Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:10][CH2:11][O:12][C:13]2[CH:45]=[CH:44][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:19]3=[O:43])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H][H]>O1CCOCC1.[Pd]>[N:1]1([CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:43])=[CH:44][CH:45]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: [H][H]
Reactant: O=C1SC(Cc2ccc(OCCn3ccc4ccccc43)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: C1COCCO1
Product: O=C1NC(=O)C(Cc2ccc(OCCn3ccc4ccccc43)cc2)S1
Reaction time: 2 h
Yield: 85.9 %

Procedure:
A solution of 2.05 g of 5-{4-[2-(Indol-1-yl)-ethoxy]benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 14) in 100 ml of dioxane was stirred in an atmosphere of hydrogen and in the presence of 3.1 g of 10% w/w palladium-on-charcoal, first at room temperature for 30 minutes, then at 60° C. for 2 hours and then at 80° C. for 3 hours. At the end of this time, the reaction mixture was filtered to remove the catalyst and the filtrate was concentrated by evaporation under reduced pressure. The concentrate was then purified by column chromatography through silica gel, using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.06 g of the title compound, melting at 42.3°-44.6° C.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[OH-].[K+].[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])[CH2:9][CH3:10]>C(O)(C)C>[CH3:10][CH2:9][CH:8]([OH:11])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCC(=O)c1ccccc1
Agent: [K+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Agent: [OH-]
Solvent: CC(C)O
Product: CCC(O)c1ccccc1
Reaction time: 4 h

Procedure:
12.2 mg (2×10-5 moles) of [Ir(PPEI)COD]+ClO4- (+) were suspended in 50 ml of isopropanol and oxidized with air for 4 hours. The resulting solution was degasified for 20 minutes at reflux in a nitrogen stream and then treated with 1.88 ml of a deaerated isopropanol solution of KOH (4 mg of KOH). The solution, after a preliminary 30-minute reduction in a nitrogen stream, was treated with 2.56 ml of deaerated propiophenone. After 150 minutes a conversion to phenylpropanol (+) of 96.6% with an e.e. of 26.1% was obtained. Ratios:
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[N:4]=1.[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]2[C:39]3[C:34](=[CH:35][C:36]([OH:42])=[C:37]([O:40][CH3:41])[CH:38]=3)[N:33]=[CH:32][N:31]=2)[CH:25]=[CH:26][C:27]=1[Cl:28].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]2[C:39]3[C:34](=[CH:35][C:36]([O:42][CH2:2][C:3]4[O:7][N:6]=[C:5]([N:8]5[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]5)[N:4]=4)=[C:37]([O:40][CH3:41])[CH:38]=3)[N:33]=[CH:32][N:31]=2)[CH:25]=[CH:26][C:27]=1[Cl:28]
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1O
Reactant: CC(C)(C)OC(=O)N1CCN(c2noc(CCl)n2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)no1
Temperature: 50 °C
Yield: 61.6 %

Procedure:
1,1-dimethylethyl 4-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]piperazine-1-carboxylate (173.6 mg, 0.57 mmol), 4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-ol (154 mg, 0.46 mmol) and potassium carbonate (315 mg, 2.85 mmol) were taken into DMF (2 mL) and the mixture was heated to 50° C. for one hour. The mixture was then cooled to room temperature and partitioned with ethyl acetate and water. The organic layer was washed once more with water and the organic layer was partitioned again with water. A precipitate forms in the organic layer at this point and hexanes was added to the biphasic mixture in portions until formation of the precipitate is complete. The solid product was then collected by filtration. The solid residue was suspended in hot methanol and diluted with water followed by collection of the solid by filtration. The solid was washed with ethyl ether and dried in vacuo to give 1,1-dimethylethyl 4-[5-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-1,2,4-oxadiazol-3-yl]piperazine-1-carboxylate (170.7 mg, 62% yield) as a tan solid. 1H-NMR (400 MHz, DMSO-d6): 9.65 (s, 1H), 8.54 (s, 1H), 8.23 (d, 1H), 7.88-7.86 (m, 2H), 7.63 (d, 1H), 7.32 (s, 1H), 5.58 (s, 2H), 3.98 (s, 3H), 3.43-3.40 (m, 4H), 3.34-3.32 (m, 4H), 1.41 (s, 9H); MS (EI) for C27H29Cl2N7O5: 602 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([N:13]1[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]1)[CH:3]=[C:2]2[N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: C1COCCN1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3CCOCC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and morpholine. MS obsd. (ESI+) [(M+H)+] 424, 1H NMR (400 MHz, CDCl3) δ ppm 8.06 (d, J=8.0 Hz, 1 H), 7.62-7.53 (m, 4 H), 7.40 (t, J=7.6 Hz, 1 H), 7.32 (d, J=7.6 Hz, 1 H), 6.42 (s, 1 H), 5.51 (s, 2 H), 4.60 (brs, 2 H), 4.00 (t, J=4.4 Hz, 4 H), 3.59 (s, 2 H), 3.10 (m, 4 H), 2.44 (s, 3 H).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([Mg]Br)#[CH:10].[Cl-].[NH4+]>C1COCC1.C(OCC)C>[C:2]1([CH:1]([OH:8])[C:9]#[CH:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: C#C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2.65 g of benzaldehyde (Formula 26) in 50 mL of THF at room temperature was added 100 mL of 0.5M ethynylmagnesium bromide in THF. The mixture was stirred at room temperature for 2 hours. Then, the mixture was diluted with diethylether and a saturated solution of ammonium chloride. The mixture was extracted with ethyl acetate. Combined ethyl acetate was washed with brine, dried over sodium sulfate and concentrated. Column chromatography (20% ethyl acetate/hexane) gave 3.17 g of 1-phenyl-prop-2-yn-1-ol (Formula 27) as a light yellow oil. 1H NMR (300 MHz, CDCl3) δ 2.68 (m, 1H), 5.46-5.49 (m, 1H), 7.34-7.43 (m, 3H), 7.55-7.57 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH3:12])[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:13]#[N:14].Cl[CH2:16][C:17]1[N:21]=[C:20]([C:22]2[C:23]([CH3:28])=[N:24][O:25][C:26]=2[CH3:27])[O:19][N:18]=1>>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH3:12])[N:7]([CH2:16][C:17]3[N:21]=[C:20]([C:22]4[C:23]([CH3:28])=[N:24][O:25][C:26]=4[CH3:27])[O:19][N:18]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:13]#[N:14]
Reactant: Cc1noc(C)c1-c1nc(CCl)no1
Reactant: CCc1nc2c(Cl)c(C#N)ccc2[nH]1
Product: CCc1nc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2c(C)noc2C)n1

Procedure:
Synthesized as described in Example 197B from 4-chloro-2-ethyl-1H-benzimidazole-5-carbonitrile and 3-(chloromethyl)-5-(3,5-dimethyl-4-isoxazolyl)-1,2,4-oxadiazole: MS (ESI) m/z 383 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:22][S:23]([O:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 109.4 %

Procedure:
Tert-butyl 3-hydroxypiperidine-1-carboxylate (3.6 g, 18 mmol) was dissolved in dichloromethane (20 mL) and cooled to 0° C., triethylamine (4 mL) was added, followed by dropwise addition of methanesulfonyl chloride (2.28 g, 20 mmol) and DMAP (10 mg). The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was quenched with saturated NaHCO3, and extracted with dichloromethane. The organic layer was washed with H2O, dried and concentrated to give crude product (5.5 g).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH2:9][O:10][C:11]1[CH:25]=[CH:24][C:14]([O:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:13][CH:12]=1.[OH-].[Na+].CO.Cl>O>[CH3:26][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH2:9][O:10][C:11]1[CH:25]=[CH:24][C:14]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:13][CH:12]=1
Reactant: CCOC(=O)CCCOc1ccc(OCc2cnccc2N(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)c1ccncc1COc1ccc(OCCCC(=O)O)cc1
Reaction time: 3 h
Yield: 73.8 %

Procedure:
A mixture containing ethyl 4-[4-[(4-dimethylaminopyrid-3-yl)methoxy]phenoxy]butanoate (25 mg), aqueous sodium hydroxide (1M, 0.2 ml), methanol (0.5 ml) and water (0.5 ml) was stirred for 3 hours then neutralised with hydrochloric acid (1M, 0.2 ml) and concentrated. The residue was dissolved in dichloromethane (5 ml), filtered, and the filtrate was concentrated to give the title compound (17 mg) as a colourless gum. NMR (d6DMSO+d4AcOH): δ2.0(2H,q); 2.4(2H,t); 3.35(6H,s); 3.95(2H,t); 5.1(2H,s); 6.8-7.0(4H, dd +1H,m); 8.15(1H,dd); 8.3(1H,d); m/e 331(M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.O.O.[C:12](O)(=[O:16])[C:13](O)=[O:14]>Cl>[CH3:9][N:8]1[C:13](=[O:14])[C:12](=[O:16])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[N:4][C:3]1=2
Reactant: O=C(O)C(=O)O
Reactant: CNc1ncccc1N
Agent: Cl
Solvent: O
Product: Cn1c(=O)c(=O)[nH]c2cccnc21

Procedure:
3-amino-2-(N-methylamino)-pyridine (0.1 mol) and oxalic acid dihydrate (0,12 mol) was dissolved in 4N HCl (400 ml). The solution was refluxed for 8 hours and then cooled to room temperature whereby the title compound precipitated as crystals. The crystals were separated by filtration and then washed with water. m.p. 271°-272° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH:9]([N:12]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13]1)([CH3:11])[CH3:10]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:17][CH:14]2[CH2:15][CH2:16][N:12]([CH:9]([CH3:11])[CH3:10])[CH2:13]2)=[N:3][CH:4]=1
Reactant: CC(C)N1CCC(O)C1
Reactant: Brc1ccc(Br)nc1
Product: CC(C)N1CCC(Oc2ccc(Br)cn2)C1

Procedure:
Prepared from 2,5-dibromopyridine and 1-isopropylpyrrolidin-3-ol by the method of Example 10 (b).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][CH:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:6][CH:5]=1.[H-].[Na+].I[CH2:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25]>CN(C)C=O>[F:28][C:23]([F:29])([C:24]([F:27])([F:26])[F:25])[CH2:22][CH2:21][C:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:16])([F:17])[F:1])=[CH:15][CH:14]=1)([C:12]#[N:13])[C:10]#[N:11]
Reactant: N#CC(C#N)Cc1ccc(OC(F)(F)F)cc1
Reactant: FC(F)(F)C(F)(F)CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)C(F)(F)F)Cc1ccc(OC(F)(F)F)cc1
Yield: 31.1 %

Procedure:
Using 0.30 g of (4-(trifluoromethoxy)benzyl)malononitrile, 10 ml of N,N-dimethylformamide, 0.06 g of sodium hydride (60% in oil), and 0.38 g of 4-iodo-1,1,1,2,2-pentafluorobutane, and according to the process described in the Production Example 1, there was obtained 0.15 g of 2-(3,3,4,4,4-pentafluorobutyl)-2-(4-(trifluoromethoxy)benzyl)malononitrile (the present compound (10)).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14](=O)[CH3:15])[CH:5]=[N:6][C:7]=1[NH:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[CH3:17][C:18]([S@:21]([NH:23][CH:14]([C:4]1[CH:5]=[N:6][C:7]([NH:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[C:2]([CH3:1])[CH:3]=1)[CH3:15])=[O:22])([CH3:20])[CH3:19]
Reactant: CC(=O)c1cnc(NCC(F)(F)F)c(C)c1
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1NCC(F)(F)F
Yield: 95 %

Procedure:
The title compound is prepared in 95% yield (1.76 g, pale yellow amorphous) from 1-(5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)ethanone (1.27 g, 5.47 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (1.33 g, 10.9 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[C:8]([Br:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:13]1[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:19]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([Br:12])[C:9]([O:11][CH2:19][C:16]2[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=2)=[CH:10][C:2]=1[O:1][CH2:4][C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=1)[C:16]1[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cc(Br)c(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCc1ccccc1)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Yield: 189.9 %

Procedure:
The mixture of 2,4-dihydroxy-5-bromobenzoic acid (23.3 g, 0.1 mol), BnBr (54 g, 0.33 mol) and excess K2CO3 (80 g, 0.58 mol) was stirred in acetone (500 ml) at 85° C. overnight. HPLC indicated the completion of the reaction. After cooling to r.t, the reaction was filtered, and the filtrate was concentrated to give 2,4-bis-benzyloxy-5-bromo-benzoic acid benzyl ester as a white solid (47.8 g, 95%). M.p.: 74-76° C.; 400 MHz 1H NMR (CDCl3) δ: 8.13 (s, 1H), 7.41-7.28 (m, 15H), 6.53 (s, 1H), 5.32 (s, 2H); 5.12 (s, 2H), 5.08 (s, 2H); LCMS: 503, 505 [M+H].
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[N:9][C:8]2[CH:7]=[C:6]([N:17]([CH2:21][CH2:22][Cl:23])[CH2:18][CH2:19][Cl:20])[CH:5]=[CH:4][C:3]1=2.Cl.[CH2:25](O)[CH2:26][CH2:27][CH3:28].C1(N=C=NC2CCCCC2)CCCCC1>CN(C1C=CN=CC=1)C>[CH2:25]([O:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]1[N:2]([CH3:1])[C:3]2[CH:4]=[CH:5][C:6]([N:17]([CH2:18][CH2:19][Cl:20])[CH2:21][CH2:22][Cl:23])=[CH:7][C:8]=2[N:9]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCO
Reactant: Cn1c(CCCC(=O)O)nc2cc(N(CCCl)CCCl)ccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CCCCOC(=O)CCCc1nc2cc(N(CCCl)CCCl)ccc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
A 250 mL three neck round bottom flask was equipped with an overhead stirrer, thermocouple, temperature controller and nitrogen sweep then charged with 10.0 g (25.34 mmol) of bendamustine hydrochloride, 1.9 g (2.35 mL, 25.6 mmol, 1.01 eq) of 1-butanol, 5.3 g (25.6 mmol, 1.01 eq) of dicyclohexylcarbodiimide (DCC), 100 mL of MDC and 0.31 g (2.54 mmol, 0.1 eq) of DMAP. The reaction was stirred at room temperature overnight at which time an in process analysis indicated the reaction was complete. Solids were removed by vacuum filtration and washed with 25 mL of MDC. The filtrate was washed with saturated aqueous sodium bicarbonate solution (2×100 mL), DI water (1×100 mL) and brine (1×100 mL) before drying over sodium sulfate, filtering and concentrating to dryness in vacuo to a brown oil. The oil was triturated with 25 mL of MDC and the solid impurities were removed by vacuum filtration and washed with 25 mL of MDC. The filtrate was concentrated to dryness in vacuo to yield 9.5 g (22.8 mmol, 90%) of the product as a clear light brown oil with an HPLC purity of 94.5 A %. 1H NMR (400 MHz, CDCl3) δ 7.17 (d, J=8.76 Hz, 1H), 7.08 (d, J=2.32 Hz, 1H), 6.77 (dd, J=2.36, 8.8 Hz, 1H), 4.05 (t, J=6.76 Hz, 2 H), 3.72 (m, 4H), 3.69 (s, 3H), 3.63 (m, 4H), 2.91 (t, J=7.4 Hz, 2H), 2.49 (t, J=7.1 Hz, 2H), 2.18 (m, 2H), 1.60 (m, 2H), 1.32 (m, 2H), 0.89 (t, J=4.56 Hz, 3H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.CN(C)[CH:22]=[O:23]>C1COCC1>[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[CH:22]=[O:23]
Reactant: CN(C)C=O
Reactant: Clc1ccncc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1cnccc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
To a solution of diisopropylamine (18.2 mL, 0.13 mol) in THF (200 mL, 0.5 M) at −78° C. was added n-butyl lithium (2.5 M in hexane, 52 mL, 0.13 mol) dropwise. After 30 min, 4-chloropyridine from Step A in THF (10 mL) was added and the reaction mixture was stirred at −78° C. for 1 h. To the resulting reddish-brown solution at −78° C. was added N,N-dimethylformamide (12.4 mL, 0.16 mol). The reaction mixture was allowed to warm slowly to room temperature over a 15 h period, and then the reaction was quenched with water (150 mL). The THF was removed in vacuo and the aqueous layer was extracted with isopropyl acetate (3×150 mL). The organic layers were combined, dried over sodium sulfate, filtered and the solvent was removed in vacuo to give the crude product as a brown oil. This residue was purified by silica gel chromatography (using 5% EtOH in EtOAc) to afford 3.97 g of the title intermediate as a yellow solid (Rf=0.6, 28% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[C:12]([C:17]1[CH:27]=[CH:26][CH:25]=[C:19]2C(N[C:23](=[O:24])[C:18]=12)=O)(OCC)=[O:13].C(N(CC)CC)C>O1CCCC1>[C:23]1(=[O:24])[N:1]([CH2:2][C:3]2[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=2)[C:12](=[O:13])[C:17]2=[CH:27][CH:26]=[CH:25][CH:19]=[C:18]12
Reactant: CCOC(=O)c1cccc2c1C(=O)NC2=O
Reactant: NCc1ccc(C(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Yield: 77.9 %

Procedure:
A mixture of 10 g of 4-aminomethylbenzoic acid, 14.5 g of carbethoxyphthalimide, 9.2 ml of triethylamine and 140 ml of tetrahydrofuran is maintained for 72 hours at reflux temperature. The precipitate formed is isolated at room temperature; after washing with an aqueous acidic solution and drying, 14.5 g of product are obtained. M.p.=264° C.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:33][C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=1.C(OCC)(=O)C>C1COCC1>[CH2:1]1[CH2:2][CH2:3][CH:4]([CH2:7][O:8][C:9]([C:11]2([CH2:33][C:34]3[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=3)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH2:5][CH2:6]1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)OCC2CCCCC2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(C#N)cc2)(C(=O)OCC2CCCCC2)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-cyclohexylmethyl ester (6.61 mmol; 2.15 g) in dry THF (30 mL) under argon at −78° C. was added, dropwise, a 2M solution of lithium diisopropylamide (2M solution in heptanes/THF/ethylbenzene; 8.59 mmol; 4.29 mL). The resulting solution was stirred at −78° C. for 2 hours. 4-Bromomethyl-benzonitrile (6.61 mmol; 1.30 g) was added and the resulting solution was stirred at −78° C. for 2 hours, then allowed to warm to room temperature overnight. Ethyl acetate (150 ml) was added. The resulting solution was washed with a 1M aqueous hydrochloric acid solution (2×50 mL) and brine (50 mL) and dried over magnesium sulfate. After filtration and evaporation, the residue was purified via flash column chromatography (eluent gradient: 0 to 50% EtOAc in heptane) to yield 4-(4-cyano-benzyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-cyclohexylmethyl ester. MS (ESI) m/z 436.38 [M+Na]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19]Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]([NH2:24])([CH3:23])[CH3:22]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:24][CH:21]([CH3:23])[CH3:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCCOc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)N
Product: CC(C)NCCCCOc1ccc(OCc2ccccc2)cc1

Procedure:
As described in Example 19, 1-benzyloxy-4-(4-bromobutoxy)benzene was reacted with isopropylamine at 100° (12 hours; 500 psi) to give 1-benzyloxy-4-[4-(1-methylethyl)aminobutoxyl]benzene. The crude product was not distilled.
Reaction SMILES: [C:1]([C:4]1[NH:13][C:12](=[O:14])[C:11]2[C:6](=[CH:7][C:8]([C:15]([F:18])([F:17])[F:16])=[CH:9][CH:10]=2)[N:5]=1)([CH3:3])=[CH2:2].[Si]([CH:23]=[N+:24]=[N-:25])(C)(C)C>>[CH3:2][C:1]1([C:4]2[NH:13][C:12](=[O:14])[C:11]3[C:6](=[CH:7][C:8]([C:15]([F:17])([F:18])[F:16])=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH:23]=[N:24][NH:25]1
Reactant: C=C(C)c1nc2cc(C(F)(F)F)ccc2c(=O)[nH]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Product: CC1(c2nc3cc(C(F)(F)F)ccc3c(=O)[nH]2)CC=NN1

Procedure:
Following the procedure in Example 7, using 2-isopropenyl-7-trifluoromethyl-3H-quinazolin-4-one and TMSCHN2 as starting materials yielded the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([CH3:27])[C:3]=1[O:4][C:5]1[N:9]([CH3:10])[C:8]2[C:11]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:12][CH:13]=[C:14]([CH:15]=O)[C:7]=2[N:6]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([CH3:27])[C:3]=1[O:4][C:5]1[N:9]([CH3:10])[C:8]2[C:11]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:12][CH:13]=[C:14]([CH2:15][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[C:7]=2[N:6]=1
Reactant: CCC(CC)c1ccc(C=O)c2nc(Oc3c(C)cc(Cl)cc3Cl)n(C)c12
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCC(CC)c1ccc(CN2CCCC2)c2nc(Oc3c(C)cc(Cl)cc3Cl)n(C)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a mixture of 2-(2,4-dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carbaldehyde (93 mg, 0.23 mmol), pyrrolidine (33 mg, 0.46 mmol), acetic acid (0.5 ml) and ethyl acetate (1.5 ml) was added sodium triacetoxyborohydride (244 mg, 1.15 mmol) and the reaction mixture was stirred at room temperature for 1 h. The residue was diluted with aqueous saturated sodium bicarbonate and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on alumina with a 5% ethyl acetate/n-hexane to give 100 mg (0.22 mmol, 94%) of the title compound as a white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]2[C:20]3=[C:21]4[C:26](=[CH:27][CH:28]=[C:19]3[C:12]3[C:13]([O:17][CH3:18])=[CH:14][CH:15]=[CH:16][C:11]=3[O:10]2)[NH:25][C:24]([CH3:30])([CH3:29])[CH:23]=[C:22]4[CH3:31])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([Sn](CCCC)(CCCC)[C:37]1[O:38][CH:39]=[CH:40][CH:41]=1)CCC>CN1CCCC1=O.C(OCC)(=O)C.[F-].[K+]>[O:38]1[CH:39]=[CH:40][CH:41]=[C:37]1[C:2]1[CH:3]=[C:4]([CH:9]2[C:20]3=[C:21]4[C:26](=[CH:27][CH:28]=[C:19]3[C:12]3[C:13]([O:17][CH3:18])=[CH:14][CH:15]=[CH:16][C:11]=3[O:10]2)[NH:25][C:24]([CH3:30])([CH3:29])[CH:23]=[C:22]4[CH3:31])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: COc1cccc2c1-c1ccc3c(c1C(c1cc(C)cc(Br)c1)O2)C(C)=CC(C)(C)N3
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1cccc2c1-c1ccc3c(c1C(c1cc(C)cc(-c4ccco4)c1)O2)C(C)=CC(C)(C)N3
Temperature: 85 °C
Reaction time: 3 h

Procedure:
A solution of Example 11 (0.253 g, 0.531 mmol) in 1-methyl-2-pyrrolidinone (25 mL) was deoxygenated with nitrogen, treated with 2-(tributylstannyl)furan (0.33 mL, 1.06 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.045 g, 0.005 mmol), heated to 85° C. for 13 hours, cooled to room temperature, diluted with ethyl acetate and saturated KF, stirred for 3 hours, and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 5-10% ethyl acetate/hexanes to provide the desired compound.