Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14](=[O:40])[C@H:15]([CH3:39])[C@H:16]([C@H:25]1[CH2:29][O:28][C:27]([CH3:31])([CH3:30])[N:26]1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])C1C=CC=CC=1.C(O)C.[Li+].[BH4-]>C1COCC1.C(OCC)C.[OH-].[Na+]>[Si:18]([O:17][C@@H:16]([C@H:25]1[CH2:29][O:28][C:27]([CH3:31])([CH3:30])[N:26]1[C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[C@@H:15]([CH3:39])[CH2:14][OH:40])([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:20])[CH3:19]
Reactant: C[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOCC
Product: C[C@@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
To a solution of (R)-tert-butyl 4-((1R,2R)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-1-(tert-butyldimethylsilyloxy)-2-methyl-3-oxopropyl)-2,2-dimethyloxazolidine-3-carboxylate (1.0 equiv.) and ethanol (3.0 equiv.) in THF (0.09M) was added LiBH4 (3.0 equiv.) at −30° C. The reaction mixture was allowed to warm up to 0° C. and stirred at that temperature for 3 hours. The solution was then diluted with diethyl ether and 1N NaOH was added. The resulting mixture was extracted with ethyl acetate, the organic layer was separated, washed with sat. NaCl, dried over magnesium sulfate, filtered, and concentrated. The residue was purified via silica gel column chromatography eluting with ethyl acetate and hexanes (1:4) to give (R)-tert-butyl 4-((1R,2S)-1-(tert-butyldimethylsilyloxy)-3-hydroxy-2-methylpropyl)-2,2-dimethyloxazolidine-3-carboxylate as the major product (5:2 ratio) in 71% yield. LC/MS=304.3 (M+H-Boc), Rt=0.95 min (Frac 65%-95% method).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]2[CH2:14][CH2:15][C@@H:9]1[C@H:10]([C:16]([OH:18])=O)[CH2:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:19]([O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)([CH3:21])[CH3:20]>>[CH:19]([O:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:16]([C@@H:10]2[CH2:11][CH2:12][C@H:13]3[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@@H:9]2[CH2:15][CH2:14]3)=[O:18])=[CH:25][CH:24]=1)([CH3:21])[CH3:20]
Reactant: CC(C)Oc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1[C@H]2CC[C@@H]1[C@H](C(=O)O)CC2
Product: CC(C)Oc1ccc(NC(=O)[C@@H]2CC[C@@H]3CC[C@H]2N3C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was synthesized as in Production Example 2(3), using the compound synthesized in (1) and 4-isopropoxyaniline.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[CH:28]=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:31][NH:32][CH2:33][CH2:34][NH:35][CH3:36]>>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:26][CH2:27]3)[CH:17]=[C:16]4[CH2:28][N:32]([CH3:31])[CH2:33][CH2:34][NH:35][CH3:36])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CNCCNC
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Product: CNCCN(C)Cc1cn(CC2CC2)c(=O)c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)cc12

Procedure:
The title compound was prepared as a solid by the method of Example 59 step iv) using product of Example 59 step iii) and N1,N2-dimethylethane-1,2-diamine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[S:22]([OH:25])(=[O:24])=[O:23]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[C:16]([S:22]([OH:25])(=[O:24])=[O:23])[CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)CC(c1ccccc1)c1ccc(OC)cc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: COC(=O)CC(c1ccccc1)c1ccc(OC)c(S(=O)(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(4-methoxy-phenyl)-3-phenyl-propionic acid methyl ester (prepared according to the procedure reported in Tetrahedron (2006), 62(41), 9610-9621) (2.50 g, 9.25 mmol) in DCM (250 mL) at 0° C. is added chlorosulfonic acid (30.7 ml, 462.5 mmol). The reaction mixture is allowed to warm to RT and is stirred at this temperature for 2 h. Ice water is added to cause precipitation of the product. The solvents are decanted and the residual solid is washed with ice water. The solid is then dried under vacuum to afford the title compound that is used without further purification.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@@H:11]([O:12]C(=O)C)[CH:10]=[CH:9][CH2:8][O:7]1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:3][CH2:4][C@H:6]1[C@@H:11]([OH:12])[CH:10]=[CH:9][CH2:8][O:7]1
Reactant: CCOC(=O)[C@@H]1OCC=C[C@@H]1OC(C)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC[C@@H]1OCC=C[C@@H]1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of cis-3-acetoxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester (52 mg, 0.25 mmol) in THF (5 ml) was added LiAlH4 (60 mg, 1.60 mmol). The resulting solution was stirred at ambient temperature for 15 min. The reaction was quenched by addition of H2O (10 ml). The solution was diluted with EtOAc (50 ml×2), washed with brine (50 ml), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography with 20% EtOAc-hexane to give cis-2-hydroxymethyl-3,6-dihydro-2H-pyran-3-ol
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([C:11]([CH3:15])([CH3:14])[C:12]#[CH:13])=[CH:7][C:4]=1[CH:5]=O.[NH2:16][C@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:18]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(OC(N1CCC[C@H](NCC2C=C(C(C#N)C)C=CC=2OC)[C@@H]1C1C=CC=CC=1)=O)(C)(C)C>>[C:26]([O:25][C:23]([N:19]1[CH2:20][CH2:21][CH2:22][C@H:17]([NH:16][CH2:5][C:4]2[CH:7]=[C:8]([C:11]([CH3:15])([CH3:14])[C:12]#[CH:13])[CH:9]=[CH:10][C:3]=2[O:2][CH3:1])[C@@H:18]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Reactant: C#CC(C)(C)c1ccc(OC)c(C=O)c1
Agent: COc1ccc(C(C)C#N)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Product: C#CC(C)(C)c1ccc(OC)c(CN[C@H]2CCCN(C(=O)OC(C)(C)C)[C@H]2c2ccccc2)c1

Procedure:
This compound was prepared from Compound 22 and Compound 17 in the same manner of Compound 18.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4](N)[C:5]([Cl:8])=[N:6][CH:7]=1.N([O-])=O.[Na+].[NH4+].[OH-].[ClH:16]>Cl[Cu]>[Cl:8][C:5]1[C:4]([Cl:16])=[CH:3][C:2]([I:1])=[CH:7][N:6]=1
Reactant: Cl
Reactant: Nc1cc(I)cnc1Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [NH4+]
Product: Clc1cc(I)cnc1Cl
Reaction time: 0.5 h
Yield: 70 %

Procedure:
5-iodo-3-amino-2-chloropyridine (1.212 g, 4.76 mmol) and concentrated HCl (10 mL) were stirred at room temperature for ten minutes. Sodium nitrite (5.3 g, 76.8 mmol) was then slowly added followed by CuCl (4.0 g, 40.4 mmol). Stirring continued for 30 min. The mixture was poured into 1:1 NH4OH:H2O, extracted with ethyl acetate, dried over sodium sulfate, then concentrated. The crude residue was purified by flash chromatography using 95:5 hexane:ethyl acetate to yield 2,3-Dichloro-5-iodopyridine (913 mg, 70%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:9])[CH2:3][C:4](=[O:8])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:20]O>CN(C)C=O.O>[CH3:20][O:6][C:5](=[O:7])[C:4](=[O:8])[CH2:3][C:2]([CH3:1])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:9]
Reactant: CC(C)(CC(=O)C(=O)O)c1ccccc1
Reactant: CO
Solvent: O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COC(=O)C(=O)CC(C)(C)c1ccccc1
Reaction time: 15 h

Procedure:
10.4 g of 4-methyl-2-oxo-4-phenylpentanoic acid (WO98/54159) in 250 ml of dimethylformamide is mixed at −5° C. with 4.1 ml of thionyl chloride and after 15 minutes, it is mixed with 4 ml of methanol. After 15 hours at room temperature, the batch is diluted with water, and extracted with ethyl acetate. The organic extracts are washed with water, dried (Na2SO4) and concentrated by evaporation, whereby 9.3 g of 4-methyl-2-oxo-4-phenylpentanoic acid-methyl ester is obtained. The latter is mixed in 558 ml of DMF at −5° C. with 15.5 ml (104.63 mmol) of (trifluoromethyl)trimethylsilane and 20.5 g (63.28 mmol) of cesium carbonate, and it is stirred for 16 hours at room temperature. Water is added, it is extracted with ethyl acetate, the organic phase is washed with water and dried (Na2SO4). The intermediate product that is concentrated by evaporation is taken up in 200 ml of THF, and 50 ml of a 1 M solution of tetrabutylammonium fluoride in THF is added. It is stirred for 2 hours, water is added, it is extracted with ethyl acetate, the organic phase is washed with water and dried (Na2SO4). After chromatography on silica gel with hexane-ethyl acetate (0-30%), 8.35 g of 2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)pentanoic acid-methyl ester is obtained. The ester (8.3 g, 28.59 mmol) is dissolved in 180 ml of THF, and over a period of 2.5 hours, 1.52 g (36.20 mmol) of lithium aluminum hydride is added in small portions. After complete conversion, 5 ml of ethyl acetate is added in drops, and after another 10 minutes, 10 ml of water is carefully added. Formed precipitate is filtered out, and it is washed carefully with ethyl acetate. After chromatography on silica gel with hexane-ethyl acetate (0-35%), 5.40 g of 4-methyl-4-phenyl-2-(trifluoromethyl)pentane-1,2-diol is obtained. 5.7 ml (40.3 mmol) of triethylamine is added to 2.5 g (9.53 mmol) of diol in 75 ml of dichloromethane and 28 ml of DMSO, and 5 g of pyridine/SO3 complex is added in portions over 20 minutes. It is stirred over 2 hours, and 40 ml of saturated ammonium chloride solution is added. The mixture is stirred for another 15 minutes, the phases are separated, and it is extracted with dichloromethane. It is washed with water, and dried on sodium sulfate. The solvent is removed in a vacuum, and 3 g of product is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[C:6]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[N:5]=[C:4]([C:28]([F:31])([F:30])[F:29])[N:3]=1.[CH3:32][NH2:33]>ClCCl>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:33][CH3:32])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[C:6]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[N:5]=[C:4]([C:28]([F:31])([F:30])[F:29])[N:3]=1
Reactant: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)nc(Cl)c2-c2ccc(S(=O)(=O)Cl)cc2)cc1
Reactant: CN
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(-c2c(Cl)nc(C(F)(F)F)nc2-c2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 90.1 %

Procedure:
To a solution of 4-{4-chloro-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonyl chloride (0.5 g, 0.98 mmol, prepared according to the procedure described for example 3) in dichloromethane (5 ml) was added methylamine solution (0.08 ml, 0.98 mmol, 40% aqueous solution) under stirring at 0-10° C. After 15 minutes of the stirring, TLC confirmed the completion of the reaction. Subsequently the solvent was distilled off under reduced pressure and the solid thus obtained was filtered, washed thoroughly with cold water to yield the title compound (0.446 g, yield 90.1%, purity by HPLC 98.1%). m.p: 226-230° C. 1H-NMR (400 MHz, DMSO-d6) δ: 2.09-2.10 (d, 3H), 3.1 (s, 3H), 7.43-7.44 (m, 1H, D2O exchangeable), 7.54-7.56 (d, 2H), 7.69-7.81 (m, 4H), 7.86-7.88 (d, 2H). IR (KBr) cm−1: 3335, 1562 and 1530; MS m/z: 506.1 (M++1).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:2]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@H]1c1ccc(I)cc1
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCCO
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@H]1c1ccc(-c2ccccc2)cc1
Temperature: 90 °C
Yield: 66 %

Procedure:
(+,−) Trans propane-2-sulfonic acid [2-(4-iodo-phenyl)-cyclopentyl]-amide (58 mg, 0.15 mmol, prepared in example 2) and phenylboronic acid (22 mg, 0.18 mmol) were dissolved in 20 mL of n-propanol and 25 mg (0.18 mmol)of potassium carbonate in 5 mL of water added. A catalytic amount of palladium acetate is added (2 mg) and the mixture refluxed at 90° C. for 4 hours. The reaction is filtered, rinsed with ethyl acetate. The filtrate is diluted with ethyl acetate and washed with saturated sodium bicarbonate (3×30 mL) and brine (1×30 mL). The organic phase is dried over sodium sulfate, filtered and concentrated in vacuo to a crude solid which is purified by reverse phase chromatography (Vydac C18 column with a CH3CN gradient of 5→55% over 2 hours with a flow rate of 20 mL/min). The fractions were freeze-dried to give 34 mg (68%) of the title compound. The NMR was consistent with. the assigned structure.
Reaction SMILES: [CH3:1][N:2]1[C@@:6]2([CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([NH:15][C:16](=[O:30])[CH2:17][NH:18][CH2:19][C:20]4[CH:29]=[CH:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH:21]=4)[CH:12]=3)[CH2:7]2)[C:5](=[O:31])[NH:4][C:3]1=[O:32].[Cl:33][CH2:34][C:35]([CH3:40])([CH3:39])[C:36](Cl)=[O:37].C(N(CC)CC)C>C(Cl)Cl>[Cl:33][CH2:34][C:35]([CH3:40])([CH3:39])[C:36]([N:18]([CH2:17][C:16]([NH:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@@:6]1([C:5](=[O:31])[NH:4][C:3](=[O:32])[N:2]1[CH3:1])[CH2:14]2)=[O:30])[CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)=[O:37]
Reactant: CN1C(=O)NC(=O)[C@@]12Cc1ccc(NC(=O)CNCc3ccc4ccccc4c3)cc1C2
Reactant: CC(C)(CCl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C(=O)NC(=O)[C@@]12Cc1ccc(NC(=O)CN(Cc3ccc4ccccc4c3)C(=O)C(C)(C)CCl)cc1C2

Procedure:
To a stirred solution of N-[(4S)-3-methyl-2,5-dioxo-1′,3′-dihydrospiro[imidazolidine-4,2′-inden]-5′-yl]-2-[(2-naphthylmethyl)amino]acetamide from Step C (19 mg, 0.044 mmol), in DCM (1 mL), at 0° C. was added 3-chloro-2,2-dimethylpropanoyl chloride (10 mg, 0.067 mmol) and triethylamine (9.0 mg, 0.089 mmol). After 1 hour the reaction mixture was applied directly to a silica gel column for purification, eluting with DCM:MeOH—99:1 to 96:4. Product containing fractions were pooled and concentrated in vacuo to give the title compound. MS: m/z=547 (M(35Cl)+1). HRMS: m/z=547.2103; calculated m/z=547.2107 for C30H32N4O5(35Cl)1.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[O:13])=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.ClC1C=C(Cl)C2N(C(C(NC3C=CN=CC=3)=O)=CN=2)N=1.[N:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[NH2:47].CC(C)([O-])C.[K+]>>[Cl:8][C:6]1[CH:7]=[C:2]([NH:47][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][N:41]=2)[C:3]2[N:4]([C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[O:13])=[CH:10][N:11]=2)[N:5]=1
Reactant: Nc1ccccn1
Reactant: O=C(Nc1ccncc1)c1cnc2c(Br)cc(Cl)nn12
Agent: CC(C)(C)[O-]
Agent: O=C(Nc1ccncc1)c1cnc2c(Cl)cc(Cl)nn12
Agent: [K+]
Product: O=C(Nc1ccncc1)c1cnc2c(Nc3ccccn3)cc(Cl)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
To a vial was added a mixture of 8-bromo-6-chloro-N-(pyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide and 6,8-dichloro-N-(pyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide 1E (0.316 g, 0.896 mmol) and pyridin-2-amine (0.084 g, 0.896 mmol). The vial was purged with nitrogen, and THF (1 mL) was added. Potassium tert-butoxide (2.69 mL, 2.69 mmol, 1M in THF) was added and the mixture was stirred at room temperature. After 1 h, the reaction was quenched with a few drops of TFA and methanol. The precipitate was filtered and the powder was washed with methanol to provide 6-chloro-8-(pyridin-2-ylamino)-N-(pyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (0.2952 g, 0.497 mmol, 55.5% yield) as a pink solid.
Reaction SMILES: Cl[C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=2[CH3:15])=[O:7])=[CH:4][CH:3]=1.[F-:18].[Cs+].CN1CCCC1=O.C1C=CC=CC=1>O>[F:18][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=2[CH3:15])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)c2ccc(Cl)cc2)c(C)c1
Reactant: [F-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: c1ccccc1
Product: Cc1ccc(C(=O)c2ccc(F)cc2)c(C)c1
Reaction time: 15 h
Yield: 78 %

Procedure:
To a mixture of 12.2 g (0.05 mols) of 4-chloro-2',4'-dimethylbenzophenone, 12.1 g (0.08 mols) of cesium fluoride and 20 g of N-methylpyrrolidone were 5 ml of benzene added and water in the reaction system was removed together with benzene by azeotropy. The reaction was carried out under nitrogen atmosphere under reflux by heating while stirring for 15 hours. After cooling, the reaction product obtained was poured into 100 ml of water and then, extracted with 50 ml of diethyl ether and further with 50 ml of ether. The extracts together were dried and distilled and thus, 8.9 g of 4-fluoro-2',4'-dimethylbenzophenone were obtained.
Reaction SMILES: Cl.[CH2:2]([C:9]1[C:10]([C:20]#[C:21][C:22]2([OH:30])[CH:27]3[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]3)[CH2:23]2)=[N:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17](=[O:19])[CH3:18])[CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[BH4-].[Na+].CO>O>[CH2:2]([C:9]1[C:10]([C:20]#[C:21][C:22]2([OH:30])[CH:27]3[CH2:26][CH2:25][N:24]([CH2:29][CH2:28]3)[CH2:23]2)=[N:11][CH:12]=[C:13]([CH2:15][CH2:16][CH:17]([OH:19])[CH3:18])[CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)CCc1cnc(C#CC2(O)CN3CCC2CC3)c(Cc2ccccc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: O
Solvent: CO
Product: CC(O)CCc1cnc(C#CC2(O)CN3CCC2CC3)c(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 117.8 %

Procedure:
A mixture of 314 mg of 3-[3-benzyl-5-(3-oxobutyl)-2-pyridyl]ethynyl-3-quinuclidinol hydrochloride, 129 mg of potassium carbonate, 35 mg of sodium borohydride and 10 ml of methanol was stirred at room temperature for one hour. A small amount of water was added thereto, and the mixture was evaporated. The residue was subjected to NH-silica gel column chromatography using chloroform and then chloroform/methanol/aqueous concentrated ammonia (46:1:0.1), to give 340 mg of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]#[C:10][Si](C)(C)C)[C:4]=1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].C([O-])([O-])=O.[K+].[K+]>CO>[C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])#[CH:10]
Reactant: COc1cccc(C#C[Si](C)(C)C)c1NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cccc(OC)c1NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To tert-butyl 2-methoxy-6-((trimethylsilyl)ethynyl)phenylcarbamate (4.21 g, 13.2 mmol) in MeOH (30 mL) was added K2CO3 (9.11 g, 65.9 mmol). The reaction was stirred for 30 minutes, then filtered and washed with DCM (50 mL). The combined organic layers were concentrated and diluted with DCM (20 mL), filtered, washed a second time with DCM (50 mL), then concentrated. The residue was purified by flash chromatography through a pad of silica gel with 10:1 Hexane/EtOAc (500 mL), affording the desired product (62%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[N:20]1[CH:25]=[CH:24][C:23]([C:26]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[O:27])=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11]([N:31]3[CH2:32][CH2:33][N:28]([C:26]([C:23]4[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=4)=[O:27])[CH2:29][CH2:30]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: O=C(c1ccncc1)N1CCNCC1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Product: O=C(c1ccncc1)N1CCN(C(=O)N2Cc3ccccc3Oc3ccc(Cl)cc32)CC1
Yield: 21 %

Procedure:
The title compound of Example 2 (0.51 g, 1.7 mmol) was reacted with the title product of Example 27 (0.33 g, 1.7 mmol) by the method of Example 4. Following chromatographic purification, 0.16 g of the title product was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].ClC(Cl)(Cl)S(O[CH2:21][C:22]([F:25])([F:24])[F:23])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:21][C:22]([F:25])([F:24])[F:23])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NC1CCN(CC(F)(F)F)CC1
Reaction time: 17 h

Procedure:
Piperidin-4-yl-carbamic acid tert-butyl ester (commercially available from ASTATECH) (5 g, 24.96 mmol), 2,2,2,-trifluoroethyl trichloromethane sulfonate (7.03 g, 1 equivalent), and potassium carbonate (4.1 g, 1.2 eq) were taken up in acetone (80 mL) and heated at reflux with stirring for 17 hours. The solvent was removed under reduced pressure at 40° C. and ethyl acetate and water were added to the residue. The layers were partitioned and then separated. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give a dark colored solid. Purification by chromatography on silica gel using 15% ethyl acetate in hexanes as the eluant gave [1-(2,2,2-trifluoroethyl)piperidin-4-yl]-carbamic acid tert-butyl ester (4.45 g) as an off-white powder, m.p. 99.2-99.8° C., (M+H)+=283.
Reaction SMILES: [CH3:1][C:2]1[O:8][CH:7]=[C:6]([OH:9])[C:4](=[O:5])[CH:3]=1.CN(C)C.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C1COCC1>[C:14]([O:9][C:6]1[C:4](=[O:5])[CH:3]=[C:2]([CH3:1])[O:8][CH:7]=1)(=[O:16])[CH3:15]
Reactant: Cc1cc(=O)c(O)co1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)C
Solvent: C1CCOC1
Product: CC(=O)Oc1coc(C)cc1=O
Reaction time: 0.08 h
Yield: 81.3 %

Procedure:
Allomaltol (600 mg; 4.76 mmol) was weighed out into a round bottom flask (100 ml) containing a stir-bar. The contents were diluted with anhydrous THF (˜20 ml) and stirred (˜5 min) to afford a solution. Next, trimethyl amine (833 μl; 6.33 mmol; 1.33 equiv.) was added drop-wise and the contents stirred (˜5 min). Acetic anhydride (641 μl; 5.00 mmol) was then added drop-wise, capped and stirred at room temperature. The reaction was monitored via silica gel TLC. Once complete, the reaction mixture was concentrated under reduced pressure and the contents purified by silica gel chromatography to afford 650 mg product (3.87 mmol; 81% yield). This compound was found to have an EC50 of 106 μM. 1H NMR (DMSO-d6) δ 8.39 (s, 1H; 2-H); 6.36 (s, 1H; 5-H); 2.30 (s, 3H); 2.24 (s, 3H).