Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[NH2:9][CH2:10][CH2:11][CH2:12][OH:13].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:9][CH2:10][CH2:11][CH2:12][OH:13])[N:7]=1
Reactant: NCCCO
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: OCCCNc1nccc(Cl)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 23 %

Procedure:
A mixture of 99.8 g (0.670 mol) 2,4-dichloropyrimidine, 52.8 g (0.703 mol) 3-amino-propan-1-ol and 135.6 g (1.34 mol) triethylamine was stirred at room temperature for 12 h. The residue was treated with a mixture of 500 ml saturated sodium carbonate solution and 1000 ml ethyl acetate. The organic phase dried (sodium sulphate) and evaporated to give an oil that solidified in the refrigerator overnight. The material was extracted with 200 ml ethyl acetate and the soluble fraction containing the 2-isomer evaporated (the 4-isomer remains insoluble in ethyl acetate). Chromatography on silica (ethyl acetate) gave 28.9 g (23%) of 3-(4-Chloro-pyrimidin-2-ylamino)-propan-1-ol.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[C:6]([CH2:17][CH2:18][CH3:19])[C:5]=1[OH:20])(=[O:3])[CH3:2].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH:22]=1>>[C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([NH:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:23]2[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=2)=[O:14])=[C:6]([CH2:17][CH2:18][CH3:19])[C:5]=1[OH:20])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCC(=O)O)ccc(C(C)=O)c1O
Reactant: NCCCCCCc1cccnc1
Product: CCCc1c(OCCCC(=O)NCCCCCCc2cccnc2)ccc(C(C)=O)c1O

Procedure:
4-(4-Acetyl-3-hydroxy-2-propylphenoxy)butanoic acid was allowed to react with 3-pyridine hexanamine according to procedure A and the product was purified by chromatography on silica gel to give 4-(4-acetyl-3-hydroxy- 2-propylphenoxy)-N-[6-(3-pyridinyl)hexyl]butanamide, the title compound, mp 69°-71° (from ether-hexane) in 84% yield.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][O:11][C:10](=[O:13])[C:9]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=1>CN(C=O)C>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:9]2[C:10](=[O:13])[O:11][CH2:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=3)=[CH:7][CH:6]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(C2=C(c3ccc(O)cc3)COC2=O)cc1
Reactant: Cc1cccc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C2=C(c3ccc(OCc4cccc(C)n4)cc3)COC2=O)cc1
Temperature: 80 °C
Yield: 2.4 %

Procedure:
To a solution of 4-(4-hydroxyphenyl)-3-(4-methoxyphenyl)furan-2(5H)-one (300 mg, 1.06 mmol) in DMF (10 mL) were added K2CO3 (294 mg, 2.12 mmol), 2-(chloromethyl)-6-methylpyridine (225 mg, 1.59 mol) at RT. The reaction mixture was then heated at 80° C. for 16 h, quenched with ice and then extracted with EtOAc (2×100 mL). The combined organic layers were washed with water, dried over Na2SO4, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 3-(4-methoxyphenyl)-4-(4-((6-methylpyridin-2-yl)methoxy)phenyl)furan-2(5H)-one (10 mg) as a solid. 1H NMR (500 MHz, d6-DMSO): δ 8.44 (d, J=7.2 Hz, 1H), 7.79 (m, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.63 (t, J=7.6 Hz, 1H), 7.38-7.27 (m, 3H), 7.16 (d, J=7.2 Hz, 2H), 6.99-6.92 (m, 2H), 5.41 (s, 2H), 5.33 (s, 2H), 2.79 (s, 3H). MS: M+H: m/z=388.2.
Reaction SMILES: [S:1]([CH2:8][C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:14]>>[C:2]1([S:1][CH2:8][C:9]([Cl:14])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CSc1ccccc1
Product: O=C(Cl)CSc1ccccc1
Yield: 98 %

Procedure:
To thiophenoxyacetic acid (8 g, 0.05 mol) was added SOCl2 (8 mL) and the reaction mixture was heated to reflux for 1 h. TLC showed disappearance of the starting material. The excess SOCl2 was removed in vacuo under a fume hood and the product was distilled to afford 8.6 g (98%) of the title compound, bp 85°-86° C., 4-5 Torr [lit 117°-119° C., 6 Torr (Mooradian, A.; Cavallito, C. J.; Bergman, A. J.; Lawson, E. J.; Suter, C. M. J. Am. Chem. Soc. 1949, 3372)]; 1H NMR (CDCl3) δ 7.48-7.34 (m, 5H), 4.06 (m, 2H); 13C NMR (CDCl3) 169.75, 132.83, 131.44, 129.35, 128.22, 48.48; MS (EI, m/z) 186 (M+).
Reaction SMILES: Cl[C:2]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[C:12]([CH3:17])=[N:13][O:14][C:15]=3[CH3:16])[CH:9]=2)[NH:4][C:3]1=[O:18].[C:25]([O-:28])(=[O:27])[CH3:26].[Na+]>O1CCOCC1>[C:25]([O:28][C:2]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[C:12]([CH3:17])=[N:13][O:14][C:15]=3[CH3:16])[CH:9]=2)[NH:4][C:3]1=[O:18])(=[O:27])[CH3:26]
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(Cl)(c1ccccc1)C(=O)N2
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)OC1(c2ccccc2)C(=O)Nc2ccc(-c3c(C)noc3C)cc21
Temperature: 85 °C
Reaction time: 6 h
Yield: 36.8 %

Procedure:
To a solution of 3-chloro-5-(3,5-dimethylisoxazol-4-yl)-3-phenylindolin-2-one (50 mg, 0.15 mmol) in dioxane (2 mL) was added sodium acetate (90 mg, 1.1 mmol), the reaction mixture was stirred at 85° C. for 6 h and quenched by the addition of saturated ammonium chloride solution (10 mL). The organic layer was extracted with CH2Cl2 (2×20 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford crude product, ant it was purified by Pre-TLC (eluent: Hexane/EtOAc=1/1) to give product (20 mg, 37%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.78 (s, 1H), 7.33-7.38 (m, 6H), 7.25 (s, 1H), 7.01 (d, J=8.0 Hz, 1H), 2.35 (s, 3H), 2.18 (s, 3H), 2.15 (s, 3H). MS (ESI) m/e [M+1]+ 363.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:12][C@@H:11]([CH3:13])[NH:10][CH2:9][C@@H:8]2[CH3:14])=[CH:4][CH:3]=1.[Br:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([C:26](O)=[O:27])=[CH:23][C:22]=2[CH:29]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=N)CCCCC1>C(Cl)(Cl)Cl>[Br:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([C:26]([N:10]3[CH2:9][C@@H:8]([CH3:14])[N:7]([CH2:6][C:5]4[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:12][C@@H:11]3[CH3:13])=[O:27])=[CH:23][C:22]=2[CH:29]=1
Reactant: O=C(O)c1cc2cc(Br)ccc2o1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1
Agent: N=C=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: C[C@@H]1CN(C(=O)c2cc3cc(Br)ccc3o2)[C@@H](C)CN1Cc1ccc(F)cc1
Yield: 93 %

Procedure:
A mixture of (trans)-1-(4-fluorobenzyl)-2,5-dimethyl-piperazine (220 mg, 1.0 mmol), 5-bromo-1-benzofuran-2-carboxylic acid (342 mg, 1.5 mmol), 1-hydroxybenzotriazol (200 mg, 1.5 mmol) and N-cyclohexylcarbodiimide, N′-methylpolystyrene (167 g, 3.0 mmol of the resin with a loading of 1.8 mmol/g) in CHCl3 was heated under 5 minutes at 110° C. in a microwave oven The mixture was allowed to attain room temperature. TBD-methyl polystyrene (1000 mg, 3 mmol of the resin with a loading of 2.9 mmol/g) was added and the mixture was agitated over night. Both resins were filtered off and washed with CHCl3 and EtOAc. The filtrate was concentrated in vacuo and the residue was submitted to flash column chromatography (toluene→toluene: EtOAc, 20:1→toluene: EtOAc, 1:1) to give the title product in 93% yield.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][N:8]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7]1)=[O:5].[H-].[Na+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C=O)C.C(OCC)(=O)C>[CH3:2][O:3][C:4]([C:6]1([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:11](=[O:12])[CH2:10][CH2:9][N:8]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7]1)=[O:5]
Reactant: COC(=O)C1CN(Cc2ccccc2)CCC1=O
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1(Cc2ccccc2)CN(Cc2ccccc2)CCC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 114.9 %

Procedure:
1-Benzyl-4-oxo-piperidine-3-carboxylic acid methyl ester hydrochloride salt (1, Z=benzyl) (15 g, 52.9 mmol) was suspended in DMF (150 mL) and cooled to 0° C. Sodium hydride (4.23 g, 105.8 mmol) was added portionwise over 1 h and the contents were allowed to warm to ambient temperature and stir for a further 1 h. Benzyl bromide (6.3 mL, 53.0 mmol) was added over 15 min and the contents were stirred for a further 68 h at ambient temperature. 10 mL of water were added and the contents were diluted with 400 mL of ethyl acetate, washed with water (200 mL), saturated sodium bicarbonate (200 mL) and brine (200 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated to give 20.5 g yellow oil that was purified by flash column chromatography (3:2 cyclohexane/CH2Cl2 to 100% CH2Cl2) to give 17.52 g (98%) of the title compound a colorless oil. LC-MS: RT=2.80 min. (M+H)+ 338, (M-OMe)+ 306.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.N1C=C(B(O)O)C=NC=1>>[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:12][C@H:11]([N:13]5[CH2:17][CH2:16][CH2:15][C@@H:14]5[CH3:18])[CH2:10]4)[S:8][C:4]=3[CH:3]=2)=[CH:25][CH:24]=1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: COc1ccc(B(O)O)cn1
Agent: OB(O)c1cncnc1
Product: COc1ccc(-c2ccc3nc([C@H]4C[C@H](N5CCC[C@@H]5C)C4)sc3c2)cn1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, except for substituting the product of Example 11A for the product of Example 1E and substituting 6-methoxy-3-pyridineboronic acid for pyrimidine-5-boronic acid. 1H NMR (500 MHz, CDCl3) δ ppm 8.43 (d, J=2.18 Hz, 1H) 8.03 (d, J=8.42 Hz, 1H) 7.97 (d, J=1.56 Hz, 1H) 7.83 (dd, J=8.58, 2.65 Hz, 1H) 7.61 (dd, J=8.42, 1.56 Hz, 1H) 6.84 (d, J=8.73 Hz, 1H) 4.00 (s, 3H) 3.81-3.92 (m, 1H) 3.47-3.58 (m, 1H) 2.97-3.15 (m, 1H) 2.66-2.85 (m, 2H) 2.44-2.64 (m, 2H) 2.26-2.39 (m, 1H) 1.92-2.03 (m, 1H) 1.79-1.89 (m, 1H) 1.67-1.77 (m, 1H) 1.46-1.64 (m, 2H) 1.14 (d, J=5.30 Hz, 3H). MS: (M+H)+=380.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([CH2:26][CH3:27])=[N:12][CH:13]=[CH:14][C:15]=2[C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([F:25])[CH:17]=2)=[CH:4][CH:3]=1.CN([C:31]([O:35]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:52][CH2:53][N:54]([CH:58](C)C)C(C)C.O.C(#N)C>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([CH2:26][CH3:27])=[N:12][CH:13]=[CH:14][C:15]=2[C:16]2[CH:24]=[CH:23][C:19]([C:20]([N:54]([CH2:53][CH2:52][O:35][CH3:31])[CH3:58])=[O:21])=[C:18]([F:25])[CH:17]=2)=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCc1nccc(-c2ccc(C(=O)O)c(F)c2)c1C#Cc1ccc(N)nc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: CCc1nccc(-c2ccc(C(=O)N(C)CCOC)c(F)c2)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP5 starting from 320 mg (0.89 mmol) 4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-benzoic acid (A-38) using 95 mg (1.06 mmoL) 2-methoxy methylamine, 370 mg (0.97 mmol) HATU and 258 μL DIPEA in 3 mL DMF. After completion of the reaction, the reaction mixture is filtered and the product is isolated from the obtained solution by RP-HPLC using a H2O/ACN-gradient. Yield: 130 mg (34%).
Reaction SMILES: O.NN.[C:4]([O:8][CH2:9][CH2:10][CH2:11][O:12][N:13]1C(=O)C2C(=CC=CC=2)C1=O)([CH3:7])([CH3:6])[CH3:5].CO>C(Cl)Cl>[C:4]([O:8][CH2:9][CH2:10][CH2:11][O:12][NH2:13])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OCCCON1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OCCCON
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
Hydrazine hydrate (1.36 mL, 43.3 mmol) was added to a solution of 2-(3-tert-Butoxy-propoxy)-isoindole-1,3-dione (6.0 g, 21.7 mmol) in CH2Cl2 (50 mL) with MeOH (5 mL), and the reaction stirred 1 h at room temperature. The precipitate was removed by filtration, and the filtrate was purified by silica gel chromatography (6% MeOH/CH2Cl2) to give 2.4 g (75%) of compound 29A as a clear oil. 1H NMR (400 MHz, CDCl3): δ 4.94 (br s, 2H), 3.71 (t, 2H, J=6.4 Hz), 3.38 (t, 2H, J=6.4 Hz), 1.70-1.79 (m, 2H), 1.15 (s, 9H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([NH:32][CH2:33][C:34]([OH:36])=O)=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.[NH2:38][C@@H:39]([C@H:44]([OH:46])[CH3:45])[C:40]([O:42][CH3:43])=[O:41].CCN(C(C)C)C(C)C>CC(N(C)C)=O.CCOC(C)=O>[C:25]([O:29][C:30]([NH:32][CH2:33][C:34]([NH:38][CH:39]([CH:44]([OH:46])[CH3:45])[C:40]([O:42][CH3:43])=[O:41])=[O:36])=[O:31])([CH3:26])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COC(=O)C(NC(=O)CNC(=O)OC(C)(C)C)C(C)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 43.5 %

Procedure:
HATU (46.9 g, 123.30 mmol) was added to a stirred solution of 2-(tert-butoxycarbonylamino)acetic acid (18 g, 102.75 mmol) DMA (230 mL) at ambient temperature. After 5 minutes a solution of (2S,3R)-methyl 2-amino-3-hydroxybutanoate hydrochloride (17.43 g, 102.75 mmol) and DIPEA (71.8 mL, 411.00 mmol) in DMA (230 mL) was added and the resulting solution was stirred at ambient temperature for 20 hours, The reaction mixture was diluted with EtOAc (300 mL), and washed with 1N citric acid (300 mL), salt was added to the aqueous layer which was re extracted with EtOAc (4×400 mL). The organic extracts were combined, washed with saturated NaHCO3 (200 mL), dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 50 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford the title compound (12.97 g, 43.5%) as a yellow glass which formed a solid on standing.
Reaction SMILES: N1C=CC([C:7]2[CH:15]=[C:14]3[C:10]([C:11](C=O)=[N:12][N:13]3[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])=[CH:9][CH:8]=2)=CC=1.NN1C=CC=C1.C(O)(=O)C>C(O)C>[CH3:21][Si:20]([CH3:23])([CH3:22])[CH2:19][CH2:18][O:17][CH2:16][N:13]1[C:14]2[C:10](=[CH:9][CH:8]=[CH:7][CH:15]=2)[CH:11]=[N:12]1
Reactant: C[Si](C)(C)CCOCn1nc(C=O)c2ccc(-c3ccncc3)cc21
Agent: Nn1cccc1
Solvent: CCO
Solvent: CC(=O)O
Product: C[Si](C)(C)CCOCn1ncc2ccccc21
Yield: 95.5 %

Procedure:
A solution of 6-pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehyde (208 mg, 0.59 mmol), N-aminopyrrole (145 mg, 1.76 mmol), and acetic acid (5.8 μl) in ethanol (1 ml) was held at 95° C. for 16 h. The solution was then evaporated under reduced pressure, and purified by silica gel chromatography to give 6-pyrid-4-yl-3-E-N-(pyrrol-1-yl)iminomethyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole as an oil (140 mg, 57%). 1H NMR (300 MHz, CDCl3) δ 9.08 (s, 1H), 8.71 (d, 2H, J=6.1 Hz), 8.46 (d, 1H, J=8.5 Hz), 8.34 (s, 1H), 7.85 (d, 2H, J=6.2 Hz), 7.80 (d, 1H, J=8.5 Hz), 7.56 (t, 2H, J=2.3 Hz), 6.25 (t, 2H, J=2.3 Hz), 5.93 (s, 1H), 5.74 (s, 2H), 3.64 (t, 2H, J=7.9 Hz), 0.86 (t, 2H, J=7.9 Hz), 0.00 (s, 9H).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[CH3:9])=[O:7].[CH3:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=O)=[C:22]([CH3:33])[C:21]=1[CH3:34]>O1CCCC1>[CH3:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=[C:8]([CH3:9])[C:6]([O:5][CH2:4][CH3:3])=[O:7])=[C:22]([CH3:33])[C:21]=1[CH3:34]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: COc1cc(C)c(C=CC=CC=O)c(C)c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)=CC=CC=Cc1c(C)cc(OC)c(C)c1C
Temperature: 0 °C

Procedure:
To a suspension of NaH (2g of 50% reagent) in 100 ml of tetrahydrofuran (THF), stirred under an atmosphere of nitrogen at 0° C., (ice bath), was added dropwise 8.8 g (37 mmol) of triethyl 2-phosphonopropionate. The resulting mixture was stirred in the ice bath for additional 2.5 hrs and a solution of 5-(4-methoxy-2,3,6-trimethylphenyl)-penta-2,4-dien-1-al (8.4 g, 37 mmol) in 20 ml of THF was added. The mixture was stirred at room temperature for 4 hrs.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([NH:5][C@@H:6]([CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH3:21])=[CH:15][CH:14]=1)=O)[C:7]([OH:9])=[O:8])=[O:4].C(O)(=O)C.[H][H]>C(OCC)(=O)C.[Pd]>[F:1][C:2]([F:22])([F:23])[C:3]([NH:5][C@@H:6]([CH2:10][CH2:11][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH3:21])=[CH:17][CH:18]=1)[C:7]([OH:9])=[O:8])=[O:4]
Reactant: CCCc1ccc(C(=O)C[C@H](NC(=O)C(F)(F)F)C(=O)O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCc1ccc(CC[C@H](NC(=O)C(F)(F)F)C(=O)O)cc1
Reaction time: 48 h
Yield: 93.1 %

Procedure:
A solution of N-trifluoroacetyl-α-(S)-(2-(4-n-propylphenyl)-2-oxoethyl)glycine 6 (140 mg, 0.43 mmol) in ethyl acetate (10 mL) containing acetic acid (0.25 mL) and 10% palladium on carbon (10 mg) was stirred under one atmosphere of hydrogen gas. After two days, the catalyst was filtered off and fresh catalyst was added and the reaction stirred under hydrogen overnight. The mixture was filtered and the solvent evaporated in vacuo to yield the product 7 (127 mg, 93% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:5][N:6]([CH3:8])[CH3:7])[CH:3]=O.CC(N)C.[NH2:14][CH2:15][CH2:16][CH2:17][Si:18]([O:23][CH3:24])([O:21][CH3:22])[O:19][CH3:20]>>[CH3:1][C:2]([CH3:9])([CH2:5][N:6]([CH3:8])[CH3:7])[CH:3]=[N:14][CH2:15][CH2:16][CH2:17][Si:18]([O:23][CH3:24])([O:19][CH3:20])[O:21][CH3:22]
Reactant: CN(C)CC(C)(C)C=O
Reactant: CO[Si](CCCN)(OC)OC
Solvent: CC(C)N
Product: CO[Si](CCCN=CC(C)(C)CN(C)C)(OC)OC

Procedure:
13.57 g 2,2-dimethyl-3-dimethylaminopropanal, 7.45 g 2-propanamine and 17.93 g 3-aminopropyltrimethoxysilane were reacted according to the general manufacturing procedure (iminosilanes). The product was distilled after manufacture in order to remove oligomer portions. Yield: 28.4 g of a clear, colorless oil having an amine content of 6.61 mmol N/g and a purity of 95%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]3[CH2:14][CH2:15][CH2:16][CH2:17][CH:10]3[C:9]2=[O:18])=[CH:4][CH:3]=1.[CH3:19][N:20]([CH3:38])[C:21]([C:23]1[N:32]([CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[C:26]2[N:27]=[C:28](Cl)[N:29]=[CH:30][C:25]=2[CH:24]=1)=[O:22]>>[CH3:19][N:20]([CH3:38])[C:21]([C:23]1[N:32]([CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[C:26]2[N:27]=[C:28]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([N:8]4[CH2:13][CH2:12][N:11]5[CH2:14][CH2:15][CH2:16][CH2:17][CH:10]5[C:9]4=[O:18])=[CH:6][N:7]=3)[N:29]=[CH:30][C:25]=2[CH:24]=1)=[O:22]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: Nc1ccc(N2CCN3CCCCC3C2=O)cn1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN5CCCCC5C4=O)cn3)nc2n1C1CCCC1
Yield: 55.7 %

Procedure:
Following general N—C coupling procedure 1, 2-(6-Amino-pyridin-3-yl)-hexahydro-pyrido[1,2-a]pyrazin-1-one (0.060 g, 0.244 mmol) was combined with 2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (0.072 g, 0.246 mmol, 1.01 eq) which gave 7-Cyclopentyl-2-[5-(1-oxo-octahydro-pyrido[1,2-a]pyrazin-2-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide, (0.070 g, 0.136 mmol) in 56% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.31-1.50 (m, 2H) 1.66-1.82 (m, 4H) 1.91 (br. s., 1H) 1.98-2.14 (m, 5H) 2.21 (td, J=11.42, 3.26 Hz, 1H) 2.40 (br. s., 1H) 2.58 (dd, J=12.30, 8.78 Hz, 2H) 2.67-2.81 (m, 2H) 2.93-3.07 (m, 2H) 3.16 (s, 7H) 3.47 (dd, J=11.29, 3.26 Hz, 1H) 4.02 (td, J=11.67, 4.77 Hz, 1H) 4.79 (dq, J=9.03, 8.87 Hz, 1H) 6.46 (s, 1H) 7.66 (dd, J=9.03, 2.51 Hz, 1H) 7.94 (s, 1H) 8.23 (d, J=2.01 Hz, 1H) 8.54 (d, J=9.03 Hz, 1H) 8.71 (s, 1H)
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([C:9]1[CH:10]=[C:11]([CH2:15][C:16](O)=[O:17])[CH:12]=[CH:13][CH:14]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].Cl.[H][H]>O1CCCC1>[F:1][C:2]([F:19])([F:20])[C:3]([C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][OH:17])[CH:12]=[CH:13][CH:14]=1)([OH:8])[C:4]([F:5])([F:7])[F:6]
Reactant: O=C(O)Cc1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1
Reactant: [H][H]
Agent: Cl
Solvent: C1CCOC1
Product: OCCc1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1
Yield: 38.9 %

Procedure:
To one liter of 1M borane-tetrahydrofuran complex was added a solution of 100 g (0.33 mole) of 3-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzeneactic acid in 200 ml of tetrahydrofuran. The solution is refluxed for 16 hours under nitrogen. The solution is then refluxed with 400 ml of 6N hydrochloric acid until evolution of hydrogen is complete. The mixture is filtered and evaporated. The residue is refluxed with 500 ml of methanol containing 10 ml of concentrated hydrochloric acid until methyl borate is no longer evolved. The solution is evaporated, and the residue is distilled at 110°-115° (0.7 mm) to give 37 g of 2-{3-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}ethanol.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][NH:13][C:12]2=[O:18])CCC>Cl>[NH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:15]([CH2:14][NH:13][C:12]2=[O:18])=[CH:16][CH:17]=1
Reactant: CCCCOC(=O)NCc1ccc2c(c1)C(=O)NC2
Agent: Cl
Product: NCc1ccc2c(c1)C(=O)NC2
Reaction time: 8 h
Yield: 92.5 %

Procedure:
A mixture of the product of Step 2 (100 g, 0.38 mol) and HCl (dissolved in MeOH, 3 M, 500 ml) was stirred overnight. Removal of the solvent gave a solid which was washed with Et2O and dried to afford 6-(aminomethyl)-2,3-dihydro-1H-isoindol-1-one (57 g, 76% yield). 1H-NMR (300 MHz, D2O) δ: 7.69-7.67 (m, 1H), 7.52 (s, 1H), 7.45-7.43 (m, 1H), 4.39 (s, 2H), 4.17 (s, 2H).
Reaction SMILES: CS([O:5][CH2:6][CH2:7][CH2:8][C:9]1[O:13][C:12]([N:14]2[CH:18]=[CH:17][N:16]=[C:15]2[CH3:19])=[N:11][C:10]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)(=O)=O.O[C:28]1[CH:42]=[CH:41][C:31]([CH2:32][P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:10]2[N:11]=[C:12]([N:14]3[CH:18]=[CH:17][N:16]=[C:15]3[CH3:19])[O:13][C:9]=2[CH2:8][CH2:7][CH2:6][O:5][C:28]2[CH:42]=[CH:41][C:31]([CH2:32][P:33](=[O:40])([O:34][CH2:35][CH3:36])[O:37][CH2:38][CH3:39])=[CH:30][CH:29]=2)=[CH:21][CH:22]=1
Reactant: CCOP(=O)(Cc1ccc(O)cc1)OCC
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCOS(C)(=O)=O)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(Cc1ccc(OCCCc2oc(-n3ccnc3C)nc2-c2ccc(Cl)cc2)cc1)OCC

Procedure:
3-[4-(4-Chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]propyl methanesulfonate (400 mg), diethyl 4-hydroxybenzylphosphonate (365 mg), potassium carbonate (276 mg) and N,N-dimethylformamide (10 ml) was stirred at 100° C. for 4 hours. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (100 ml×2). The organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, and diethyl 4-[3-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]propyloxy]benzylphosphonate was obtained as a yellow oil (526 mg, 97%) from an ethyl acetate-eluted fraction.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)[CH3:9].[Br:19]([O-])(=O)=O.[K+]>O>[Br:19][C:11]1[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=1[CH:8]([CH2:7][F:6])[CH3:9]
Reactant: [O-][Br+2]([O-])[O-]
Reactant: CC(CF)c1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: CC(CF)c1ccc([N+](=O)[O-])cc1Br

Procedure:
To 80 ml of concentrated sulfuric acid, 80 ml of water and 18.3 g (0.1 Mol) of 4(fluoromethyl-ethyl)-nitrobenzene are added portionwise with stirring 18.3 g (0.11 Mol) potassium bromate at such a rate that the temperature does not exceed 35°.