Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([I:8])=[CH:6][N:5]=[C:4]([Cl:9])[CH:3]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[Cl:9][C:4]1[CH:3]=[C:2]([N:1]([S:18]([CH3:17])(=[O:20])=[O:19])[S:18]([CH3:17])(=[O:20])=[O:19])[C:7]([I:8])=[CH:6][N:5]=1
Reactant: Nc1cc(Cl)ncc1I
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N(c1cc(Cl)ncc1I)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 72.9 %

Procedure:
4-Amino-2-chloro-5-iodopyridine (11) (1.01 g, 3.97 mmol) was dissolved in dichloromethane (8.5 mL) and triethylamine (2.48 mL, 1.78 g 17.6 mmol) was added. The suspension was cooled in an ice/water bath. A solution of methanesulfonyl chloride (1.56 mL, 2.31 g, 20.1 mmol) in dichloromethane (4.2 mL) was added dropwise. The reaction was stirred at room temperature for 100 min. More triethylamine (1.25 mL) was added to the reaction, which was then cooled in ice. To the cooled reaction was added dropwise a solution of methanesulfonyl chloride (0.78 mL, 1.15 g, 10 mmol) in dichloromethane (2.1 mL) and stirring at room temperature was continued for 16 h. The reaction was diluted with dichloromethane and washed twice with water. The residue was purified by flash chromatography eluting with dichloromethane, then 5% ethyl acetate in dichloromethane to give the title compound (13) (1.188 g 72%). 1H-NMR (500 MHz, DMSO-d6): 3.69 (s, 6H), 8.03 (s, 1H), 8.99 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.CC1(C)C(C)(C)OB([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH:25]=[C:24]([NH:29][C:30]([C:32]2[CH:36]=[CH:35][S:34][CH:33]=2)=[O:31])[CH:23]=[CH:22]3)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Pd].O>[NH:6]1[C:7]2[C:3](=[C:2]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH:25]=[C:24]([NH:29][C:30]([C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)=[O:31])[CH:23]=[CH:22]4)[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)OC1(C)C
Reactant: Brc1cccc2[nH]ccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccc2cc(-c3cccc4[nH]ccc34)ccc2c1)c1ccsc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 22 %

Procedure:
4-bromo-1H-indole (31.0 mg, 0.158 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (114.5 mg, 0.302 mmol), Fibercat palladium catalyst (Johnson-Matthey, 34.5 mg), and K2CO3 (2 M in water, 0.45 ml, 0.90 mmol) were combined in a microwave reaction vessel and 1,4-dioxane (1.5 ml) was added. The reaction tube was sealed and heated in the microwave (CEM microwave) at 60 Watts and 80 C, first for 10 minutes, and then for 20 minutes. The reaction was cooled to room temperature, diluted with water (5 ml), and extracted with EtOAc (10 ml, 2×5 ml). The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on HPLC (10%->95% MeCN/water with 0.1% TFA). The fractions with product were purified on silica gel (3:1->1:1 hexanes/EtOAc) to afford title compound (12.8 mg, 22%). MS (ESI pos. ion) m/z: 369 (M+H). Calc'd Exact Mass for C23H16N2OS: 368.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[H-].[Na+].Cl[CH2:24][S:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C)C=O>[Br:1][C:2]1[N:3]([CH2:24][S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2
Reactant: ClCSc1ccccc1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CSc3ccccc3)c2c1
Reaction time: 1 h
Yield: 81.6 %

Procedure:
To a solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (1.00 g, 2.97 mmol) in N,N-dimethylformamide (10 ml) was added sodium hydride (60% in oil, 139 mg, 3.47 mmol) under ice-cooling, and the mixture was stirred for 1 hr. To this reaction mixture was added chloromethylsulfanylbenzene (0.38 ml, 2.94 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1.5 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=20:1-7:1) to give methyl 2-bromo-3-cyclohexyl-1-phenylsulfanylmethyl-1H-indole-6-carboxylate (1.10 g, yield 84.0%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C@H:5]([CH2:7][S:8][CH2:9][CH2:10][CH3:11])[NH2:6])[CH3:2].[C:13]([O:17][C:18](=[O:22])[CH:19](Br)[CH3:20])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>CN(P(N(C)C)(N(C)C)=O)C>[C:13]([O:17][C:18](=[O:22])[C@H:19]([CH3:20])[NH:6][C@H:5]([C:4]([O:3][CH2:1][CH3:2])=[O:12])[CH2:7][S:8][CH2:9][CH2:10][CH3:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCCSC[C@H](N)C(=O)OCC
Reactant: CC(Br)C(=O)OC(C)(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCN(CC)CC
Product: CCCSC[C@H](N[C@@H](C)C(=O)OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 40 h

Procedure:
In 40 ml of HMPA were dissolved 7.9 g of S-propyl-L-cysteine ethyl ester and 12.4 g of 2-bromopropionic acid t-butyl ester. To the solution was added 8.3 ml of triethylamine, and the mixture was stirred at room temperature for 40 hours. The reaction mixture was poured into ice water, followed by extraction with ethyl acetate. The extract was sufficiently washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (a 1:3 mixture of ether and n-hexane as an eluent), producing the α-isomer of the title compound as a colorless oil from the first eluate. Yield 4.4 g
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([CH2:10][CH:11]=O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:18][CH:17]=1)([O-:15])=[O:14].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.CC(O)=O>[CH3:1][C:2]1[CH:9]=[C:8]([CH2:10][CH2:11][N:27]2[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][C:19]3[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][CH:20]=3)[CH2:25][CH2:26]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=[N+]([O-])c1ccc(CCN2CCNCC2)cc1
Reactant: Cc1cc(CC=O)ccc1C#N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(CCN2CCN(CCc3ccc([N+](=O)[O-])cc3)CC2)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-methyl-4-(2-oxoethyl)benzonitrile (130 mg, 0.8 mmol), 1-[2-(4-nitrophenyl)ethyl]piperazine (190 mg, 0.8 mmol) in 25 mL of dry methanol were added 2 drop of HOAc and then stirred at room temperature for 1 hr. Then NaBH(OAc)3 (380 mg, 1.8 mmol) was added an the then the mixture was stirred overnight. Concentrated and the residue was purified via prep-TLC to give 2-Methyl-4-(2-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}ethyl)benzonitrile. 1H-NMR (300 MHz, CDCl3) δ ppm 8.15 (d, J=8.6 Hz, 2H), 7.36˜7.53 (m, 3H), 7.12 (t, J=9.4 Hz, 2H), 2.65˜2.97 (m, 16H), 2.52 (s, 3H). MS m/e: 379 (M+1)+. (0.19 μM)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.C([Li])CCC.[CH3:14][C:15]([CH3:17])=[O:16]>C1COCC1.CCOCC>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:15]([OH:16])([CH3:17])[CH3:14])=[CH:6][CH:7]=1
Reactant: Brc1ccc(I)cn1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(O)c1ccc(Br)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
To 2-bromo-5-iodo-pyridine (2.974 g, 10.2 mmol) in a mixture of THF (15 mL) and ether (20 mL) at −78° C. is added dropwise n-butyl lithium (2.5 M in hexane, 4 L, 10.2 mmol). The mixture is stirred at −78° C. for 30 min, then acetone (anhydrous, 0.749 uL, 10.2 mmol) is added drop wise. The mixture is slowly warmed up to −50° C. over 1.5 h and is quenched with saturated ammonium chloride, extracted with ethyl acetate. The organic phase is separated, dried and rotavaped. The residue is purified by silica gel chromatography (10-20% ethyl acetate in heptane) to give the title compound as white solid (1.40 g, 64%).
Reaction SMILES: [CH3:1][O:2][C:3]([O:11][Si](C)(C)C)=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.F[B-](F)(F)F.[C:21]1([N+:27]#[N:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1.C(OCC)C>[C:5]1([C:4](=[N:28][NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:3]([O:2][CH3:1])=[O:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(=Cc1ccccc1)O[Si](C)(C)C
Reactant: N#[N+]c1ccccc1
Agent: F[B-](F)(F)F
Solvent: c1ccncc1
Solvent: CCOCC
Product: COC(=O)C(=NNc1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
1.0 mmol of (1-methoxy-2phenylethenyl)oxytrimethylsilane was placed in a 20-ml flask, followed by the addition of 3 ml of pyridine as a solvent. 1.3 mmol of benzenediazonium tetrafluoroborate was added to the flask. The obtained mixture was stirred at 0° C. in a nitrogen atmosphere for 2 hours. The reaction mixture was diluted with diethyl ether and washed with 1.5N hydrochloric acid, water and a saturated aqueous solution of common salt successively. The obtained organic phase was dried over magnesium sulfate and distilled under a reduced pressure to remove the solvent. The obtained oily mixture was subjected to silica gel thin-layer chromatography to obtain 0.84 mmol of methyl 2-phenyl-2-phenylhydrazonoacetate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([Br:18])[C:3]=1[NH:19][C:20]([C:22]1[C:23]([O:38][CH3:39])=[C:24]([N:28]([CH3:37])[C:29]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[O:30])[CH:25]=[CH:26][CH:27]=1)=[O:21].[H-].[Na+].I[CH3:43].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])[CH:5]=[C:4]([Br:18])[C:3]=1[N:19]([CH3:43])[C:20]([C:22]1[C:23]([O:38][CH3:39])=[C:24]([N:28]([CH3:37])[C:29]([C:31]2[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=2)=[O:30])[CH:25]=[CH:26][CH:27]=1)=[O:21]
Reactant: CI
Reactant: COc1c(C(=O)Nc2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Br)cccc1N(C)C(=O)c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(C(=O)N(C)c2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Br)cccc1N(C)C(=O)c1ccncc1
Reaction time: 0.5 h

Procedure:
To a solution of N-[3-[[2,6-dibromo-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]carbamoyl]-2-methoxy-phenyl]-N-methyl-pyridine-4-carboxamide (0.100 g, 0.145 mmole) in N,N-dimethylformamide (4 ml) was added sodium hydride (55% suspension in oil, 0.0067 g, 0.153 mmole). After the gas evolution had stopped, iodomethane (0.010 ml, 0.023 g, 0.160 mmole) was added. After 0.5 hour, the reaction mixture was poured on to water (15 ml) and the product was extracted with ethyl acetate. The organic solution was washed with water, then brine and dried over sodium sulfate. After removal of the solvent the crude was purified by column chromatography over silica gel using ethyl acetate-cyclohexane to yield the title compound (Compound G17 of Table G) as amorphous material showing by LC-MS analysis under the conditions 6 (described hereafter) a retention time of 1.09 min and a M+H+ mass of 700.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.Cl[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][N:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO.[Pd]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:11][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([NH2:1])[CH:10]=2)=[N:14][CH:15]=1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccc(N)c(N)c2)nc1

Procedure:
2-Nitro-4-hydroxyaniline was reacted with 2-chloro-5-nitropyridine and K2CO3 in DMF at rt, followed by hydrogenation over Pd/C in MeOH, afforded the title compound; MS m/e 217 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>S(=O)(=O)(O)O>[C:1]([C:5]1[CH:6]=[C:7]([N+:16]([O-:18])=[O:17])[C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C(C)(C)C)cc1C(=O)O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COc1c(C(=O)O)cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5 g 5-tert-butyl-2-methoxy-benzoic acid are dissolved in 15 ml sulphuric acid, cooled to 0° C. and combined dropwise with a solution of 2.3 ml nitric acid in 2.6 ml sulphuric acid. The mixture is stirred for 1.5 hours at 0° C. and for 1 hour at ambient temperature. Then it is added to ice water. The precipitate is filtered off, taken up in dichloromethane and dried on magnesium sulphate. The solvent is eliminated in vacuo and the product thus obtained is further reacted directly.
Reaction SMILES: Cl.[CH:2]1([NH:5][C:6](=[NH:8])[CH3:7])[CH2:4][CH2:3]1.Br[C:10](=[CH:13]OC(C)C)[CH:11]=[O:12].C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl.O>[CH:2]1([N:5]2[C:10]([CH:11]=[O:12])=[CH:13][N:8]=[C:6]2[CH3:7])[CH2:4][CH2:3]1
Reactant: CC(=N)NC1CC1
Reactant: CC(C)OC=C(Br)C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ncc(C=O)n1C1CC1
Reaction time: 8 h
Yield: 35.8 %

Procedure:
Ethyl acetimidate hydrochloride (5.0 g, 40 mmol) and cyclopropylamine (2.3 mL, 40 mL) were dissolved in 45 mL of EtOH and heated to 85° C. in a sealed pressure vessel overnight. The mixture was cooled and concentrated to provide N-cylcopropyl-acetamidine hydrochloride as a viscous oil. N-Cyclopropyl-acetamidine hydrochloride (1.00 g, 7.43 mmol) and 2-bromo-3-isopropoxy-propenal (Shilcrat, S. C. et al. J. Org. Chem., 1997, 62, 8449–8454) (1.45 g, 7.50 mmol) were dissolved in 13 mL of CHCl3 and 1.6 mL of water. Then K2CO3 (1.5 g, 11 mmol) was added and the mixture was stirred overnight. The reaction was partitioned between CH2Cl2 (60 mL) and water (30 mL). The layers were separated and the aqueous portion was extracted with CH2Cl2 (40 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4), filtered, concentrated, and chromatographed to provide 400 mg of 3-cyclopropyl-2-methyl-3H-imidazole-4-carbaldehyde.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: O=C(O)CCCCCBr
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CCCCCBr)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
6-Bromohexanoic Acid (10.0 g, 0.051 mol), benzyl alcohol (6.1 g, 0.056 mol) and DMAP (dimethylaminopyridine, 0.63 g, 0.005 mol) were dissolved in 100 mL CH2Cl2, then cooled to 0° C. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 10.8 g, 0.056 mol) was added and the reaction stirred overnight at room temperature. The organics were diluted with CH2Cl2 and washed with water, aq. NaHCO3, and brine. The organic phase was dried (Na2SO4), filtered, and solvent was removed. Intermediate 12 was obtained as a colorless oil (11.6 g, 0.04 mol). MS(MH+): m/z=286.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8](I)[N:7]=3.C([Sn](CCCC)(CCCC)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)CCC>CN(C=O)C.[Cu](I)I>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[N:7]=3
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Brc1ccc2c(c1)OCCn1cc(I)nc1-2
Agent: I[Cu]I
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)OCCn1cc(-c3ccccn3)nc1-2
Temperature: 100 °C
Yield: 73.2 %

Procedure:
A mixture of 8-bromo-2-iodo-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (300 mg, 0.767 mmol), 2-tributylstannanylpyridine (339 mg, 0.921 mmol), Pd2(PPh3)2Cl2 (54 mg, 0.077 mmol) and copper iodide (44 mg, 0.23 mmol) in DMF (6 mL) was purged with nitrogen and then heated at 100° C. for 1 h using microwave irradiation. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were concentrated in vacuo and the resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in DCM followed by Si-PCC, gradient 0-2% 2M NH3/MeOH in DCM) affording the title compound as a white solid (192 mg, 73%). LCMS: RT 3.37 min [M+H]+ 341.9/343.9
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([C:9]2[CH:30]=[CH:29][C:12]3[NH:13][C:14]([NH:16][C:17]([C:19]4[N:20]=[C:21]5[CH:26]=[CH:25][C:24](Cl)=[N:23][N:22]5[CH:28]=4)=[O:18])=[N:15][C:11]=3[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[N:33]1([CH2:39][CH2:40][OH:41])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.[H-].[Na+].O>CN(C=O)C>[F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([C:9]2[CH:30]=[CH:29][C:12]3[NH:13][C:14]([NH:16][C:17]([C:19]4[N:20]=[C:21]5[CH:26]=[CH:25][C:24]([O:41][CH2:40][CH2:39][N:33]6[CH2:38][CH2:37][O:36][CH2:35][CH2:34]6)=[N:23][N:22]5[CH:28]=4)=[O:18])=[N:15][C:11]=3[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: OCCN1CCOCC1
Reactant: O=C(Nc1nc2cc(-c3cccc(C(F)(F)F)c3)ccc2[nH]1)c1cn2nc(Cl)ccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1nc2cc(-c3cccc(C(F)(F)F)c3)ccc2[nH]1)c1cn2nc(OCCN3CCOCC3)ccc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide (100 mg) and 2-morpholin-4-yl-ethanol (250 μL) in dry DMF (1 mL) was added NaH (100 mg, 60% dispersion in mineral oil) and the mixture was stirred at room temperature for 1 h. To this was added water (20 mL) and the reaction mixture stirred for 10 minutes. The precipitated solid was filtered and purified by column chromatography (12 g pre-packed silica gel column cartridge) using DCM and 2N ammonia in methanol to afford 6-(2-morpholin-4-yl-ethoxy)-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide (42 mg). LCMS (m/z): 552.8.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23]C(=O)C(F)(F)F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH3:30][N:31]([CH2:33][C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=1)[NH2:37])[CH3:32].Cl>O1CCOCC1.CC(O)C>[NH2:23][C:19]1[CH:18]=[C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:37][C:36]4[CH:38]=[CH:39][CH:40]=[C:34]([CH2:33][N:31]([CH3:30])[CH3:32])[CH:35]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)C(F)(F)F
Reactant: CN(C)Cc1cccc(N)c1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CN(C)Cc1cccc(Nc2nccc(-c3c(-c4cccc(N)c4)nn4ccccc34)n2)c1
Temperature: 90 °C
Yield: 41 %

Procedure:
To a solution of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide (3.0 g, 0.007 mols) (see Example 1, Step C) in 1,4-dioxane (60 mL) and i-PrOH (60 mL) was added 3-[(dimethylamino)methyl]aniline (1.61 g, 0.011 mol) followed by catalytic 12M HCl. After heating four days at 90° C., reaction was quenched with saturated NaHCO3 (100 mL), solvent removed by rotary evaporation, aqueous layer extracted with DCM (3×200 mL), organic layers concentrated, and purified by column chromatography (0-100% 9:1:0.1 DCM:MeOH:NH4OH) to provide the product (1.25 g, 40%) as tan foam. ES-LC/MS m/z=436 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([C:17]2[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[NH:10][S@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])=[CH:5][CH:4]=1)=[O:2].[CH3:27][Mg]Br>C1COCC1>[OH:2][CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]([C:17]2[C:22]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[NH:10][S@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])=[CH:7][CH:8]=1)[CH3:27]
Reactant: CC(C)(C)[S@](=O)N[C@@H](c1ccc(C=O)cc1)c1ncccc1C(F)(F)F
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1ccc([C@H](N[S@@](=O)C(C)(C)C)c2ncccc2C(F)(F)F)cc1

Procedure:
(S)—N—((S)-(4-Formylphenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (0.200 g, 0.520 mmol) was dissolved in dry THF (30 mL) and cooled in an ice bath. Methylmagnesium bromide (3M in Et2O, 0.50 mL, 1.50 mmol) was added dropwise and the reaction stirred. The resulting mixture was stirred for 1 h and then quenched by addition of saturated aqueous NH4Cl (10 mL). H2O (100 mL) and EtOAc (100 mL) were added, and the phases were mixed and separated. The organic layer was dried with MgSO4 and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to EtOAc gradient) gave impure material which was further purified using reverse phase HPLC to give the desired (S)—N-((1 S)-(4-(1-hydroxyethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide.
Reaction SMILES: N[C:2]1[C:13]([C:14]([O:16]N2C3C=CC=CC=3N=N2)=O)=C2N=CC(CC#N)=CN2N=1.[Cl:26][C:27]1[CH:28]=[N:29][CH:30]=[C:31]([F:39])[C:32]=1[C:33]1[CH2:34][CH2:35][NH:36][CH2:37][CH:38]=1.O1CC(=O)C1.CO>C1COCC1>[Cl:26][C:27]1[CH:28]=[N:29][CH:30]=[C:31]([F:39])[C:32]=1[C:33]1[CH2:34][CH2:35][N:36]([CH:13]2[CH2:14][O:16][CH2:2]2)[CH2:37][CH:38]=1
Reactant: N#CCc1cnc2c(C(=O)On3nnc4ccccc43)c(N)nn2c1
Reactant: Fc1cncc(Cl)c1C1=CCNCC1
Agent: O=C1COC1
Solvent: C1CCOC1
Solvent: CO
Product: Fc1cncc(Cl)c1C1=CCN(C2COC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
Sodium triacetoxyborohydride (Sodium Ion (1)) (1.026 g, 4.842 mmol) was added in portions to a stirred solution of 3-chloro-5-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)pyridine (468 mg, 2.201 mmol) and 3-oxetanone (269.7 mg, 239.9 μL, 3.742 mmol) in THF (10 mL) at 0° C. under an atmosphere of nitrogen. The reaction was allowed to warm to ambient temperature over 16 hours. MeOH (2 mL) was added dropwise and the mixture stirred at ambient temperature for 30 minutes. The mixture was concentrated in vacuo and partitioned between water and EtAOc. The pH of the aqueous layer was adjusted to pH 7-8 by the addition of NH4OH and the layers separated. The aqueous layer was extracted with EtOAc (×3) and the combined organic extracts washed with brine (×1), dried (MgSO4), filtered and concentrated in vacuo to give 3′-chloro-5′-fluoro-1-(oxetan-3-yl)-1,2,3,6-tetrahydro-4,4′-bipyridine as a white solid (573 mg, 97% Yield). MS (ES+) 269.1.