1H NMR (400 MHz, CDCl3) δ 7.98 (m, 2H), 7.89 (d, J=7.6 Hz, 2H), 7.48 (s, 1H), 7.46-7.27 (m, 5H), 3.86-3.81 (m, 4H), 3.69-3.64 (m, 2H), 2.91 (s, 2H), 2.36 (m, 2H), 2.03-1.97 (ddd, J=13.7 Hz, 9.7 Hz, 4 Hz, 2H). MS (ESI) m/z: Calculated for C25H23F3N4O2S: 500.15. found: 501.0 (M−H)−.