Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[C:5](=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7]>[OH-].[Na+]>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:23])=[O:2])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cccc(OCc2cccc(F)c2)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cccc(OCc2cccc(F)c2)c1C(=O)O

Procedure:
A solution of 3-(3-fluoro-benzyloxy)-phthalic acid dimethyl ester (2.4 g crude, 6.7 mmol) in reagent alcohol (100 mL) and 3 N sodium hydroxide (60 mL) was refluxed for two hours. The solution was evaporated and the residue was dissolved in water (100 mL) and washed with methylene chloride (3×100 mL) then acidified to pH around 4. The resulting mixture was extracted with ethyl acetate (2×100 mL) and the combined organic layers was washed with water (2×100 mL), dried and concentrated to give 3-(3-fluoro-benzyloxy)-phthalic acid as an off-white solid (1.9 g, 101% crude yield). The product was used in the next step without further purification.
Reaction SMILES: CON(C)[C:4](=[O:38])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]3[N:16]=[CH:17][CH:18]=[C:19]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:14]3=[N:13][C:12]=2[C:26]#[C:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]=2)=[CH:7][CH:6]=1.[CH3:40][Mg]Br>C1COCC1>[O:23]1[CH2:22][CH2:21][N:20]([C:19]2[C:14]3[N:15]([C:11]([C:8]4[CH:7]=[CH:6][C:5]([C:4](=[O:38])[CH3:40])=[CH:10][CH:9]=4)=[C:12]([C:26]#[C:27][C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]=4)[N:13]=3)[N:16]=[CH:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: CON(C)C(=O)c1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of compound 65a (140 mg, 0.270 mmol) in 10 mL of THF at 0° C. was added methylmagnesium bromide (0.270 mL, 0.810 mmol, 3.0 M in Et2O) dropwise under an Argon atmosphere. After stirring at 0° C. for 1 h, the reaction was quenched with 2 mL of saturated NH4Cl. The mixture was treated with 50 mL of EtOAc and washed with water (25 mL), brine (25 mL) and then dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (0:1-1:4 EtOAc/DCM) to afford the title compound 159 as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ=8.09-8.22 (m, 2H), 8.00 (s, 1H), 7.77-7.93 (m, 3H), 7.44-7.59 (m, 2H), 6.43 (d, J=5.6 Hz, 1H), 5.99 (d, J=6.1 Hz, 2H), 5.81 (s, 1H), 5.71 (s, 1H), 4.06 (br. s., 4H), 3.99 (s, 3H), 3.86 ppm (br. s., 4H). Mass spectrum (ESI, m/z): Calcd. for C29H25N5O4, 508.2 (M+H). found 508.5.
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])(=O)=O.O[CH:17]1[C:21]([CH3:23])([CH3:22])[CH2:20][NH:19][C:18]1=[O:24].C(N(CC)CC)C.N12CCCN=C1CCCCC2>ClCCl.CN(C)C1C=CN=CC=1>[Si:7]([O:6][CH:17]1[C:21]([CH3:23])([CH3:22])[CH2:20][NH:19][C:18]1=[O:24])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC1(C)CNC(=O)C1O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC1(C)CNC(=O)C1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
tert-Butyldimethylsilyl trifluoromethanesulfonate (0.810 ml, 3.45 mmol) was added to a mixture of 3-hydroxy-4,4-dimethyl-2-pyrrolidinone (405 mg, 3.1 mmol) and triethylamine (0.481 mmol, 3.45 mmol) in anhydrous dichloromethane (20 mL) at 0° C. under nitrogen. The reaction mixture was allowed to warm to room temperature, and was stirred for 18 h. A catalytic portion of 4-(dimethylamino)pyridine was added, and the mixture was stirred for 5 h. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.470 mL, 3.13 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (0.360 ml, 1.61 mmol) were then added. After an additional 16 h, a third portion of tert-butyldimethylsilyl trifluoromethanesulfonate was added (0.360 ml, 1.61 mmol). The reaction mixture was then stirred for a further 7.5 h, before being diluted with dichloromethane (75 mL). It was then washed with two 30 mL portions of 1N hydrochloric acid. The washes were combined and back-extracted with dichloromethane (30 mL). The dichloromethane layers were then combined, washed with saturated aqueous sodium chloride (20 mL), dried over magnesium sulfate, and concentrated to a tan oil. Further purification of this oil by column chromatography on silica gel, eluting with a gradient of 20-50% ethyl acetate in hexane afforded 3-{[tert-butyl(dimethyl)silyl]oxy}-4,4-dimethyl-2-pyrrolidinone as a colorless oil that crystallized upon standing (362 mg, 48%). 1H NMR (300 MHz, DMSO-d6) δ 7.63 (br s, 1H), 3.85 (s, 1H), 2.96-2.84 (m, 2H), 1.08 (s, 3H), 0.92 (s, 3H), 0.91 (s, 9H), 0.13 (s, 3H), 0.10 (s, 3H). ES-LCMS m/z 244 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[C:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][N:4](CC2C=CC=CC=2)[C:3]=1[C:24]([O:26]CC1C=CC=CC=1)=[O:25].[K]>O1CCCC1.O>[Br:1][C:2]1[C:3]([C:24]([OH:26])=[O:25])=[N:4][CH:5]=[C:6]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:7]=1[O:8][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(OCc1ccccc1)c1c(Br)c(=O)c(OCc2ccccc2)cn1Cc1ccccc1
Agent: [K]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ncc(OCc2ccccc2)c(OCc2ccccc2)c1Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3.8 g of 3-Bromo-1,4-dihydro-4-oxo-5-(phenylmethoxy)-1-(phenylmethyl)-2-pyridinecarboxylic acid, phenylmethyl ester and 0.54 g potassium hydroxyde were dissolved in 30 ml tetrahydrofuran and 3 ml H2O. After stirring for 24 hours at room temperature, the THF was distilled off and 20 ml H2O were added to the residue. The pH was adjusted to 3.5 with 2NHCl. Crystals of the title compound were formed and filtered off, washed with 20 ml H2O and dried; yield 3 g of the title compound white crystals.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[C:30]([CH3:31])=[CH:29][C:10]([O:11][C:12]2[CH:13]=[CH:14][C:15]3[S:21](=[O:23])(=[O:22])[CH2:20][CH2:19][C:18]([C:24]([O:26]C)=[O:25])=[CH:17][C:16]=3[CH:28]=2)=[CH:9][C:8]=1[CH3:32])[CH3:2].C1COCC1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[C:8]([CH3:32])=[CH:9][C:10]([O:11][C:12]2[CH:13]=[CH:14][C:15]3[S:21](=[O:23])(=[O:22])[CH2:20][CH2:19][C:18]([C:24]([OH:26])=[O:25])=[CH:17][C:16]=3[CH:28]=2)=[CH:29][C:30]=1[CH3:31])[CH3:2]
Reactant: CCOCCOc1c(C)cc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOCCOc1c(C)cc(Oc2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1C
Temperature: 70 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To methyl 7-[4-(2-ethoxyethoxy)-3,5-dimethylphenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.39 g) dissolved in methanol (5 ml) and THF (10 ml) was added a 1 M aqueous solution of potassium carbonate (2.5 ml), and the resulting mixture was stirred overnight at 70° C. The reaction mixture was concentrated, was then neutralized with 1 N hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, and was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain 7-[4-(2-ethoxyethoxy)-3,5-dimethylphenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (0.33 g) as colorless crystals.
Reaction SMILES: C[NH-].[Cl:3][C:4]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([S:18](Cl)(=[O:20])=[O:19])[CH:10]=[CH:11][C:12]=1[NH:13][S:14]([CH3:17])(=[O:16])=[O:15].ClC1C=C(Cl)C=CC=1OC1C=C(S(Cl)(=O)=O)C=C[C:36]=1[NH:37]S(C)(=O)=O.Cl.CN.[OH-].[Na+].Cl>O1CCOCC1>[CH3:36][NH:37][S:18]([C:9]1[CH:10]=[CH:11][C:12]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[C:7]([O:6][C:5]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:4]=2[Cl:3])[CH:8]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Nc1ccc(S(=O)(=O)Cl)cc1Oc1ccc(Cl)cc1Cl
Agent: CN
Agent: C[NH-]
Agent: Cl
Solvent: C1COCCO1
Product: CNS(=O)(=O)c1ccc(NS(C)(=O)=O)c(Oc2ccc(Cl)cc2Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-(2,4-Dichlorophenoxy)4-methylsulphonylaminobenzene-sulphonic acid chloride N-methylamide (HN-56203) 3-(2,4-dichlorophenoxy)-4-methylsulphonylaminobenzenesulphonic acid chloride (0.56 g, 1.3 mmol) was dissolved in dioxan (15 ml) and at 0° C. it was added dropwise to a solution of methylamine hydrochloride (1.18 g, 17 mmol) in 1N aqueous NaOH (15 ml, 15 mmol) and dioxan (20 ml). The mixture was stirred for 1 hour at 0° C., acidified with 1N HCl and extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and the solvent was evaporated off. The residue was purified by chromatography (silica gel, CH2Cl2 /ethyl acetate 9/1). Yield: 0.25 g=45% 13C (100 MHz, CDCl3) δ 148.35, 146.21, 134.97, 132.03, 131.28, 131.16, 128.98, 127.15, 123.15, 123.12, 119.56, 113.81, 40.45, 29.18
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11](=[O:12])[N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](=[O:23])[NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=3)=[C:15]2[CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Nc1ccccn1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)Nc3ccccn3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 59.1 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.15 g, 0.27 mmol), 2-aminopyridine (51 g, 0.54 mmol) and triethylamine (0.25 mL, 1.62 mmol) were dissolved in 10 mL of dichloromethane under stirring. After stirring for 20 minutes, bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.14 g, 0.54 mmol) was added to the solution. The reaction mixture was stirred at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-oxo-3-[1-(pyridin-2-ylcarbamoyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 31a (0.1 g, yield 59%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]([CH3:31])[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:22]4[CH:27]=[C:26]([NH2:28])[C:25]([F:29])=[CH:24][C:23]=4[Cl:30])[C:15](=[O:21])[N:16]3[CH2:19][CH3:20])=[CH:11][N:10]=2)=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].Cl[C:40]([O:42][C:43]([CH3:45])=[CH2:44])=[O:41].CCCCCC>CCOC(C)=O>[Cl:30][C:23]1[C:22]([C:14]2[C:15](=[O:21])[N:16]([CH2:19][CH3:20])[C:17]3[C:12]([CH:13]=2)=[CH:11][N:10]=[C:9]([N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:33][CH:32]=2)[CH3:31])[CH:18]=3)=[CH:27][C:26]([NH:28][C:40](=[O:41])[O:42][C:43]([CH3:45])=[CH2:44])=[C:25]([F:29])[CH:24]=1
Reactant: C=C(C)OC(=O)Cl
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(N(C)Cc4ccc(OC)cc4)cc3n(CC)c2=O)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A bi-phasic mixture of Example A4 (1.00 g, 2.142 mmol) in EtOAc (25 mL) and satd. NaHCO3 (25 mL) was treated with isopropenyl chloroformate (516 mg, 4.28 mmol) and stirred vigorously at RT for 3 h. Hexane (10 mL) was added and the resulting solid collected via filtration and dried. The layers of the filtrate were separated, the organic layer washed with brine, dried over Na2SO4, concentrated to dryness and combined with the above-isolated solid to afford prop-1-en-2-yl (4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)carbamate (1.168 g, 98% yield). MS (ESI) m/z: 551.2 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Cl.[NH2:16][CH2:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[CH2:22][CH2:21]1)=[O:19].O[Li].O>CN(C=O)C>[C:6]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:8][C:3]([CH2:2][NH:16][CH2:17][C:18]([N:20]2[CH2:25][CH2:24][CH:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])[CH2:22][CH2:21]2)=[O:19])=[CH:4][CH:5]=1
Reactant: BrCc1ccc(-c2ccccc2)cc1
Reactant: NCC(=O)N1CCC(Oc2ccccc2Cl)CC1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CNCc1ccc(-c2ccccc2)cc1)N1CCC(Oc2ccccc2Cl)CC1
Reaction time: 8 h
Yield: 11.5 %

Procedure:
A mixture of biphenyl-4-yl-methanol (250 mg, 1.35 mmol) and aqueous HBr (48%) (3 mL) was stirred at 10° C. for 3 hrs. After completion of the reaction, the mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer collected was concentrated under reduced pressure to afford 330 mg (98.5% Yield) 4-bromomethyl-biphenyl. 4-Bromomethyl-biphenyl (120 mg, 0.485 mmol) was added to a stirred mixture of 2-amino-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (134 mg, 0.44 mmol) (prepared according to Step 1 and 5 of the General Scheme), LiOH.H2O (40 mg, 0.97 mmol) and 4 Å molecular sieves (350 mg) in DMF (4 mL) and stirring was continued overnight. The reaction mixture was filtered and filtrate was diluted with cold water, extracted with ethyl acetate and organic layer was dried over sodium sulfate. The organic layer was concentrated under reduced pressure. Purification by column chromatography (using neutral alumina and 5% MeOH in DCM as eluent) to afford 22 mg (11.4% Yield) of 2-[(biphenyl-4-ylmethyl)-amino]-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone. LC/MS [M+H]+: 435, 90.56%. 1H NMR (CDCl3): δ7.64-7.52 (m, 4H), 7.5-7.3 (m, 6H), 7.24-7.15 (dt, 1H), 7.0-6.86 (m, 2H), 4.6 (q, 1H), 4.0-3.8 (m, 3H), 3.7-3.6 (m, 3H), 3.5 (s, 2H), 3.4-3.3 (m, 1H), 2.0-1.8 (m, 4H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15](=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>FC(F)(F)C(O)=O.C(Cl)Cl.C(OCC)(=O)C>[C:15]([NH:14][CH:10]1[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1)(=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)NC1CCCN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NC1CCCNC1
Yield: 91198.7 %

Procedure:
A solution 464 mg of 1-(t-butoxycarbonyl)-3-(oleoylamino)piperidine in 6 ml of 50% trifluoroacetic acid-methylene chloride was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off. The residue obtained was dissolved in 20 ml of ethyl acetate. After adding saturated aqueous sodium carbonate solution to the solution to neutralize it, the organic layer was separated. The organic layer was washed with saturated saline, and dried over anhydrous sodium sulfate, followed by removal of the solvent therefrom by evaporation. The residue obtained was purified by silica gel column chromatography to obtain 332 g of the objective compound (yield: 91%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:8][C:6](=[O:7])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.CC1CC(=O)C(C(C)C)CC1>>[CH3:1][C:2]1[CH2:3][CH2:4][C:5](=[C:9]([CH3:10])[CH3:11])[C:6](=[O:7])[CH:8]=1
Reactant: CC(C)[C@@H]1CC[C@@H](C)CC1=O
Agent: CC1CCC(C(C)C)C(=O)C1
Product: CC1=CC(=O)C(=C(C)C)CC1
Yield: 64.6 %

Procedure:
A similar process is described by S. Ohshiro et al (Yakugaku Zasshi, 88, 417 (1968)). Here again the reaction of methyl vinyl ketone with excess mesityl oxide takes place in the presence of potassium hydroxide powder but without addition of tetrahydrofuran as the solvent. The piperitenone obtained is converted into a mixture of menthone and isomenthone by catalytic hydrogenation. However, in this process of yields of piperitenone are again only about 53%; furthermore, using this process the menthone/isomenthone mixture is obtained in only 64.6% yield and in a purity of only 89.8%. For this reason, the further reaction to give pure methol has to be carried out in an involved manner via menthone-oxime (Jap. Pat. No. 7,009,375) and menthylamine, which makes it doubtful whether the process is suitable for commercial operation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:5]([CH3:14])=[CH:4][C:3]=1[NH:15][C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[C:19]([C:29]([F:32])([F:31])[F:30])=[CH:18][N:17]=1.Br[CH2:34][CH:35]1[CH2:37][C:36]1([F:39])[F:38].C(N(CC)CC)C>CN(C=O)C>[F:38][C:36]1([F:39])[CH2:37][CH:35]1[CH2:34][N:11]1[CH2:10][CH2:9][CH:8]([C:6]2[C:5]([CH3:14])=[CH:4][C:3]([NH:15][C:16]3[N:21]=[C:20]([NH:22][C:23]4[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=4)[C:19]([C:29]([F:32])([F:30])[F:31])=[CH:18][N:17]=3)=[C:2]([F:1])[CH:7]=2)[CH2:13][CH2:12]1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2C(F)(F)F)n[nH]1
Reactant: FC1(F)CC1CBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CC5CC5(F)F)CC4)cc3F)ncc2C(F)(F)F)n[nH]1
Temperature: 60 °C

Procedure:
A mixture of N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (100 mg, 0.22 mmol), 2-(bromomethyl)-1,1-difluorocyclopropane (76.4 mg, 0.45 mmol) and triethylamine (60.6 μL, 0.42 mmol) in 1 mL of DMF was heated at 60° C. in a microwave reactor for 2 h. The crude product was purified by RP-HPLC to afford N2-(4-(1-((2,2-difluorocyclopropyl)methyl)piperidin-4-yl)-2-fluoro-5-methylphenyl)-N4-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine; ESMS m/z 540.2 (M+H+).
Reaction SMILES: C([O:5][C:6](=[O:69])[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][N:14]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33](=[O:68])[NH:34][CH2:35][CH2:36][CH2:37][CH2:38][C@@H:39]([C:61]([O:63]C(C)(C)C)=[O:62])[NH:40][C:41](=[O:60])[NH:42][C@H:43]([C:53]([O:55]C(C)(C)C)=[O:54])[CH2:44][CH2:45][C:46]([O:48]C(C)(C)C)=[O:47])[CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])(C)(C)C.C(Cl)Cl>C(O)(C(F)(F)F)=O>[C:6]([CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][N:14]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33](=[O:68])[NH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:39]([C:61]([OH:63])=[O:62])[NH:40][C:41](=[O:60])[NH:42][CH:43]([C:53]([OH:55])=[O:54])[CH2:44][CH2:45][C:46]([OH:48])=[O:47])[CH2:15][C:16]([OH:18])=[O:17])([OH:69])=[O:5]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)CCCCCCCCCCN(CC(=O)OC(C)(C)C)Cc1nccn1CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCC(NC(=O)NC(CCCCNC(=O)CCCCCCCCCCN(CC(=O)O)Cc1nccn1CC(=O)O)C(=O)O)C(=O)O

Procedure:
A solution of (19S,23S)-tetra-tert-butyl 2-((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)-13,21-dioxo-2,14,20,22-tetraazapentacosane-1,19,23,25-tetracarboxylate (18.8 mg, 0.019 mmol) in TFA (1.0 mL)/DCM (1.0 mL) was stirred at room temperature for overnight. The solvent was evaporated to give 19S,23S)-2-((1-(carboxymethyl)-1H-imidazol-2-yl)methyl)-13,21-dioxo-2,14,20,22-tetraazapentacosane-1,19,23,25-tetracarboxylic acid as a colorless oil. To a solution of the above deprotected product in water (1.0 mL) that was adjusted to pH=9 by 2 N NaOH was added Re(CO)3(H2O)OTf (0.50 mL, 0.10 mL/mmol). The reaction mixtures were stirred at room temperature for overnight and purified by HPLC to afford the title compound (4.0 mg, 19%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 7.70 (t, J=5.6 Hz, 1H), 7.33 (s, 1H), 7.13 (s, 2H), 6.29 (d, J=8.4 Hz, 1H), 6.26 (d, J=8.4 Hz, 1H), 4.96 (d, J=4.8 Hz, 2H), 4.56 (d, J=16.4 Hz, 1H), 4.12 (d, J=16.8 Hz, 1H), 4.07-3.90 (m, 2H), 3.70 (d, J=17.2 Hz, 1H), 3.40 (d, J=17.2 Hz, 1H), 2.98-2.94 (m, 4H), 2.21 (q, J=7.73, 2 H), 1.99 (t, J=7.6 Hz, 2H), 1.70-1.22 (m, 24H); MS (ESI), 485.2 (M/2+H)+.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:11]=[C:12]([C:13]([OH:15])=O)[C:7]=2[CH:6]=[N:5]1)[CH3:3].FC(F)(F)C(O)=O.[NH2:29][CH2:30][C:31]1[C:32](=[O:44])[NH:33][C:34]([CH3:43])=[CH:35][C:36]=1[CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.O>[CH:37]1([C:36]2[CH:35]=[C:34]([CH3:43])[NH:33][C:32](=[O:44])[C:31]=2[CH2:30][NH:29][C:13]([C:12]2[C:7]3[CH:6]=[N:5][N:4]([CH:2]([CH3:1])[CH3:3])[C:8]=3[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:11]=2)=[O:15])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(-c3ccncc3)nc21
Reactant: Cc1cc(C2CCCCC2)c(CN)c(=O)[nH]1
Agent: On1nnc2cccnc21
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCOCC1
Solvent: O
Product: Cc1cc(C2CCCCC2)c(CNC(=O)c2cc(-c3ccncc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 144 h
Yield: 47.1 %

Procedure:
A mixture of 1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (169 mg, 0.6 mmol), 3-(aminomethyl)-4-cyclohexyl-6-methyl-2(1H)-pyridinone trifluoroacetate (221 mg, 0.660 mmol), EDC (150 mg, 0.780 mmol), HOAT (106 mg, 0.780 mmol), and N-methylmorpholine (0.264 mL, 2.400 mmol) in DMF(3 mL) were stirred at room temperature for 6 days. water (15 mL) was added to the slurry, and it was stirred for an hour. The precipitate was then collected by vacuum filtration and rinsed with EtOH (4 mL), and the solid was dried in the vacuum oven overnight to give the title compounds as an off-white solid (137 mg, 45%). LCMS E-S (M+H)=485.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09-1.44 (m, 5 H), 1.56 (d, J=6.57 Hz, 6 H), 1.55-1.72 (m, 5 H), 2.15 (s, 3 H), 2.80-2.92 (m, 1 H), 4.53 (d, J=4.55 Hz, 2 H), 5.36 (spt, J=6.53 Hz, 1 H), 6.03 (s, 1 H), 8.18-8.23 (m, 2 H), 8.26 (s, 1 H), 8.45 (s, 1 H), 8.75-8.82 (m, 2 H), 9.01 (t, J=4.55 Hz, 1 H), 11.59 (s, 1 H).
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:11]1[C:12]([CH3:18])=[N:13][CH:14]=[C:15]([CH3:17])[N:16]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[NH4+].[Cl-]>O1CCCC1>[CH3:18][C:12]1[C:11]([CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]#[N:9])=[N:16][C:15]([CH3:17])=[CH:14][N:13]=1
Reactant: N#CCc1ccccc1
Reactant: Cc1cnc(C)c(Cl)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cnc(C)c(C(C#N)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 128.4 %

Procedure:
To a solution of benzyl cyanide (2.00 g, 17.1 mmol) and 3-Chloro-2,5-dimethyl-pyrazine (2.03 g, 14.2 mmol) in tetrahydrofuran (100 mL) was added dropwise sodium bis-(trimethylsilyl)amide (1 M in THF, 35.6 mL, 35.6 mmol). After stirring at room temperature for 18 h, the reaction mixture was poured into sat. aq. NH4Cl (150 mL). After extraction with ethyl acetate (150 mL), the organic layer was washed with water (100 mL), dried over MgSO4 and concentrated in vacuo to afford (3,6-dimethylpyrazin-2-yl)(phenyl)acetonitrile [4.07 g, yield 96%; HPLC/MS: m/z=223 (M+H); log P(HCOOH)=2.28].