Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([CH:4]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:5][CH2:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH3:18])=[CH:10][CH:9]=1)(O)=O.C([N:27]([CH2:30]C)CC)C.ClC(OCC)=[O:34].[N-]=[N+]=[N-].[Na+]>O.C1(C)C=CC=CC=1.CC(C)=O>[N:27]([CH:4]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:5][CH2:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH3:18])=[CH:10][CH:9]=1)=[C:30]=[O:34]
Reactant: Cc1ccc(OCCC(C(=O)O)c2ccccc2)c2ccccc12
Reactant: CCN(CC)CC
Reactant: CCOC(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(OCCC(N=C=O)c2ccccc2)c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 1 l. one-neck round bottom flask fitted with a nitrogen inlet tube and addition funnel was added 7.05 g (220 mmol) of 1-carboxy-1-phenyl-3-(4-methyl-1-naphthalenyloxy)propane and 400 ml of acetone. To the mixture was added 3.2 ml (22.9 mmol) of triethylamine and the resulting mixture was cooled to approximately 0° C. To the mixture was added 2.2 ml of ethyl chloroformate dropwise. The mixture was stirred 30 minutes at about 0° C. and 2.72 g (41.8 mmol) of sodium azide dissolved and a small amount of water was added dropwise. The mixture was stirred for about 60 minutes at about 0° C. and 200 ml of toluene was added. Water was added to the reaction mixture and the aqueous phase was separated and extracted twice with 200 ml of toluene. The organic extracts were combined, washed with water and a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was heated on a steam bath for two hours to induce formation of the isocyanate. The mixture was concentrated under vacuum to provide 7.6 g of the title compound which was used directly in the following reaction.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[N:11]=[C:10]([CH:12]([NH:24][CH3:25])[CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[O:9][N:8]=1)=[O:6])[CH3:3].Cl.[CH3:27]C(O)C>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[CH3:3][CH:2]([O:4][C:5]([C:7]1[N:11]=[C:10]([CH:12]([NH:24][CH3:25])[CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[O:9][N:8]=1)=[O:6])[CH3:27]
Reactant: CC(C)O
Reactant: CCOC(=O)c1noc(C(Cc2ccc3ccccc3c2)NC)n1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Product: CNC(Cc1ccc2ccccc2c1)c1nc(C(=O)OC(C)C)no1

Procedure:
5-(1-methylamino-2-(2-naphthyl)ethyl)-[1,2,4]oxadiazole-3-carboxylic acid ethyl ester hydrochloride (1.64 g, 4.5 mmol) was suspended in 2-propanol (35 ml). After addition of tetraisopropyl titanate (1.3 g, 4.5 mmol) the reaction mixture was refluxed for 18 h. Hydrochloric acid (1N, 30 ml) was added and the reaction mixture was extracted with ethyl acetate (150 ml). The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 ml) and water (3×50 ml). After drying (magnesium sulfate) the solution was concentrated in vacuo to give 1.3 g of (R) 5-(1-methylamino-2-(2-naphthyl)ethyl)-[1,2,4]oxadiazole-3-carboxylic acid (2-propyl)ester that was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][C:24](=[O:29])[NH:25][CH2:26][CH2:27]C)[CH:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][C:24](=[O:29])[NH:25][CH2:26][CH3:27])[CH:21]=4)[CH:16]=[CH:15]3)[CH2:12][CH2:13]2)=[CH:30][CH:31]=1
Reactant: CCCNC(=O)Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCNC(=O)Cc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A suspension of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[(n-propylcarbamoyl)methyl]indoline (0.04 g) obtained in Example 150 and active manganese dioxide (0.08 g) in chloroform (30 ml) was vigorously stirred at 50° C. overnight. Then the reaction mixtures were filtered through celite and the residue was washed with chloroform. After concentrating the filtrate under reduced pressure, the residue was recrystallized from chloroform/hexane to give the title compound (0.03 g) as white needles (yield: 84.6%).
Reaction SMILES: C(N1CCCC(C(OCC)=O)C1)(=O)C1C=CC=CC=1.[OH:20][CH:21]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]1.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH2:32][C:33](Cl)=[O:34].C(N(C(C)C)CC)(C)C>>[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH2:32][C:33]([N:23]1[CH2:24][CH2:25][CH2:26][CH:21]([OH:20])[CH2:22]1)=[O:34]
Reactant: O=C(Cl)Cc1cccs1
Reactant: OC1CCCNC1
Agent: CCOC(=O)C1CCCN(C(=O)c2ccccc2)C1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1cccs1)N1CCCC(O)C1
Yield: 66.1 %

Procedure:
This reaction was run in the same manner as ethyl 1-benzoyl-3-piperidinecarboxylate, starting with commercially available 3-hydroxypiperidine (1.03 g; 10.2 mmol) and 2-thiopheneacetyl chloride (1.2 ml; 10 mmol) and diisopropylethylamine (1.9 ml; 10.9 mmol). The crude product was purified by chromatography on silica, eluting with 100% ethyl acetate, giving 1-(2-thiopheneacetyl)-3-hydroxypiperidine (1.49 g) as a yellow oil, which solidified on standing. MS m/z (positive ion) 248 (M+Na+; 50), 226 (MH+; 100).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:10]=[CH:9][C:8]=2[NH:21][C:22]([C:24]2[N:25](COCC[Si](C)(C)C)[C:26]([S:29][CH3:30])=[N:27][CH:28]=2)=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>C(Cl)Cl>[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][CH2:14][N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)[CH:10]=[CH:9][C:8]=2[NH:21][C:22]([C:24]2[NH:25][C:26]([S:29][CH3:30])=[N:27][CH:28]=2)=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CSc1ncc(C(=O)Nc2ccc(CCN3CCOCC3)cc2C2=CCCCC2)n1COCC[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSc1ncc(C(=O)Nc2ccc(CCN3CCOCC3)cc2C2=CCCCC2)[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 36 %

Procedure:
To a solution of 2-methylsulfanyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazole-4-carboxylic acid [2-cyclohex-1-enyl-4-(2-morpholin-4-yl-ethyl)-phenyl]-amide (100 mg, 0.18 mmol)(as prepared in the previous step) in 1 mL of DCM was added 1 mL of TFA and the mixture stirred at RT for 6 h. The mixture was concentrated and the title compound purified by RP-HPLC on a C18 column eluting with a linear gradient of 35-55% CH3CN in 01% TFA/H2O over 8 min to give 35 mg (36%) of a white solid. 1H-NMR (400 MHz, CD3OD): δ 8.22 (d, J=8.4 Hz, 1H), 7.71 (s, 1H), 7.20 (dd, J=8.4, 2.2 Hz, 1H), 7.12 (d, J=2.2 Hz, 1H), 5.79 (m, 1H), 4.07 (m 2H), 3.82 (m, 2H), 3.57 (m, 2H), 3.40 (m, 2H), 3.20 (m, 2H), 3.15 (m, 2H), 2.65 (s, 3H), 2.30-2.22 (m, 4H), 1.88-1.72 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C23H30N4O2S, 427.2 (M+H). found 427.1.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH3:11][CH:12]([N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1)[CH3:13].C(=O)([O-])O.[Na+]>>[CH3:13][CH:12]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([CH:8]=[O:9])=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1)[CH3:11]
Reactant: CN(C)C=O
Reactant: CC(C)N1CCCc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)N1CCCc2cc(C=O)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
18.6 g (0.12 mol) of phosphorus oxychloride was dropped into 29.2 g (0.4 mol) of N,N-dimethylformamide under cooling with ice. The obtained mixture was stirred at room temperature for 30 minutes and cooled again on an ice bath. 17.5 g (0.1 mol) of 1-(1-methylethyl)-1,2,3,4-tetrahydroquinoline was gradually dropped into the resulting mixture. The mixture thus obtained was stirred at room temperature for one hour and poured onto ice-water. The resulting mixture was neutralized with an aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated in a vacuum. The residue was purified by silica gel column chromatography (10% ethyl acetate/n-hexane) to give 11.4 g of the title compound as a reddish-brown oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:25])=[C:20](B(O)O)[CH:21]=1>CCCCCCC.CCOC(C)=O>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:25])=[C:18]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:17]=1
Reactant: CC(C)(C)C(=O)Nc1cnccc1I
Reactant: Cc1ccc(Cl)cc1B(O)O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(Cl)cc1-c1ccncc1NC(=O)C(C)(C)C

Procedure:
The title compound was prepared in analogy to example 72, from N-(4-iodo-pyridin-3-yl)-2,2-dimethyl-propionamide (CAS RN 113975-32-9) and 5-chloro-2-methylphenylboronic acid (CAS RN 148839-33-2) and using a gradient of n-heptane:EtOAc (100:0 to 0:100). Light yellow solid (99%). MS (ESI): m/z=303.126 [M+H]+.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:10][N:11]([CH2:14][C@@H:15]([NH:23][C:24]([O:26][C:27](C)(C)[CH3:28])=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:12][CH3:13])=O)(C)(C)C.FC(F)(F)C(O)=O.[C:45](=[O:63])([O:56][CH2:57][C:58]1[S:62][CH:61]=[N:60][CH:59]=1)OC1C=CC([N+]([O-])=O)=CC=1>ClCCl.C(OCC)(=O)C>[CH2:12]([N:11]([CH2:10][C@H:9]([NH:8][C:45]([O:56][CH2:57][C:58]1[S:62][CH:61]=[N:60][CH:59]=1)=[O:63])[CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:14][C@@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]1[S:62][CH:61]=[N:60][CH:59]=1)=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:13]
Reactant: O=C(OCc1cncs1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCN(C[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(C[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Temperature: 60 °C
Reaction time: 2 h
Yield: 33.8 %

Procedure:
The product from Example 71B (86 mg, 0.17 mmol) in dichloromethane (1.8 mL) was treated with trifluoroacetic acid (1.0 mL) at ambient temperature. After stirring for 2 hours, the mixture was concentrated and treated with aqueous 10% K2CO3 (2.4 mL). The aqueous mixture was extracted with ethyl acetate (3×3 mL). The ethyl acetate extracts were combined and treated with 4-nitrophenyl 1,3-thiazol-5-ylmethyl carbonate [prepared from 4-nitrophenyl 1,3-thiazol-5-ylmethyl carbonate hydrochloride salt (99 mg, 0.35 mmol) by extraction with aqueous NaHCO3] in ethyl acetate (6 mL). After heat at 60° C. for 18 hours, the mixture was allowed to cool to ambient temperature and was concentrated. The residue was purified by flash column chromatography on silica gel eluting with (chloroform:methanol, 98:2) to provide the title compound (34.1 mg, 32%). 1H NMR (CDCl3) δ 8.78 (s, 2H), 7.85 (s, 2H), 7.32-7.05 (m, 10H), 5.40-5.17 (m, 6H), 4.20 (brs, 2H), 3.49-2.55 (m, 10H), 0.85 (t, 3H); MS (ESI+) m/z 594 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=[O:4].[Br:29][C:30]1[CH:31]=[C:32](I)[C:33]([NH2:36])=[N:34][CH:35]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCO.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>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:32]2[C:33]([NH2:36])=[N:34][CH:35]=[C:30]([Br:29])[CH:31]=2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=[O:4]
Reactant: Nc1ncc(Br)cc1I
Reactant: COC(=O)c1sc(B2OC(C)(C)C(C)(C)O2)cc1OC(C)c1ccccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1sc(-c2cc(Br)cnc2N)cc1OC(C)c1ccccc1Cl
Yield: 79.4 %

Procedure:
3-[1-(2-Chloro-phenyl)-ethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiophene-2-carboxylic acid methyl ester (150 mg, 0.37 mmol, 1.1 Eq.), 5-Bromo-3-iodo-pyridin-2-ylamine (100 mg, 0.34 mmol, 1.0 Eq.) and Pd(PPh3)4 (39 mg, 0.04 mmol, 0.1 Eq.) were dissolved in toluene (1.6 mL) and EtOH (0.4 mL). 2M K2CO3 (0.5 mL, 1.0 mmol, 3.0 Eq) and the reaction heated under microwave conditions at 140° C. for 15 minutes. The reaction was partitioned between EtOAc (10 mL) and water (10 mL) and the aqueous phase extracted with EtOAc (3×10 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (40% EtOAc/petroleum Ether) to give the sub-title compound as an off-white solid (125 mg, 0.27 mmol, 80%); 1H NMR (400 MHz, CDCl3) δ 1.74 (3H, d), 3.92 (3H, s), 4.71 (2H, br s), 5.81 (1H, q), 6.81 (1H, s), 7.24-7.32 (2H, m), 7.38 (1H, dd), 7.54 (1H, d), 7.66 (1H, dd), 8.10 (1H, d)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([S:11][C:12]#[N:13])=O)=[CH:4][CH:3]=1.[BrH:14].C(O)(=O)C>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([Br:14])[S:11][CH:9]=2)=[CH:4][CH:3]=1
Reactant: N#CSC(=O)Cc1ccc(Cl)cc1
Reactant: Br
Solvent: CC(=O)O
Product: Clc1ccc(-c2csc(Br)n2)cc1
Temperature: 80 °C
Yield: 44 %

Procedure:
The compound (40) (2.1 g, 10.0 mmol) was suspended in acetic acid (10 ml) and 47% HBr-acetic acid (1 ml) was added. The mixture was stirred with heating at 80° C. for 2 hrs. The reaction mixture was concentrated under reduced pressure to dryness and the residue was partitioned between ethyl acetate and 5% NaHCO3 aq. The aqueous layer was extracted with ethyl acetate, and the extracts were combined, washed with saturated brine and dried (MgSO4). The solvent was evaporated under reduced pressure and isopropyl ether was added to the obtained residue, which was filtrated to give the title compound (1.2 g, 44%).
Reaction SMILES: [CH:1](/N1CCCC1)=[CH:2]\[CH2:3][CH2:4][CH3:5].[C:11](#[N:14])[CH:12]=[CH2:13].[OH2:15]>O1CCOCC1>[CH:1]([CH:2]([CH2:3][CH2:4][CH3:5])[CH2:13][CH2:12][C:11]#[N:14])=[O:15]
Reactant: CCC/C=C/N1CCCC1
Reactant: O
Reactant: C=CC#N
Solvent: C1COCCO1
Product: CCCC(C=O)CCC#N
Yield: 33 %

Procedure:
A solution of 142.23 g (1.02 mol) of N-[1-(E)-penten-1-yl]pyrrolidine and 100 mL (80.6 g, 1.52 mol) of acrylonitrile in 570 mL of 1,4-dioxane was heated at gentle reflux, under argon, for 16 hr. 50 mL of water was then added and the mixture was stirred at reflux for a further 8 hr. After concentration in vacuo, 200 g of ice, 400 mL of 3N hydrogen chloride solution, and 600 mL of methylene chloride were added, and the mixture was stirred for 15 min. The aqueous layer was separated and extracted with 3×300 mL of methylene chloride, and the combined organic layers were washed with 2×150 mL of saturated brine, dried (MgSO4), filtered and concentrated. The residue (140.2 g) was distilled to give 46.96 g (33.0%) of 4-formylheptanenitrile bp 103°-104° C. (1.33 mm Hg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1)[CH3:2].CN(C)CCN(C)CCN(C)C.[Li]CCCC.CN([CH:31]=[O:32])C>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:10])=[C:8]([CH:9]=1)[CH:31]=[O:32])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOc1ccc(F)cc1
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1ccc(F)c(C=O)c1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a solution of 1-ethoxy-4-fluorobenzene (1.1 g, 7.9 mmol) and pentamethyl diethylene triamine (2 mL) in anhydrous THF (6 mL) was added BuLi dropwise (1.38 M, 5.98 mL, 8.3 mmol) at −78° C. After addition, the reaction mixture was warmed up to −40° C. and stirred for 30 min, the reaction mixture was then cooled to −78° C. and DMF (0.7 mL) was added. The solution was warmed to rt, and stirred for 1 h. The reaction mixture was then partitioned between EtOAc and sat. NH4Cl, the organic layer was dried over (Na2SO4), filtered and concentrated. The residue was subjected to chromatographic purification (0-10% EtOAc/hexanes gradient), 600 mg (55%) of Intermediate 53.1 was obtained. 1H NMR (CDCl3) δ 1.40 (t, 3H), 4.08 (q, 2H), 6.81 (m, 1H), 7.15 (m, 1H), 7.29 (m, 1H), 10.33 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:3]([C:16]2[CH:21]=[C:20]([O:22][CH:23]([CH3:25])[CH3:24])[C:19]([Cl:26])=[CH:18][C:17]=2[F:27])[C:4](=[O:15])[CH:5]=[C:6]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[N:7]=1.[Na]>C(O)(C)C>[Cl:26][C:19]1[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:21][C:16]([N:3]2[C:4](=[O:15])[CH:5]=[C:6]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[N:7]=[C:2]2[O:22][CH:20]([CH3:21])[CH3:19])=[C:17]([F:27])[CH:18]=1
Reactant: CC(C)Oc1cc(-n2c(Cl)nc(C(F)(F)C(F)(F)F)cc2=O)c(F)cc1Cl
Agent: [Na]
Solvent: CC(C)O
Product: CC(C)Oc1cc(-n2c(OC(C)C)nc(C(F)(F)C(F)(F)F)cc2=O)c(F)cc1Cl

Procedure:
using 2-chloro-1-(4-chloro-2-fluoro-5-isopropoxyphenyl)-4-pentafluoroethyl-6(1H)-pyrimidinone and sodium isopropylate in isopropanol there is obtained 1-(4-chloro-2-fluoro-5-isopropoxyphenyl)-2-isopropoxy-4-pentafluoroethyl-6(1H)-pyrimidinone, 1H-NMR (CDCl3, 400 MHz): 7.30 ppm (d,1H), 6.81 ppm (d,1H), 6.62 ppm (s,1H), 5.33 ppm (m,1H), 4.47 ppm (m,1H), 1.38 ppm (d,3H), 1.37 ppm (d,3H), 1.28 ppm (d,3H), 1.27 ppm (d,3H);
Reaction SMILES: [O:1]1C2C=CC(C(C3C4C(=C(CSC)C=CC=4)NC=3)(C3CC3)C)=CC=2[O:3][CH2:2]1.Cl[C:28]1[CH:33]=[CH:32][C:31]([C:34]([C:39]2[C:47]3[C:42](=[C:43]([CH2:48][S:49]([CH3:52])(=[O:51])=[O:50])[CH:44]=[CH:45][CH:46]=3)[NH:41][CH:40]=2)([CH:36]2[CH2:38][CH2:37]2)[CH3:35])=[CH:30][CH:29]=1>>[O:1]1[C:28]2[CH:33]=[CH:32][C:31]([C:34]([C:39]3[C:47]4[C:42](=[C:43]([CH2:48][S:49]([CH3:52])(=[O:51])=[O:50])[CH:44]=[CH:45][CH:46]=4)[NH:41][CH:40]=3)([CH:36]3[CH2:38][CH2:37]3)[CH3:35])=[CH:30][C:29]=2[O:3][CH2:2]1
Reactant: CSCc1cccc2c(C(C)(c3ccc4c(c3)OCO4)C3CC3)c[nH]c12
Reactant: CC(c1ccc(Cl)cc1)(c1c[nH]c2c(CS(C)(=O)=O)cccc12)C1CC1
Product: CC(c1ccc2c(c1)OCO2)(c1c[nH]c2c(CS(C)(=O)=O)cccc12)C1CC1

Procedure:
The title compound was prepared starting from 214 mg (0.59 mmol) of the compound from Example 189 in analogy to the synthesis of the compound from Example 209. 162 mg (69% of theory) of the target compound were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[CH:16]=[C:15]([F:25])[CH:14]=3)[O:10][N:9]=2)=[N:6][CH:7]=1.C(#N)C.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:14]=[C:15]([F:25])[CH:16]=[C:17]([C:19]4[CH2:20][N:21]([CH2:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH2:22][CH2:23][CH:24]=4)[CH:18]=3)[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: Fc1ccc(-c2noc(-c3cc(F)cc(-c4cccnc4)c3)n2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: Fc1ccc(-c2noc(-c3cc(F)cc(C4=CCCN(Cc5ccccc5)C4)c3)n2)nc1
Temperature: 25 °C
Yield: 7.8 %

Procedure:
In a screw cap vial equipped with stir bar added 3-(5-Fluoro-2-pyridyl)-5-(3-fluoro-5-(3-pyridyl)phenyl)-1,2,4-oxadiazole (100 mg, 0.30 mmol), acetonitrile (2 ml) and benzyl bromide (0.05 ml, 0.39 mmol). Stirred the resulting mixture at 90° C. for 4h. Cooled the mixture to room temperature, concentrated in-vacuo and triturated the residue with 30% ethyl acetate in hexanes to isolate the quarternary salt. The isolated solid was dissolved in methanol (2 ml) and treated with sodium borohydride (22.6 mg, 0.60 mmol) at 0° C. The bright yellow reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in-vacuo and the residue was dissolved in dichloromethane (20 ml). The organic phase was sequentially washed with water (20 ml) and brine (20 ml), dried (sodium sulfate), filtered and concentrated in-vacuo. The crude residue was purified on silica gel using 30% ethyl acetate in hexanes to isolate the title compound (10.1 mg, 8%) as yellow oil. 1H-NMR (CDCl3), δ (ppm): 8.69 (d, 1H), 8.26 (dd, 1H), 8.02 (s, 1H), 7.80 (dd, 1H), 7.60 (dt, 1H), 7.32 (m, 6H), 6.34 (m, 1H), 3.73 (s, 2H), 3.40 (bs, 2H), 2.63 (t, 2H), 2.39 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[S:23][C:14]=2[N:15]=[C:16]([C:18]2[O:22][N:21]=[CH:20][CH:19]=2)[N:17]=1>>[O:22]1[C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[S:23][C:14]=3[N:15]=2)=[CH:19][CH:20]=[N:21]1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccno3)nc2s1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: O=[N+]([O-])c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(isoxazol-5-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-dichlorobenzylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([O:17][CH2:18][CH2:19]Cl)[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:33]1([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(N(CC)C(C)C)(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([O:17][CH2:18][CH2:19][N:42]3[CH2:43][CH2:44][CH:39]([N:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)[CH2:40][CH2:41]3)[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(-c2nc3ccc(OCCCl)cc3n2Cc2ccccc2)cc(OC)c1OC
Reactant: C1CCN(C2CCNCC2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2nc3ccc(OCCN4CCC(N5CCCCC5)CC4)cc3n2Cc2ccccc2)cc(OC)c1OC
Reaction time: 8 h

Procedure:
The title compound was prepared by reacting the compound of Example 76, supra, (0.45 g, 1.0 mmol) with 4-(piperdin-1-yl)piperidine (2.0 g, 11.9 mmol) in the presence of the base N,N-diisopropylethylamine, tetra-n-butylammonium iodide and acetonitrile at 80° C. After incubating overnight at 80° C. the reaction was washed with water (2×500 ml), followed by a wash with a saturated sodium chloride solution (1×500 ml). The organic phase was then dried over potassium carbonate and the solvents were removed in vacuo to yield a light brown oil. The desired product was purified by chromatography and triturated with diethyl ether to yield a light brown powder, which was removed by filtration and washed with diethyl ether to yield the purified title compound. MS 584, 585, NMR, IR, mp 143° C.