Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.[N+:18]([O-])([O-:20])=[O:19].[K+]>S(=O)(=O)(O)O>[N+:18]([C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([C:11]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=4[N:8]3[CH2:7][CH2:6][CH2:5]2)[CH:1]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])[O-]
Reactant: c1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
Following the procedure of Block et al. (J. Med. Chem. 2002, 45, 3509), 5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinoline (1 g, 4.4 mmol) was stirred in concentrated sulfuric acid (12 mL) at 0° C. for 30 min and then KNO3 (0.45 g, 4.4 mmol) was introduced in portions. The reaction mixture was stirred for 2 hours at 0° C. and was then poured into ice water and extracted with ethyl acetate. The combined organic extracts were dried over MgSO4 and concentrated to give 0.95 g of 2-nitro-5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinoline as a brown solid. MS (ESI) m/z 271
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[N:10]([CH3:13])[C:9](=[O:14])[N:8]([CH3:15])[C:7]1=[O:16])(=O)[CH2:2][CH2:3][CH3:4].[CH2:17]([O:20][NH2:21])[CH:18]=[CH2:19]>C(O)C>[CH2:17]([O:20][NH:21][C:1](=[C:6]1[C:11](=[O:12])[N:10]([CH3:13])[C:9](=[O:14])[N:8]([CH3:15])[C:7]1=[O:16])[CH2:2][CH2:3][CH3:4])[CH:18]=[CH2:19]
Reactant: CCCC(=O)C1C(=O)N(C)C(=O)N(C)C1=O
Reactant: C=CCON
Solvent: CCO
Product: C=CCONC(CCC)=C1C(=O)N(C)C(=O)N(C)C1=O
Reaction time: 2 h

Procedure:
2.3 g of 5-butyryl-1,3-dimethylbarbituric acid was dissolved in 30 ml of ethanol and 1 g of allyloxyamine was added to it at a temperature of 30° C. After stirring during 2 hours, said ethanol was distilled off and thereby 2.6 g of white crystals was separated. The purified compound was obtained as needles by recrystallization from methanol.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[NH:12]C(=O)C(F)(F)F.Br[CH2:20][CH:21]=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(O)C>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]2[O:2][CH2:20][CH:21]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[NH:12][C:4]=2[CH:5]=1)([O-:11])=[O:10]
Reactant: O=C(Nc1cc([N+](=O)[O-])ccc1O)C(F)(F)F
Reactant: CCOC(=O)C=CCBr
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CC1COc2ccc([N+](=O)[O-])cc2N1
Temperature: 0 °C

Procedure:
220 ml of ethanol are introduced into a 1 l three-necked flask, with magnetic stirring, cooled to 0° C., and 3 g (0.133 mol) of sodium are added slowly, in small portions, followed by successive dropwise addition of 22.29 g (0.088 mol) of N-(2-hydroxy-5-nitrophenyl)trifluoroacetamide and 22.65 g (0.088 mol) of 75% pure ethyl 4-bromo-2-butenoate, and the mixture is heated at reflux for 3 h.
Reaction SMILES: C[O:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][C:8]2[C:9]([CH3:26])=[CH:10][C:11]([NH:17][C:18](=[O:25])[CH2:19][C:20]([O:22]CC)=[O:21])=[C:12]3[C:16]=2[CH2:15][CH2:14][CH2:13]3)=[CH:5][C:4]=1[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37]C)=[CH:33][CH:32]=1.B(Br)(Br)Br.CO.Cl>ClCCl>[OH:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][C:8]2[C:9]([CH3:26])=[CH:10][C:11]([NH:17][C:18](=[O:25])[CH2:19][C:20]([OH:22])=[O:21])=[C:12]3[C:16]=2[CH2:15][CH2:14][CH2:13]3)=[CH:5][C:4]=1[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1
Reactant: CCOC(=O)CC(=O)Nc1cc(C)c(Oc2ccc(OC)c(CCc3ccc(OC)cc3)c2)c2c1CCC2
Agent: BrB(Br)Br
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(NC(=O)CC(=O)O)c2c(c1Oc1ccc(O)c(CCc3ccc(O)cc3)c1)CCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.1 %

Procedure:
Ethyl N-(7-{4-methoxy-3-[2-(4-methoxyphenyl)ethyl]phenoxy}-6-methylindan-4-yl)malonamate (40 mg) was dissolved in dichloromethane (5 mL). Adding dropwise a 1 mol/L solution of boron tribromide in dichloromethane (1 mL) under dry ice/acetone-cooling, the solution was stirred at room temperature for 24 hours. To the reaction mixture was added dropwise methanol (5 mL) under ice-cooling with stirring. Adding diluted hydrochloric acid, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. To the residue were added methanol (5 mL) and a 1 mol/L aqueous solution of sodium hydroxide (5 mL), and the mixture was stirred under an argon atmosphere at 50° C. for 30 min. The reaction mixture was evaporated under reduced pressure to dryness and water (10 mL) was added thereto. The mixture was washed with diethyl ether (10 mL) twice. To the aqueous layer were added 1 mol/L hydrochloric acid (20 mL) and brine (10 mL), and the aqueous layer was extracted with ethyl acetate (10 mL) twice. The organic layer was dried over anhydrous magnesium sulfate and evaporated-under reduced pressure to dryness to give the title compound (20 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[C:4]([CH3:17])[N:3]=1.NC1N=C(N)C(C2C=C([N+:32]([O-:34])=[O:33])C=C(Cl)C=2Cl)=C(C)N=1>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([N+:32]([O-:34])=[O:33])=[C:11]([Cl:15])[C:10]=2[Cl:16])=[C:4]([CH3:17])[N:3]=1
Reactant: Cc1nc(N)nc(N)c1-c1cc([N+](=O)[O-])cc(Cl)c1Cl
Reactant: Cc1nc(N)nc(N)c1-c1cccc(Cl)c1Cl
Product: Cc1nc(N)nc(N)c1-c1ccc([N+](=O)[O-])c(Cl)c1Cl

Procedure:
This compound was made from the compound of Example 15 in an analogous manner to the compound of Example 3 g, mp. 265° C. Also obtained from this reaction was 2,4-diamino-5(2,3-dichloro-5-nitrophenyl)-6-methylpyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([O:11][CH2:12]/[CH:13]=[C:14](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])\[CH3:15])=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:22][CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH2:29][CH3:30]>>[CH2:29]([N:25]1[CH2:26][CH2:27][CH2:28][CH:24]1[CH2:23][NH:22][C:5](=[O:7])[C:4]1[C:8]([O:11][CH2:12]/[CH:13]=[C:14](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])\[CH3:15])=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=1)[CH3:30]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(F)cc1C(=O)O
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=O)c1cc(F)ccc1OC/C=C(\C)CCC=C(C)C
Yield: 84 %

Procedure:
In a manner identical to Example 15, 3-fluoro-6-geranyloxybenzoic acid(1.46 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.7 ml), thereby yielding 1.68 g(84%) of the aimed compound.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:6]([N:13]=1)=[N:7][C:8]([CH3:12])=[CH:9][C:10]=2[CH3:11])[CH3:2].[H-].[Na+].[CH2:16]([O:18][C:19](=[O:33])[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH2:31]Br)[CH:27]=2)[CH:22]=1)[CH3:17]>CN(C=O)C.CCOC(C)=O>[CH2:16]([O:18][C:19](=[O:33])[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH2:31][N:13]3[C:6]4=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]4[N:4]=[C:3]3[CH2:1][CH3:2])[CH:27]=2)[CH:22]=1)[CH3:17]
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Reactant: CCOC(=O)Cc1ccc2cc(CBr)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc2cc(Cn3c(CC)nc4c(C)cc(C)nc43)ccc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-ethyl-5,7-dimethylimidazo[4,5-b]pyridine (7) (1.38 g, 6.5 mmol) in 4 ml DMF was added sodium hydride (250 mg, 6.5 mmol) and the reaction mixture was stirred 15 minutes at ambient temperature. The product of Step 2, above (51) (3.07 mmol), was dissolved in 3 ml DMF and added to the reaction mixture and stirred at ambient temperature for 16 hours. The reaction mixture was diluted with EtOAc and washed with saturated sodium bicarbonate solution and brine. The combined organics were then dried over MgSO4, filtered and concentrated to dryness. The crude material was then chromatographed on silica gel using 50% EtOAc in hexanes as the eluant to yield the title compound (52) (95 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH2:27]([C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1)[CH2:28][CH2:29][CH3:30]>>[CH2:27]([C:31]1[CH:32]=[CH:33][C:34]([NH:35][CH:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:17]3[CH:16]=[CH:15][N:14]=[C:13]([C:5]4[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:18]=3)[CH2:21][CH2:22]2)=[CH:36][CH:37]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCc1ccc(N)cc1
Reactant: COc1cc(-c2cc(CN3CCC(=O)CC3)ccn2)cc(OC)c1OC
Product: CCCCc1ccc(NC2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc1

Procedure:
1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]-4-piperidone (1.24 g) and 4-butylaniline (149 mg) were reacted in the same manner as described in Preparation Example 37 to give the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][N:14]1[CH:18]=[CH:17][C:16]([C:19](O)=[O:20])=[N:15]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:19]([C:16]3[CH:17]=[CH:18][N:14]([CH3:13])[N:15]=3)=[O:20])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: Cn1ccc(C(=O)O)n1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cn1ccc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.1 %

Procedure:
TEA (1.21 mL, 8.69 mmol) was added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (400 mg, 1.74 mmol, Example 1, Step H), 1-methyl-1H-pyrazole-3-carboxylic acid (260 mg, 2.09 mmol) and BOP-Cl (60 mg, 2.61 mmol) in DCM (5 mL). The reaction was stirred at room temperature for 1 hour, and then a LiOH solution (3 mL, 2N) was added. The mixture was stirred for 30 minutes, and water (10 mL) was added. The solid formed was collected by filtration, washed with DCM (5 mL) and dried to give N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-1H-pyrazole-3-carboxamide (30 mg, 66% yield) as a solid.
Reaction SMILES: [N+](C1C=CC(C[C:9]2[S:15][CH:14]3[N:11]([C:12](=[O:34])[C:13]3(C(OC(=O)C)C3C=CC4N5C=CN=C5SC=4C=3)Br)[C:10]=2[C:35]([O-:37])=[O:36])=CC=1)([O-])=O.C(#N)C.P([O-])([O-])([O-])=O>C1COCC1.[Pd]>[O:34]=[C:12]1[N:11]2[CH:14]([S:15][CH:9]=[C:10]2[C:35]([OH:37])=[O:36])[CH2:13]1
Reactant: CC(=O)OC(c1ccc2c(c1)sc1nccn12)C1(Br)C(=O)N2C(C(=O)[O-])=C(Cc3ccc([N+](=O)[O-])cc3)SC21
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CC#N
Product: O=C(O)C1=CSC2CC(=O)N12
Temperature: 3 °C

Procedure:
4-Nitrobenzyl-6-[(acetyloxy) (imidazo[2,1-b][1,3]benzothiazol-7-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (900 mg, 1.4 mmol) was dissolved in THF (20 mL) and acetonitrile (20 mL) and 0.5 M phosphate buffer (pH 6.5, 20 mL) and hydrogenated over Pd/C (10%) at 40 psi pressure for 6 hrs. The reaction vessel was covered with foil to exclude light. The reaction mixture was filtered, cooled to 3° C., and 0.1 N NaOH was added to adjust the pH to 8.5. The filtrate was concentarted and the aqueous layer was washed with ethyl acetate. The aqueous layer was separated. The aqueous layer was concentrated under high vacuum at 35° C. to give a yellow precipitate. The product was purified by HP21 resin reverse phase column chromatography. Initially the column was eluted with deionized water (2 L) and latter with 10% acetonitrile:water. The fractions containing the product were collected and concentrated under reduced pressure at room temperature. The yellow solid was washed with acetone, filtered and dried. Yield: 180 mg, 36%; as yellow crystals; mp 235° C.; (M+H+Na) 378.
Reaction SMILES: [C:1]([NH:9][C@@H:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@H:11]([C:13]([OH:15])=[O:14])[OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:23]([O:25][CH2:26][CH3:27])[CH3:24]>>[C:1]([NH:9][C@@H:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@H:11]([C:13]([O:15][CH:23]([O:25][CH2:26][CH3:27])[CH3:24])=[O:14])[OH:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](c1ccccc1)[C@@H](O)C(=O)O)c1ccccc1
Reactant: CCOC(C)Cl
Product: CCOC(C)OC(=O)[C@H](O)[C@@H](NC(=O)c1ccccc1)c1ccccc1

Procedure:
The N-benzoyl-(2R,3S)-3-phenylisoserine, as prepared in Example 34, is treated with 1-chloroethyl ethyl-ether in the presence of a tertiary amine to produce optically pure (2R,3S)-N-benzoyl-O-(1-ethoxyethyl)-3-phenyl-isoserine (2). 7-tri-ethylsilyl baccatin III (1), as synthesized according to Denis et at. (J. Amer. Chem. Soc. 110:5417, 1988), is added to 6 equiv of optically pure (2R,3S)-N-benzoyl-O-(1-ethoxyethyl)-3-phenyl-isoserine (2), 6 equiv of di-2-pyridyl carbonate (DPC), and 2 equiv of 4-(dimethylamino) pyridine (DMAP) in toluene solution (0.02M). This mixture reacts at 73° C. for 100 hours to produce the C-2', C-7-protected taxol derivative (3).
Reaction SMILES: FC(F)(F)C([O-])=O.[CH:8]1[C:20]2[C:19]3[CH2:18][CH2:17][NH2+:16][CH2:15][C:14]=3[CH:13]=[N:12][C:11]=2[NH:10][N:9]=1.CCN(C(C)C)C(C)C.[N:30]([C:33]1[CH:34]=[C:35]([C:39]2[N:40]=[C:41]([CH3:44])[S:42][CH:43]=2)[CH:36]=[CH:37][CH:38]=1)=[C:31]=[O:32]>C1COCC1>[CH3:44][C:41]1[S:42][CH:43]=[C:39]([C:35]2[CH:34]=[C:33]([NH:30][C:31]([N:16]3[CH2:15][C:14]4[CH:13]=[N:12][C:11]5[NH:10][N:9]=[CH:8][C:20]=5[C:19]=4[CH2:18][CH2:17]3)=[O:32])[CH:38]=[CH:37][CH:36]=2)[N:40]=1
Reactant: c1nc2[nH]ncc2c2c1C[NH2+]CC2
Reactant: Cc1nc(-c2cccc(N=C=O)c2)cs1
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1nc(-c2cccc(NC(=O)N3CCc4c(cnc5[nH]ncc45)C3)c2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
To a solution of 6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7-ium 2,2,2-trifluoroacetate (0.100 g, 0.25 mmol) in THF (5 mL) and Hunig's Base (0.26 mL, 1.50 mmol) was added 4-(3-isocyanatophenyl)-2-methylthiazole (0.0567 g, 0.25 mmol). The reaction was shaken at room temperature for 2 hours. The solvent was then removed under reduced pressure followed by addition of 1 M Na2CO3 (5 mL) and EtOAc (10 mL). The organic layer was separated, washed with water (3×10 mL) followed by adding water (10 mL). The EtOAC was then removed under reduced pressure. A white solid crashed out which was filtered, washed with water, dried under reduced pressure to give the pure desired product, N-(3-(2-methylthiazol-4-yl)phenyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxamide as a white solid (0.069 g, 71%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:18]=O)[CH3:13].Cl.O>CO>[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([CH:18]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH3:13]
Reactant: O=C1COc2cc(O)ccc21
Reactant: CCOc1cc(C=O)ccc1OC
Agent: Cl
Solvent: O
Solvent: CO
Product: CCOc1cc(C=C2Oc3cc(O)ccc3C2=O)ccc1OC
Temperature: 25 °C
Yield: 47.6 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3-ethoxy-4-methoxybenzaldehyde 1.33 g were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, and water 150 ml was added. Precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 0.99 g.
Reaction SMILES: O1CCCC1.[H-].[Na+].[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.F[C:17]1[CH:18]=[C:19]([CH:56]=[C:57]([C:59]([F:62])([F:61])[F:60])[CH:58]=1)[CH2:20][N:21]([CH2:34][C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][C:36]=1[C:45]1[CH:50]=[C:49]([CH:51]([CH3:53])[CH3:52])[CH:48]=[CH:47][C:46]=1[O:54][CH3:55])[C:22]1[N:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:24][N:23]=1>[Cl-].[Na+].O>[CH2:8]([O:15][C:17]1[CH:18]=[C:19]([CH:56]=[C:57]([C:59]([F:62])([F:60])[F:61])[CH:58]=1)[CH2:20][N:21]([CH2:34][C:35]1[CH:40]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:38]=[CH:37][C:36]=1[C:45]1[CH:50]=[C:49]([CH:51]([CH3:53])[CH3:52])[CH:48]=[CH:47][C:46]=1[O:54][CH3:55])[C:22]1[N:27]=[CH:26][C:25]([N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)=[CH:24][N:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Reactant: OCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(OCc2ccccc2)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Reaction time: 0.5 h

Procedure:
To tetrahydrofuran (6 ml) is added sodium hydride (60%) (390 mg) under nitrogen atmosphere, followed by an addition dropwise of benzyl alcohol (1.01 ml) under water-cooling, and the mixture is stirred at the same temperature for 30 minutes. To this reaction mixture is added a mixture of (3-fluoro-5-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amine (430 mg) and tetrahydrofuran (4 ml) and the mixture is stirred under nitrogen atmosphere at 70° C. overnight. To the reaction solution are added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane:ethyl acetate=97:3→17:3) to give (3-benzyloxy-5-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amine (221 mg). MS (m/z): 751 [M+H]+
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)=O.[NH2:13][C:14]([NH2:16])=[S:15]>C(O)C>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:3]2[N:13]=[C:14]([NH2:16])[S:15][CH:2]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: COc1cccc(C(=O)CBr)c1
Reactant: NC(N)=S
Solvent: CCO
Product: COc1cccc(-c2csc(N)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
2-Bromo-1-(3-methoxy-phenyl)-ethanone (0.7291 g, 3.183 mmol) and thiourea (0.2665 g, 3.501 mmol) were dissolved in a 20 mL of ethanol. The reaction mixture was allowed to stir overnight at room temperature. The ethanol was evaporated to dryness and the crude product was dissolved in a minimum of dichloromethane. The crude product was then extracted twice with 1M sodium hydroxide and once with a saturated aqueous solution of sodium chloride. The organic layer was then dried over sodium sulfate, filtered, and evaporated to dryness to yield the product (0.619 g, 3.00 mmol, 94.3%). ESI-MS m/z calc. 206.3. found 207.0 (M+1)+ Retention time 1.86 minutes. 1H NMR (400 MHz, CD3CN) δ 3.84 (s, 3H), 5.67 (s, 2H), 6.85-6.91 (m, 2H), 7.31 (t, J=7.9 Hz, 1H), 7.36-7.43 (m, 2H).
Reaction SMILES: [CH:1]1(/[CH:7]=[C:8](\[CH2:12][P:13]([OH:19])([CH2:15][CH:16]([CH3:18])[CH3:17])=[O:14])/[C:9]([OH:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:21]O>>[CH:1]1(/[CH:7]=[C:8](\[CH2:12][P:13]([OH:19])([CH2:15][CH:16]([CH3:17])[CH3:18])=[O:14])/[C:9]([O:11][CH3:21])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CO
Reactant: CC(C)CP(=O)(O)C/C(=C\C1CCCCC1)C(=O)O
Agent: Cl
Product: COC(=O)/C(=C/C1CCCCC1)CP(=O)(O)CC(C)C

Procedure:
(Z)-3-cyclohexyl-2-(hydroxyisobutylphosphinoyl)methylpropenoic acid was treated in a similar manner as in Example 52 except that HCl-methanol was used instead of HCl-ethanol used in Example 52. The captioned compound was obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:20]=[C:21]([OH:22])[C:4]=2[N:3]=1.N1C=CN=C1.[CH3:34][C:35]([Si:38](Cl)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([CH3:37])[CH3:36]>C(Cl)Cl>[CH3:37][C:35]([Si:38]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[O:22][C:21]1[C:4]2[N:3]=[C:2]([CH3:1])[N:6]([CH2:7][C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH:11]=[CH:10][CH:9]=3)[C:5]=2[CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:20]=1)([CH3:34])[CH3:36]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Cc1nc2c(O)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: Cc1nc2c(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of crude 2-methyl-6-morpholino-1-(naphthalen-1-ylmethyl)-1H-benzo[d]imidazol-4-ol (200 mg), imidazole (73 mg) and TBDPSCl (162 mg) in dry DCM (30 mL) was stirred at room temperature for 1 h. LCMS analysis showed desired product so the solvent was removed in-vacuo. The residue was purified by silica gel chromatography eluted with EtOAc:petroleum ether=1:2 to afford the TBDP ether desired product as a white solid (260 mg, 79%). 1H NMR (300 MHz, CDCl3) δ ppm 1.24 (s, 9H), 2.53-2.56 (m, 7H), 3.55 (t, 4H, J=4.8 Hz), 5.69 (s, 2H), 5.92 (d, 1H, J=1.8 Hz), 6.12 (d, 1H, J=1.8 Hz), 6.55 (d, 1H, J=7.5 Hz), 7.25-7.45 (m, 7H), 7.56-7.67 (m, 2H), 7.78 (d, 1H, J=8.7 Hz), 7.84-7.87 (m 4H), 7.94 (d, 1H, J=7.5 Hz), 8.06 (d, 1H, J=8.7 Hz); LC-MS: m/e=612 [M+1]+.
Reaction SMILES: [C:1]([N:11]([CH2:13][C:14]([OH:16])=[O:15])[CH3:12])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:17][C:18]([C:21]1[CH:22]=[C:23]([C:32](=[O:35])[CH2:33]Br)[CH:24]=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:26]=1[OH:27])([CH3:20])[CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:12][N:11]([C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2])[CH2:13][C:14]([O:16][CH2:33][C:32]([C:23]1[CH:24]=[C:25]([C:28]([CH3:30])([CH3:29])[CH3:31])[C:26]([OH:27])=[C:21]([C:18]([CH3:20])([CH3:19])[CH3:17])[CH:22]=1)=[O:35])=[O:15]
Reactant: CN(CC(=O)O)C(=O)OCc1ccccc1
Reactant: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN(CC(=O)OCC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)OCc1ccccc1

Procedure:
This intermediate is obtained in a standard fashion starting from Cbz-Sarcosine and 1-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-bromo-ethanone in the presence of caesium carbonate in DMF.
Reaction SMILES: [C:1]([CH2:9][C:10]#[N:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15](OCC)(OCC)[CH2:16][CH3:17])C.C(OC(=O)C)(=O)C>>[C:1]([C:9](=[C:15]([O:14][CH3:12])[CH2:16][CH3:17])[C:10]#[N:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCC(=O)c1ccccc1
Reactant: CCOC(CC)(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCC(OC)=C(C#N)C(=O)c1ccccc1

Procedure:
A solution containing 30 g. of benzoylacetonitrile, 36.4 g. of triethylorthopropionate and 57 g. of acetic anhydride is heated in an oil bath at 130° for 3 hours. The ethanol and excess acetic anhydride is distilled off and the residue is diluted with chloroform. The chloroform solution is passed quickly through Magnesol® and concentrated, then cooled to produce the title product. Similarly prepared is 2-benzoyl-3-methoxy-2-hexenonitrile and 2-benzoyl-3-methoxy-2-heptenonitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:12]2[NH:16][C:15]([CH3:17])=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.Br[CH2:20][CH:21]=[CH2:22]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([C:12]2[N:16]([CH2:22][CH:21]=[CH2:20])[C:15]([CH3:17])=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)CCc2ccc(F)cc2)[nH]c1C
Reactant: C=CCBr
Product: C=CCn1c(C(=O)CCc2ccc(F)cc2)cc(C)c1C
Yield: 60.3 %

Procedure:
The title compound was prepared as a pale yellow oil in 60.3% yield in a similar procedure to that described in Referential Example 97 by using. -5-[3-(4-fluorphenyl)propionyl)-2,3-dimethylpyrrole and 3-bromo-1-propene.