Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][O:9]1
Reactant: OCCCCCCBr
Reactant: C1=COCCC1
Product: BrCCCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
First, 197.8 g (1.09 mol) of 6-bromo-1-hexanol were fed into a 500 mL reactor vessel and cooled to 5° C. or less, and further 102.1 g (1.21 mol) of dihydropyran were dripped at a temperature of 10° C. or less. After completion of dripping, the mixture was warmed to room temperature to carry out a reaction under stirring for one hour. Residues obtained by this reaction were purified by silica gel column with hexane/IPE (diisopropylether)=5/1, and thus 263.4 g of 6-bromo-1-(tetrahydropyranyloxy)hexane were obtained. The yield was 90.9%. Formula (26) below shows the reaction formula of the step 1.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:19][C:20]3([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][CH2:24][N:23]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)[CH2:22][CH2:21]3)=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH2:35]([O:34][C:32]([C:20]1([CH2:19][O:18][C:12]2[CH:11]=[C:10]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9]3)=[CH:14][CH:13]=2)[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH2:22][CH2:21]1)=[O:33])[CH3:36]
Reactant: CCOC(=O)C1(COc2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3)CCN(c2ccncc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1(COc2ccc3c(c2)CNCC3)CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
To a solution of 7-[4-ethoxycarbonyl-1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (10.87 g) in chloroform (50 ml) was dropwise added trifluoroacetic acid (30 ml) with ice-cooling, and the mixture was stirred at room temperature for 30 min. The solvent was evaporated and to the obtained residue was added aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was dried under reduced pressure to give the title compound (8.29 g).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14]CC=C)[C:7]([O:9][CH3:10])=[O:8])[CH:2]=[CH2:3].C(OCC)(=O)C.[CH3:24][CH2:25][CH2:26]CCC>>[OH:14][C:13]1[C:12]([CH2:26][CH:25]=[CH2:24])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[CH2:1][CH:2]=[CH2:3]
Reactant: CCCCCC
Reactant: C=CCOc1ccc(C(=O)OC)cc1CC=C
Solvent: CCOC(C)=O
Product: C=CCc1cc(C(=O)OC)cc(CC=C)c1O
Yield: 97 %

Procedure:
The product of Step A (3.2g, 13.8 mmol) was refluxed in 12-dichlorobenzene for 3 days in the presence of a catalytic amount of BHT (10 mg). Flash column chromatography of the mixture using hexane and then 10% and 20% ethyl acetate in hexane afforded 3.1 g (97%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:31][C:32]1[C:33]([OH:46])=[C:34]([S:42](Cl)(=[O:44])=[O:43])[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1>C(Cl)Cl>[Cl:31][C:32]1[C:33]([OH:46])=[C:34]([S:42]([N:15]([CH2:14][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][CH:11]=2)[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)(=[O:44])=[O:43])[CH:35]=[C:36]([C:38]([F:40])([F:41])[F:39])[CH:37]=1
Reactant: Fc1ccc(CNCc2cccc(-c3ccc(Cl)cc3)c2)cc1
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)cc(Cl)c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1cc(C(F)(F)F)cc(Cl)c1O)N(Cc1ccc(F)cc1)Cc1cccc(-c2ccc(Cl)cc2)c1
Temperature: 0 °C
Yield: 57 %

Procedure:
1-(4′-Chlorobiphenyl-3-yl)-N-(4-fluorobenzyl)methanamine (Compound A of Example 232, 200 mg, 0.6 mmol, 1.0 eq) was dissolved in dry DCM (20 mL) then stirred and cooled to 0° C. Triethylamine (186 mg, 1.86 mmol, 3.0 eq) was added slowly and the mixture was stirred for 30 minutes. 3-Chloro-2-hydroxy-5-(trifluoromethyl)benzene-1-sulfonyl chloride (180 mg 0.6 mmol 1.0 eq) dissolved in DCM was added to the above solution and the resulting mixture was stirred for 12 h at ambient temperature. The solution was concentrated under reduced pressure and the residue was purified by silica gel (240-280) column chromatography using 20-30% ethyl acetate/hexane as the eluent to afford the title compound (0.2 g, 56%). 1H NMR (400 MHz, CD3OD) δ 7.92 (d, 1H), 7.79 (d, 1H), 7.43 (d, 5H), 7.32-7.29 (t, 1H), 7.27-7.25 (m, 2H), 7.23 (s, 1H), 7.15-7.13 (d, 1H), 6.98-6.94 (t, 2H), 4.89 (s, 1H), 4.58-4.53 (d, 2H). MS (ESI): 585.8 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]([F:17])([F:16])[C:4]1[NH:8][C:7]2[CH:9]=[CH:10][C:11]([C:13]([OH:15])=[O:14])=[CH:12][C:6]=2[N:5]=1.[CH3:18]O>>[F:17][C:3]([F:2])([F:16])[C:4]1[NH:8][C:7]2[CH:9]=[CH:10][C:11]([C:13]([O:15][CH3:18])=[O:14])=[CH:12][C:6]=2[N:5]=1
Reactant: O=C(O)c1ccc2[nH]c(C(F)(F)F)nc2c1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc2[nH]c(C(F)(F)F)nc2c1

Procedure:
Gaseous hydrogen chloride is passed through a solution of 59.7 g (0.241 mol) of 14a in 1,000 ml of methanol for 2 hours, simultaneously boiling under reflux. The methanol is then removed by distillation, and the residue is dissolved in ethyl acetate/water and the pH is adjusted to 7 with 2N solution hydroxide solution. The ethyl acetate phase is separated off, the aqueous phase is extracted twice with ethyl acetate, and the organic phase is washed with sodium chloride solution, dried over Na2SO4 and evaporated.
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:17][C:18]([CH3:22])([OH:21])[C:19]#[CH:20]>ClCCl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[NH2:1][C:2]1[C:7]([C:20]#[C:19][C:18]([CH3:22])([OH:21])[CH3:17])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1
Reactant: C#CC(C)(C)O
Reactant: Nc1ncc(Br)cc1I
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(O)C#Cc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
A suspension of 2-amino-5-bromo-3-iodopyridine (10.0 g, 33.5 mmol), bis-(triphenylphosphine)-palladium(II)-dichloride (117 mg, 0.17 mmol), copper(I)iodide (79 mg, 0.41 mmol) and triethylamine (6.1 mL, 43.5 mmol) in dichloromethane (40 mL) was treated at 23 to 30° C. within 1 to 2 hours with a solution of 1,1-dimethyl-2-propyn-1-ol (3.70 g, 44 mmol) in dichloromethane (10 mL) and the resulting mixture was stirred at 25° C. for 3 hours. The mixture was diluted with dichloromethane (20 mL) and washed with water (2×50 mL). The organic phase was then treated with 1 M HCl (80 mL). The layers were separated and the organic layer was extracted with 1 M HCl (20 mL). The combined product containing aqueous layers were washed with dichloromethane (2×10 mL). The pH of the aqueous layer was adjusted to pH 7-9 by the drop wise addition of sodium hydroxide solution (28% in water, 18 g). The resulting suspension was stirred at 20° C. for 2 hours and the crystals were then filtered off and washed with water (2×20 mL). The wet crystals were dried at 50° C./<30 mbar affording 6.99 g (82%) of 4-(2-amino-5-bromo-pyridin-3-yl)-2-methyl-but-3-yn-2-ol as a melted mass with a purity of 99.5% (HPLC, area %). 1H NMR (400 MHz, CDCl3): δ ppm 1.63 (s, 6H); 4.0 (br., 3H); 7.59 (d, J=2.4, 1H); 8.03 (d, J=2.4, 1H).
Reaction SMILES: [Br:1][C:2]1[N:10]([CH2:11][CH3:12])[C:9]2[C:8](=[O:13])[N:7]([CH2:14][CH2:15][CH2:16][OH:17])[C:6](=[O:18])[N:5]([CH3:19])[C:4]=2[N:3]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.[O:37]1[CH:42]=[CH:41][CH2:40][CH2:39][CH2:38]1>C(Cl)Cl>[Br:1][C:2]1[N:10]([CH2:11][CH3:12])[C:9]2[C:8](=[O:13])[N:7]([CH2:14][CH2:15][CH2:16][O:17][CH:38]3[CH2:39][CH2:40][CH2:41][CH2:42][O:37]3)[C:6](=[O:18])[N:5]([CH3:19])[C:4]=2[N:3]=1
Reactant: CCn1c(Br)nc2c1c(=O)n(CCCO)c(=O)n2C
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCn1c(Br)nc2c1c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
To a solution of 8-bromo-7-ethyl-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.4 g, 1.2 mmol) in DCM (10 mL) was added PPTS (27 mg, 0.1 mmol); then dihydropyran (0.15 g, 1.8 mmol) was added dropwise at 0° C. The mixture was stirred at room temperature overnight. The mixture was partitioned between DCM and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by a column chromatography eluting with petroleum ether/ethyl acetate (3:1) to give 8-bromo-7-ethyl-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (0.38 g, 76.9% yield) as white solid. LCMS retention time 1.871 min; LCMS MH+-THP 331.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([SH:10])=[C:6]([CH:9]=1)[CH:7]=O.[F:11][C:12]([F:21])([F:20])/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16].C([O-])([O-])=O.[K+].[K+].Cl>C(OCC)(=O)C.CN(C=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH:13]([C:12]([F:11])([F:21])[F:20])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:9]=1
Reactant: Cc1ccc(S)c(C=O)c1
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(C)ccc2SC1C(F)(F)F
Yield: 69.4 %

Procedure:
The 5-methyl-2-mercaptobenzaldehyde (Step 1) (3.25 g, 21.3 mmol) was added to DMF (5 mL) and ethyl 4,4,4-trifluorocrotonate (4.32 g, 25.7 mmol). With stirring, K2CO3 (3.78 g, 27.3 mmol) was added causing the reaction to become a deep red. The reaction was stirred at room temperature for 20 hours, acidified with 3N HCl, diluted with ethyl acetate and washed with water, saturated NaHCO3 solution, brine, dried over MgSO4, filtered and concentrated in vacuo yielding an oil. The oil was crystallized from diethyl ether-petroleum ether to give ethyl 6-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylate as a light yellow solid (4.47 g, 69%),: mp 93.1–94.7° C. 1H NMR (acetone-d6/300 MHz) 7.94 (s, 1H), 7.41 (s, 1H), 7.31 (d, 1H, J=7.9 Hz), 7.25 (d, 1H, J=7.9 Hz), 4.96 (q, 1H, J=8.5 Hz), 4.33 (m, 2H), 2.34 (s, 3H), 1.35 (t, 3H, J=7.0 Hz). FABLRMS m/z 309 (M+Li).
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]1[NH:8][C:7](=[O:9])[O:6][N:5]1[CH2:10][C:11]1[CH:34]=[CH:33][C:14]([O:15][CH2:16][C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([O:31]C)=[O:30])=[CH:25][CH:24]=3)[CH:20]=[CH:21][CH:22]=2)=[CH:13][CH:12]=1.CO.Cl>C1COCC1>[O:3]=[C:4]1[NH:8][C:7](=[O:9])[O:6][N:5]1[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([OH:31])=[O:30])=[CH:25][CH:24]=3)[CH:20]=[CH:21][CH:22]=2)=[CH:33][CH:34]=1
Reactant: COC(=O)c1ccc(-c2cccc(COc3ccc(Cn4oc(=O)[nH]c4=O)cc3)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(-c2cccc(COc3ccc(Cn4oc(=O)[nH]c4=O)cc3)c2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
A 1 M sodium hydroxide aqueous solution (5 ml) was added to a mixture of methyl 3′-({4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy}methyl)-4-biphenylcarboxylate (196 mg), methanol (5 ml) and THF (5 ml), followed by stirring for 1 hour with heating at 60° C. A 1 M hydrochloric acid (7 ml) was added to the reaction mixture, followed by stirring at room temperature. The solid precipitated was collected by filtration and dried by heating under a reduced pressure to obtain 3′-({4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy}methyl)-4-biphenylcarboxylic acid (176 mg) as a white solid.
Reaction SMILES: [N:1]1([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=O.Cl.[CH2:21]([O:23][C:24](=[O:28])[CH2:25][NH:26][CH3:27])[CH3:22].ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[N:1]1([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([N:26]([CH3:27])[CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:28])=[O:5]
Reactant: O=C(O)[C@H]1CCCCN1C(=O)OCc1ccccc1
Reactant: CCOC(=O)CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN(C)C(=O)[C@H]1CCCCN1C(=O)OCc1ccccc1
Reaction time: 12 h
Yield: 80.1 %

Procedure:
To a stirring solution of Cbz-D-hPro-OH (6.0 g, 22.8 mmol), sarcosine ethyl ester hydrochloride (4.38 g, 28.5 mmol), 1-hydroxybenzotriazole (3.08 g, 22.8 mmol), and N,N-diisopropylethylamine (11.9 mL, 68.4 mmol) in dichloromethane (200 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.46 g, 28.5 mmol). After stirring for 12 hours, the solvent was removed in vacuo and the residue was dissolved in ethyl acetate (500 mL), washed twice with 1N citric acid (200 mL), twice with saturated aqueous NaHCO3, and twice with a saturated aqueous sodium chloride solution. The organic phase was then dried with MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed over silica gel, eluting with a step gradient of hexanes through 50% ethyl acetate/hexanes. Fractions containing product (based on TLC) were combined and concentrated to give 6.62 g (80%) of a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]#N)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.P(Cl)(Cl)(Cl)=[O:15]>CN(C)C=O>[Cl:1][C:2]1[C:11]([CH:12]=[O:15])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: N#Cc1cc2ccccc2nc1Cl
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=Cc1cc2ccccc2nc1Cl

Procedure:
Where the starting material above is a 2-chloro-3-cyanoquinoline, this can be prepared by starting from an appropriate substituted acetanilide. This is heated with phosphoryl chloride and dimethylformamide to give the corresponding 2-chloro-3-quinolinecarboxaldehyde. The process involved is discussed in detail by meth-Cohn et al., J. Chem. Soc., Perkin Trans. 1, 1981, 1520. The chloroquinolinecarboxaldehyde is then reacted with hydroxylamine hydrochloride, formic acid and sodium formate with heating to give the corresponding 3-cyano-2(1H)-quinolinone. This is then heated with an excess of phosphoryl chloride to give the desired 2-chloro-3-cyanoquinoline.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[OH:9][CH2:10][C:11]([N:13]([C@H:15]([CH3:37])[CH2:16][O:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[C:20]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([CH3:36])[CH:30]=1)=[N:21][CH:22]=[N:23]2)[CH3:14])=[O:12]>>[OH:9][CH2:10][C:11]([N:13]([CH3:14])[C@H:15]([CH3:37])[CH2:16][O:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[C:20]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=3)=[C:31]([CH3:36])[CH:30]=1)=[N:21][CH:22]=[N:23]2)=[O:12]
Reactant: ClCc1ccccn1
Reactant: Cc1cc(Nc2ncnc3cccc(OC[C@@H](C)N(C)C(=O)CO)c23)ccc1O
Product: Cc1cc(Nc2ncnc3cccc(OC[C@@H](C)N(C)C(=O)CO)c23)ccc1OCc1ccccn1
Yield: 15 %

Procedure:
The procedure described in Example 3 was repeated using 2-(chloromethyl)pyridine and 2-hydroxy-N-[(1R)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)-1-methylethyl]-N-methylacetamide to give the title compound as a white solid in 15% yield; NMR spectrum (DMSO-d6 373K) 1.25 (d, 3H), 2.28 (s, 3H), 2.83 (s, 3H), 3.96 (s, 2H), 4.35 (m, 1H), 4.46 (t, 1H), 4.97 (m, 1H), 5.19 (s, 2H), 7.01 (d, 1H), 7.18 (d, 2H), 7.33 (m, 2H), 7.44 (m, 1H), 7.56 (d, 1H), 7.68 (t, 1H), 7.83 (td, 1H), 8.40 (s, 1H), 8.58 (d, 1H), 9.48 (s, 1H); Mass spectrum MH+ 488.
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Br[C:19]1[CH:20]=[C:21]2[O:27][C:26](=[O:28])[N:25]([CH3:29])[C:22]2=[N:23][CH:24]=1>O1CCCC1.[Zn].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>[CH3:29][N:25]1[C:22]2=[N:23][CH:24]=[C:19]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:20]=[C:21]2[O:27][C:26]1=[O:28]
Reactant: Cn1c(=O)oc2cc(Br)cnc21
Reactant: BrCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: Cn1c(=O)oc2cc(Cc3ccccc3)cnc21
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Zinc (227 mg, 3.48 mmol) is suspended in tetrahydrofuran (10 ml) and 1,2-dibromoethane (0.22 ml, 0.2 mmol) is added. The mixture is heated at 60° C. for 3 minutes, the solution is allowed to cool until the temperature is 35° C., and trimethylsilyl chloride (0.06 ml, 0.5 mmol) is slowly added. Stirring is maintained for 30 minutes and then benzyl bromide (0.11 ml, 0.9 mmol) is added. Wait a further 30 minutes before introducing 6-bromo-3-methyloxazolo[4,5-b]pyridin-2(3H)-one (200 mg, 0.87 mmol) and tetrakis(triphenylphosphine)palladium (4 mg). Heat at 50° C. for 20 minutes. After the solution has been cooled, the zinc is removed by filtration, the flitrate is taken up in water, and then a 10% aqueous hydrochloric acid solution is added until the aqueous phase becomes clear. Extraction is carried out with dichloromethane. The organic phase is dried over magnesium sulfate and filtered, and then the solvent is evaporated off under reduced pressure. The title product is purified by chromatography on silica gel (eluant: dichloromethane). The yield obtained is 91%. ##STR51##
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:15]3[CH:23]=[CH:24][C:25]([C:27]([O:29][CH3:30])=[O:28])=[CH:26][C:14]=3[N:13]=2)=[C:8]([F:31])[CH:7]=1.[Cl:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1.C(=O)([O-])O.[Na+].O>C(COC)OC.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>[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([C:2]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:3]=2[CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[C:15]4[CH:23]=[CH:24][C:25]([C:27]([O:29][CH3:30])=[O:28])=[CH:26][C:14]=4[N:13]=3)=[C:8]([F:31])[CH:7]=2)=[CH:42][CH:41]=1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc([N+](=O)[O-])ccc3Br)cc1F)n2C1CCCCC1
Reactant: OB(O)c1ccc(Cl)cc1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc([N+](=O)[O-])ccc3-c3ccc(Cl)cc3)cc1F)n2C1CCCCC1
Yield: 90.1 %

Procedure:
Methyl 2-[4-(2-bromo-5-nitrobenzyloxy)-2-fluorophenyl]-1-cyclohexylbenzimidazole-5-carboxylate (2.0 g) obtained in Example 336, 4-chlorophenylboronic acid (590 mg) and tetrakis(triphenylphosphine)palladium (396 mg) were suspended in dimethoxyethane (40 ml), and saturated aqueous sodium hydrogencarbonate solution (20 ml) was added, which was followed by refluxing under heating for 1 hr. The reaction mixture was allowed to cool, water was added and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (n-hexane:ethyl acatate=2:1) to give the title compound (1.9 g, yield 90%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([F:54])[C:40]=1[OH:55]>>[C:33]([O:32][C:31](=[O:37])[NH:30][C@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:21]2[CH:20]=[CH:19][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:43]5[CH:42]=[C:41]([F:54])[C:40]([OH:55])=[C:39]([Cl:38])[CH:44]=5)[N:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:15][CH2:16]3)=[O:13])=[CH:23][N:22]=2)[CH2:25]1)([CH3:36])([CH3:34])[CH3:35]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Cl)nc34)cn2)C1
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)nc34)cn2)C1
Yield: 63.2 %

Procedure:
Following general procedure II, (S)-tert-Butyl 1-{5-[6-chloro-3-(cyclopropanecarbonyl)-1,5-naphthyridin-4-ylamino]pyridin-2-yl}piperidin-3-ylcarbamate (131 mg, 0.25 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (102 mg, 0.38 mmol) to afford the desired product (100 mg, 63%) as an orange red solid. ESI MS m/z 633 [M+H]+.
Reaction SMILES: C(OC(=O)[C@H:7]([CH2:19][CH2:20][CH2:21][NH2:22])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])(C)(C)C.[C:24]([O:31]C([O-])=O)(=O)[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl>[C:26]([O:25][C:24](=[O:31])[C@H:21]([CH2:20][CH2:19][CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])[NH:22][C:24]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:31])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)[C@H](CCCN)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Nδ -(Benzyloxycarbonyl-L-ornithine tert-butyl ester (7.50 g, 23.3 mmol) was dissolved in 27 ml of methylene chloride, and the solution was cooled to 0° C. To that solution was added dropwise tert-butyl pyrocarbonate (5.87 g, 26.9 mmol) in 10 ml of methylene chloride. The reaction mixture was stirred at 0° C. for 1 hour, and stirring was continued for 3 additional hours at room temperature. The solvent was evaporated at reduced pressure and the oily residue was chromatographed on a column of silica gel (25 cm×30 mm) using hexane:ethyl acetate (3:1) as solvent. Fractions of approximately 5 ml were collected, and those containing product were identified by thin layer chromatography (see below). Chromatographic fractions containing product were pooled and evaporated to a thick oil by rotary evaporation at reduced pressure. The yield was 8.63 gm (93.5%). 1H NMR (DCCl3) δ1.44 (s,9H), 1.46 (s,9H), 1.5-1.9 (m,4H), 3.23 (t,2H), 4.17 (t,1H), 4.88 (s,1H broad), 5.09 (s,2H and s,1H broad) 7.35 (s,5H).
Reaction SMILES: N[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH2:10]([O:12]C=O)C>CN(C)C=O>[CH:10]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:12]
Reactant: NCCCCCC(=O)O
Reactant: CCOC=O
Solvent: CN(C)C=O
Product: O=CCCCCCC(=O)O
Temperature: 100 °C
Yield: 95 %

Procedure:
6-Aminocaproic acid (100 g, 0.76 mol) was suspended in a mixture of ethylformate and N,N-dimethylformamide (1 l, 1:1) and heated at 100° C. for 18 h. The volatiles were evaporated in vacuo and the residue treated with ethyl acetate. The solid matter was filtered off and washed with ethyl acetate and air dried which afforded 115 g (95%) of 6-formyl hexanoic acid.