Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:17]([C:18]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][N:22]4C3CCCCO3)=[CH:16][C:13]([CH:14]=O)=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[CH3:34][O:35][C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][CH:42]=1)[NH2:39].C(Cl)Cl.[BH4-].[Na+]>C(O)C.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C.CO>[CH3:34][O:35][C:36]1[CH:37]=[C:38]([NH:39][CH2:14][C:13]2[CH:16]=[C:17]([C:18]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][NH:22]4)[C:10]([NH:9][C:6]3[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[N:11][CH:12]=2)[CH:40]=[CH:41][CH:42]=1
Reactant: COc1ccc(Nc2ncc(C=O)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Reactant: COc1cccc(N)c1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: COc1cccc(NCc2cnc(Nc3ccc(OC)nc3)c(-c3nc(C)nc4[nH]cnc34)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)nicotinaldehyde (191.7 mg, 0.4303 mmol) was suspended in ethanol (4.0 mL) and tetraisopropoxytitanium (0.26 mL, 0.878 mmol) and 3-methoxyaniline (0.080 mL, 0.716 mmol) were added. The reaction was stirred under nitrogen at room temperature overnight, and then more DCM (about 3 mL) was added, along with more Ti(OiPr4) (0.13 mL, 0.44 mmol) and 3-methoxyaniline (0.050 mL, 0.45 mmol). Stirring was continued overnight, and then sodium borohydride (32.3 mg, 0.854 mmol) was added, along with MeOH (1 mL). The reaction was stirred at room temperature for 35 minutes and then quenched with 5 N HCl (0.60 mL), which was added dropwise. Stirring was continued at room temperature over the weekend. Then, the suspension was diluted with DCM and MeOH and filtered through a pad of Celite® (diatomaceous earth). The Celite® (diatomaceous earth) pad was washed with DCM and MeOH, and the filtrate was concentrated, treated with water, and filtered again through a fritted filter (no Celite® (diatomaceous earth)). The solid was washed with water, collected, and dried under high vacuum in a water bath at 50° C., and then at room temperature overnight, to give 5-((3-methoxyphenylamino)methyl)-N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)pyridin-2-amine (162.8 mg, 81% yield). MS (ESI pos. ion) m/z 469 (M+H)+. 1H NMR (d6-DMSO, 400 MHz) δ 12.53 (s, 1H), 9.74 (s, 1H), 8.62 (s, 1H), 8.51 (d, J=2.54 Hz, 1H), 8.27 (d, J=2.15 Hz, 1H), 8.13 (dd, J=8.80 Hz, 2.74 Hz, 1H), 7.00 (t, J=8.12 Hz, 1H), 6.87 (d, J=8.80 Hz, 1H), 6.38-6.17 (m, 3H), 4.29 (s, 2H), 3.85 (s, 3H), 3.66 (s, 3H), 2.84 (s, 3H).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][CH2:3][C:4]([O-])=[O:5].C1N=CN(C(N2C=NC=C2)=O)C=1.O/[N:23]=[C:24](\[NH2:32])/[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH2:25]([C:24]1[N:32]=[C:4]([CH2:3][CH2:2][C:1]([O:8][CH3:9])=[O:7])[O:5][N:23]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: N/C(Cc1ccccc1)=N\O
Reactant: COC(=O)CCC(=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COC(=O)CCc1nc(Cc2ccccc2)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.7 %

Procedure:
Butanedioic acid, monomethyl ester (4.0 g, 30.3 mmole) and CDI (5.40 g, 33.3 mmole) were dissolved in anhydrous DMF (15 ml) and stirred at room temperature for 3 hours. (1Z)-N′-hydroxy-2-phenylethanimidamide (5.0 g, 33.3 mmole) was added to above solution and the mixture was stirred at 90° C. for 20 hours. The reaction mixture was concentrated and the residue was diluted with water and EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (elution with 1:3 ethyl acetate:hexane) to give the desired product as light yellowish oil (5.2 g, 70% yield). LCMS calculated for C13H15N2O3 (M+H): 247.1. found: 247.1.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4].[CH2:18]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33]Br)=[CH:28][CH:27]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].OS(O)(=O)=O>CN(C)C=O.O>[C:3]([NH:6][C:7]([CH2:33][CH2:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:31][CH:30]=1)([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4]
Reactant: CCCCCCCCc1ccc(CCBr)cc1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc(CCC(NC(C)=O)(C(=O)OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
60% NaH in oil (9.65 g) is added portionwise to a solution of diethyl acetamidomalonate (58.5 g) in dimethylformamide (240 ml) at such a rate to keep the temperature below 10° C. The resulting mixture is stirred for 90 min., the temperature being allowed to increase to room temperature. To this mixture is added dropwise within 15 min. a solution of 2-(4-octylphenyl)ethyl bromide (19) (40 g) in dimethylformamide (40 ml). The reaction mixture is heated to ca. 80° C. within ca. 25 min. and further stirred for ca. 3-5 hrs. After cooling to room temperature, water (280 ml) is added and the resulting mixture is further stirred until a beige precipitate is formed. The mixture is adjusted to pH 7 with 10% H2SO4. After cooling to ca. 2° C., the residue is filtered, washed with 200 ml water and then recrystallized in heptane to yield compound (8) as colorless crystals. The resulting compound (8) exhibits the same physico-chemical characteristics as indicated in Example 7.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][O:11][CH2:10][CH2:9][C:8]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=O)=O.[CH:20]([N:23]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[N:24]1)([CH3:22])[CH3:21].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:20]([N:23]1[C:27]([C:7]2[CH2:12][O:11][CH2:10][CH2:9][C:8]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:26][CH:25]=[N:24]1)([CH3:22])[CH3:21]
Reactant: CC(C)n1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)COCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(c2ccnn2C(C)C)COCC1
Temperature: 100 °C

Procedure:
To a solution of ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydro-2H-pyran-4-carboxylate (crude from step 1) and 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.37 g, 5.82 mmol) in dioxane (20 ml) was added Pd(dppf)Cl2 (430 mg, 0.58 mmol) and Na2CO3 (1.85 g, 17.46 mmol) in water (6 mL), the mixture was degassed with N2 for 5 min, and was heated at 100° C. for 15 h, after cooling to room temperature the mixture was diluted with EtOAc and washed with Sat. NaHCO3 and brine, organic layer was combined, dried and concentrated to give crude product, which was purified by column chromatography (Hexanes/EtOAc=3:1) to give ethyl 5-(1-isopropyl-1H-pyrazol-5-yl)-3,6-dihydro-2H-pyran-4-carboxylate (850 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([Cl:17])[CH:11]=2)=O)=[CH:4][CH:3]=1.[C:18]1(=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([Cl:17])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)cc1)c1ccc(O)c(Cl)c1
Reactant: O=C1CCCCCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Oc1ccc(C(=C2CCCCCC2)c2ccc(Br)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 63.6 %

Procedure:
To a stirred suspension of zinc powder (1.35 g, 20.5 mmol) in THF (40 mL) was slowly added TiCl4 (1.13 mL, 10.3 mmol) via syringe at room temperature under a nitrogen atmosphere. The mixture was heated at reflux for 2 h. A solution of (4-bromophenyl)(3-chloro-4-hydroxyphenyl)methanone (105) (0.80 g, 2.57 mmol) and cycloheptanone (0.89 g, 7.70 mmol) in THF (15 mL) was added to the mixture. The reaction mixture was heated at reflux with stirring under a nitrogen atmosphere for 1.5 h. The reaction mixture was allowed to cool to room temperature. To the reaction mixture was slowly added 10% aqueous K2CO3 (40 mL). The reaction mixture was filtered through a pad of Celite and the pad was washed with EtOAc (100 mL). The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was further extracted with EtOAc (50 mL). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as brown oil. The crude product was purified by flash chromatography on silica gel with hexanes:EtOAc (20:1) to give 0.64 g (64%) of compound 124 as a yellow viscous oil. 1H NMR (400 MHz, DMSO-d6): δ 1.50 (br s, 8H), 2.10-2.25 (m, 4H), 6.85-6.92 (m, 2H), 7.02 (br s, 1H), 7.07 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 10.1 (s, 1H). LCMS (APCI): m/z 413 (M+Na)+.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:17][S:18]([CH2:21][C:22](O)=[O:23])(=[O:20])=[O:19].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([NH:14][C:22](=[O:23])[CH2:21][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:15][CH:16]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)CC(=O)O
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)CC(=O)Nc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-benzyloxyaniline hydrochloride (4.0 g, 17.0 mmol), methanesulfonylacetic acid (2.35 g, 17.0 mmol) and HBTU (6.89 g, 18.2 mmol) in DMF (70 mL) was stirred at ambient temperature one minute. DIEA (6.5 mL, 37.2 mmol) was added all at once, and the resultant solution was stirred at ambient temperature. The solution was poured into water, and the product crystallized. The product, 5.4 g (99%), was collected by filtration and was used without any further purification in the subsequent reaction. MS m/z 320 (MH+). 1H NMR (DMSO-d6) δ 3.17 (s, 3H), 4.25 (s, 2H), 5.07 (s, 2H), 7.00 (d, 2H), 7.32-7.55 (m, 7H) and 10.32 (s, 1H).
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11](B4OC(C)(C)C(C)(C)O4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.Br[C:32]1[S:33][C:34]([CH3:38])=[C:35]([CH3:37])[N:36]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.COCCOC>[CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11]([C:32]4[S:33][C:34]([CH3:38])=[C:35]([CH3:37])[N:36]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: Cc1nc(Br)sc1C
Reactant: C[C@@H](Oc1cc(B2OC(C)(C)C(C)(C)O2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: Cc1nc(-c2cc(O[C@H](C)[C@H]3CNC(=O)C3)c3c(c2)ncn3C2CC2)sc1C
Temperature: 100 °C
Yield: 48.4 %

Procedure:
To a microwave tube equipped with a stifling bar, (R)-4-((R)-1-((1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one: (120 mg, 0.292 mmol), 2-bromo-4,5-dimethylthiazole (112.1 mg, 0.584 mmol), 1,2-dimethoxyethane (2 mL), 1 N Na2CO3 aqueous solution (0.73 mL, 0.73 mmol) were added, the mixture was bubbled N2 for 5 minutes before Pd(PPh3)4 (14.0 mg, 0.012 mmol) were added. The tube was sealed and heated in an oil bath at 100° C. for 2 hrs. DCM (200 mL) was added and the resulting mixture was washed with saturated NaHCO3 aqueous solution (20 mL×4), brine (20 mL×1), dried over anhydrous Na2SO4, filtered, removed solvents in vacuo. The resulting residue was passed a ISCO silica gel column (MeOH:DCM=5:95) to give off-white solids, 56.0 mg (yield 48.4%). 1H NMR (300 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.59 (s, 1H), 7.58 (d, J=1.2 Hz, 1H), 7.32 (d, J=1.4 Hz, 1H), 4.79 (p, J=6.0 Hz, 1H), 3.70 (m, 1H), 3.44-3.35 (m, 1H), 3.25-3.15 (m, 1H), 2.91-2.72 (m, 1H), 2.37 (s, 3H), 2.32 (s, 3H), 2.41-2.22 (m, 2H), 1.33 (d, J=6.0 Hz, 3H), 1.16-1.07 (m, 2H), 1.07-0.97 (m, 2H) ppm; MS (ESI+) m/z 397.14 (M+H).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:23])[N:6]([C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19](Br)=[CH:20][N:21]=3)[N:18]=2)[CH2:9]1)[CH3:7])([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[C:31](B(O)O)=[CH:30][C:29]([CH3:35])=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH:1]([O:4][C:5](=[O:23])[N:6]([C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([C:31]4[C:26]([O:25][CH3:24])=[N:27][CH:28]=[C:29]([CH3:35])[CH:30]=4)=[CH:20][N:21]=3)[N:18]=2)[CH2:9]1)[CH3:7])([CH3:3])[CH3:2]
Reactant: COc1ncc(C)cc1B(O)O
Reactant: CC(C)OC(=O)N(C)[C@H]1CCN(c2ccc3ncc(Br)n3n2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: COc1ncc(C)cc1-c1cnc2ccc(N3CC[C@H](N(C)C(=O)OC(C)C)C3)nn12
Yield: 51 %

Procedure:
[(S)-1-(3-Bromo-imidazo[1,2-b]pyridazin-6-yl)-pyrrolidin-3-yl]-methyl-carbamic acid isopropyl ester (120 mg, 0.3 mmol), 2-methoxy-5-methylpyridine-3-boronic acid (105 mg, 0.6 mmol), potassium carbonate (65 mg, 0.45 mmol), and Pd(dppf)Cl2 dichloromethane (26 mg, 0.03 mmol) were taken up in 2 mL acetonitrile and 1 mL water and microwaved in a sealed tube at 140° C. for 15 minutes. Reaction was then filtered through celite with acetonitrile reduced in vacuo, the purified on shimadzu neutral phase prep and product fractions lyophilized to afford 65 mg (S)-isopropyl(1-(3-(2-methoxy-5-methylpyridin-3-yl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)(methyl)carbamate. 1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J=2.02 Hz, 1H), 7.99 (s, 1H), 7.94-7.97 (m, 1H), 7.91 (d, J=9.60 Hz, 1H), 6.92 (d, J=9.85 Hz, 1H), 4.75-4.85 (m, 2H), 3.95 (s, 3H), 3.64-3.70 (m, 2H), 3.38-3.51 (m, 2H), 2.81 (s, 3H), 2.29 (s, 3H), 2.11-2.23 (m, 2H), 1.21 (d, J=6.32 Hz, 6H). (ESI) m/z 425 [(M+H)]+, calc'd for C22H28N6O3: 424.5.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].S(Cl)(Cl)=O.[CH3:23][NH:24][C:25]([C:27]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:28]=1[NH2:29])=[O:26].O>ClCCl.CN(C=O)C.N1C=CC=CC=1>[Cl:34][C:31]1[CH:32]=[CH:33][C:27]([C:25](=[O:26])[NH:24][CH3:23])=[C:28]([NH:29][C:14]([C:13]2[CH:12]=[CH:11][C:10]([CH2:9][P:4](=[O:5])([O:3][CH2:1][CH3:2])[O:6][CH2:7][CH3:8])=[CH:18][CH:17]=2)=[O:16])[CH:30]=1
Reactant: CNC(=O)c1ccc(Cl)cc1N
Reactant: CCOP(=O)(Cc1ccc(C(=O)O)cc1)OCC
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1ccc(C(=O)Nc2cc(Cl)ccc2C(=O)NC)cc1)OCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.8 %

Procedure:
27.2 g of 4-[(diethoxyphosphoryl)methyl]benzoic acid was suspended in a mixture of 60 ml of dichloromethane and 2 ml of DMF. 13.1 g of thionyl chloride was added, and the resulting mixture was refluxed for 1 hour. After completion of reaction, the reaction mixture was allowed to cool and then slowly added dropwise, with ice-cooling and stirring, to a solution of 18.5 g of 2-(N-methylcarbamoyl)-5-chloroaniline in a mixture of 50 ml of pyridine and 30 ml of dichloromethane. After completion of addition, the resulting mixture was stirred at room temperature for 48 hours. Then, 50 ml of water was added to the reaction mixture to precipitate crystals. The crystals were then collected by filtration, fully washed with water and dried, giving 23.6 g of diethyl 4-{[5-chloro-2-(N-methylcarbamoyl)phenyl]carbamoyl}benzylphosphonate.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N+:4]=1[O-:9].[NH2:10][CH2:11][CH2:12][CH2:13][OH:14].C([O-])(O)=O.[Na+].C(O)(CC)(C)C>C(Cl)Cl.CO.C(Cl)(Cl)Cl>[OH:14][CH2:13][CH2:12][CH2:11][NH:10][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N+:4]=1[O-:9]
Reactant: [O-][n+]1ccccc1Cl
Reactant: NCCCO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)(C)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: [O-][n+]1ccccc1NCCCO
Reaction time: 21 h
Yield: 92.9 %

Procedure:
A mixture of 2-chloropyridine-N-oxide hydrochloride (16.6 g, 0.1 mole), 3-amino-1-propanol (15.3 mL, 0.2 mole), NaHCO3 (42 g, 0.5 mole), and tert-amyl alcohol (100 mL) was heated to reflux. After 21 hr, the reaction was cooled, diluted with CH2Cl2 (300 mL), and suction filtered to remove insoluble materials. The filtrate was concentrated and reconcentrated from toluene to leave a yellow oil. Silica gel chromatography (20% MeOH/CHCl3) gave the title compound (15.62 g, 93%) as a yellow solid: TLC (20% MeOH/CHCl3) Rf0.48; 1H NMR (250, CDCl3) δ8.07 (dd, J=6.6, 1.2 Hz, 1 H), 7.34 (br t, 1 H), 7.10-7.30 (m, 1 H), 6.64 (dd, J=8.5, 1.4 Hz, 1 H), 6.40-6.60 (m, 1 H), 4.49 (br s, 1 H), 3.65-3.90 (m, 2 H), 3.35-3.60 (m, 2 H), 1.75-2.00 (m, 2 H); MS (ES) m/e 169 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[CH2:3][CH2:2]1.CO.[CH:13](I)([CH3:15])[CH3:14]>C(N(CC)CC)C>[CH:13]([NH:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1)([CH3:15])[CH3:14]
Reactant: CC(C)I
Reactant: Nc1ccc2c(c1)CCO2
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)Nc1ccc2c(c1)CCO2

Procedure:
To a solution of 40 g. of 2,3-dihydro-5-benzofuranamine in 200 ml. of methanol is added 23 ml. of isopropyl iodide and 35 ml. of triethylamine. The solution is refluxed for 55 hours and then concentrated in vacuo. The resultant oil is extracted several times with diethyl ether, the extract combined, filtered through Celite, and the ether removed in vacuo to obtain an oil of N-isopropyl-2,3-dihydro-5-benzofuranamine.
Reaction SMILES: Cl.[CH2:2]([O:4][CH:5]([C:13]1[CH:22]=[CH:21][C:16]2[C:17](=[O:20])[O:18][CH2:19][C:15]=2[C:14]=1[CH3:23])[CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)[CH3:3].[CH3:24][O:25][C:26]1[CH:33]=[C:32]([CH2:34][CH:35]=O)[CH:31]=[CH:30][C:27]=1[C:28]#[N:29].C([BH3-])#N.[Na+].CC(O)=O>CO.CCOC(C)=O>[CH2:2]([O:4][CH:5]([C:13]1[CH:22]=[CH:21][C:16]2[C:17](=[O:20])[O:18][CH2:19][C:15]=2[C:14]=1[CH3:23])[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:35][CH2:34][C:32]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([O:25][CH3:24])[CH:33]=2)[CH2:9][CH2:8]1)[CH3:3]
Reactant: CCOC(CN1CCNCC1)c1ccc2c(c1C)COC2=O
Reactant: COc1cc(CC=O)ccc1C#N
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(CN1CCN(CCc2ccc(C#N)c(OC)c2)CC1)c1ccc2c(c1C)COC2=O
Reaction time: 12 h

Procedure:
5-[1-(Ethyloxy)-2-piperazin-1-ylethyl]-4-methyl-2-benzofuran-1(3H)-one hydrochloride (50 mg, 0.16 mmol), 2-(methyloxy)-4-(2-oxoethyl)benzonitrile (40 mg, 0.23 mmol), sodium cyanoborohydride (14 mg, 1.7 mmol) and a stir bar were added to a 25 mL flask and few drops of AcOH. The resulting mixture was then dissolved in MeOH (3 mL) and stirred for 12 h; Analysis by LC indicated that reaction had gone to completion. The reaction mixture was treated with EtOAc (20 mL) and washed with aq. NaHCO3 and aq. NaCl. The organic phase was then dried over Na2SO4, filtered and concentrated to dryness; the resulting residue was then dissolved in MeOH (3.5 mL), filtered and shot into Mass-directed HPLC for separation to give the desired product. LC-MS (IE, m/z): 464 [M+1]+.
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][C:8]([CH3:30])=[CH:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:31][C:32]([F:42])([F:41])[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=O.O>CCCCCC.O1CCCC1>[F:31][C:32]([F:42])([F:41])[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[CH:10][CH:9]=[C:8]([CH3:30])[CH3:7]
Reactant: O=C(c1ccccc1)C(F)(F)F
Reactant: CC(C)=CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)=CC=C(c1ccccc1)C(F)(F)F
Yield: 56.6 %

Procedure:
65 ml of 15% strength solution of n-butyl-lithium in hexane were added dropwise to a suspension of 41.1 g (0.1 mol) of dry 3,3-dimethylallyl-triphenyl-phosphonium bromide in 300 ml of anhydrous tetrahydrofuran at 0° C. under nitrogen, while stirring. The deep red solution thus obtained was stirred at 0° C. for a further 15 minutes and 17.4 g (0.1 mol) of ≃,≃,≃-trifluoroacetophenone were then added dropwise at 0°-10° C. The mixture was subsequently stirred at room temperature until it was decolorized (about 12 hours). 600 ml of water were then added and the reaction mixture was extracted 5 times with 200 ml of petroleum ether each time. The petroleum ether phases were dried over magnesium sulphate and the solvent was then stripped off in a rotary evaporator under a waterpump vacuum. 150 ml of n-hexane were added to the residue and residual triphenyl-phosphine oxide was filtered off. The solvent was subsequently distilled off from the filtrate under normal pressure and the oily residue was then distilled in vacuo. 12.8 g (56.6% of theory) of 1,1,1-trifluoro-2-phenyl-5-methyl-hexa-2,4-diene were obtained as a slightly reddish liquid with a boiling point of 80°-85° C. under 3 mbar.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]([OH:16])=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[NH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[OH:30].C(N(CC)CC)C>C(Cl)Cl.O.CN(C=O)C>[OH:30][C@@H:25]1[CH2:26][CH2:27][CH2:28][CH2:29][C@H:24]1[NH:23][C:14]([CH:10]1[O:11][CH2:12][CH2:13][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9]1)=[O:16]
Reactant: O=C(O)C1CN(Cc2ccccc2)CCO1
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CCCC[C@H]1O)C1CN(Cc2ccccc2)CCO1
Reaction time: 1 h
Yield: 73.7 %

Procedure:
To a mixture of 4-(phenylmethyl)-2-morpholinecarboxylic acid (5 g, 22.60 mmol) and DMF (0.1 mL) in CH2Cl2 (113 mL) was added oxalyl chloride (2.97 mL, 33.9 mmol) at 25° C. The mixture was stirred at this temperature for 1 hour and the mixture turned clear. The solvent and excess of oxalyl chloride were removed in vacuo, and the resulting residue was dissolved in CH2Cl2 (113 mL). (1R,2R)-2-Aminocyclohexanol (2.60 g, 22.60 mmol) and triethylamine (12.60 mL, 90 mmol) were added, and the resulting mixture was stirred overnight. Water (80 mL) was added to quench the reaction. the organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2×80 mL). The combined organics were washed with sat. NaHCO3(aq) (80 mL), then brine (2×80 mL), dried (MgSO4), and evaporated to afford the title compound (5.3 g). LC-MS (ES) m/z=319 [M+H]+.