Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:8])[CH:5]=[CH:6][CH:7]=1.[Mg].[CH3:10][CH:11]1[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH2:12]1.Cl>C(OCC)C.O>[F:8][C:4]1[CH:3]=[C:2]([C:13]2([OH:17])[CH2:14][CH2:15][CH2:16][CH:11]([CH3:10])[CH2:12]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CC1CCCC(=O)C1
Reactant: Fc1cccc(Br)c1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Product: CC1CCCC(O)(c2cccc(F)c2)C1
Temperature: 5 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
A solution of 50.0 g (0.28 mole) of 3-bromofluorobenzene in 100 ml of diethyl ether was added dropwise with stirring to a cooled reaction vessel containing 7.0 g (0.29 mole) of freshly dried magnesium turnings. The reaction began after 10-20% of the 3-bromofluorobenzene-ether solution had been added. The remainder of the addition was done at a rate sufficient to promote gentle reflux. Upon complete addition an additional 210 ml of diethyl ether was added and the reaction mixture was heated under reflux for 1 hour. The reaction mixture was cooled to 5° C. and 32.5 g (0.29 mole) of 3-methylcyclohexanone in 100 ml of diethyl ether was added dropwise during 30 minutes. Upon complete addition the reaction mixture was stirred for 1 hour at 5° C., heated to reflux temperature for 30 minutes, then allowed to cool to ambient temperature and stand for 16 hours. The reaction mixture was slurried in 450 ml of water and made acidic with aqueous 10% hydrochloric acid. The two phases were separated and the aqueous phase was extracted with three portions of diethyl ether. The combined ether extracts and organic phase were washed with two portions of a saturated aqueous solution of sodium bicarbonate, then one portion of water. The organic layer was dried with sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give 58.0 g of 1-(3-fluorophenyl)-3-methyl-1-cyclohexanol as a solid. The compound was used without further purification.
Reaction SMILES: [I:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9](I)=[CH:10][CH:11]=3)[CH2:6][CH2:5][C:4]=2[CH:3]=1.B(OC(C)C)(OC(C)C)[O:18]C(C)C.C([Li])CCC.Cl>C1COCC1.CCCCCC>[I:1][C:2]1[CH:3]=[C:4]2[C:13]([C:12]3[CH:11]=[CH:10][C:9]([OH:18])=[CH:8][C:7]=3[CH2:6][CH2:5]2)=[CH:14][CH:15]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Ic1ccc2c(c1)CCc1cc(I)ccc1-2
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Oc1ccc2c(c1)CCc1cc(I)ccc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8.8 g (20.4 mmol) of 2,7-diiodo-9,10-dihydrophenanthrene are dissolved in 250 ml of THF, and, after addition of 7.0 ml (30.5 mmol) of triisopropyl borate, 16.5 ml of a 15 percent soln. of n-butyllithium in hexane are added at −70° C. After 1 h, the batch is hydrolysed using 2 N hydrochloric acid and warmed to room temperature. The solution is extracted twice with MTB ether, dried over sodium sulfate, the solvent is removed in vacuo, and the resultant crude product is suspended in 80 ml of toluene and 30 ml of 2 N sodium hydroxide solution with vigorous stirring. After addition of 8 ml of 30% hydrogen peroxide, the batch is stirred at 30-40° C. for 30 min with gentle cooling, 200 ml of water are added, and the mixture is acidified using 2 N hydrochloric acid. The aqueous phase is separated off and extracted three times with ethyl acetate. The combined org. phases are washed with dil. ammonium iron(II) sulfate soln. and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is filtered through silica gel with dichloromethane, giving 7-iodo-9,10-dihydrophenanthren-2-ol as colourless solid.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[NH2:26][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[NH:26][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)=[O:13])[CH2:8]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Reactant: NCc1cccnc1
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1NCc1cccnc1

Procedure:
Phenyl-5-[(pyridin-3-ylmethyl)-amino]-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and 3-(aminomethyl)pyridine. Mass spectrum (ES) MH+=428.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][N:13]1[CH2:18][CH2:17][C:16]([CH2:25][NH2:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:26][CH2:25][C:16]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]1)=[O:6]
Reactant: CN1CCC(CN)(c2ccccc2)CC1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: CN1CCC(CNC(=O)c2cccc(Cl)c2Cl)(c2ccccc2)CC1

Procedure:
From 2,3-dichlorobenzoic acid and C-(1-methyl-4-phenyl-piperidin-4-yl)-methylamine. LCMS (MH+): m/z=376.9, tR (minutes, Method A)=0.69
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5](Br)[S:4][C:3]=1[CH3:8].[F:9][C:10]([F:21])([F:20])[C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCCC1>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.O>[Br:1][C:2]1[CH:6]=[C:5]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:10]([F:21])([F:20])[F:9])[CH:16]=2)[S:4][C:3]=1[CH3:8]
Reactant: Cc1sc(Br)cc1Br
Reactant: OB(O)c1cccc(C(F)(F)F)c1
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: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1sc(-c2cccc(C(F)(F)F)c2)cc1Br
Yield: 85.7 %

Procedure:
Under a nitrogen atmosphere, a mixture of 3,5-dibromo-2-methylthiophene (2.00 g), 3-(trifluoromethyl)phenylboronic acid (2.23 g), tetrakis(triphenylphosphine)palladium (0.45 g), cesium carbonate (5.09 g) and tetrahydrofuran (40 mL) was heated under reflux for 16 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (2.15 g) as a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18]C)=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)[C:5](=[O:20])[N:4]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)[C:3]1=[O:32].Cl.N1C=CC=CC=1.O>C(Cl)Cl>[CH3:1][C:2]1([CH3:33])[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)[C:5](=[O:20])[N:4]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]([F:30])([F:31])[F:29])=[CH:25][CH:26]=2)[C:3]1=[O:32]
Reactant: COc1ccc2c(CN3C(=O)N(c4ccc(OC(F)(F)F)cc4)C(=O)C3(C)C)ccnc2c1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)cc2)C(=O)N1Cc1ccnc2cc(O)ccc12
Temperature: 220 °C
Yield: 9.9 %

Procedure:
A mixture of 0.89 g of 5,5-dimethyl-1-(7-methoxyquinolin-4-ylmethyl)-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione and 5.5 g of pyridine hydrochloride is heated at a temperature in the region of 220° C. for 4 hours. After cooling, 200 ml of water and 100 ml of CH2Cl2 are added. After separation of the phases by settling, the organic phase is dried over sodium sulfate, filtered and then concentrated under reduced pressure. The solid obtained is purified by flash chromatography (SiO2, EtOAc/CH2Cl2 40/60 by volume as eluent, Ar). The fractions containing the product are concentrated under reduced pressure. 85 mg of 5,5-dimethyl-1-(7-hydroxyquinoline-4-ylmethyl)-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione are thus obtained, the characteristics of which product are as follows:
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[C:8]([O:12][N:13]1[C:22](=[O:23])[C:21]2[CH:24]=[C:25]([Cl:28])[C:26](Cl)=[C:19]3[C:20]=2[C:15](=[CH:16][CH:17]=[CH:18]3)[C:14]1=[O:29])([CH3:11])([CH3:10])[CH3:9].O>CC(N(C)C)=O>[C:8]([O:12][N:13]1[C:22](=[O:23])[C:21]2[CH:24]=[C:25]([Cl:28])[C:26]([N:5]3[CH2:6][CH2:7][CH:3]([O:2][CH3:1])[CH2:4]3)=[C:19]3[C:20]=2[C:15](=[CH:16][CH:17]=[CH:18]3)[C:14]1=[O:29])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)ON1C(=O)c2cccc3c(Cl)c(Cl)cc(c23)C1=O
Reactant: COC1CCNC1
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC1CCN(c2c(Cl)cc3c4c(cccc24)C(=O)N(OC(C)(C)C)C3=O)C1
Yield: 91 %

Procedure:
Following the procedure of Example Q2, 3-methoxypyrrolidine (0.2 g, 2.0 mmol) and 2-tert-butyloxy-5,6-dichloro-benzo[de]isoquinoline-1,3-dione (0.4 g, 1.2 mmol, from Example V2) were reacted in DMA (1.0 mL) at 120° C. overnight followed by addition of water (10 mL). The precipitate that formed was filtered to give 0.44 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9]C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:28]=[CH:27][C:26]([S:29](=[O:35])(=[O:34])[NH:30][CH:31]2[CH2:33][CH2:32]2)=[CH:25][C:19]=1[C:20]([N:22]=[C:23]=[O:24])=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:18]1[CH:28]=[CH:27][C:26]([S:29]([NH:30][CH:31]2[CH2:33][CH2:32]2)(=[O:35])=[O:34])=[CH:25][C:19]=1[C:20]1[NH:22][C:23](=[O:24])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: O=C=NC(=O)c1cc(S(=O)(=O)NC2CC2)ccc1Cl
Reactant: CC(C)(C)OC(=O)NNc1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]c(-c2cc(S(=O)(=O)NC3CC3)ccc2Cl)nn1-c1ccc(Cl)cc1

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(4-chlorophenyl)hydrazinecarboxylate (Intermediate-62, 0.050 g, 0.20 mmol), 2-chloro-5-(N-cyclopropylsulfamoyl)benzoyl isocyanate (step-4 of Intermediate-40, 0.123 g, 0.41 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.025 g, of pure product. 1H NMR (400 MHz, DMSO de): δ 0.39-0.41 (m, 2H), 0.49-0.52 (m, 2H), 2.17-2.20 (m, 1H), 7.52-7.55 (d, J=8.0 Hz, 2H), 7.91-8.00 (m, 5H), 8.14 (m, 1H), 12.60 (br s, 1H); MS (m/z): 425.10 (M+).
Reaction SMILES: [CH2:1]1[O:31][C:30]2[CH:29]=[CH:28][C:5]([CH2:6][O:7][C:8](=[O:27])[C@H:9]([NH:12][S:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([O:23][CH3:24])=[C:18](C)[C:17]=3[CH3:26])(=[O:15])=[O:14])[CH2:10][OH:11])=[CH:4][C:3]=2[O:2]1.O.[C:33]1(C)C=[CH:37][C:36](S(O)(=O)=O)=[CH:35][CH:34]=1.C(=O)(O)[O-:45].[Na+]>C(Cl)Cl.O1C=CCCC1>[CH2:1]1[O:31][C:30]2[CH:29]=[CH:28][C:5]([CH2:6][O:7][C:8](=[O:27])[C@H:9]([NH:12][S:13]([C:16]3[C:17]([CH3:26])=[CH:18][C:19]([O:23][CH3:24])=[CH:20][C:21]=3[CH3:22])(=[O:15])=[O:14])[CH2:10][O:11][CH:37]3[CH2:36][CH2:35][CH2:34][CH2:33][O:45]3)=[CH:4][C:3]=2[O:2]1
Reactant: COc1cc(C)c(S(=O)(=O)N[C@H](CO)C(=O)OCc2ccc3c(c2)OCO3)c(C)c1C
Reactant: O=C([O-])O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C1=COCCC1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1cc(C)c(S(=O)(=O)N[C@H](COC2CCCCO2)C(=O)OCc2ccc3c(c2)OCO3)c(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2(R)-(4-methoxy-2,3,6-trimethylbenzenesulfonylamino)-3-hydroxypropionic acid 3,4-methylenedioxybenzyl ester (38.4 g) was dissolved in methylene chloride (140 mL) and dihydropyran (23 mL). The reaction mixture was cooled to 0° C. and p-toluenesulfonic acid monohydrate (0.78 g) was added. After 1 h, the reaction mixture was poured into saturated aqueous sodium bicarbonate (200 mL). The organic layer was separated, dried over magnesium sulfate, and concentrated in vacuo. This residue was chromatographed (300 g SiO2, 15% ethyl acetate-hexanes) to afford 2(R)-(4-methoxy-2,6-dimethylbenzenesulfonyl-amino)-3-(tetrahydropyran-2-yloxy)propionic acid 3,4-methylenedioxybenzyl ester (41.4 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6]Cl)[CH3:2].[Mg].C([Mg]Br)C.[F:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#N)=[CH:18][CH:17]=1.[O:24]1CCCC1>C(OCC)C>[CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6][C:20]([C:19]1[CH:22]=[CH:23][C:16]([F:15])=[CH:17][CH:18]=1)=[O:24])[CH3:2]
Reactant: CCN(CC)CCCCl
Reactant: N#Cc1ccc(F)cc1
Reactant: C1CCOC1
Agent: CC[Mg]Br
Agent: [Mg]
Solvent: CCOCC
Product: CCN(CC)CCCC(=O)c1ccc(F)cc1
Temperature: 40 °C

Procedure:
A suspension of 73.1 g (0.489 mol) 3-(diethylamino)-propyl chloride and 11.87 g (0.489 mol) of magnesium in 300 mL of tetrahydrofuran is initiated with 0.25 mL of 3M ethylmagnesium bromide in diethyl ether and is refluxed overnight. After this time, the reaction is allowed to cool to 40° C. and is treated with 29.6 g (0.245 mol) of 4-fluorobenzonitrile. The initial exotherm is followed by applied heat and the reaction is refluxed for 3 hr. After this time, the reaction is allowd to cool to room temperature and is quenched with 250 mL of water. This mixture is extracted with 2×250 mL of methylene chloride. The combined organic layers are acidifed to pH=1 with 2N aq. hydrochloric acid and the resulting layers separated. The aqueous extract is washed with 100 mL of methylene chloride and is made basic with 4N of sodium hydroxide. The aqueous mixture is extracted with 3×300 mL of methylene chloride. The combined organic layers are dried over sodium sulfate, filtered and the solvent distilled in vacuo to provide crude title compound. This liquid is distilled under vacuum to provide the title compound.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([OH:5])[CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:20]=[C:19](C(Cl)(Cl)Cl)[N:18]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH2:31])[N:26]=3)[C:17]=2[CH:32]=1.O>CN(C=O)C>[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:20]=[C:19]([O:5][CH:3]3[CH2:4][O:1][CH2:2]3)[N:18]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH2:31])[N:26]=3)[C:17]=2[CH:32]=1
Reactant: OC1COC1
Reactant: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(Br)cc32)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nccc(-n2c(OC3COC3)nc3ccc(Br)cc32)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of oxetan-3-ol (0.04 ml, 0.61 mmol) in DMF (5 ml) at 0° C. was added cesium carbonate (499.75 mg, 1.53 mmol) followed by 4-[6-bromo-2-(trichloromethyl)-1,3-benzodiazol-1-yl]pyrimidin-2-amine (250 mg, 0.61 mmol). The reaction was stirred at RT overnight, then re-charged with oxetan-3-ol (3 eq) and stirred for a total of 5 days at RT. Water was added (15 ml) to the combined reaction mixtures and the product extracted into DCM (2×30 ml). The combined organic extracts were washed with water and brine (10 ml each), dried (Na2SO4), filtered and concentrated in vacuo to give the title compound; 1H NMR (500 MHz, DMSO) delta 4.83-4.70 (2H, m), 5.03-4.89 (2H, m), 5.85-5.75 (1H, m), 7.19-7.05 (3H, m), 7.51-7.34 (2H, m), 8.40 (1H, d, J=5.5 Hz), 8.45 (1H, d, J=1.7 Hz); LC-MS: m/z=+362/364 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([CH2:16][CH2:17][O:18][C:19]3[NH:20][CH:21]=[C:22]([CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[N:31][CH:32]=4)[C:23](=[O:25])[N:24]=3)=[CH:11][C:10]=2[F:33])=[CH:4][C:3]=1[C:34]([F:37])([F:36])[F:35].[CH3:38]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([CH2:16][CH2:17][O:18][C:19]3[N:20]([CH3:38])[CH:21]=[C:22]([CH2:26][C:27]4[CH:32]=[N:31][CH:30]=[N:29][CH:28]=4)[C:23](=[O:25])[N:24]=3)=[CH:11][C:10]=2[F:33])=[CH:4][C:3]=1[C:34]([F:35])([F:36])[F:37]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=c1nc(OCCc2cc(F)c(Oc3ccc(Cl)c(C(F)(F)F)c3)c(F)c2)[nH]cc1Cc1cncnc1
Solvent: ClCCl
Solvent: CI
Product: Cn1cc(Cc2cncnc2)c(=O)nc1OCCc1cc(F)c(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 6.1 %

Procedure:
To the solution of 2-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-3,5-difluorophenyl)ethyl]oxy}-5-(5-pyrimidinylmethyl)-4(1H)-pyrimidinone (80 mg, 0.148 mmol) and DIPEA (0.078 mL, 0.445 mmol) in DCM (3.0 mL) was added MeI (0.019 mL, 0.297 mmol) dropwise. The reaction mixture was stirred at room 25° C. for 3 h. Purification via MDAP then afforded the title compound (5 mg, 9.04 μmol, 6.0% yield). LCMS: rt=3.46 min, [M+H+]=553
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1([OH:16])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:18]1[CH:23]=[CH:22][N+:21]([O-:24])=[CH:20][CH:19]=1.C(=O)([O-])O.[Na+].O>C(O)CC(C)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1([OH:16])[CH2:11][CH2:12][N:13]([C:18]2[CH:23]=[CH:22][N+:21]([O-:24])=[CH:20][CH:19]=2)[CH2:14][CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [O-][n+]1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NCC1(O)CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)CCO
Product: CC(C)(C)OC(=O)NCC1(O)CCN(c2cc[n+]([O-])cc2)CC1
Yield: 36.8 %

Procedure:
To a suspension in isoamyl alcohol (35 ml) of conventionally known compounds: 4-[(t-butoxycarbonylamino)methyl]-4-hydroxypiperidine (2.00 g) and 4-chloropyridine 1-oxide (1.12 g), was added sodium hydrogencarbonate (1.75 g) and the mixture was heated under reflux for 4 hours. The reaction mixture was allowed to cool and water was added thereto. The reaction mixture was extracted with methylene chloride and the organic layer was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent:methylene chloride:methanol=9:1-4:1) to obtain the title compound (1.03 g).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([OH:10])=[O:9].C(=O)([O-])[O-].[Na+].[Na+].[O:17]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>O1CCOCC1>[O:17]([C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[C:8]([OH:10])=[O:9])(=[O:32])=[O:31])=[CH:26][CH:25]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N[C@@H]1CCCC[C@H]1C(=O)O
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(Oc2ccccc2)cc1

Procedure:
This compound was prepared from trans-2-amino-1-cyclohexanecarboxylic acid (1.0 g, 7.0 mmol) by reacting it with sodium carbonate (1.48 g, 14.0 mmol) and 4-phenoxybenzenesulfonyl chloride (2.25 g, 8.38 mmol) in dioxane:water (40:20 mL) in the same manner as described in Example 1. This yielded 1.275 g (48%). The melting point was 192-194° C. Mass spectrometry revealed a molecular ion (MH)+ peak at m/z 376.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:18]([CH:28]=C)[CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:9][CH:10]([OH:17])[C:11](=C)[C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C>C1(C)C=CC=CC=1.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[Si:21]([O:20][CH2:19][C@@H:18]1[CH:28]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C@H:10]([OH:17])[CH2:9][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])([C:24]([CH3:26])([CH3:27])[CH3:25])([CH3:22])[CH3:23]
Reactant: C=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(O)C(=C)C(=O)OC)C(=O)OC(C)(C)C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)C1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C[C@H]1O

Procedure:
A stirred solution of methyl 4-(tert-butoxycarbonyl((S)-1-(tert-butyldimethylsilyloxy)but-3-en-2-yl)amino)-3-hydroxy-2-methylenebutanoate (Intermediate 100, 16 g, 37 mmol) in toluene (about 300 mL), at ambient temperature in a heat-dried flask, was thoroughly degassed with argon and placed under a nitrogen atmosphere. To this was added Hoveyda-Grubbs Catalyst 2nd Generation (460 mg, 0.74 mmol). Analysis of the mixture 3.5 hours later by LCMS and TLC (15% ethyl acetate in hexanes) indicated very high conversion of starting material to two major products. The reaction mixture was concentrated in vacuo in the presence of enough silica gel to give a free-flowing powder upon reaching dryness. Normal-phase chromatography (0-100% ethyl acetate in hexanes, 330-g column, 45 minutes) was used to isolate the two compounds; the diastereomer shown above (6.4 g, 43%, dark oil) eluted first.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.CC1NC(=O)CC(=O)N=1.C(OCCO)C.[NH2:25][C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1>>[CH3:9][C:4]1[N:5]=[C:6]([Cl:8])[CH:7]=[C:2]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)[N:3]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: Nc1cccc(O)c1
Agent: CC1=NC(=O)CC(=O)N1
Solvent: CCOCCO
Product: Cc1nc(Cl)cc(Nc2cccc(O)c2)n1
Temperature: 130 °C

Procedure:
4,6-dichloro-2-methylpyrimidine (1.63 g, 10.0 mmol) prepared based on the method described in Production Example 2A above using 2-methyl-1H-pyrimidine-4,6-dione instead of the 2-ethyl-1H-pyrimidine-4,6-dione, was slowly added to a 2-ethoxyethanol (5.0 mL) solution of 3-aminophenol (1.09 g, 10.0 mmol) and the reaction mixture heated for 4 hours at 130° C. The reaction was monitored by thin layer chromatography and, following the end of the reaction, the reaction mixture was cooled to room temperature and the precipitated white powder filtered off. The crude product filtered off was used in the subsequent reaction without further purification (1.76 g, crude yield 75%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:32][C:33]([CH3:38])([CH3:37])[CH2:34][CH:35]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCl>ClCCCl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:35][CH2:34][C:33]([CH3:38])([CH3:37])[CH3:32])[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:30][CH:31]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc(F)c(C(=O)OC)c3)cc2)cc1
Reactant: CC(C)(C)CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCCc1ccc(C#Cc2ccc(CN(CCC(C)(C)C)c3ccc(F)c(C(=O)OC)c3)cc2)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
Methyl 5-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2-fluorobenzoate (800 mg, 1.93 mmol) was dissolved in DCE (15 mL), then 3,3-dimethyl-butyraldehyde (289 mg, 2.89 mmol) was added followed by sodium triacetoxyborohydride (Aldrich, 1224 mg, 5.78 mmol) and the resulting mixture stirred at 70° C. for 2 h. Reaction was allowed to cool down, dichloromethane (40 mL) was added and the organic layer was washed twice with H2O and once with brine, dried over MgSO4, filtered and concentrated under reduced pressure. Purification on silicagel afforded 541 mg (56%) of the title compound as a colorless oil. HPLC, Rt: 6.42 min, purity: 98.3%); LC/MS, M+(ESI): 500.4; 1H NMR (CDCl3) δ: 7.44 (m, 4H), 7.17 (m, 5H), 6.93 (t, J=9.6 Hz, 1H), 6.73 (m, 1H), 4.46 (s, 2H), 3.88 (s, 3H), 3.40 (m, 2H), 2.60 (t, J=7.7 Hz, 2H), 1.70-1.46 (m, 4H), 1.34 (m, 2H), 0.99-0.87 (m, 12H).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([CH3:18])([N:7]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:9]=[CH:8]1)[CH3:6])C.[H-].C([Al+]CC(C)C)C(C)C.CO.C(OCC)(=O)C>C(Cl)Cl>[CH3:18][C:5]([N:7]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:9]=[CH:8]1)([CH3:6])[CH:4]=[O:3]
Reactant: CCOC(=O)C(C)(C)n1cnc(-c2cccnc2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C=O)n1cnc(-c2cccnc2)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a solution of 2-methyl-2-(4-pyridin-3-yl-imidazol-1-yl)-propionic acid ethyl ester (1 eq) in DCM at −78° C. was added diisobutylaluminum hydride (4 eq). After leaving the reaction mixture stir at −78° C. for 3 hours, methanol (4 eq) was added to the reaction mixture at −78° C. and the solution was warmed to room temperature over 60 minutes. Ethyl acetate was added to the solution and after 30 minutes the solution was filtered and concentrated to give 2-methyl-2-(4-pyridin-3-yl-imidazol-1-yl)-propionaldehyde (70%). MH++H2O (234)