Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][CH2:16][O:17][CH2:18][C:19]([OH:21])=O)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:22])[CH:4]=1.Cl.Cl.[N:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]2([OH:38])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:27][CH:26]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[OH:38][C:32]1([CH2:31][C:28]2[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=2)[CH2:37][CH2:36][N:35]([C:19](=[O:21])[CH2:18][O:17][CH2:16][CH2:15][N:13]([CH3:14])[S:10]([C:6]2[C:5]([CH3:22])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=2[CH3:9])(=[O:11])=[O:12])[CH2:34][CH2:33]1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)CCOCC(=O)O)c(C)c1
Reactant: OC1(Cc2ccncc2)CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)CCOCC(=O)N2CCC(O)(Cc3ccncc3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N′-Carbonyldiimidazole (77 mg, 0.475 mmol) was added to a solution of 2-(2-(4-methoxy-N,2,6-trimethylphenylsulfonamido)-ethoxy)acetic acid (acid unit S2) (150 mg, 0.453 mmol) in methylene chloride (7 ml), and the mixture was stirred for 1 h at room temperature. A solution of 4-(pyridin-4-ylmethyl)piperidin-4-ol dihydrochloride (120 mg, 0.453 mmol) dissolved in methylene chloride (3 ml) and triethylamine (0.18 ml) was then added, and the reaction mixture was stirred overnight at room temperature. Saturated sodium bicarbonate solution (10 ml) was then added to the reaction mixture, and the aqueous phase was then extracted with methylene chloride (20 ml). The combined organic phases were extracted with saturated sodium chloride solution (10 ml), dried with sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography with ethyl acetate/methanol (10:1). Yield: 130 mg (57%).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][Mg+].[Br-]>C1COCC1.CCOCC>[CH3:14][C:10]1([OH:13])[CH2:11][CH2:12][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9]1
Reactant: C[Mg+]
Reactant: O=C1CCN(Cc2ccccc2)C1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(O)CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 45.9 %

Procedure:
To a solution of commercially available 1-(phenylmethyl)-3-pyrrolidinone (1.0 g, 5.71 mmol) in THF (30 mL) and ether (30 mL) at 0° C. was added MeMgBr (1.4 M solution in toluene:THF (3:1)) (6.1 mL, 8.65 mmol). The reaction was stirred at 0° C. for 1.5 hours, then quenched with water and extracted. Removed organic solvent in vacuo and extracted again with ether, dried organics (Na2SO4) and removed solvent in vacuo. Purified by RP-HPLC to provide racemic 3-methyl-1-(phenylmethyl)-3-pyrrolidinol as a yellow oil (0.501 g, 46%). LCMS: (M+H)+=192.3.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].I[CH:15]([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:15]([CH3:17])[CH3:16])[C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: CC(C)I
Reactant: COC(=O)c1ccc(O)c(C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(C)C)c(C#N)c1
Temperature: 50 °C
Yield: 98.5 %

Procedure:
To a solution of methyl 3-cyano-4-hydroxybenzoate (82 g, 463 mmol; J. Med. Chem., 2002, 45, 5769) in dimethylformamide (800 mL) was added 2-iodopropane (93 mL, 926 mmol) and potassium carbonate (190 g, 1.4 mol). The resulting mixture was heated at 50° C. for 16 h, at which time it was allowed to cool to room temperature. The reaction was filtered and the mother liquor diluted with 0.5 N sodium hydroxide (1 L). The resulting mixture was extracted with ether (2×1 L) and the organics washed with 1 N HCl (1 L) and brine (700 mL), dried (MgSO4) and concentrated to give 100 g (˜100%) of methyl 3-cyano-4-[(1-methylethyl)oxy]benzoate as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3I)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][C:36]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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>[F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:36]3[CH:37]=[C:38]([C:41]([F:44])([F:43])[F:42])[CH:39]=[CH:40][C:35]=3[O:34][CH3:33])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C1OC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1Cc1cc(C(F)(F)F)ccc1I
Reactant: COc1ccc(C(F)(F)F)cc1B(O)O
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+]
Product: COc1ccc(C(F)(F)F)cc1-c1ccc(C(F)(F)F)cc1CN1CC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC1=O

Procedure:
5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one (Example 66, 100 mg; 0.171 mmol) was treated with [2-methoxy-5-(trifluoromethyl)phenyl]boronic acid (Step B, 113 mg; 0.514 mmol), tetrakis(triphenylphosphine)palladium (0) (24 mg; 0.0206 mmol), and sodium carbonate (148 mg) as described in Example 291 to afford 5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-4,5′-bis(trifluoromethyl)-biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one as a clear glass. LCMS=612.1 (M−19)+. 1H NMR (benzene-d6, 500 MHz, mixture of atropisomers): δ 7.61 (s, 1H), 7.40-7.36 (m, 1H), 7.31 (s, 1H), 7.27-7.23 (m, 4H), 6.74-6.72 (m, 1H), 6.35 (d, J=8.7 Hz, 1H), 4.42-4.32 (m, 2H), 3.70 (d, J=15.8 Hz, 1H), 3.14 (s, 3H), 2.28 (t, J=8.7 Hz, 1H), 1.98 (t, J=8.2 Hz, 1H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][C@H:15]([C:19]([OH:21])=O)[CH:16]([CH3:18])[CH3:17])(=[O:13])=[O:12].C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:37]([C:39]1[CH:55]=[CH:54][C:42]([CH2:43][C@@H:44]([C:46]([N:48]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)=[O:47])[NH2:45])=[CH:41][CH:40]=1)#[N:38]>ClCCl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][CH:15]([C:19]([NH:45][C@H:44]([C:46]([N:48]1[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1)=[O:47])[CH2:43][C:42]1[CH:41]=[CH:40][C:39]([C:37]#[N:38])=[CH:55][CH:54]=1)=[O:21])[CH:16]([CH3:18])[CH3:17])(=[O:13])=[O:12]
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc2ccccc2c1)C(=O)O
Reactant: N#Cc1ccc(C[C@H](N)C(=O)N2CCCCC2)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(NS(=O)(=O)c1ccc2ccccc2c1)C(=O)N[C@@H](Cc1ccc(C#N)cc1)C(=O)N1CCCCC1
Reaction time: 1 h

Procedure:
To a suspension of 7 g (0.023 mole) of N-betanaphthylsulphonylvaline (III: R1 =CH(CH3)2 ; Ar=betanaphthyl) racemic (RS) in 10 ml of dichloromethane, kept at between 0° and +5° C., 2.6 g (0.023 mole) triethylamine is added, then 3.4 g (0.025 mole) of isobutyl chloroformate is added drop by drop, and the whole is left for one hour at this temperature. Then 6.2 g (0.024 mole) of 1-(p-cyanophenylalanyl)piperidine (II: NR2R3 =piperidino) dissolved in 50 ml of dichloromethane is added, and the reactional medium is left for 20 hours at ambient temperature. After evaporating to dryness, the residue is taken up with water. The aqueous phase is extracted with dichloromethane. The organic extracts are dried on anhydrous sodium sulphate and evaporated to dryness. The oily residue is purified by chromatography on a silica column (elution: toluene-ethyl acetate, 1:1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.[CH3:9][N:10]([CH3:14])[CH2:11][CH2:12][NH2:13]>C(OCCO)C.CCOC(C)=O>[CH3:9][N:10]([CH3:14])[CH2:11][CH2:12][NH:13][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1
Reactant: CN(C)CCN
Reactant: Clc1ccc(I)cn1
Solvent: CCOC(C)=O
Solvent: CCOCCO
Product: CN(C)CCNc1ccc(I)cn1
Yield: 34.7 %

Procedure:
A stirred solution of 2-chloro-5-iodopyridine (0.50 g, 2.18 mmol) and N,N-dimethylethylenediamine (0.81 g, 1.00 mL, 9.20 mmol) in 2-ethoxyethanol (5 mL) was heated in a sealed tube under microwave irradiation at 125° C. for 1 h. The reaction mixture was then diluted with EtOAc (50 mL), washed with water (3×20 mL), dried (MgSO4), filtered and concentrated in vacuo. The residual oil was purified by column chromatography (SiO2, 3:1 EtOAc/MeOH) to give the title compound (0.22 g, 36%) as a viscous oil which solidified on standing. δH (CDCl3) 8.19 (1H, br. s), 7.53 (1H, m), 6.23 (1H, m), 3.29 (2H, m), 2.52 (2H, m), 2.24 (6H, s). Exchangeable proton not observed. LCMS (ES+) 292.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@H:4]([CH2:20][SH:21])[NH:5][CH2:6][C:7]([S:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)([CH3:9])[CH3:8].[C:23](N1C=CN=C1)(N1C=CN=C1)=[S:24]>C(Cl)(Cl)Cl>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][S:10][C:7]([CH3:9])([CH3:8])[CH2:6][N:5]2[C@H:4]([C:3]([O:2][CH3:1])=[O:22])[CH2:20][S:21][C:23]2=[S:24])=[CH:17][CH:16]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)[C@H](CS)NCC(C)(C)SCc1ccc(OC)cc1
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H]1CSC(=S)N1CC(C)(C)SCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.9 %

Procedure:
To a solution of N-[2-(4-methoxybenzylthio)-2-methylpropyl]L-cysteine methyl ester (5.0 g) in chloroform (90ml), thiocarbonyldiimidazole (3.0 g) was added and the mixture was stirred for 1.5 hr at room temperature. The reaction mixture was washed with 3N hydrochloric acid, water and then saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 5.10 g(91%) of (4R)-3-[2-(4-methoxy-benzylthio)-2-methylpropyl]-4-methoxycarbonylthiazolidine-2-thion
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6](Br)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3].[S:27]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]([C:4]1[CH:5]=[C:6]([C:29]2[CH:30]=[CH:31][S:27][CH:28]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: OB(O)c1ccsc1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4ccsc4)cc23)CC1
Yield: 55.7 %

Procedure:
Following the general procedure of Example 65, a mixture of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-bromo-1H-indazol-3-yl]-1-piperidinecarboxylate (Intermediate 5) (100 mg, 0.24 mmols), 3-thienylboronic acid (92 mg, 0.72 mmols), potassium carbonate (197 mg), and Pd(PPh3)4 (28 mg) in dioxane/water (3/1, 4 mL) was reacted. The reaction mixture was concentrated, redissolved in methylene chloride and filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (57 mg, 55%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2([C:23]([O-:25])=[O:24])[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[Na+].[CH3:27]N(C)P(=O)(N(C)C)N(C)C.IC>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2([C:23]([O:25][CH3:27])=[O:24])[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(NC2(C(=O)[O-])CCN(CCc3ccccc3)CC2)cc1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COC(=O)C1(Nc2ccc(C)cc2)CCN(CCc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of 19 parts of sodium 4-[N-(4-methylphenyl)amino]-1-(2-phenylethyl)-4-piperidinecarboxylate and 200 parts of hexamethylphosphoric triamide is heated to 80° C for a while. After cooling, 12.3 parts of iodomethane are added dropwise at a temperature below 15° C. Upon completion, stirring is continued for 24 hours at room temperature. The reaction mixture is poured onto 600 parts of water and the product is extracted with trichloromethane. The extract is washed twice with water, dried, filtered and evaporated. The oily residue is poured onto 200 parts of water while stirring. The supernatant aqueous phase is decanted and the residual oil is dissolved in trichloromethane. The solution is washed with water, dried, filtered and evaporated. The residue is purified twice by column-chromatography over silica gel using a mixture of trichloromethane and 7% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is suspended in 2,2'-oxybispropane. The product is filtered off and dried, yielding methyl 4-(4-methylphenylamino)- 1-(2-phenylethyl)-4-piperidinecarboxylate; mp. 94.5° C.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([O:18]C)=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH3:20][C:21]1[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=1>>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2]([N:22]3[C:21]([CH3:20])=[CH:25][C:24]([CH3:26])=[N:23]3)[O:3][C:4]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1
Reactant: COC(=O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: Cc1cc(C)[nH]n1
Product: Cc1cc(C)n(-c2nc(-c3ccc(Cl)cc3)c(CCC(=O)O)o2)n1
Yield: 90 %

Procedure:
In the same manner as in Example 30, obtained was: 4-(4-chlorophenyl)-2-(3,5-dimethyl-1-pyrazolyl)-5-oxazolepropionic acid (yield: 90%) by reaction of methyl 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionate with 3,5-dimethylpyrazole followed by hydrolysis of the resulting product. This was recrystallized from ethanol to give colorless needles. mp 201-202° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@:12]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:18][CH:17]=2)([CH3:13])[CH2:11]OS1(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:32]#[N:33].[Na+].CCOC(C)=O.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@:12]([CH2:11][C:32]#[N:33])([CH3:13])[CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:20][CH:21]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCOc1ccc(CC[C@]2(C)COS(=O)(=O)N2C(=O)OC(C)(C)C)cc1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(CC[C@](C)(CC#N)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 25 h

Procedure:
To a stirred solution of (R)-4-[2-(4-heptyloxy-phenyl)-ethyl]-4-methyl-2,2-dioxo-2λ*6*-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (174 mg, 0.40 mMol) in DMF (5 ml) is added sodium cyanide (94 mg, 1.91 mMol). The mixture is stirred at RT for 25 hours. Additional sodium cyanide (37 mg, 0.76 mMol) is added and the mixture is stirred at RT for 18 hours. The reaction mixture is then poured onto a biphasic mixture of AcOEt and NaHCO3 (saturated aqueous solution). The aqueous phase is extracted twice with AcOEt. The combined organic layers are dried (Na2SO4) and concentrated under reduced pressure. Column chromatography eluting with 5% AcOEt in toluene gives the title compound as a colourless oil.
Reaction SMILES: [Na].[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=1)[C:13]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[C:21]([OH:23])=[O:22])=[O:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:27]1([C:33]([CH:35](Br)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)C.S(=O)(=O)(O)O>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=1)[C:13]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[C:21]([O:23][CH:35]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:33](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:22])=[O:14])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(c1ccccc1)C(Br)c1ccccc1
Reactant: O=C(O)C1CCCCN1C(=O)c1cccc(OCc2ccccc2)c1
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CCO
Product: O=C(c1ccccc1)C(OC(=O)C1CCCCN1C(=O)c1cccc(OCc2ccccc2)c1)c1ccccc1
Temperature: 70 °C
Reaction time: 48 h
Yield: 28.4 %

Procedure:
Sodium (54 mg) was dissolved in ethanol (8.0 ml), and then 1-(3-benzyloxybenzoyl)-2-piperidinecarboxylic acid (665 mg), conc. sulfuric acid (1 drop), and desyl bromide (539 mg) was successively dissolved thereto. The resulting mixture was stirred at 70° C. for 2 days, cooled to room temperature, and partitioned between ethyl acetate and 1N HCl. The organic layer was washed with 1N HCl, aqueous sodium bicarbonate, and brine, dried over MgSO4, and evaporated in vacuo. The residue was chromatographed over silica gel to afford 2-oxo-1,2-diphenylethyl 1-(3-benzyloxybenzoyl)-2-piperidinecarboxylate (297 mg) as a pale yellow oil.
Reaction SMILES: Br.[NH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=O.[C:10]1([N:16]=[C:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CC=CC=1>O>[C:3]1([N:2]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=3[NH:16][C:17]2=[O:18])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C=Nc1ccccc1
Reactant: NC1CCCCC1=O
Agent: Br
Solvent: c1ccncc1
Solvent: O
Product: O=c1[nH]c2c(n1-c1ccccc1)CCCC2
Temperature: 125 °C
Reaction time: 4 h
Yield: 33 %

Procedure:
A mixture of 1.94 g (0.01 mol) of 2-aminocyclohexanone hydrobromide, 1.19 g (0.01 mol) of phenyl isocyanate and 4 ml of pyridine is stirred at 125° C. for 4 hours. Water is added, the mixture is stirred until crystallization is obtained, drained, washed with water and dried. The compound is purified by flash chromatography on silica, eluting with a 95:5 CH2Cl2/CH3OH mixture. 0.7 g of product is recovered. Yield=33% (m.p.=224° C.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][CH2:13][CH2:14][NH2:15])=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.Br[CH2:17][C:18]([O:20][CH3:21])=[O:19].C(N(CC)CC)C>O1CCCC1>[CH3:21][O:20][C:18](=[O:19])[CH2:17][NH:15][CH2:14][CH2:13][NH:12][C:10]([C:3]1[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=1)=[O:11]
Reactant: COC(=O)CBr
Reactant: NCCNC(=O)c1nc(Cl)c(N)nc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CNCCNC(=O)c1nc(Cl)c(N)nc1N
Yield: 74.2 %

Procedure:
A mixture of 13.7 g (59.4 mmol) of 3,5-diamino-6-chloro-N-(2-aminoethyl)pyrazine-2-carboxamide, 3.03 g (19.8 mmol) of methyl bromoacetate and 2.0 g (19.8 mmol) of triethylamine was stirred overnight in 250 ml of tetrahydrofuran at ambient temperature. The solvent was evaporated and the residue was chromatographed on silica gel (300 g) using 3.5:96.5 (v/v) methanol:methylene chloride as eluent. There was obtained 4.45 g (14.7 mmol, 74%) of N-[2-[[(3,5-diamino-6-chloropyrazinyl)carbonyl]amino]ethyl]glycine methyl ester as a white powder; mp 145°-146.5° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][OH:5].[CH3:6][S:7](Cl)(=[O:9])=[O:8].CCOCC>C(N(CC)CC)C>[CH3:6][S:7]([O:5][CH2:4][CH2:3][CH2:2][Br:1])(=[O:9])=[O:8]
Reactant: OCCCBr
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCBr
Reaction time: 1 h

Procedure:
A mixture containing 13.9 ml. of 3-bromo-1-propanol, 7.6 ml. of methane sulfonyl chloride and 100 ml. ether was formed. The mixture was mixed together and 14 ml. of triethylamine was added over a period of 45 minutes at 5°-10° C. and then stirred at 5°-10° C. for 1 hour. The mixture was allowed to come to room temperature and was stirred for an additional 15 minutes. To the mixture was added 100 ml. of water and the ether solution dried over magnesium sulfate and evaporated to yield 14.5 g. of a colorless oil. nD30 1.4749.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(OCC)C.[CH:17]([Mg]Br)([CH3:19])[CH3:18].Cl>[Cu]Cl.O>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](=[O:5])[CH:17]([CH3:19])[CH3:18]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: CC(C)[Mg]Br
Agent: Cl[Cu]
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: CC(C)C(=O)c1ccc(F)cc1F
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a mixture of 120 g (0.68 mmol) of 2,4-difluorobenzoyl chloride, 3.7 g (37 mmol) of copper (I) chloride, and 400 ml of diethyl ether was added dropwise 442 ml of diethyl ether containing 130.2 g (0.88 mol) of isopropylmagnesium bromide at -25° C. over 4 hours. The temperature was elevated up to -5° C., and the mixture was stirred at that temperature for 30 minutes. To the reaction mixture were added dropwise 150 ml of water and then 120 ml of 6N hydrochloric acid. The organic layer was separated, washed successively with 5% hydrochloric acid, a saturated sodium chloride aqueous solution, a saturated sodium carbonate aqueous solution, and a saturated sodium chloride aqueous solution, and dried. The solvent was removed by distillation under reduced pressure, and the residue was distilled under reduced pressure to obtain 104.3 g (83%) of 1-(2,4-difluorophenyl)-2-methylpropan-1-one as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][O:10][C@@H:11]1[C@@H:17]([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[O:16][C@H:13](OC)[C@:12]1([CH:30]=[CH2:31])[OH:29].Br.[Na].[Cl:34][C:35]1[N:40]=[CH:39][NH:38][C:37]2=[N:41][CH:42]=[CH:43][C:36]=12>ClCCl.NC1C2C=CN([C@@H]3O[C@H](CO)[C@@H](O)[C@@]3(C)O)C=2N=CN=1>[Cl:34][C:35]1[C:36]2[CH:43]=[CH:42][N:41]([C@@H:13]3[O:16][C@H:17]([CH2:11][O:10][CH2:9][C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])[C@@H:18]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])[C@@:12]3([CH:30]=[CH2:31])[OH:29])[C:37]=2[N:38]=[CH:39][N:40]=1
Reactant: C=C[C@]1(O)[C@@H](OC)O[C@H](COCc2ccc(Cl)cc2Cl)[C@H]1OCc1ccc(Cl)cc1Cl
Reactant: Clc1nc[nH]c2nccc1-2
Agent: Br
Agent: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(N)ncnc21
Agent: [Na]
Solvent: ClCCl
Product: C=C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(Cl)ncnc21
Reaction time: 4 h
Yield: 22.1 %

Procedure:
To a solution of the compound from Step A (6.4 g, 12.6 mmol) in anhydrous dichloromethane (150 mL) at −20° C. was added HBr (30% solution in AcOH, 20 mL, 75.6 mmol) dropwise. The resulting solution was stirred between −10° C. and 0° C. for 4 h, evaporated in vacuo and co-evaporated with anhydrous toluene (3×40 mL). The oily residue was dissolved in anhydrous acetonitrile (100 mL) and added to a solution of the sodium salt of 4-chloro-1H-pyrrolo[2,3-d]pyrimidine (5.8 g, 37.8 mmol) in acetonitrile (generated in situ as described in Example 62) at −20° C. The resulting mixture was allowed to come to room temperature and stirred at room temperature for 24 h. The mixture was then evaporated to dryness, taken up in water and extracted with EtOAc (2×300 mL). The combined extracts were dried over Na2SO4, filtered and evaporated. The crude mixture was purified by flash chromatography (SiO2, 10% EtOAc in hexanes) and the title compound (1.75 g) isolated as a white foam.