Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([S:9][C@@H:10]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:11]([NH:13][C@H:14]([C:19]([OH:21])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:12])(=O)C1C=CC=CC=1.[OH-].[Na+]>CO>[SH:9][C@@H:10]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:11]([NH:13][C@H:14]([C:19]([OH:21])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:12]
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)SC(=O)c1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@@H](S)Cc1ccccc1)C(=O)O
Reaction time: 4 h
Yield: 98.1 %

Procedure:
2 g N-[(S)-2-benzoylthio-3-phenyl-propionyl]-L-leucine dissolved in 10 ml MeOH are stirred at 0° C. for 1 hour with 10 ml 1N NaOH, and then for 4 hours at 25° C. under a nitrogen atmosphere. The methanol is evaporated off, the material is taken up into water and made acidic to pH 1 with 1N HCl. The resulting gummy precipitate is extracted with ethyl acetate. The organic phase is dried, and evaporated in vacuo, to give 1.45 g N-[(S)-2-mercapto-3-phenyl-propionyl]-L-leucine which crystallizes slowly. M.P.=67°-71° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([C:21]3[O:22][C:23]([CH3:26])=[N:24][N:25]=3)[CH:18]=[CH:17][C:16]=2[CH3:27])=[CH:11][CH:10]=1)=[O:8].I[CH2:32][CH3:33]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]([CH2:32][CH3:33])[C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([C:21]3[O:22][C:23]([CH3:26])=[N:24][N:25]=3)[CH:18]=[CH:17][C:16]=2[CH3:27])=[CH:11][CH:10]=1)=[O:8]
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4cccc(Cl)c4)cc3)c2)o1
Reactant: CCI
Product: CCN(Cc1cccc(Cl)c1)C(=O)c1ccc(-c2cc(-c3nnc(C)o3)ccc2C)cc1

Procedure:
N-(3-Chlorobenzyl)-N-ethyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from N-(3-chlorobenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide and iodoethane using method L. NMR; δH [2H6]—DMSO 7.89,(1H, d), 7.76,(1H, b), 7.58-7.34,(8H, m), 7.24,(1H, b), 4.71-4.55,(2H, m), 3.25,(2H, b), 2.56,(3H, s), 2.32,(3H, s), 1.09,(3H, b). LCMS; retention time 3.67 min, MH+ 446/448.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17](S(C)=O)[O:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[NH2:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[OH:31].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17]([NH:24][C@@H:25]5[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]5[OH:31])[O:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2o1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2o1
Temperature: 120 °C
Yield: 37.7 %

Procedure:
A stirred mixture of 6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole (150 mg, 0.384 mmol) from Step 3 of this Example, (1R,2R)-(−)-2-aminocyclohexanol (88 mg, 0.768 mmol), and DIEA (99 mg, 0.768 mmol) in anhydrous DMA (3 mL) in a sealed vial was heated in a Biotage microwave synthesizer at 120° C. for 30 min. After the reaction mixture was cooled to rt, it was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford (1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol (64 mg, 38%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.49 (d, J=2.0 Hz, 1H), 8.38 (d, J=1.7 Hz, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.39 (s, 1H), 7.10-7.16 (m, 2H), 5.48 (s, 2H), 4.69 (d, J=4.2 Hz, 1H), 3.30-3.40 (m, 2H), 1.83-1.97 (m, 2H), 1.57-1.67 (m, 2H), 1.15-1.30 (m, 4H). LCMS (ESI) m/z 442 and 444 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][CH2:10][OH:11])[CH:5]=[N:6][CH:7]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][CH2:10][O:11][S:13]([CH3:12])(=[O:15])=[O:14])[CH:5]=[N:6][CH:7]=1
Reactant: OCC#Cc1cncc(Br)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCC#Cc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(5-Bromo-pyridin-3-yl)-prop-2-yn-1-ol (Intermediate 218) (1 eq, 2.41 mmol, 510 mg) is dissolved in DCM (5 ml), then TEA (1.5 eq, 3.61 mmol, 0.5 ml) and methanesulfonyl chloride (1.5 eq, 3.61 mmol, 0.28 ml) are added. The resulting mixture is stirred for 30 min at r.t. After addition of water the layers are separated, and the organic layer is dried with MgSO4, filtered, and concentrated under reduced pressure giving the title compound.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl[CH2:10][CH:11]([CH3:14])[CH2:12][CH3:13]>>[CH3:10][CH:11]([CH2:12][CH3:13])[CH2:14][S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8]
Reactant: Oc1ccccc1S
Reactant: CCC(C)CCl
Product: CCC(C)CSc1ccccc1O
Yield: 57 %

Procedure:
This compound was prepared in 57% yield from 2-mercaptophenol and 1-chloro-2-methylbutane according to the procedure for 1p in Example VIII. 1H NMR (CDCl3): δ 0.86 (t, J=4.85 Hz, 3H), 1.00 (d, J=6.60 Hz, 3H), 1.18-1.27 (m, 1H), 1.46-1.58 (m, 2H), 2.55 (dd, J=7.15, J=12.35, 1H), 2.70 (dd, J=5.75, 12.65, 1H), 6.75 (d, J=1.1 Hz), 6.86 (dt, J=1.1 Hz, J=4.93 Hz, 1H), 6.98 (dd, J=1.4 Hz, J=8.25 Hz, 1H), 7.24 (dt, J=1.65 Hz, J=7.40 Hz, 1H, 7.45 (dd, J=1.65 Hz, J=7.70 Hz, 1H); 13C NMR (CDCl3): δ 11.26, 18.74, 28.56, 34.80, 44.36, 114.77, 119.98, 120.81, 130.89, 135.80, 156.80; HRMS (FAB): 196.09219 calcd for C11H16OS [M]+. found 196.09293 (3.6 ppm, 0.7 mmu).
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21]>O>[CH2:18]([NH:22][C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCN
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Solvent: O
Product: CCCCNc1c([N+](=O)[O-])cc(C(=O)O)cc1S(N)(=O)=O
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (8.4 g), n-butylamine (8.7 g), and water (25 ml) was stirred at 90°C for 1.5 hours. After cooling, the pH was adjusted to pH 2, and the precipitated 4-butylamino-3-nitro-5-sulphamyl-benzoic acid was collected by filtration. After several recrystallizations from aqueous methanol the melting point was 192.5°C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.[CH3:28]I>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH3:28])[S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(NS(C)(=O)=O)cc3)CC2)c(C)c1
Reactant: CI
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N(C)S(C)(=O)=O)cc3)CC2)c(C)c1

Procedure:
Using N-{4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}methanesulfonamide (194 mg) described in Example 461 and methyl iodide (34 μL) and by the reaction and treatment in the same manner as in Example 36, the title compound (57 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([CH3:13])([CH3:12])[C:9](=O)[NH:10][C:4]=2[CH:3]=1.C1COCC1>CO>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([CH3:13])([CH3:12])[CH2:9][NH:10][C:4]=2[CH:3]=1
Reactant: CC1(C)C(=O)Nc2cc(Cl)ncc21
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)CNc2cc(Cl)ncc21
Temperature: 65 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
6-Chloro-3,3-dimethyl-1,3-dihydro-pyrrolo[3,2-c]pyridin-2-one (1.4 g, 7.14 mmol) was dissolved in a solution of borane-dimethyl sulfide complex in THF (2 M, 36 mL, 71.4 mmol) and heated to 65° C. for 3 h, then cooled to ambient temperature. MeOH was added and the reaction heated at reflux for 1.5 h. After stirring overnight, the solvent was removed in vacuo. Column chromatography on silica gel (gradient elution, 0-100% EtOAc/petrol), gave the title compound (1.23 g, 95%) as a colourless solid. 1H NMR (Me-d3-OD): 7.65 (1H, s), 6.42 (1H, s), 3.43 (2H, s), 1.34 (6H, s).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1.[CH3:34][N:35]([CH:37]([CH3:40])[CH2:38]Cl)[CH3:36]>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([O:15][CH2:38][CH:37]([N:35]([CH3:36])[CH3:34])[CH3:40])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=1
Reactant: CC(CCl)N(C)C
Reactant: COc1cc(-c2nc3ccc(O)cc3n2Cc2ccccc2C(F)(F)F)cc(OC)c1OC
Product: COc1cc(-c2nc3ccc(OCC(C)N(C)C)cc3n2Cc2ccccc2C(F)(F)F)cc(OC)c1OC

Procedure:
The title compound was prepared by reacting the compound of Example 104 with 2-(N,N-dimethylamino)propyl chloride essentially as previously described. mp 163° C., NMR, IR, MS 543, 544.
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=[O:4].[CH2:13](O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(Cl)CCl.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([O:5][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:4]
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCC(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of N-Boc-Gly (3.0 g) in methylene chloride (100 ml) was added benzyl alcohol (1.6 ml), EDC (4.4 g) and a catalytic amount of DMAP. After 2 hours, the mixture was poured into 1N HCl and extracted with methylene chloride, dried over sodium sulfate, filtered and concentrated to give N-Boc-Gly-OBn (4.5 g). To a solution of N-Boc-Gly-OBn (1.32 g) in THF (10 ml) was added potassium bis(trimethylsilyl)amide (1.19 g) in THF (20 ml) at -78° C. After 30 minutes at -78° C. allyl bromide (0.52 ml) was added to the reaction mixture slowly. The resulting mixture was slowly warmed up to room temperature and stirred for an additional 12 hours. The mixture was poured into 1N HCl and extracted with ether, the combined organics were dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatotron (hexanes/ethyl acetate=10/1) to give desired product (585 mg). ##STR91##
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.Br[CH:14]1[CH2:19][CH2:18][CH2:17][CH:16]=[CH:15]1>C1COCC1.CCCCCC>[CH:19]1([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:18][CH2:17][CH2:16][CH:15]=[CH:14]1
Reactant: Cc1ccccn1
Reactant: BrC1C=CCCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C1=CC(Cc2ccccn2)CCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 46.9 %

Procedure:
Following a modified version of the procedure given in J. M. Ontoria et al., Bioorg. Med. Chem. Lett. 16 (2006), 4026, a solution of 2-methyl-pyridine (0.50 g, 5.37 mmol) in 10 ml of anhydrous THF was cooled to −78° C. under an atmosphere of argon. n-Butyllithium (2.36 ml of a 2.5 M solution in hexane, 5.91 mmol) was added dropwise and the solution was stirred at −78° C. for 1 h. 3-bromo-cyclohexene (0.68 ml, 5.91 mmol) was added then dropwise and the temperature was allowed to rise to ambient temperature over 3 h. After stirring overnight, the mixture was quenched by addition of 20 ml of water and extracted twice with EA. The combined organic phases were washed with a saturated solution of sodium chloride, dried over sodium sulfate, filtered and evaporated to dryness to give 0.436 g of 2-(cyclohex-2-en-1-ylmethyl)-pyridine as an orange oil. This product was dissolved in 8.4 ml of ethanol, 5% palladium on charcoal (50% in water; 0.087 g) was added, and the mixture was hydrogenated under a hydrogen pressure of 3.2 bar for 4 h at room temperature. The catalyst was then filtered off and the filtrate was evaporated to dryness under reduced pressure to give 0.415 g of the title compound as an oil.
Reaction SMILES: Cl.O[CH2:3][C:4]1[CH:9]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][C:5]=1[N-]C(=O)C(C)(C)C.[NH2:22][C:23]([NH2:25])=[S:24]>O1CCOCC1.C(O)(C)C>[NH2:22][C:23]1[S:24][CH2:3][C:4]2[CH:9]=[C:8]([O:10][C:11]([F:12])([F:14])[F:13])[CH:7]=[CH:6][C:5]=2[N:25]=1
Reactant: CC(C)(C)C(=O)[N-]c1ccc(OC(F)(F)F)cc1CO
Reactant: NC(N)=S
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: NC1=Nc2ccc(OC(F)(F)F)cc2CS1
Temperature: 80 °C
Yield: 84 %

Procedure:
Concentrated HCl (4 ml) is added slowly to a solution of N-[2-hydroxymethyl-4-(trifluoromethoxy)phenyl]-pivaloylamide (0.35 g, 1.2 mmol) in dioxane (3 ml) and the resulting reaction mixture heated at 80° C. for 4 hours, then diluted with isopropanol (20 ml), and thiourea (0.14 g, 1.8 mmol) added and the mixture refluxed for 20 hours. The solvent is then evaporated under vacuum and the residue diluted with H2O, basified with 2 N NaOH, and extracted with CH2Cl2. The combined organic extracts are dried over Na2SO4 and concentrated under vacuum. The residue is purified by chromatography through silica, eluting with AcOEt/petroleum ether (1:1). The product is obtained as a yellow solid, with a yield of 84%. Recrystallisation from EtOH gives a solid with m.p. 115-118° C. 1H-NMR (CDCl3): 3.87 (s, 2H), 5.16 (br s, 2H), 6.97-7.11 (m, 3H). MS (ESI): m/z 249 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH2:16].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:16][CH2:15][CH2:14][N:13]([CH3:17])[CH3:12])=[O:8])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: CN(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(C(=O)NCCN(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-bromo-3-methylbenzoic acid (430 mg), N, N-dimethylethylenediamine (180 mg), 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride (600 mg) and 4-dimethylaminopyridine (244 mg) in dichloromethane (20 mL) was stirred at ambient temperature for 4 hours, diluted with ethyl acetate (200 mL), washed with water and brine, and dried (Na2SO4), filtered and concentrated. The concentrate was purified by flash column chromatography with 10% ethyl acetate in ammonia saturated dichloromethane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[CH:18]=[CH:19][C:20]3[N:21]([C:23]([C:26]([OH:29])([CH3:28])[CH3:27])=[N:24][N:25]=3)[N:22]=1)[CH:14]=[CH:13]O2.[CH3:30][NH2:31]>O1CCOCC1.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:31]([CH3:30])[CH:13]=[CH:14][N:15]2[C:16]=1[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([C:26]([OH:29])([CH3:27])[CH3:28])=[N:24][N:25]=2)[N:22]=1
Reactant: CC(C)(O)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4occn34)nn12
Reactant: CN
Solvent: C1COCCO1
Solvent: O
Product: Cn1ccn2c(-c3ccc4nnc(C(C)(C)O)n4n3)c(-c3ccc(F)cc3F)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
The 2-(6-(6-(2,4-difluorophenyl)imidazo[2,1-b]oxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)propan-2-ol (0.200 g, 0.505 mmol, Example #35) in 1,4-dioxane (1 mL) and 40% methylamine in water (1.5 mL, 17 mmol) was heated in a CEM microwave at about 120° C. for about 55 minutes, (100 psi maximum pressure, 5 min ramp, 300 max watts). The mixture was evaporated and then dissolved in HOAc (2 mL). The solution was stirred at room temperature for about 1 hour then the material was purified by RP-HPLC (Table 1, Method f). The combined fractions were concentrated under reduced pressure to remove the acetonitrile then the solution was basified with saturated aqueous NaHCO3 solution gave an oil. The mixture was extracted with 20% EtOAc in DCM (25 mL) then EtOAc (approx. 15 mL). The combined organics solutions were dried over MgSO4 then filtered and evaporated. The solid was triturated with about 10 mL water then collected by filtration. The material was dissolved in hot acetonitrile (1 mL) then added dropwise to about 10 mL water. The solution was allowed to stand at ambient temperature until a solid formed then the mixture was diluted with water (5 mL). The solid was collected by filtration then dried under vacuum at about 80° C. to give the title compound (0.040 g, 20%); 1H NMR (DMSO-d6) δ 8.15 (d, 1H), 8.10 (d, 1H), 7.76-7.67 (m, 1H), 7.46 (m, 2H), 7.31-7.23 (m, 1H), 6.85-6.80 (m, 1H), 5.66 (s, 1H), 3.72 (s, 3H), 1.78 (s, 6H); LC/MS (Table 1, Method g) Rt=1.65 min; MS m/z: 410.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH2:15])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4].ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)(Cl)Cl>[CH3:1][N:2]([CH2:13][C:14]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:30][CH2:15]1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: C=C(CN(C)S(=O)(=O)c1ccc(C)cc1)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)N(C)CC2(c3ccccc3)CO2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 74.6 %

Procedure:
A mixture of 9.8 g of N-methyl-N-(2-phenyl-2-propenyl)-p-toluenesulfonamide, 9.63 g of m-chloroperbenzoic acid and 280 ml of chloroform were stirred at 60° C. for 3 hours. After cooling, the reaction mixture was washed subsequently with 10% aqueous sodium bisulfite and water, dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (developing solvent:ethyl acetate -n-hexane) to obtain 7.7 g of the titled compound.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:10](O)(=[O:16])[CH2:11][CH2:12][CH2:13][C:14]#[CH:15].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:16])[CH2:11][CH2:12][CH2:13][C:14]#[CH:15])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: C#CCCCC(=O)O
Reactant: CC(C)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C#CCCCC(=O)N1CCN(C(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.4 %

Procedure:
1-Isopropylpiperazine (228 mg, 1.78 mmol) was added over a mixture of hex-5-ynoic acid (200 mg, 1.78 mmol), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (393 mg, 2.05 mmol) and N,N-dimethylpyridin-4-amine (10 mg, 0.05 mmol) in dichloromethane (10 ml) at 0° C. and the resulting mixture was stirred at room temperature overnight. 100 ml of dichloromethane were added and washed with sodium bicarbonate 4%. Then a solution of hydrogen chloride 0.5 N was added to the organic phase. The aquose phase was separated and neutralised with a solution of NaOH 2N and treated with ethyl acetate. The ethyl acetate phase was washed with water and brine, dried over magnesium sulphate and the solvent removed to give 152 mg (34% yield) of the title compound. Purity 90%.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:11][C:12]2[NH:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=3[N:21]=2)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31]>>[Br:1][C:2]1[C:3]([S:11][C:12]2[N:13]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])[C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=3[N:21]=2)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: Clc1ccccc1CCBr
Reactant: Nc1nccc2[nH]c(Sc3cc4c(cc3Br)OCO4)nc12
Product: Nc1nccc2c1nc(Sc1cc3c(cc1Br)OCO3)n2CCc1ccccc1Cl

Procedure:
The title compound was prepared by a similar procedure described for step 7 of example 1 using 2-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-1H-imidazo[4,5-c]pyridin-4-amine and 1-(2-bromoethyl)-2-chloro-benzene. 1H NMR (DMSO-d6) δ; 7.69 (d, J=6.0 Hz, 1H), 7.36 (dd, J=8.0, 1.6 Hz, 1H), 7.32 (s, 1H), 7.23 (td, J=8.0, 1.6 Hz, 1H), 7.06 (td, J=7.2, 1.6 Hz, 1H), 6.72 (d, J=6.0 Hz, 1H), 6.52 (s, 1H), 6.38 (s, 2H), 6.06 (s, 2H), 4.45 (t, J=6.8 Hz, 2H), 3.09 (t, J=6.8 Hz, 2H); LC-MS [M+H]+ 502.99.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]([C:10]#[N:11])[C:8]#[N:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:26][C:27]([F:32])([F:31])[CH:28]([F:30])[F:29])(=O)=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]([CH2:26][C:27]([F:32])([F:31])[CH:28]([F:30])[F:29])([C:8]#[N:9])[C:10]#[N:11])=[CH:12][CH:13]=1
Reactant: O=S(=O)(OCC(F)(F)C(F)F)C(F)(F)F
Reactant: N#CC(C#N)Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(Cc1ccc(Cl)cc1)CC(F)(F)C(F)F
Yield: 7.5 %

Procedure:
Using 1.0 g of (4-chlorobenzyl)malononitrile, 15 ml of N,N-dimethylformamide, 0.073 g of cesium carbonate, and 1.47 g of 2,2,3,3-tetrafluoropropyl trifluoromethanesulfonate, and according to the process described in the Production Example 1, there was obtained 0.12 g of 2-(4-chlorobenzyl)-2-(2,2,3,3-tetrafluoropropyl)malononitrile (the present compound (25)).
Reaction SMILES: C[O-].[Na+].[C:4](#[N:7])[CH:5]=[CH2:6].Cl.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[C:19]([F:25])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CO.CCOC(C)=O>[NH2:7][C:4]1[NH:24][N:23]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:18][C:19]=2[F:25])[CH2:6][CH:5]=1
Reactant: C=CC#N
Reactant: NNc1ccc(OCc2ccccc2)cc1F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: NC1=CCN(c2ccc(OCc3ccccc3)cc2F)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaOMe (25 wt. % solution in MeOH, 7.75 mL) and acrylonitrile (2.1 mL) were added to a solution of 4-benzyloxy-2-fluorophenylhydrazine hydrochloride (4.15 g) in MeOH (40 mL) at room temperature. The mixture was stirred at room temperature for 30 minutes and refluxed overnight. Additional NaOMe (25 wt. % solution in MeOH, 3.9 mL) and acrylonitrile (1.05 ml) were added to the reaction mixture and refluxed for 7.5 hours. The mixture was diluted with EtOAc and washed with sat. NaHCO3 and brine. The organic layer was dried over anhydrous MgSO4 and concentrated. The residue was crystallized from CHCl3/hexane to yield 3.86 g of the title compound.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]([CH3:9])[C:6](Cl)=[O:7])=[O:4].[F-:10].[K+].C1OCCOCCOCCOCCOCCOC1>ClCCl>[Cl:1][CH2:2][C:3]([N:5]([CH3:9])[C:6]([F:10])=[O:7])=[O:4]
Reactant: [F-]
Reactant: CN(C(=O)Cl)C(=O)CCl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: ClCCl
Product: CN(C(=O)F)C(=O)CCl
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
A mixture of 10.0 g of N-Chloroacetyl-N-methylcarbamoyl chloride, 3.8 g of anhydrous potassium fluoride and 0.5 g of 18-crown-6 in 50 cc of dichloromethane was stirred at room temperature under nitrogen for about 16 hours. The liquid was decanted and the residue was extracted with 50 cc dichlormethane. The dichloromethane layers were combined and the solvent stripped off to afford 9.0 g. (Yield 100%) of N-chloroacetyl-N-methylcarbamoyl fluoride. The product was further purified by distillation under reduced pressure. B.p. 59° C./0.2 mm.