Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[C:6](/Cl)=[N:7]\[OH:8])=[O:5].[CH3:10][CH:11]([CH3:16])[CH:12]([OH:15])[C:13]#[CH:14].CCN(CC)CC>C1(C)C=CC=CC=1.CCOC(C)=O>[OH:15][CH:12]([C:13]1[O:8][N:7]=[C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:14]=1)[CH:11]([CH3:16])[CH3:10]
Reactant: C#CC(O)C(C)C
Reactant: CCOC(=O)/C(Cl)=N\O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(C(O)C(C)C)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
Ethyl chlorooximidoacetate (6.79 mmol, 1.029 g) and 4-methyl-1-pentyn-3-ol (20.38 mmol, 2 g) were dissolved in toluene (20 ml). Et3N (6.79 mmol, 0.947 ml) dissolved in toluene was added dropwise. The mixture was stirred overnight at RT. The mixture was diluted with EtOAc and washed with water. The organic phase was dried, filtered and evaporated. The crude product was purified by flash chromatography. 0.828 g of the title compound was obtained. 1H-NMR (400 MHz, MeOH-d4): δ 0.92 (d, 3H), 0.97 (d, 3H), 1.39 (t, 3H), 2.03-2.16 (m, 1H), 4.41 (q, 2H), 4.58 (d, 1H), 6.65 (s, 1H).
Reaction SMILES: N.[Na].[C:3](#[N:5])[CH3:4].[Cl:6][C:7]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10]>O1CCCC1.C(OCC)C>[NH2:10][C:9]([C:8]1[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:7]=1[Cl:6])=[CH:4][C:3]#[N:5]
Reactant: CC#N
Reactant: N#Cc1ccc(Cl)cc1Cl
Agent: N
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#CC=C(N)c1ccc(Cl)cc1Cl

Procedure:
A 150 ml. portion of ammonia is condensed in a reaction flask and a small piece of sodium is added. The blue color is discharged by the addition of ferric chloride and 3.22 g. of sodium are added. After the color is discharged, 5.75 ml. of acetonitrile in 10 ml. of diethyl ether are added. The reaction is cooled in a dry ice-acetone bath and 16.6 g. of 2,4-dichlorobenzonitrile in 25 ml. of tetrahydrofuran are added dropwise. The ammonia is allowed to evaporate, the solvent is blown off with nitrogen and water is added. The mixture is extracted with methylene chloride. The organic extracts are dried over sodium sulfate and filtered through Magnesol®. The filtrate is evaporated with the addition of hexanes giving β-amino-2,4-dichlorocinnamonitrile as a white crystalline solid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])(C)(C)C.[Cl:17][C:18]1[CH:28]=[CH:27][C:21]([O:22][CH2:23]C(Cl)=O)=[CH:20][CH:19]=1.[CH2:29]([N:31]1[C:43]2[CH:42]=[CH:41][C:40]([NH2:44])=[CH:39][C:38]=2[C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH3:30]>>[Cl:17][C:18]1[CH:28]=[CH:27][C:21]([O:22][CH2:23][C:6]([N:8]2[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]2[C:10]([NH:44][C:40]2[CH:41]=[CH:42][C:43]3[N:31]([CH2:29][CH3:30])[C:32]4[C:37]([C:38]=3[CH:39]=2)=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:12])=[O:7])=[CH:20][CH:19]=1
Reactant: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Product: C=C1C[C@@H](C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)N(C(=O)COc2ccc(Cl)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from 1-(tert-butoxycarbonyl)-4-methyleneproline, (4-chlorophenoxy)acetyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 100% purity by LC/MS. MS(ESI+): m/z=488.4.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH:16]=O)[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3]1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:31][CH:32]([CH3:34])[CH3:33])=[C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.C(OCC)(=O)C>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:31][CH:32]([CH3:34])[CH3:33])=[C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:8]3[N:9]=[C:10]4[C:5]([CH:4]=[CH:3][C:2](=[O:1])[NH:11]4)=[CH:6][CH:7]=3)[CH2:29][CH2:30]2)[CH:24]=1
Reactant: CC(C)Oc1ccc(Cl)cc1N1CCNCC1
Reactant: O=CCCCOc1ccc2ccc(=O)[nH]c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CC(C)Oc1ccc(Cl)cc1N1CCN(CCCCOc2ccc3ccc(=O)[nH]c3n2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.3 %

Procedure:
To a suspension of 4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (0.206 g, 0.887 mmol, 1 eq) and 1-(5-chloro-2-isopropoxy-phenyl)-piperazine (0.328 g, 0.977 mmol, 1.1 eq) in dichloroethane (5 mL) was added NaBH(OAc)3 (0.535 g, 2.524 mmol, 2.84 eq). The slurry was allowed to stir overnight at room temperature (18 h). Analysis by HPLC showed reaction mostly complete. The mixture was diluted with Ethyl Acetate and quenched with saturated NaHCO3. The organic phase was washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. Purification by silica gel chromatography (2% MeOH/CH2Cl2) followed by formation of the HCl salt using 1N HCl in ether provided the title compound (0.164 g, 39%). MS: APCI: M+1: 471.2 (Exact Mass: 470.21).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][CH2:14]CCCC)[CH:6]=[C:5]2[CH2:19][C:20]([NH2:22])=[O:21].Br[CH2:24]CCCCCCC>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH:12]=[C:13]([CH3:14])[CH3:24])[CH:6]=[C:5]2[CH2:19][C:20]([NH2:22])=[O:21]
Reactant: CCCCCCCCBr
Reactant: CCCCCCCCn1cc(CC(N)=O)c2cc(F)ccc21
Product: CC(C)=CCn1cc(CC(N)=O)c2cc(F)ccc21

Procedure:
2-(5-Fluoro-1-octyl-1H-indol-3-yl)acetamide) (1-8). The reaction between Amide A-2 and bromooctane can be carried out as described by Na, Y. M.; Le Borgne, M.; Pagniez, F.; Le Baut, G.; Le Pape, P. Synthesis and antifungal activity of new 1-halogenobenzyl-3-imidazolylmethylindole derivatives. Eur J Med Chem 2003, 38, 75-87. Yield: 70%; 1H NMR (300 MHz, CDCl3): δ7.26-7.18 (m, 2 H), 7.09 (s, 1 H), 6.97 (dt, J1=9 Hz, J2=2.4 Hz, 1 H), 5.73 (br. s, 2 H), 4.06 (t, J=7.2 Hz, 2 H), 3.65 (s, 2 H), 1.83 (t, J=6.3 Hz, 2 H), 1.29-1.25 (m, 10 H), 0.86 (t, J=6.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 174.10, 159.39, 156.27, 139.66, 133.03, 128.67, 127.68, 127.55, 110.66, 117.23, 103.88, 46.63, 32.81, 31.70, 30.17, 29.09 (2C), 26.94, 22.55, 14.02; MS (APCI): m/z 305.5 [M+H]+
Reaction SMILES: [CH3:1][C:2]1([N:7]2[CH2:12][CH2:11][CH:10]([N:13]3[C@@H:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C@H:16]4[NH:15][C:14]3=[O:22])[CH2:9][CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3]1.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[O:22]=[C:14]1[N:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:2]3([CH3:1])[CH2:6][CH2:5][N:4]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:3]3)[CH2:8][CH2:9]2)[C@@H:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C@H:16]2[NH:15]1
Reactant: CC1(N2CCC(N3C(=O)N[C@@H]4CCCC[C@H]43)CC2)CCNC1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1CCC(C)(N2CCC(N3C(=O)N[C@@H]4CCCC[C@H]43)CC2)C1

Procedure:
Following the procedure used in step G of the example 8 and starting with (3aR,7aR)-1-[1-(3-methylpyrrolidin-3-yl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-2-one (160 mg, 0.522 mmol) and ethyl chloroformate (85 mg, 0.783 mmol), the title compound was obtained as a gum (120 mg). 1H NMR (Methanol-D4) δ 4.60 (brs, 1H), 4.13-4.08 (q, 2H), 3.74-3.51 (m, 4H), 3.43-3.34 (m, 2H), 3.20 (br d, 1H), 3.04-2.90 (m, 3H), 2.73 (br s, 1H), 2.4-2.31 (m, 3H), 1.98-1.60 (br m, 8H), 1.43 (m, 3H), 1.25 (t, 3H), 1.10 (s, 3H). MS (M+1): 379.34.
Reaction SMILES: Cl.O1CCOCC1.C(OC(=O)[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[C:26]([Cl:28])[N:25]=[CH:24][N:23]=2)=[CH:17][CH:16]=1)(C)(C)C>C(Cl)Cl>[Cl:28][C:26]1[N:25]=[CH:24][N:23]=[C:22]([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([NH2:14])=[CH:16][CH:17]=2)[CH:27]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cc2cc(Cl)ncn2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1ccc(Cc2cc(Cl)ncn2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 148.5 %

Procedure:
A 4 N solution of HCl in dioxane (1.2 mL, 4.96 mmol, 30 equiv) is added to a solution of [4-(6-chloro-pyrimidin-4-ylmethyl)-phenyl]-carbamic acid tert-butyl ester (50 mg, 0.156 mmol) in CH2Cl2 (0.67 mL), under an argon atmosphere. The resulting white suspension is stirred at rt for 4 h and concentrated in vacuo to afford 50.9 mg of crude 4-(6-chloro-pyrimidin-4-ylmethyl)-phenylamine as a white solid. DIEA (80 μL, 0.454 mmol, 2 equiv) is added to a suspension of crude 4-(6-chloro-pyrimidin-4-ylmethyl)-phenylamine (50 mg, 0.227 mmol) in THF (0.4 mL), under an argon atmosphere. 4-Ethyl-phenyl-isocyanate (40 μL, 0.250 mmol, 1.1 equiv) is then added. The resulting yellow solution is stirred at rt for 2 h and concentrated in vacuo. The residue is purified by silica gel (20 g) column chromatography (CH2Cl2/MeOH, 98/2). A second purification affords the title compound as a white solid: ES-MS: 367.0 [M+H]+; single peak at tR=8.94 min (System 2); Rf=0.32 (CH2Cl2/MeOH, 95/5).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[CH2:35]Br>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:35][C:34]3[CH:37]=[CH:38][C:39]([O:40][CH3:41])=[C:32]([F:31])[CH:33]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Reactant: COc1ccc(CBr)cc1F
Product: COc1ccc(Cn2ccc3c(-c4ccc5c(c4)CCCO5)c(C(OC(C)(C)C)C(=O)O)c(C)nc32)cc1F

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 3-fluoro-4-methoxybenzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.51-7.41 (m, 1 H), 7.25-7.18 (m, 1 H), 7.07-6.99 (m, 3 H), 6.97-6.88 (m, 2 H), 6.31-6.23 (m, 1 H), 5.63-5.56 (m, 1 H), 5.53-5.36 (m, 2 H), 4.32-4.26 (m, 2 H), 3.90-3.86 (m, 3 H), 2.96-2.80 (m, 2 H), 2.75 (s, 3 H), 2.14-2.04 (m, 2 H), 0.97 (s, 9H); LC/MS (m/z) ES+=533.28 (M+1).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[N:9]1([CH2:14][CH2:15][CH2:16][C:17]#N)[CH2:13][CH2:12][CH2:11][CH2:10]1.C(O)(C(F)(F)F)=[O:20].CC#N>CCOCC.C(Cl)Cl>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:17](=[O:20])[CH2:16][CH2:15][CH2:14][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Cc1ccccc1I
Reactant: O=C(O)C(F)(F)F
Reactant: N#CCCCN1CCCC1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CC#N
Product: Cc1ccccc1C(=O)CCCN1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 10 mL oven-dried flask was charged Mg turnings (30 mg, 1.2 mmol) which were activated under vacuum by the use of a heat-gun. Under inert atmosphere was added a solution of 2-iodotoluene (0.22 g, 1.0 mmol) in Et2O (2 mL) and the reaction mixture was allowed to reflux for 1 hour. A mixture of 4-pyrrolidin-1-yl-butyronitrile (Burckhalter et. al. J. Org. Chem. 1961, 26, 4070-4076) (0.14 g, 1.0 mmol) in CH2Cl2 (2 mL) was added via a syringe and the reaction mixture was stirred at rt overnight. The reaction mixture was quenched by addition of H2SO4 (10 mL, 2 M) and stirred at rt for 2 hours followed by addition of NaOH (10 mL, 2 M). Addition of THF (15 mL) was followed by extraction with ethyl acetate (3×20 mL), and the organic phases were dried (MgSO4) and evaporated to dryness to produce 0.12 g of crude 13. The crude product was subjected to preparative HPLC [eluent: Buffer A: 0.1% TFA; Buffer B: 80% CH3CN+0.1% TFA] to produce an analytical pure sample of compound 13. LC-MS [M+H]+ 231 (cald. 231.3).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9]Cl)[CH:4]=1.[C:11]([OH:15])(=[O:14])[CH:12]=[CH2:13]>>[C:11]([O:15][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][O:15][C:11](=[O:14])[CH:12]=[CH2:13])[CH:4]=1)(=[O:14])[CH:12]=[CH2:13]
Reactant: C=CC(=O)O
Reactant: ClCc1cccc(CCl)c1
Product: C=CC(=O)OCc1cccc(COC(=O)C=C)c1

Procedure:
The above compound was synthesized from α,α′-dichloro-m-xylene and acrylic acid.
Reaction SMILES: N[C:2](N)=S.C[C:6]1([CH:13]=[CH:12][CH:11]=[CH:10][CH2:9]1)[CH2:7]Br.C[S:15]([C:18]1[CH2:22][C:21]([CH3:24])([CH3:23])[O:20][N:19]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH3:23][C:21]1([CH3:24])[O:20][N:19]=[C:18]([S:15][CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:2])[CH2:22]1
Reactant: NC(N)=S
Reactant: CC1(C)CC(S(C)(=O)=O)=NO1
Reactant: CC1(CBr)C=CC=CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(SC1=NOC(C)(C)C1)c1ccccc1
Temperature: 25 °C
Yield: 40.6 %

Procedure:
Thiourea (180 mg, 2.4 mmol) was added to a solution of 1-methyl benzyl bromide (0.3 ml, 2.2 mmol) in ethanol (10 ml) at room temperature. The mixture was heated under reflux for 5 hours. 3-Methanesulfonyl-5,5-dimethyl-4,5-dihydroisoxazole (420 mg, 2.4 mmol) and potassium carbonate (330 mg, 2.4 mmol) were added and the mixture was heated under reflux for 3 hours. The mixture was allowed to cool to room temperature, poured into water and the mixture extracted with ethyl acetate. The combined organic phases were washed with water, dried over magnesium sulfate and concentrated. The crude product was purified by chromatography on silica gel (eluent: ethyl acetate/hexane) to give the product as a white solid (210 mg, 43% yield) which was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[S:10][CH:11]=[CH:12][C:4]=2[CH2:3]1.[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](O)=[CH:16][CH:15]=1>>[ClH:13].[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([O:9][CH:6]2[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][C:4]3[CH:12]=[CH:11][S:10][C:5]2=3)=[CH:16][CH:15]=1
Reactant: Oc1ccc(Cl)c2ccccc12
Reactant: CN1CCC(O)c2sccc2C1
Product: CN1CCC(Oc2ccc(Cl)c3ccccc23)c2sccc2C1
Product: Cl

Procedure:
The same method as in Example 47 was conducted using 5-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-8-ol (Reference Example 25) instead of 6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 1) and was conducted using 4-chloro-1-naphthol instead of 4-chloro-3-methylphenol to give the objective compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH:15]3[C:20](=[O:21])[C:19]([CH3:23])([CH3:22])[O:18][C:17]([CH3:25])([CH3:24])[C:16]3=[O:26])[CH:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:30])(=O)=O>C(Cl)(Cl)Cl>[Cl:30][C:15]1([C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:13]=[CH:12][C:11]=2[CH3:14])[C:20](=[O:21])[C:19]([CH3:22])([CH3:23])[O:18][C:17]([CH3:25])([CH3:24])[C:16]1=[O:26]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1C1(Cl)C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4′-chloro-4-methylbiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione in anhydrous chloroform (3 ml) at 0° C. is added a second solution of sulfuryl chloride (0.025 ml, 0.315 mmol) in anhydrous chloroform (0.3 ml) dropwise. The reaction mixture is stirred for 30 minutes at 0° C. then for a further 1 hour at room temperature. Additional sulfuryl chloride (0.025 ml, 0.315 mmol) is next added, followed by warming to 60° C. for 2 hours, followed by addition of further sulfuryl chloride (0.20 ml, 2.52 mmol). The reaction mixture is finally stirred at room temperature overnight then quenched with saturated aqueous sodium bicarbonate, and extracted with ethylacetate. Purification by flash column chromatography (20% ethylacetate in hexane eluant) afforded 4-chloro-4-(4′-chloro-4-methylbiphenyl-3-yl)-2,2,6,6-tetramethyl-pyran-3,5-dione (0.033 g) as a yellow oil.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1.[C:20](=[O:23])([O-])[O-].[Na+].[Na+].O>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.C1(C)C=CC=CC=1>[CH2:20]([O:23][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: c1ccccc1
Reactant: Brc1ccc(C2CCCCC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(COc2ccc(-c3ccc(C4CCCCC4)cc3)cc2)cc1
Yield: 70.1 %

Procedure:
First, 80 ml of ethanol containing 7.18 g of 4-benzyloxyphenylboronic acid obtained from the synthesis (10-b) above dissolved therein, 50 ml of benzene containing 5.00 g of 1-bromo-4-cyclohexylbenzene dissolved therein, 21.0 ml of a sodium carbonate aqueous solution with a concentration of 2 mol/l, and 0.24 g of tetrakis(triphenylphosphine)palladium(0) were put in an argon-replaced 200 ml flask, and stirred under reflux for eight hours. After the reaction, water and toluene were added to the reaction solution for extraction. The resultant toluene layer was washed with a saturated brine and dried with sodium sulfate. The solvent was then distilled off. The residue was purified by silica gel column chromatography (eluent:toluene/hexane=1/4), to obtain 5.04 g (Y: 70.1%) of 4-benzyloxy-4′-cyclohexylbiphenyl. The purity of the resultant compound was 98.3% as measured by GC.
Reaction SMILES: [CH2:1]([C:5]1([CH2:31][CH2:32][CH2:33][CH3:34])[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]([OH:16])=[C:7]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][C:25](I)=[CH:26][C:20]=3[S:19](=[O:29])(=[O:28])[N:18]=2)[C:6]1=[O:30])[CH2:2][CH2:3][CH3:4].[C:35]([NH2:39])(=[O:38])[CH:36]=[CH2:37].C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([C:5]1([CH2:31][CH2:32][CH2:33][CH3:34])[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]([OH:16])=[C:7]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][C:25](/[CH:37]=[CH:36]/[C:35]([NH2:39])=[O:38])=[CH:26][C:20]=3[S:19](=[O:29])(=[O:28])[N:18]=2)[C:6]1=[O:30])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3cc(I)ccc3N2)=C(O)c2cc(F)ccc21
Reactant: C=CC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3cc(/C=C/C(N)=O)ccc3N2)=C(O)c2cc(F)ccc21
Temperature: 100 °C
Yield: 55.6 %

Procedure:
A solution of the compound of Example 20B (65 mg, 0.11 mmol), acrylamide (9 mg, 0.12 mmol), triethylamine (45 μL, 0.33 mmol), and palladium (II) acetate (1.2 mg, 0.005 mmol) in N,N-dimethylformamide (1.5 mL) in a resealable pressure tube was degassed by evacuation and purging with nitrogen. The pressure tube was sealed and warmed at 100° C. for 1 h. The solution was cooled and diluted with ethyl acetate and water. The mixture was acidified by addition of citric acid solution (1 M, 2 mL). The organic layer was extracted with water (2×) and with saturated NaCl solution. Drying (Na2SO4) and concentration in vacuo afforded a solid, which was purified by flash chromatography eluting with methanol in dichloromethane. These procedures afforded the title compound (33 mg, 56%) as a light amber solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:28][CH2:29]N2CC(N3CCC(O)CC3)C2)[CH2:9][N:10]([CH3:27])[C:11](=[O:26])[C:12]2[CH:17]=[C:16](C(F)(F)F)[CH:15]=[C:14](C(F)(F)F)[CH:13]=2)=[CH:4][CH:3]=1.[ClH:41].[ClH:42].[NH:43]1[CH2:46][CH:45]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)[CH2:44]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[Cl:41][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([Cl:42])[CH:15]=1)[C:11]([N:10]([CH2:9][C@H:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:28][CH2:29][N:43]1[CH2:46][CH:45]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)[CH2:44]1)[CH3:27])=[O:26]
Reactant: Cl
Reactant: C1CN(C2CNC2)CCO1
Reactant: CN(C[C@@H](CCN1CC(N2CCC(O)CC2)C1)c1ccc(F)cc1)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C[C@@H](CCN1CC(N2CCOCC2)C1)c1ccc(F)cc1)C(=O)c1cc(Cl)cc(Cl)c1
Reaction time: 0.42 h
Yield: 62.7 %

Procedure:
3,5-Dichloro-N-[(2S)-2-(4-fluorophenyl)-4-oxobutyl]-N-methylbenzamide (see Method 21; 146 mg, 0.40 mmol) was dissolved in CH2Cl2 (8 mL) and to the resultant solution were added 4-azetidin-3-ylmorpholine dihydrochloride (see WO 00/63168; 62 mg, 0.44 mmol) and DIPEA (179 mg, 1.39 mmol) together with 5 drops of acetic acid. The mixture was stirred for 25 minutes and then sodium triacetoxyborohydride (118 mg, 0.55 mmol) was added. The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate and saturated NaHCO3 aq. The phases were separated and the aqueous solution was extracted with ethyl acetate. The combined organic solutions were dried over MgSO4 and the solvent was removed by evaporation. The residue was chromatographed on silica gel using a mixture of methanol and CH2Cl2 as eluent (gradient 0 to 20% methanol). There was obtained 124 mg (63%) of the title compound as an oil. 1H NMR (500 MHz, CDCl3): 1.4-1.8 (cm, 2H), 2.2-3.8 (cm, 21H), 6.7 (s, 1H), 6.8-7.2 (m, 5H), 7.3 (s, 1H); LCMS: m/z 494 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22](=O)[CH3:23])[N:20]=2)[N:15]=[N:14]1.Cl.[NH:26]1[CH2:30][CH2:29][C@H:28]([O:31][NH2:32])[CH2:27]1>>[NH:26]1[CH2:30][CH2:29][C@H:28]([O:31]/[N:32]=[C:22](/[C:19]2[N:20]=[C:21]3[N:13]([CH2:12][C:3]4[CH:4]=[C:5]5[C:10](=[CH:11][C:2]=4[F:1])[N:9]=[CH:8][CH:7]=[CH:6]5)[N:14]=[N:15][C:16]3=[N:17][CH:18]=2)\[CH3:23])[CH2:27]1
Reactant: CC(=O)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Reactant: NO[C@H]1CCNC1
Agent: Cl
Product: C/C(=N\O[C@H]1CCNC1)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Yield: 75.9 %

Procedure:
The title compound (37.0 mg, 70%) was synthesized from 1-[3-(7-fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (15.4) (40.0 mg, 0.12 mmol) and (S)—O-pyrrolidin-3-yl-hydroxylamine hydrochloride (30.0 mg, 0.17 mmol) using the same procedure as described in the synthesis of example 15. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.30 (s, 1H), 8.92 (dd, 1H), 8.41 (dd, 1H), 8.18 (d, 1H), 7.82 (d, 1H), 7.53 (dd, 1H), 6.23 (s, 2H), 4.95 (m, 1H), 3.16-2.87 (m, 3H), 2.77-2.71 (m, 1H), 2.25 (s, 3H), 2.01-1.87 (m, 2H). LCMS (method A): [MH]+=407, tR=3.09 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([OH:12])[CH2:9][N:8]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>ClCCl>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([O:12][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:9][N:8]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CC[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.4 %

Procedure:
To a stirred mixture of tert-butyl (2R,4R)-2-(3-ethoxy-3-oxopropyl)-4-hydroxypyrrolidine-1-carboxylate (335 mg, 1.2 mmol, step 2 of Example 8) and triethylamine (0.25 mL, 1.8 mmol) in dichloromethane (5 mL) at 0° C. was added methanesulfonyl chloride (0.14 mL, 1.8 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 3 h. To the mixture was added water (10 mL) and extracted with dichloromethane (100 mL). The organic layer was dried over sodium sulfate, and concentrated under reduced pressure to give 462 mg (100%) of the title compound as a yellow oil, which was used for the next step without further purification.