Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:12]([CH2:13][CH2:14][NH2:15])=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].[C:18]1([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.ON1C(=O)C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.C(Cl)CCl>CN(C=O)C>[C:1]([C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:12]([CH2:13][CH2:14][NH:15][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][C:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:25][CH:26]=3)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Cn2cncc2CCN)cc1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: N#Cc1ccc(Cn2cncc2CCNC(=O)c2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(4-cyanobenzyl)-5-aminoethylimidazole (107 mg, 0.358 mmol), 4-phenylbenzoic acid (70.9 mg, 0.358 mmol), 3-hydroxy-1,2,3-benzotriazin-4(3H)-one, (72.6 mg, 0.445 mmol) and triethylamine (0.215 mL, 1.54 mmol) in DMF (4.0 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, EDC, (83.3 mg, 0.435 mmol) and the mixture stirred for 16 hours at ambient temperature. The reaction was partitioned between sat. aq. NaHCO3 solution and EtOAc. The organic layer was dried, (Na2SO4) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 5% MeOH in CH2Cl2) to afford the imidazole which was converted to the HCl salt by treatment with one equivalent of HCl in aqueous acetonitrile. Evaporation of the solvent in vacuo afforded the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:5]=[N:6][CH:7]=1.CCN(CC)CC.[CH2:23]([OH:29])[CH2:24][CH2:25][CH2:26][C:27]#[CH:28].C(=O)(O)[O-].[Na+]>C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O>[OH:29][CH2:23][CH2:24][CH2:25][CH2:26][C:27]#[C:28][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:5]=[N:6][CH:7]=1
Reactant: CN1CCC[C@H]1COc1cncc(Br)c1
Reactant: C#CCCCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CN1CCC[C@H]1COc1cncc(C#CCCCCO)c1
Temperature: 25 °C
Yield: 93.6 %

Procedure:
To a solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine (272 mg, 1.00 mmol), bis(triphenylphosphine)palladium(II) chloride (28 mg, 0.039 mmol), copper (I) iodide (5 mg, 0.039 mmol) and NEt3 (1.0 mL) in CH2Cl2 (3.0 mL) was added 5-hexyn-1-ol (0.172 mL, 1.5 mmol). The mixture was refluxed overnight and then cooled to room temperature. Water (2 mL) was added, and solid sodium bicarbonate was added until the aqueous layer was saturated. The mixture was extracted with EtOAc, which was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with NH4OH/MeOH/EtOAc 0:1:9 and 1:10:90 to afford a light yellowish oil (270 mg, 94%). MS (CI/NH3) m/z 289 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 1.55-1.90 (m, 8H), 1.97-2.07 (m, 1H), 2.25-2.46 (m, 1H), 2.27 (s, 3H), 2.46-2.53 (m, 1H), 2.60-2.71 (m, 1H), 3.07-3.16 (m, 1H), 3.68-3.74 (m, 2H), 3.88-4.03 (m, 2H), 7.19 (dd, J=3.0, 1.8 Hz, 1H), 8.22 (d, J=3.0 Hz, 1H), 8.23 (d, J=1.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[C:8]([OH:13])=[CH:7]2.Cl[C:15]1[C:16]([C:21]#[N:22])=[N:17][CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O.C(OCC)(=O)C>[C:21]([C:16]1[C:15]([O:13][C:8]2[C:9]([CH3:12])=[N:10][C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[F:1])=[CH:20][CH:19]=[CH:18][N:17]=1)#[N:22]
Reactant: N#Cc1ncccc1Cl
Reactant: Cc1nc2c(F)cccc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1nc2c(F)cccc2cc1Oc1cccnc1C#N
Temperature: 130 °C
Reaction time: 3 h
Yield: 83.3 %

Procedure:
4.9 g of 8-fluoro-3-hydroxy-2-methylquinoline, 3.2 g of 3-chloro-2-cyanopyridine and 3.8 g of potassium carbonate were dissolved in 20 ml of N-methylpyrrolidone followed by stirring for 3 hours at 130° C. Subsequently, the reaction solution was cooled to room temperature followed by addition of water and extraction with ethyl acetate. The extract was washed with saturated saline and dried with magnesium sulfate followed by distilling off the solvent under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 5.37 g of 3-(2-cyano-pyridin-3-yloxy)-8-fluoro-2-methylquinoline.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)(=O)OCC)C.[CH3:22][CH:23]([N:27]1[C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([CH:36]=O)[C:30]=2[CH:29]=[CH:28]1)[CH2:24][CH2:25][CH3:26]>COC>[C:12]1(/[CH:11]=[CH:36]\[C:31]2[CH:32]=[CH:33][CH:34]=[C:35]3[C:30]=2[CH:29]=[CH:28][N:27]3[CH:23]([CH2:24][CH2:25][CH3:26])[CH3:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CCCC(C)n1ccc2c(C=O)cccc21
Reactant: CCOP(=O)(Cc1cccc2ccccc12)OCC
Agent: COC
Agent: [H-]
Agent: [Na+]
Product: CCCC(C)n1ccc2c(/C=C\c3cccc4ccccc34)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
To a suspension of 95% sodium hydride (NaH, 347 mg, 13.76 mmol) in dimethyl ether (DME, 17 mL) was added diethyl(naphthalen-1-ylmethyl)phosphonate (4) (960 mg, 3.44 mmol) dropwise at 0° C. The resulting solution was stirred at room temperature for 1 h, then semi-pure 1-(pentan-2-yl)-1H-indole-4-carbaldehyde (3) (˜3.44 mmol) in DME (2 mL) was added dropwise and the reaction mixture was stirred for 8 h at room temperature. After the reaction completed as indicated by thin layer chromatography, the reaction mixture was poured into ice-cold water (30 mL), extracted with ethyl acetate (3×30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography (6:1 hexane/ethyl acetate) gave (Z)-4-(2-(naphthalen-1-yl)vinyl)-1-(pentan-2-yl)-1H-indole (5) (580 mg, 1.70 mmol) in 50% yield. 1H NMR (CDCl3): 8.30 (d, 1H, J=8.0 Hz), 8.09 (d, 1H, J=16.0 Hz), 7.91 (dd, 1H, J=7.5, 1.5 Hz), 7.86 (d, 1H, J=7.0 Hz), 7.84 (d, 1H, J=8.0 Hz), 7.59 (d, 1H, J=16.0 Hz), 7.58-7.52 (m, 3H), 7.48 (d, 1H, J=7.0 Hz), 7.39 (d, 1H, J=8.0 Hz), 7.32 (d, 1H, J=3.5 Hz), 7.29 (d, 1H, J=7.5 Hz), 6.91 (d, 1H, J=3.0 Hz), 4.61-4.53 (m, 1H), 2.00-1.92 (m, 1H), 1.88-1.80 (m, 1H), 1.56 (d, 3H, J=7.0 Hz), 1.36-1.20 (m, 4H), 0.93 (t, 3H, J=7.5 Hz).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[C:4]([N:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]([OH:19])=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:34][NH:35][O:36][CH3:37].CCN(C(C)C)C(C)C>C1COCC1.O.Cl>[Br:1][C:2]1[C:3]([F:20])=[C:4]([N:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]([N:35]([O:36][CH3:37])[CH3:34])=[O:19])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CNOC
Reactant: COc1cn(-c2cccc(Br)c2F)nc(C(=O)O)c1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cn(-c2cccc(Br)c2F)nc(C(=O)N(C)OC)c1=O
Temperature: 40 °C
Reaction time: 18 h
Yield: 99.3 %

Procedure:
A mixture of 1-(3-bromo-2-fluorophenyl)-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (3.76 g, 11.0 mmol) and CDI (1.95 g, 12.1 mmol) in THF (38 mL) was heated to 40° C. for 2 h. To the solution were added N,O-dimethylhydroxylamine hydrochloride (1.60 g, 16.4 mmol) and i-Pr2NEt (2.86 mL, 16.4 mmol) at room temperature. The mixture was stirred at room temperature for 18 h. The mixture was diluted with water and 1 M HCl aqueous solution, extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on basic silica gel (EtOAc/MeOH=100/0 to 80/20) to yield the title compound (4.22 g, >99% yield) as a white solid: NMR (DMSO-d6, 300 MHz): δ ppm 3.25 (3H, s), 3.58 (3H, s), 3.80 (3H, s), 7.39 (1H, td, J=8.1, 1.5 Hz), 7.78 (1H, ddd, J=8.2, 6.9, 1.5 Hz), 7.92 (1H, ddd, J=8.0, 6.3, 1.5 Hz), 8.58 (1H, s).
Reaction SMILES: O1CCCC1.[C:6]([C:8]1[CH:18]=[CH:17][C:11]2[S:12][C:13]([CH:15]=O)=[CH:14][C:10]=2[CH:9]=1)#[N:7].[Cl-].[CH2:20]([O:22][C:23]1[C:24]([O:56][CH3:57])=[CH:25][C:26]([CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])=[C:27]([C:29]2C=CC=CC=2[P+](C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:28]=1)[CH3:21].C1CCN2C(=NCCC2)CC1>C(O)C>[C:6]([C:8]1[CH:18]=[CH:17][C:11]2[S:12][C:13]([CH2:15][CH2:29][C:27]3[CH:28]=[C:23]([O:22][CH2:20][CH3:21])[C:24]([O:56][CH3:57])=[CH:25][C:26]=3[CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])=[CH:14][C:10]=2[CH:9]=1)#[N:7]
Reactant: CCOC(=O)CCc1cc(OC)c(OCC)cc1-c1ccccc1[P+](C)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc2sc(C=O)cc2c1
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CCc1cc(OC)c(OCC)cc1CCc1cc2cc(C#N)ccc2s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.2 %

Procedure:
9.3 g of ethyl 3-(4-ethoxy-3-methoxyphenyl)-propionate obtained in the above step c) was dissolved in 10 ml of acetic acid, followed by adding 7.4 g of chloromethyl methyl ether and subsequently stirring at room temperature for 22 hours. The resulting reaction solution was poured into ice water, extracted with ethyl acetate, washed with water and then dried to distill off the solvent. The residue thus obtained was dissolved in 10 ml of xylene, and the solution was mixed with 8.54 g of triphenylphosphine. The resulting mixture was stirred at room temperature for 18 hours and then at 70 to 80° C. for 5 hours. After cooling, xylene was removed by decantation, and the remaining portion was solidified by adding n-hexane to obtain 6.0 g of crude [5-ethoxy-2-(2-ethoxycarbonylethyl)-4-methoxyphenyl]methyltriphenylphosphonium chloride. e) To a mixture solution of 50 ml of tetrahydrofuran and 50 ml of ethanol were dissolved 1.5 g of 5-cyanobenzo[b]thiophene-2-carbaldehyde and 6.34 g of crude [5-ethoxy-2-(2-ethoxycarbonylethyl)-4-methoxyphenyl]-methyltriphenylphosphonium chloride obtained in the above step d). 1.83 g of 1,8-diazabicyclo[5.4.0]-7-undecene was added thereto, followed by stirring at room temperature for 18 hours. The resulting reaction solution was concentrated under a reduced pressure, and the residue was dissolved in a mixture solution of 20 ml of tetrahydrofuran and 20 ml of ethanol. The thus prepared solution was mixed with 1.70 g of 10% palladium carbon catalyst (50% wet type) and subjected to catalytic hydrogenation under normal pressure until hydrogen absorption was completed. After removing the catalyst by filtration, the solvent was distilled off. By subjecting the resulting residue to silica gel column chromatography, 1.2 g of oily ethyl 3-[2-[2-(5-cyanobenzo-[b]thien-2-yl)ethyl]-4-ethoxy-5-methoxyphenyl]propionate was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16](=[O:18])[CH3:17])[CH:13]=[CH:12][O:11]3)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2cn3ccoc3n2)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)c1c(-c2ccc(F)cc2)nc2occn12
Temperature: 135 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a mixture of 6-(4-fluorophenyl)-imidazo[2,1-b]oxazole (2675 g, 13.23 mol) and acetic anhydride (6.35 l) is added 160 ml of concentrated sulfuric acid. The reaction mixture is heated at 135° C. for 1.5 hours, then cooled to 80° C. with an ice bath. The reaction mixture is slowly quenched with 12.5 l of water. The solids are stirred overnight, filtered and air-dried. The solids are again suspended in water (15 l), stirred overnight, filtered, and washed with water (4 l) and then with toluene (4 l). The solid is dried under vacuum at 60° C., to give 2771 g (86%) of a dark brown solid; M.p.=173° C.; 300 MHz 1H NMR (DMSO-d6) δ 8.25-8.19 (m, 2H), 7.75-7.68 (m, 2H), 7.35-7.25 (m, 2H), 2.15 (s, 3H). LCMS: 245 [M+H].
Reaction SMILES: C([O:5][C:6](=[O:27])[C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[NH:14][C:15]1[CH:16]=[N:17][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:19][CH:20]=1)(C)(C)C.C(O)(C(F)(F)F)=O>>[CH3:13][C:11]1[CH:10]=[CH:9][C:8]([NH:14][C:15]2[CH:16]=[N:17][C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:19][CH:20]=2)=[C:7]([CH:12]=1)[C:6]([OH:27])=[O:5]
Reactant: Cc1ccc(Nc2ccc(N3CCOCC3)nc2)c(C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(Nc2ccc(N3CCOCC3)nc2)c(C(=O)O)c1

Procedure:
A solution of 5-methyl-2-(6-morpholinopyridin-3-ylamino)benzoate tert-butyl ester in TFA (0.6 ml, 7.58 mmol) was stirred at room temperature for 1 hour. The solvent was evaporated and the residue was triturated in diethyl ether. The solid formed was filtered off to afford 0.047 g (73% of yield) of the expected product.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[C:6]2[N:13]([CH2:14][O:15][CH3:16])[CH:12]=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1>C(O)(=O)C.[Fe]>[F:1][C:2]1[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[C:6]2[N:13]([CH2:14][O:15][CH3:16])[CH:12]=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: COCn1ccc2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c21
Agent: [Fe]
Solvent: CC(=O)O
Product: COCn1ccc2ncnc(Oc3ccc(N)cc3F)c21
Reaction time: 0.08 h
Yield: 23.4 %

Procedure:
To as solution of 244 (85 mg, 0.267 mmol) in acetic acid (8 mL) at 100° C., was added iron powder (75 mg, 1.34 mmol). The reaction mixture was stirred for 5 minutes, filtered through Celite® pad and concentrated to dryness; the residue was purified by flash chromatography, eluent DCM/MeOH (30:1) to afford title compound 245 (18 mg, 23% yield) as an orange solid. MS (m/z): 289.1 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].[CH2:13](I)[CH3:14].[Cl-].[Na+]>C(O)C.O>[CH2:13]([S:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:14]
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: CCI
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCSc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.2 %

Procedure:
16.56 g (106.72 mmol) of 4-nitrothiophenol was added, while cooling with water, to a solution of 4.27 g (106.76 mmol) sodium hydroxide in 320 ml ethanol and it was stirred for 15 minutes at room temperature. Then, while cooling with water, 8.63 ml (106.79 mmol) of ethyl iodide was added and the mixture was stirred overnight at room temperature. The mixture was added to saturated sodium chloride solution and was extracted with ethyl acetate (2×). The combined organic phases were dried (Na2SO4), filtered and concentrated by evaporation. Then it was dissolved in DCM and filtered again and evaporated to dryness. 16.86 g (92.02 mmol) of the raw product was obtained.
Reaction SMILES: NC[C@@H]1[C@H](C)CCCN1C(C1C=C(C)C=CC=1C1C=NN(C)C=1)=O.[CH3:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32](=[O:46])[C:33]2[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:34]=2[C:40]2[N:41]=[N:42][CH:43]=[CH:44][CH:45]=2)[C@@H:27]1[CH2:47][N:48]1C(=O)C2C(=CC=CC=2)C1=O>>[NH2:48][CH2:47][C@@H:27]1[C@H:26]([CH3:25])[CH2:31][CH2:30][CH2:29][N:28]1[C:32]([C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:34]=1[C:40]1[N:41]=[N:42][CH:43]=[CH:44][CH:45]=1)=[O:46]
Reactant: Cc1ccc(-c2cccnn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN2C(=O)c3ccccc3C2=O)c1
Agent: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-c2cccnn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, using 2-(((2S,3R)-3-methyl-1-(5-methyl-2-(pyridazin-3-yl)benzoyl)piperidin-2-yl)methyl)isoindoline-1,3-dione. ESI-MS (m/z): 325 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1/C(=N\O)/C.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+].[C:23](#[N:25])[CH3:24]>CC(N(C)C)=O>[CH3:24][C:23]1[O:1][C:2]2[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=2[N:25]=1
Reactant: CC#N
Reactant: C/C(=N/O)c1ccc(O)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(=O)N(C)C
Product: Cc1nc2ccc(O)cc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a cooled (5° C.) solution of (1Z)-1-(2,4-dihydroxyphenyl)ethanone oxime (9.7 g, 57.7 mmol) in acetonitrile (65 mL) and dimethylacetamide (11 mL) was added phosphorus oxychloride (5.6 mL, 60.3 mmol) drop wise. The temperature was not allowed to exceed 10° C. during the addition. After 1 hrs stirring at room temperature the yellow slurry was poured on a mixture of sodium hydrogen carbonate and ice. The resulting precipitate was filtered off and dried yielding 6.3 g (73%) the titled compound.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C@@H:5]([CH2:18][O:19]C2CCCCO2)[CH2:4][S:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>CCO>[OH:19][CH2:18][C@H:5]1[CH2:4][S:3][C:2](=[O:1])[N:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CCCCCCN1C(=O)SC[C@@H]1COC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCCCN1C(=O)SC[C@@H]1CO
Yield: 60.1 %

Procedure:
To a solution of 3-5 (0.5 g, 2.3 mmol) in 10 mL EtOH was added p-toluene sulfonic acid (50 mg) and the resulting solution was stirred overnight at room temperature Triethylamine (0.1 mL) was added and the solution was concentrated in vacuo. The compound was purified by flash chromatography using 80% EtOAc/hexanes to yield 0.4 g of 3-6 as a colorless oil. 1H NMR (400 MHz, acetone-d6): □ 4.2 (t, 1H), 4.1 (q, 3H), 3.9 (m, 1H), 3.7 (m, 2H), 3.6 (m, 1H), 3.4 (dd, 1H), 3.3 (dd, 1H), 3.1 (m, 1H), 2.3 (t, 2H), 1.3–1.7 (m, 8H), 1.2 (t, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[C:8]([C:9]#[N:10])=[C:7]([F:11])[C:6]([CH:12]=O)=[CH:5][CH:4]=1.[CH3:15][O:16][C:17]1[N:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[C:20]2[N:27]1[CH:35]=[C:34]2[C:29]([CH2:30][CH2:31][CH:32]([NH2:36])[CH2:33]2)=[N:28]1.[BH4-].[Na+]>CO.O>[CH3:1][N:2]([CH3:14])[C:3]1[C:8]([C:9]#[N:10])=[C:7]([F:11])[C:6]([CH2:12][NH:36][CH:32]2[CH2:31][CH2:30][C:29]3[C:34](=[CH:35][N:27]([C:20]4[C:19]5[C:24](=[CH:25][CH:26]=[C:17]([O:16][CH3:15])[N:18]=5)[N:23]=[CH:22][CH:21]=4)[N:28]=3)[CH2:33]2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C=O)c(F)c1C#N
Reactant: COc1ccc2nccc(-n3cc4c(n3)CCC(N)C4)c2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2nccc(-n3cc4c(n3)CCC(NCc3ccc(N(C)C)c(C#N)c3F)C4)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
To a solution of 6-dimethylamino-2-fluoro-3-formyl-benzonitrile (69 mg, 0.36 mmol) in CH3OH (7 mL) was added 2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamine (11 mg, 0.34 mmol). The reaction mixture was stirred overnight at RT. NaBH4 (19 mg, 0.50 mmol) was then added and the suspension was stirred for 30 min at RT. The reaction mixture was diluted with a few drops of H2O, and the solvents were removed under reduced pressure. The crude material was purified by basic reverse phase to provide 70 mg (44%) of the title compound. MS (ESI): exact mass calculated for C26H26FN7O, 471.22; m/z found, 472.5 [M+H]+. 1H NMR (500 MHz, CDCl3): 9.09 (s, 1H), 8.75 (d, J=5.1, 1H), 8.26 (d, J=9.1, 1H), 8.14 (d, J=5.1, 1H), 7.38 (t, J=8.7, 1H), 7.18 (d, J=9.1, 1H), 6.58 (d, J=8.7, 1H), 4.75 (br s, 1H), 4.10 (s, 3H), 3.86 (s, 2H), 3.08 (s, 6H), 3.02-2.97 (m, 3H), 2.84-2.77 (m, 1H), 2.52 (dd, J=16.6, 9.9, 1H), 2.15-2.11 (m, 1H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:21])([F:20])[C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=1)[O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[I-].[CH3:23][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[F:3][C:4]([F:21])([F:20])[C:5]1[CH:19]=[CH:18][CH:17]=[C:7]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[CH2:23])=[CH:11][CH:10]=2)[CH:6]=1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=Cc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
NaH (23.66 g, 592 mmol) was added to the solution of 4-(3-(trifluoromethyl)phenoxy)-benzaldehyde (25 g, 94 mmol) and methyltriphenylphosphonium iodide (36.2 g, 101 mmol) in THF (180 mL) at 0° C. The reaction mixture was stirred at room temperature overnight. Purification via a flash column chromatography then afforded the title compound as a colorless oil (24.4 g, 98% yield).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[NH2:39][C:40]1[CH:49]=[C:48]2[C:43]([CH2:44][CH2:45][CH2:46][N:47]2[CH3:50])=[CH:42][CH:41]=1>C(Cl)Cl>[CH3:50][N:47]1[C:48]2[C:43](=[CH:42][CH:41]=[C:40]([NH:39][C:11](=[O:13])[C:10]3[CH:14]=[CH:15][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:8][CH:9]=3)[CH:49]=2)[CH2:44][CH2:45][CH2:46]1
Reactant: CN1CCCc2ccc(N)cc21
Reactant: O=C(O)c1ccc(-c2ccccc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CN1CCCc2ccc(NC(=O)c3ccc(-c4ccccc4)nc3)cc21
Reaction time: 8 h

Procedure:
To a solution of 6-phenylnicotinic acid (D48) (500 mg, 2.51 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (963 mg, 5.03 mmol) and 1-hydroxybenzotriazole hydrate (340 mg, 2.51 mmol) in DCM (20 ml) was added a solution of 7-amino-1-methyl-1,2,3,4-tetrahydroquinoline (D3) (407 mg, 2.51 mmol) in DCM (5 ml). The reaction mixture was stirred overnight then washed with sat. aq. sodium hydrogen carbonate solution (2×20 ml) and brine (20 ml). The organics were dried over MgSO4 and concentrated in vacuo to give the crude product which was purified by flash column chromatography. Elution with 10-20% EtOAc/DCM gave the title compound as a yellow solid. 1H NMR (250 MHz, CDCl3) δ (ppm): 9.14 (d, 1H), 8.25 (dd, 1H), 8.07 (m, 2H), 7.85 (d, 1H), 7.71 (br, 1H), 7.48 (m, 3H), 7.03 (br, 1H), 6.93 (d, 1H), 6.75 (dd, 1H), 3.25 (m, 2H), 2.93 (s, 3H), 2.75 (t, 2H), 1.98 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: [Pd]
Solvent: CCO
Product: N#Cc1ccc(N)cc1C#N
Temperature: 30 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
4-nitrophthalonitrile (3, 60.0 g, 0.346 mol) was dissolved in 190 proof EtOH (528 g) in a pressure reactor to which was added 10% Pd/C (5.59 g) and then heated to 30° C. and pressurized to 60 psi with H2. After 3 hrs, gas consumption ceased. The reaction mixture was purged with N2, filtered through Celite® and concentrated to give 39.5 g (80%) product as a light brown powder. It was used without further purification in the next step. 1H NMR (DMSO-d6) δ: 7.63 (d, J=8.8 Hz, 1H); 7.02 (d, J=2.0 Hz, 1H); 6.87 (dd, J=8.5, 2.0 Hz, 1H); 6.71 (s, 2H). 13C{1H}NMR (DMSO-d6): 153.5, 135.4, 118.0, 117.7, 117.4, 116.9, 116.0, 98.2 ppm. mp 174-176° C.