Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:22][CH3:23])=[C:5]([CH:10]([CH2:20][CH3:21])[CH2:11][C@:12]([OH:19])([C:15]([F:18])([F:17])[F:16])[CH:13]=O)[CH:6]=[CH:7][C:8]=1[F:9])[CH3:2].[NH2:24][C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27]=[CH:28][C:29](=[O:35])[NH:30]2.C(O)(=O)C.O>C1(C)C=CC=CC=1.CC(C)([O-])C.[Ti+4].CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-])C>[CH2:1]([C:3]1[C:4]([O:22][CH3:23])=[C:5]([CH:10]([CH2:20][CH3:21])[CH2:11][C@:12]([OH:19])([C:15]([F:16])([F:17])[F:18])[CH:13]=[N:24][C:25]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:26]=2[CH:27]=[CH:28][C:29](=[O:35])[NH:30]3)[CH:6]=[CH:7][C:8]=1[F:9])[CH3:2]
Reactant: CCc1c(F)ccc(C(CC)C[C@@](O)(C=O)C(F)(F)F)c1OC
Reactant: Nc1cccc2[nH]c(=O)ccc12
Agent: [Ti+4]
Agent: CC(C)(C)[O-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1c(F)ccc(C(CC)C[C@@](O)(C=Nc2cccc3[nH]c(=O)ccc23)C(F)(F)F)c1OC

Procedure:
45 mg (0.13 mmol) of (2R,4R/S)-4-(3-ethyl-4-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal and 21.4 mg (0.13 mmol) of 5-aminoquinolin-2(1h)-one are dissolved in 20 ml of toluene and the solution is admixed with 0.56 ml (1.86 mmol) of titanium tert-butoxide and 0.11 ml of acetic acid. The reaction mixture is heated at 1000 for 2 hours, cooled, poured into water and stirred vigorously. The suspension is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. The phases of the filtrate are separated and extraction is carried out again with ethyl acetate. The extracts are washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is removed in vacuo to give 80 mg of (5-{[(2R,4R/S)-4-(3-ethyl-4-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexylidene]amino}quinolin-2(1H)-one as a crude product. The imine is dissolved in 4.4 ml of CH2Cl2 and the solution is cooled to −30° C. 1.5 ml (1.5 mmol) of a 1M BBr3 solution in dichloromethane are added slowly dropwise over 15 minutes and the reaction solution is allowed to warm to room temperature over 22 hours. It is poured onto a mixture of saturated NaHCO3 solution and ice. It is extracted repeatedly with ethyl acetate and the extracts are washed with saturated NaCl solution and dried over Na2SO4. Purification by column chromatography on silica gel (hexane/isopropanol 16%) and subsequent preparative thin-layer chromatography on an amine phase (Merck NH2F254, ethyl acetate/triethylamine, 2%) yield 8 mg of the title compound and 6 mg of the corresponding 8R-diastereomer.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH:20]C(=O)C)=[CH:16][CH:15]=1.C([O-])C.[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1
Reactant: CC(=O)Nc1ccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)cc1
Agent: CC[O-]
Agent: [Na+]
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(N)cc2)C1

Procedure:
3.0 g (8.59 mmol) of N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-phenyl]acetamide (example 3, intermediate 5) were heated to reflux in 100 ml of 21% strength sodium ethanolate solution. Solid sodium ethanolate was added depending on the progress of the reaction, until complete conversion was achieved. For workup, the solvent was removed and the residue was taken up in H2O. It was extracted twice with dichloromethane. The combined organic phases were dried with MgSO4 and concentrated. Further purification takes place by chromatography on silica gel with an ethyl acetate/heptane mixture, resulting in the aniline compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[CH2:11]([NH2:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(O)CC>O>[CH2:11]([NH:23][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCN
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCCO
Solvent: O
Product: CCCCCCCCCCCCNc1ncnc2nc[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
A mixture of 6-chloropurine (2.5 g, 0.016 mole) and n-dodecylamine (7.4 g, 0.04 mole) in 40 ml. of n-propanol was refluxed for 5 hours. The reaction mixture was stirred at room temperature for 1 hour and cooled with water (15° C.) for another hour. The product was collected by filtration, washed by two 5 ml. portions of n-propanol and dried in a vacuum oven overnight to give 4.5 g (92% yield) of 6-n-dodecylaminopurine, a colorless solid, m.p. 159°-160° C., λ max (H2O)=268 nm, ε=17.3×103.
Reaction SMILES: [CH2:1]([O:3][P:4]([SH:9])(=[S:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH3:10][C:11]([CH3:19])([SH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:20]O>>[P:4]([S:9][CH2:20][S:18][C:11]([CH3:19])([CH3:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[S:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2]
Reactant: CC(C)(S)c1ccccc1
Reactant: CO
Reactant: CCOP(=S)(S)OCC
Product: CCOP(=S)(OCC)SCSC(C)(C)c1ccccc1

Procedure:
A mixture of 37.2 grams (0.200 mole) of O,O- diethyl phosphorodithioic acid, 30.5 grams (0.200 mole) of α,α-dimethyl α-toluenethiol and 16.5 ml. (0.220 mole) of methanol-free formalin is stirred vigorously at room temperature for 3 days. The mixture is extracted with 250 ml. of methylene chloride, and this solution is washed with two 30 ml. portions of saturated sodium chloride solution, four 30 ml. portions of 5% potassium hydroxide solution, and three 30 ml. portions of saturated sodium chloride. Evaporation of the solvent from the dried (magnesium sulfate) solution gives a colorless, moderately viscous liquid residue. The proton magnetic resonance spectrum of this material establishes that the desired product is the major component.
Reaction SMILES: F[C:2]1[CH:18]=[CH:17][C:5]([C:6]([N:8]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:7])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH2:29][NH:30][CH2:31][CH2:32][CH2:33][NH2:34].[C:35](=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:9]([N:8]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6](=[O:7])[C:5]1[CH:17]=[CH:18][C:2]([NH:34][CH2:33][CH2:32][CH2:31][N:30]([CH3:35])[CH2:29][CH2:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=2)=[C:3]([N+:19]([O-:21])=[O:20])[CH:4]=1)[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)CN(CC(C)C)C(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: NCCCNCCc1ccccn1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)CN(CC(C)C)C(=O)c1ccc(NCCCN(C)CCc2ccccn2)c([N+](=O)[O-])c1
Yield: 92 %

Procedure:
A mixture of 4-fluoro-N,N-diisobutyl-3-nitrobenzamide (2.07 g, 1 eq), N-(2-pyridin-2-ylethyl)propane-1,3-diamine (1.6 g, 1.2 eq) and cesium carbonate (4.5 g, 2 eq) in acetonitrile (70 ml) is heated under reflux for 3 hours then concentrated under reduced pressure at 40° C. The residue is taken up in dichloromethane (100 ml) and water (40 ml). After decantation and extraction, the combined organic phases are washed with salt water, dried over Na2SO4 then evaporated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent: dichloromethane 100 to dichloromethane/methanol 8:2) produces the expected compound in the form of a yellow oil (3.1 g; 92% yield).
Reaction SMILES: Cl[C:2]1[C:7]2=[C:8]([CH:17]([CH3:19])[CH3:18])[C:9]([C:11]3[O:12][C:13]([CH3:16])=[CH:14][N:15]=3)=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][C:31]=1[F:32])[C:24]([NH:26][O:27][CH3:28])=[O:25]>CN(C)C=O.C(OCC)(=O)C>[F:32][C:31]1[CH:30]=[CH:29][C:23]([C:24]([NH:26][O:27][CH3:28])=[O:25])=[CH:22][C:21]=1[NH:20][C:2]1[C:7]2=[C:8]([CH:17]([CH3:19])[CH3:18])[C:9]([C:11]3[O:12][C:13]([CH3:16])=[CH:14][N:15]=3)=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CONC(=O)c1ccc(F)c(N)c1
Reactant: Cc1cnc(-c2cn3ncnc(Cl)c3c2C(C)C)o1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CONC(=O)c1ccc(F)c(Nc2ncnn3cc(-c4ncc(C)o4)c(C(C)C)c23)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 47.1 %

Procedure:
To a solution of Example 58 (30 mg, 0.11 mmol) in dimethyl formamide (0.7 mL) at RT was added 3-amino-4-fluoro-N-methoxy-benzamide (30 mg, 0.16 mmol). After stirring at ambient temperature for 19 h, the mixture was dissolved in ethyl acetate and washed with 10% LiCl solution. The organic layer was separated, dried and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 5% methanol in chloroform to afford the title compound (22 mg, 48%) as an off-white solid. LC/MS; (M+H)+=425.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10]S(C(C)(C)C)=O)[CH3:9])=[C:4]([F:17])[CH:3]=1.[ClH:18].O1CCOCC1>CO>[Cl-:18].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH3+:10])[CH3:9])=[C:4]([F:17])[CH:3]=1
Reactant: C[C@@H](NS(=O)C(C)(C)C)c1ccc(Br)cc1F
Reactant: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@@H]([NH3+])c1ccc(Br)cc1F
Product: [Cl-]

Procedure:
To a solution of N-[(1R)-1-(4-bromo-2-fluorophenyl)ethyl]-2-methylpropane-2-sulfinamide (26.29 g, 81.58 mmol) in 40 mL methanol was added HCl/dioxane (4M, 40.8 mL, 0.163 mol) solution. The reaction mixture was concentrated in vacuo, and ether was added. The white solid was collected, washing with cold ether, and dried under vacuum to yield (1R)-1-(4-bromo-2-fluorophenyl)ethanaminium chloride that gave proton NMR spectra consistent with theory.
Reaction SMILES: [N:1]1([C:6]2[CH:19]=[CH:18][C:9]([C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[C:27][CH2:28][O:29][C:30](=[O:35])/[CH:31]=[C:32](\[NH2:34])/[CH3:33])[CH:21]=1.[CH:36](=O)[CH:37]=[CH:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(O)(=O)C>CO>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[C:27][CH2:28][O:29][C:30]([C:31]2[CH:36](/[CH:37]=[CH:38]/[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([C:9]3[CH:18]=[CH:19][C:6]([N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)=[CH:7][CH:8]=3)[NH:34][C:32]=2[CH3:33])=[O:35])[CH:21]=1
Reactant: CCOC(=O)CC(=O)c1ccc(-n2ccnc2)cc1
Reactant: O=CC=Cc1ccccc1
Reactant: C/C(N)=C/C(=O)OCC#Cc1cccnc1
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C1=C(c2ccc(-n3ccnc3)cc2)NC(C)=C(C(=O)OCC#Cc2cccnc2)C1/C=C/c1ccccc1

Procedure:
520 mg of ethyl 4-(1-imidazolyl)benzoylacetate, 420 mg of 3-aminocrotonate 3-(3-pyridyl)-2-propynylester, and 300 mg of cinnamaldehyde were allowed to stand in 20 ml methanol solution containing 1 ml of acetic acid at room temperature for 1 week. The reaction solution was extracted with ethyl acetate and then the solvent was concentrated to dryness. The oily substance was purified by silica gel column chromatography to obtain the target compound in an amount of 520 mg (48.2%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:16]([O-])=O.[Na+].O.O.[Sn](Cl)[Cl:23].C(O)[C@H]1OC(=O)[C@H](O)[C@@H](O)[C@@H]1O>Cl.O.C(O)C>[ClH:23].[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:13][NH2:16])=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: O=N[O-]
Reactant: Cl[Sn]Cl
Agent: Cl
Agent: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NNc1ccc(OCc2ccccc2)cc1
Temperature: -2 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
To a slurry of 4-benzyloxyaniline (250 g) and ethanol 300 ml) in 30% HCl (350 ml) and 37% HCl (150 ml) was added a solution of sodium nitrite (77 g) in water (350 ml), while maintaining the temperature between -8 and -2° C. The reaction was stirred for an additional four hours at -2° C. A solution of tin (II) chloride dihydrate (710 g) in 30% HCl (770 ml) was added slowly followed by d-gluconic acid lactone (575 g), and the resulting white suspension was cooled overnight. The crude product was collected by vacuum filtration and washed with 1 N hydrochloric acid, ether, and vacuum dried to give 248.9 g of the desired product, m.p. 173-174° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([N:7]1[C:11]([NH:12][C:13](=[O:32])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])=[C:10]2[CH2:33][NH:34][C:35]([CH3:37])([CH3:36])[C:9]2=[N:8]1)=[O:6])[CH3:3].C(N(CC)C(C)C)(C)C.[F:47][C:48]1[CH:49]=[C:50]([S:55](Cl)(=[O:57])=[O:56])[CH:51]=[C:52]([F:54])[CH:53]=1>ClCCl>[CH2:2]([O:4][C:5]([N:7]1[C:11]([NH:12][C:13](=[O:32])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])=[C:10]2[CH2:33][N:34]([S:55]([C:50]3[CH:49]=[C:48]([F:47])[CH:53]=[C:52]([F:54])[CH:51]=3)(=[O:57])=[O:56])[C:35]([CH3:36])([CH3:37])[C:9]2=[N:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)n1nc2c(c1NC(=O)c1ccccc1CN1C(=O)c3ccccc3C1=O)CNC2(C)C
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)n1nc2c(c1NC(=O)c1ccccc1CN1C(=O)c3ccccc3C1=O)CN(S(=O)(=O)c1cc(F)cc(F)c1)C2(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzoylamino]-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester hydrochloride (1.24 g, 2.4 mmol) in dry dichloromethane (30 mL) was added N,N-diisopropylethylamine (1.67 mL, 9.6 mmol) and 3,5-difluorobenzenesulfonyl chloride (0.77 g, 3.6 mmol). After stirring at room temperature for 3 hours the mixture was diluted with dichloromethane (50 mL), washed with 1N HCl, water, saturated solution of NaHCO3, brine, dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel eluting with ethyl acetate and then with dichloromethane/methanol 98:2 affording the title compound as white solid (1.4 g).
Reaction SMILES: C[O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([CH3:11])[CH:4]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([CH3:11])[CH:4]=1
Reactant: COc1ccc(C#N)c(C)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(O)ccc1C#N
Temperature: 0 °C
Reaction time: 120 h
Yield: 103.9 %

Procedure:
A solution of 4-methoxy-2-methylbenzonitrile (5.0 g, 33.97 mmol) in DCM (150 mL) is cooled down to 0° C. before adding dropwise a 1M BBr3 in DCM solution (136 mL, 136 mmol). The reaction mixture is allowed to reach rt and stirring is then continued at 45° C. for 5 days. Ice water (500 mL) is then added and the reaction mixture is stirred for 1 h before sat. aq. NaHCO3 (250 mL) is added. The mixture is extracted with DCM (200 mL then 4×100 mL) and the combined org. extracts are dried over MgSO4, filtered and evaporated to give the title compound as a brown solid (4.7 g); LC-MS: tR=0.76 min. 1H NMR (D6-DMSO): δ 2.38 (s, 3H), 6.73 (dd, J=8.5, 2.0 Hz, 1H), 6.79 (d, J=2.0 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 10.49 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([N:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][N:16]=[C:15]4[C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[N:9]=[N:8]2)[CH2:2]1.F[C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:29]=1[CH:30]=O.[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[F:36][C:32]1[CH:33]=[CH:34][CH:35]=[C:28]([CH3:37])[C:29]=1[CH2:30][N:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([N:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][N:16]=[C:15]4[C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[N:9]=[N:8]2)[CH2:2]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: c1cc(-c2n[nH]c3ccc(-c4cn([C@@H]5CCCNC5)nn4)cc23)ccn1
Reactant: O=Cc1c(F)cccc1F
Agent: [Na+]
Solvent: CO
Product: Cc1cccc(F)c1CN1CCC[C@@H](n2cc(-c3ccc4[nH]nc(-c5ccncc5)c4c3)nn2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.9 %

Procedure:
(R)-5-(1-(piperidin-3-yl)-1H-1,2,3-triazol-4-yl)-3-(pyridin-4-yl)-1H-indazole (0.05 g, 0.14 mmol) was dissolved in MeOH (3 mL) at 0° C., added 2,6-difluorobenzaldehyde (0.2 g, 1.4 mmol) and then sodium triacetoxyborohydride (0.0761 g, 0.37 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 3 h. Evaporated the solvent, subjected to Preparative Thin Layer chromatography to give (R)-5-(1-(1-(2-fluoro-6-methylbenzyl)piperidin-3-yl)-1H-1,2,3-triazol-4-yl)-3-(pyridin-4-yl)-1H-indazole (0.034 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5](=[O:23])[N:6]([CH2:8][CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)[N:7]=1.[S:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C([O-])(O)=O.[Na+].CCOC(C)=O>[CH3:22][O:21][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][CH2:9][CH2:8][N:6]3[C:5](=[O:23])[CH:4]=[CH:3][C:2]([C:26]4[CH:27]=[CH:28][S:24][CH:25]=4)=[N:7]3)=[CH:12][CH:13]=[N:14]2)=[CH:19][CH:18]=1
Reactant: COc1ccc2c(OCCn3nc(Cl)ccc3=O)ccnc2c1
Reactant: OB(O)c1ccsc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc2c(OCCn3nc(-c4ccsc4)ccc3=O)ccnc2c1
Temperature: 120 °C
Yield: 72.2 %

Procedure:
To a solution of 6-chloro-2-(2-(7-methoxyquinolin-4-yloxy)ethyl)pyridazin-3(2H)-one (0.090 g, 0.27 mmol) and 3-thiopheneboronic acid (0.069 g, 0.54 mmol) in 4 mL of dioxane was added 1 mL of 1N Na2CO3 followed by 30 mg of FibreCat, in a microwave vial. The reaction was heated to 120° C. for 30 minutes. The mixture was then diluted with 40 mL of NaHCO3 and 60 mL of EtOAc. The organic phase was separated, washed with 30 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtAOc to 10% MeOH/EtOAc) to give a white solid (0.074 g, 72% yield). MS (ESI pos. ion) m/z (MH+): 380.1. Calc'd Exact Mass for C20H17N3O3S: 379.1.
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[O:6][C:5]=1[NH:15][C@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:17][CH3:18])(=O)[CH3:2].[Cl:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:32]=1[Cl:33])[NH2:29]>C(#N)C>[C:19]1([C@@H:16]([NH:15][C:5]([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:14])[N:29]([C:28]3[CH:30]=[CH:31][C:32]([Cl:33])=[C:26]([Cl:25])[CH:27]=3)[C:1]=2[CH3:2])=[O:6])[CH2:17][CH3:18])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CC[C@H](Nc1oc(=O)c2ccccc2c1C(C)=O)c1ccccc1
Solvent: CC#N
Product: CC[C@H](NC(=O)c1c(C)n(-c2ccc(Cl)c(Cl)c2)c(=O)c2ccccc12)c1ccccc1
Temperature: 160 °C
Yield: 25.3 %

Procedure:
A mixture of 4-acetyl-3-((S)-1-phenyl-propylamino)-isochromen-1-one (60 mg) and 3,4-dichloroaniline (250 mg) in acetonitrile (0.5 ml) were heated under microwave irradiation at 160° C. for 15 min. The reaction mixture was partitioned between 2M HCl (3 ml) and ethyl acetate (3 ml). The organic solution was absorbed on SiO2 (600 mg) and flash chromatographed on SiO2 (20 g) with gradient heptane-ethyl acetate to give 22 mg of the title compound as a white solid. LC-MS (m/z) 465.4 & 467.4 (MH+); tR=1.63.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:13])([F:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Cl[C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][N:16]=1>CS(C)=O.CCOCC>[CH3:22][O:21][C:19](=[O:20])[C:18]1[CH:23]=[CH:24][C:15]([O:11][C:8]2[CH:7]=[CH:6][C:5]([C:4]([F:12])([F:13])[F:3])=[CH:10][CH:9]=2)=[N:16][CH:17]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: COC(=O)c1ccc(Oc2ccc(C(F)(F)F)cc2)nc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 50.5 %

Procedure:
To a suspension of NaH (60% dispersion in oil; 1.2 g, 30 mmol) in 30 mL of DMSO was added a solution of 4-(trifluoromethyl)phenol (1.86 g, 30 mmol) in 20 mL of DMSO and the mixture was stirred for 30 min. To this was added methyl 6-chloronicotinate (5.13 g, 30 mmol) and the solution was heated overnight at 70° C. The reaction was cooled to room temperature and then diluted with Et2O. The solution was washed with H2O, brine, dried with Na2SO4, suction filtered, and the solvent removed in vacuo. The residue was purified via normal phase column chromatography over SiO2 using 15% Et2O/pentane to yield 6-(4-trifluoromethylphenoxy)-nicotinic acid methyl ester (4.5 g) as a colorless solid: 1H-NMR (300 MHz, CDCl3) δ 8.81 (dd, J=2.5, 0.6 Hz, 1H), 8.33 (dd, J=8.6, 2.4 Hz, 1H), 7.69 (d, J=8.5 Hz, 2H), 7.31-7.24 (m, 2H), 7.02 (dd, J=8.5, 0.6 Hz, 1H), 3.93 (s, 3H); EIMS m/z 297 ([M]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]1[CH2:10][C@H:9]1[C:11](=O)[CH3:12].N1C=CC=CC=1.Cl.[CH3:21][O:22][NH2:23]>CO.O>[CH3:21][O:22][N:23]=[C:11]([C@@H:9]1[CH2:10][C@H:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH3:12]
Reactant: CC(=O)[C@@H]1C[C@H]1c1ccccc1Cl
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Solvent: O
Product: CON=C(C)[C@@H]1C[C@H]1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.4 %

Procedure:
To a stirred solution of trans 1-[2-(2-chloro-phenyl)-cyclopropyl]-ethanone (1.0 g; 5.1 mmol) in methanol (10 ml) at ambient temperature was added pyridine (0.85 ml; 10 mmol) and methoxyamine hydrochloride (0.86 g; 10 mmol). The reaction mixture was stirred for 16 hours at ambient temperature then poured in water (50 mL) and extracted with dichloromethane (3×30 ml). Combined organic layers were dried over anhydrous sodium sulphate. The solvent was removed in vacuo to afford 1.1 g (98% of theory) of trans 1-[2-(2-chloro-phenyl)-cyclopropyl]-ethanone O-methyl-oxime as an oil.
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:36]2[N:40](COCC[Si](C)(C)C)[N:39]=[CH:38][CH:37]=2)O1>>[CH2:26]([N:22]([CH2:23][CH2:24][OH:25])[C:3]1[C:2]([C:36]2[NH:40][N:39]=[CH:38][CH:37]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1)[CH3:27]
Reactant: CC1(C)OB(c2ccnn2COCC[Si](C)(C)C)OC1(C)C
Reactant: CCN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Product: CCN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1ccn[nH]1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 19 using 5-bromo-6-(ethyl(2-hydroxyethyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 21.1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole to afford a yellow wax UPLC-MS (Condition 3) tR=0.97 min, m/z=436.2 [M+H]+, m/z=434.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.93 (t, J=6.97 Hz, 3H) 3.26 (br. s, 2H) 3.36-3.44 (m, 2H) 3.44-3.52 (m, 2H) 4.59 (br. s, 1H) 6.53 (d, J=1.96 Hz, 1H) 7.34 (d, J=8.31 Hz, 2H) 7.80 (br. s, 1H) 7.84-7.90 (m, 2H) 8.13 (s, 1H) 8.71 (d, J=1.96 Hz, 1H) 10.28 (s, 1H) 12.94 (br. s, 1H).
Reaction SMILES: CC1C=CN=C(NC2N=C(C3OC(NCC4C=CN=CC=4)=NC=3)C=CC=2)C=1.Cl[C:29]1[O:30][C:31]([C:34]2[CH:35]=[C:36]([NH:40][C:41]3[N:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N:42]=3)[CH:37]=[CH:38][CH:39]=2)=[CH:32][N:33]=1.FC(F)(F)C(O)=O.[CH3:55][O:56][CH2:57][CH2:58][N:59]1[CH2:64][CH2:63][NH:62][CH2:61][C:60]1=[O:65]>CC(O)C>[CH3:55][O:56][CH2:57][CH2:58][N:59]1[CH2:64][CH2:63][N:62]([C:29]2[O:30][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([NH:40][C:41]4[N:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N:42]=4)[CH:35]=3)=[CH:32][N:33]=2)[CH2:61][C:60]1=[O:65]
Reactant: COCCN1CCNCC1=O
Reactant: Cc1ccnc(Nc2cccc(-c3cnc(Cl)o3)c2)n1
Agent: Cc1ccnc(Nc2cccc(-c3cnc(NCc4ccncc4)o3)n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: COCCN1CCN(c2ncc(-c3cccc(Nc4nccc(C)n4)c3)o2)CC1=O

Procedure:
Prepared as for 5-[6-(4-methylpyridin-2-ylamino)pyridin-2-yl]-N-(pyridin-4-ylmethyl)oxazol-2-amine above from [3-(2-chloro-oxazol-5-yl)-phenyl]-(4-methyl-pyrimidin-2-yl)-amine and 1-(2-methoxy-ethyl)-2-oxopiperazine trifluoroacetic acid salt in iPrOH. 1H NMR (400 MHz, DMSO-d6) δ 9.56 (s, 1H), 8.35 (d, J=5.0 Hz, 1H), 8.10 (s, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.31-7.20 (m, 2H), 7.15 (d, J=7.6 Hz, 1H), 6.76 (d, J=5.0 Hz, 1H), 4.10 (s, 2H), 3.79-3.72 (m, 2H), 3.58-3.46 (m, 6H), 3.25 (dd, J=2.7, 2.2 Hz, 3H), 2.38 (s, 3H). (ESI+) m/z 409 (M+H)+. Retention time=2.94 mins (method 1).