Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[CH3:35])[C:9](=[O:26])[N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH2:12][CH2:11]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[ClH:34].[ClH:34].[NH2:7][CH:8]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[CH3:35])[C:9]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH2:12][CH2:11]1)=[O:26]
Reactant: Cc1cc(Cl)ccc1CC(NC(=O)OC(C)(C)C)C(=O)N1CCN(c2ncnc3ccccc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Cl)ccc1CC(N)C(=O)N1CCN(c2ncnc3ccccc23)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 228.5 %

Procedure:
To a solution containing [1-(4-Chloro-2-methylbenzyl)-2-oxo-2-(4-quinazolin-4-yl-piperazin-1-yl)-ethyl]-carbamic acid tert-butyl ester (0.30 g, 0.59 mmol) in 30 mL of DCM under a nitrogen atmosphere was added TFA (1.4 mL.) After stirring at room temperature overnight, the reaction was concentrated under reduced pressure. The residue was dissolved in DCM and 2N HCl in ether added. The solids were filtered and dried to afford 2-Amino-3-(4-chloro-2-methyl-phenyl)-1-(4-quinazolin-4-yl-piperazin-1-yl)-propan-1-one dihydrochloride (0.217 g) as an off-white solid. LCMS (APCI+) m/z 410 [M+H]+; Rt: 1.87 min. 1H NMR (D2O, 400 MHz) δ 8.48 (1H, s), 7.91-7.86 (2H, m), 7.66-7.59 (2H, m), 7.08-7.02 (2H, m), 4.60-4.54 (1H,m), 4.20-4.12 (1H, m), 3.86-3.72 (3H, m), 3.61-3.38 (2H, m), 3.28-3.16 (2H, m), 3.01-2.94 (1H, m), 2.76-2.68 (1H, m), 2.19 (3H, s.)
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([S:15]([C:18]2[CH:31]=[CH:30][C:21]3[O:22][C:23]([CH3:29])([CH3:28])[C@@:24]4([CH3:27])[O:26][C@H:25]4[C:20]=3[CH:19]=2)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1)(C(C)(C)C)(C)C.[NH3:32]>C(O)C>[NH2:32][C@H:25]1[C@@:24]([OH:26])([CH3:27])[C:23]([CH3:29])([CH3:28])[O:22][C:21]2[CH:30]=[CH:31][C:18]([S:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=3)(=[O:17])=[O:16])=[CH:19][C:20]1=2
Reactant: CC1(C)Oc2ccc(S(=O)(=O)c3cccc(O[Si](C)(C)C(C)(C)C)c3)cc2[C@@H]2O[C@@]21C
Reactant: N
Solvent: CCO
Product: CC1(C)Oc2ccc(S(=O)(=O)c3cccc(O)c3)cc2[C@@H](N)[C@]1(C)O
Temperature: 45 °C

Procedure:
(3S,4S)-6-(3-tert-Butyldimethylsilyloxyphenyl)sulphonyl-3,4-dihydro-3,4-epoxy-2,2,3-trimethyl-2H-benzo[b]pyran (2.2 g) (see Preparation 15) was dissolved in ethanol (25 ml) and 35% aqueous ammonia solution (25ml) was added. The mixture was heated at 40-50° C. for 24 hours. The solvent was removed under reduced pressure and the residue was chromatographed on silica using 7.5:92.5 methanol: dichloromethane as the eluent to yield (3S,4R)-4-amino-3,4-dihydro-3-hydroxy-6-(3-hydroxyphenyl)sulphonyl-2,2,3-trimethyl-2H-benzo[b]pyran (1.42 g) as a foam. Found: C,54.39; H,5.22; N,3.19. C18H21NO5S, 0.50 CH2Cl2 requires C,54.75; H,5.46; N,3.45%.
Reaction SMILES: N1[C:5](=O)[CH2:4][CH2:3][C@@H:2]1[C:7](O)=O.[NH2:10][C@@H:11]1[CH2:17][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[NH:13][C:12]1=[O:22].[H-].[Na+].[F:25][C:26]([F:37])([F:36])[CH2:27]OS(C(F)(F)F)(=O)=O>C(OCC)(=O)C>[F:25][C:26]([F:37])([F:36])[CH2:27][N:13]1[C:14]2[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=2[CH2:16][CH2:17][C@@H:11]([NH:10][C:2]([C:7]2[CH:5]=[CH:4][CH:3]=[CH:2][CH:7]=2)([C:21]2[CH:14]=[CH:15][CH:18]=[CH:19][CH:20]=2)[C:3]2[CH:12]=[CH:11][CH:17]=[CH:5][CH:4]=2)[C:12]1=[O:22]
Reactant: N[C@@H]1CCc2ccccc2NC1=O
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=C1CC[C@H](C(=O)O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C1[C@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)CCc2ccccc2N1CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A round-bottom flask containing the product of Step 4 for the preparation of Example 1 (2.00 g, 4.80 mmol) was fitted with a stirbar and septa and flushed with nitrogen. Tetrahydrofuran (20 mL) was added, giving a solution that was cooled to 0° C. Sodium hydride (0.781 g, 60%/oil, 19.5 mmol) was added, and the reaction was stirred for 30 minutes. Trifluoromethanesulfonic acid-2,2,2-trifluoroethyl ester (2.26 g, 9.74 mmol) was then added, and stirring was continued with gradual warming to room temperature. After 18 hours, the reaction mixture was poured into ethyl acetate (75 mL) and washed first with 1:1 H2O:saturated aqueous NaHCO3 solution (2×30 mL), then with saturated aqueous NaCl solution (20 mL). The aqueous wash layers were combined and extracted with ethyl acetate (30 mL). The ethyl acetate layers were then combined, dried over MgSO4, filtered and concentrated in vacuo to give an oil that was purified via flash chromatography on silica gel (5% to 15% ethyl acetate/hexanes linear gradient) to give the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]2=[O:27])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][C:11](=O)[C:10]([CH3:16])([CH3:15])[CH2:9]1.[C-:28]#[N:29].[Na+].[CH3:31][O:32][C:33]1[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=1[NH2:35]>>[CH3:31][O:32][C:33]1[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=1[NH:35][C:11]1([C:28]#[N:29])[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([N:17]3[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]3=[O:27])=[CH:3][C:2]=2[F:1])[CH2:9][C:10]1([CH3:16])[CH3:15]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)C(C)(C)C3)c(F)c2)C(=O)O1
Reactant: [C-]#N
Reactant: COc1ccccc1N
Agent: [Na+]
Product: COc1ccccc1NC1(C#N)CCN(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1(C)C
Yield: 64 %

Procedure:
By using procedure as described in Example 45 and by reacting (S)-N-{3-[3-fluoro-4-(4-oxo-3,3-dimethylpiperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide with sodium cyanide and 2-methoxyaniline the compound was obtained in 64% yield.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.[C:15](=O)([O:24]N1C(=O)CCC1=O)[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.CC#N>[CH2:17]([O:16][C:15]([NH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4])=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(N)C(=O)O
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-2-methyl-propanoic acid (10 g, 96.97 mmol) in water (75 mL) was added triethylamine (13.48 mL, 96.97 mmol) followed by the dropwise addition of a solution of benzyl (2,5-dioxopyrrolidin-1-yl) carbonate (24.17 g, 96.97 mmol) in MeCN (30 mL). The pH was monitored during the addition and afterwards was adjusted with triethylamine (1.5 mL) from pH 7 to 8. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated by removal of MeCN. To the aqueous was added saturated aqueous sodium bicarbonate (2 mL) which gave a suspension. This was filtered and the solid kept to one side. The filtrate was extracted with ether (three times). The aqueous phase was acidified to pH 3 with approximately 1 M aqueous potassium bisulphate and then extracted into EtOAc (three times). The combined EtOAc extracts were dried over magnesium sulphate, filtered and evaporated to yield 2-(benzyloxycarbonylamino)-2-methyl-propanoic acid (D32) as a waxy white solid, (18.001 g);
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[CH2:15][CH2:16][NH2:17].CCN(CC)CC>C1COCC1>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:15][CH2:16][NH:17][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: COc1cccc(CCN)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(CCNC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 107.3 %

Procedure:
Benzoyl chloride (0.922 g, 6.61 mmol) was added to a solution of 3-methoxyphenethylamine (1.000 g, 6.61 mmol) and Et3N (2.8 ml, 19.8 mmol) in anhydrous THF (30 ml) at rt under N2. The resulting suspension was stirred at rt under N2 for 20 hr. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 1.811 g of white solid. Purification by flash chromatography, eluting with hexane:EtOAc (7:3) gave 1.689 g (100% yield) of white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]([NH:20][C:21]3[C:22]4[CH:29]=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:14]2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CO>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:19][CH:18]3[CH2:17][CH:16]2[CH:15]([NH:20][C:21]2[C:22]4[CH:29]=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][N:26]=2)[CH2:14]3)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(CNc1cc(Cl)cc(Cl)c1)N1CCCCC(Nc2ncnc3[nH]ccc23)C1
Solvent: ClCCl
Solvent: CO
Product: O=C(CNc1cc(Cl)cc(Cl)c1)N1CC2CC(Nc3ncnc4[nH]ccc34)C1C2
Yield: 51 %

Procedure:
A similar procedure was used as describe for the synthesis of 2-(3,5-dichlorophenylamino)-1-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino) azepan-1-yl) ethanone to afford a residue which was subjected to column chromatography (silica gel, gradient MeOH in CH2Cl2) to afford (45 mg, 51%) the titled compound. 1H NMR (DMSO-d6, 400 MHz): 11.50 and 11.40 (2s, 1H), 8.18-8.10 (2s, 1H), 7.18 (bs, 1H), 7.08 (bs, 1H), 6.66 and 6.60 (2s, 2H), 6.58 and 6.50 (2s, 1H), 6.21 and 6.08 (2s, 2H), 4.62 and 4.46 (2s, 1H), 3.88-3.48 (m, 2H), 3.10-2.90 (m, 2H), 2.72-2.50 (m, 1H), 2.24-2.10 (m, 2H), 1.82-1.62 (m, 3H). LC-MS: m/z [M+1]=431.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:16])=[CH:5][C:6]([CH:13]([CH3:15])[CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].P(OCC)(OCC)([S-])=[S:18]>O1CCCC1.O>[C:1]([C:3]1[C:4]([CH3:16])=[CH:5][C:6]([CH:13]([CH3:14])[CH3:15])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])(=[S:18])[NH2:2]
Reactant: CCOP(=S)([S-])OCC
Reactant: COC(=O)c1cc(C#N)c(C)cc1C(C)C
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(C(N)=S)c(C)cc1C(C)C
Temperature: 85 °C
Reaction time: 15 h
Yield: 86.5 %

Procedure:
To a round-bottom flask was added a solution of methyl 5-cyano-2-isopropyl-4-methylbenzoate (compound 196.3, 800 mg, 3.68 mmol, 1.00 equiv) in tetrahydrofuran/H2O (10/5 mL). O,O′-diethyl dithiophosphate (2.05 g, 11.0 mmol, 3.00 equiv) was added to the reaction mixture. The resulting solution was stirred for 15 h at 85° C. in an oil bath (CAUTION: significant gas evolution occurs—this and all other reactions described herein should be carried out in well ventilated fume hoods). After cooling to ambient temperature, the mixture was extracted with 2×100 mL of ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:100-1:50-1:0) as eluent to furnish 0.800 g (86%) of methyl 5-carbamothioyl-2-isopropyl-4-methylbenzoate as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1)=[O:4].[CH:12](=O)/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: O=C/C=C/c1ccccc1
Reactant: COC(=O)c1ccc(N)cn1
Solvent: c1ccccc1
Product: COC(=O)c1ccc(N=CC=Cc2ccccc2)cn1

Procedure:
The starting material is prepared as follows: The mixture of 7.61 g of 5-amino-pyridine-2-carboxylic acid methyl ester, 7.61 g of trans-cinnamaldehyde and 130 ml of benzene is stirred and refluxed on a water trap for 41/2 hours. It is evaporated and the residue recrystallized from ethyl acetate, to yield the 5-cinnamylideneaminopyridine-2-carboxylic acid methyl ester melting at 128°-131°.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:18]O>>[C:1]1([NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([O:14][CH3:18])=[O:13])=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(Nc2ccccc2)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(Nc2ccccc2)cc1

Procedure:
30 ml of 10% hydrogen chloride-methanol was added to 1.59 g (7.46 mmol) of 4-(phenylamino)benzoic acid and the mixture was refluxed overnight under heating. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed with a sodium hydrogencarbonate aqueous solution and brine, and dried (MgSO4). The solvent was distilled off and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1 (v/v)) to obtain 1.66 g (7.30 mmol) of methyl 4-(phenylamino)benzoate as a pale yellow solid. Its spectroscopic data are as follows:
Reaction SMILES: [CH2:1](N(CC)CC)C.O[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].IC.CN([CH:35]=[O:36])C>C(Cl)Cl>[CH3:1][O:23][C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:36][CH3:35])=[CH:10][CH:11]=2)=[CH:16][CH:17]=1)=[O:22]
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CCN(CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(OC)cc2)cc1
Reaction time: 0.08 h
Yield: 96 %

Procedure:
Triethylamine (9.76 mL, 70 mmol) was added under nitrogen to a solution of 4′-hydroxy-biphenyl-4-carboxylic acid (15.0 g, 70 mmol) in 200 mL of anhydrous DMF at room temperature. After stirring for 5 minutes potassium carbonate (58.0 g, 420 mmol) was added and the reaction stirred an additional 5 minutes. Iodomethane (26.0 mL, 420 mmol) was then added (exothermic reaction) and the reaction stirred overnight. The reaction was diluted with methylene chloride, extracted multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 4′-methoxy-biphenyl-4-carboxylic acid methyl ester (16.26 g, 96%) as a tan solid, mp 170-173° C. Elemental Analysis for C15H14O3: Calc'd: C, 74.36; H, 5.82; N, 0.00; Found: C, 73.97; H, 5.66; N, 0.03.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.Cl.O.[NH:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1.C(N(CC)CC)C>C(O)C>[Cl:9][C:4]1[N:3]=[C:2]([CH3:1])[N:7]=[C:6]([N:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)[CH:5]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nc(Cl)cc(N2CCC(=O)CC2)n1
Yield: 87.4 %

Procedure:
A mixture of 2-methyl-4,6-dichloropyrimidine (12.2 g), 4-piperidinone monohydrate monohydrochloride (10.9 g) and triethylamine (42 ml) in ethanol (300 ml) was heated to reflux. The resulting solution was stirred at reflux for 18 hours. The solution was evaporated to dryness. The solid residue was partitioned between ethyl acetate (1 l) and water (50 ml). The ethyl acetate layer was washed with water (3×50 ml), saturated brine (50 ml), dried (Na2SO4) and evaporated to dryness. The solid residue was recrystallised from ethyl acetate/isohexane to give a cream solid. This was further purified by column chromatography on alumina (ICN alumina N32-63), using dichloromethane as eluent, to give 1-(6-chloro-2-methylpyrimidin-4-yl)piperidin-4-one (14.0 g) as an off-white solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18](=[O:19])[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:16]([CH3:27])[NH:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C1CC=CCC=1>CCO.[OH-].[OH-].[Pd+2]>[CH2:20]([C:17]1[C:18](=[O:19])[N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[NH:15][C:16]=1[CH3:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1[nH]n(C2CCN(Cc3ccccc3)CC2)c(=O)c1Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCC=CC1
Product: Cc1[nH]n(C2CCNCC2)c(=O)c1Cc1ccccc1
Yield: 110.2 %

Procedure:
To a solution of 0.52 g of 1-benzyl-4-(4-benzyl-5-methyl-1H-pyrazol-3(2H)-on-2-yl)-piperidine in 20 mL of EtOH under nitrogen was added 0.2 g of Pearlman's catalyst and 2.5 mL of 1,4-cyclohexadiene. This mixture was refluxed for 3 hours, filtered through Celite and concentrated under reduced pressure to give 0.43 g of 4-(4-benzyl-5-methyl-1H-pyrazole-3(2H)-on-2-yl)-piperidine. ESI-MS 271.9 (M+H); HPLC A: 1.68 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][C@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:30][N:31]1[CH:35]=[CH:34][C:33]([NH2:36])=[N:32]1.C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][C@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=1)[C:12]([NH:36][C:33]1[CH:34]=[CH:35][N:31]([CH3:30])[N:32]=1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC[C@@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Reactant: Cn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC[C@@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C)n2)c1
Reaction time: 3 h

Procedure:
DMF (2 drops) was added to a solution of 3-(benzyloxy)-5-[(1R)-2-methoxy-1-methylethoxy]benzoic acid (3.79 g, 0.012 mol) and oxalyl chloride (1.25 mL, 0.015 mol) in DCM (60 mL) and stirred for 3 hours, following which the organics were removed in vacuo. The crude material was dissolved in DCM (30 mL) and slowly added, at 0° C., to a stirred suspension of 1-methyl-1H-pyrazol-3-amine (1.22 g, 0.013 mol) and triethylamine (3.5 mL, 0.025 mol) in DCM (30 mL). The mixture was stirred at ambient temperature for 24 hours and the organics evaporated in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with 1M aqueous hydrochloric acid (50 mL) and brine (50 mL), dried (MgSO4), filtered and evaporated in vacuo to give the crude product which was chromatographed on silica, eluting with a 50% ethyl acetate in isohexane, to give the desired compound. (4.23 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[N:16][C:17]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[C:18]([CH3:21])[C:19]=2[CH3:20])[CH:10]([CH3:29])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.Cl>C1COCC1.O1CCOCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[N:16][C:17]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)=[C:18]([CH3:21])[C:19]=2[CH3:20])[CH:10]([CH3:29])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(-c2ccc(F)cc2)nnc(N2CCN(Cc3ccccc3)C(=O)C2C)c1C
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Cc1c(-c2ccc(F)cc2)nnc(N2CCN(Cc3ccccc3)CC2C)c1C
Temperature: 50 °C

Procedure:
Treat a solution of 1-benzyl-4-(6-(4-fluorophenyl)-4,5-dimethylpyridazin-3-yl)-3-methylpiperazin-2-one (2.84 g, 7.02 mmol) in THF (70 mL) with borane-methyl sulfide complex (1.96 mL, 21.1 mmol). Heat the resulting mixture at 50° C. for 2 h. Cool the reaction mixture in an ice bath, add MeOH (20 mL) via a dropping funnel followed by 4 M HCl in 1,4-dioxane (20 mL). Heat the resulting mixture at 65° C. for 1 h. Concentrate the mixture under reduced pressure. Partition the residue between CH2Cl2 and saturated NaHCO3 (aq). Separate the layers, and extract the aqueous layer with CH2Cl2. Combine the organic layers, dry over Na2SO4, filter, and concentrate under reduced pressure. Purify the residue by flash silica gel chromatography (gradient of 0 to 3% 2 M NH3/MeOH in CH2Cl2) to afford the title compound as a waxy solid (2.45 g, 89%). ES/MS m/z 391.2 (M+1).
Reaction SMILES: O.[NH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([SH:10])[N:4]=1.[OH-].[Na+].O.Cl.Cl[CH2:16][C:17]1[N:18]=[C:19]([CH3:22])[S:20][CH:21]=1>CN(C=O)C>[NH2:2][C:3]1[N:4]=[C:5]([S:10][CH2:16][C:17]2[N:18]=[C:19]([CH3:22])[S:20][CH:21]=2)[NH:6][C:7](=[O:9])[CH:8]=1
Reactant: Cc1nc(CCl)cs1
Reactant: Nc1cc(O)nc(S)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(CSc2nc(N)cc(=O)[nH]2)cs1
Reaction time: 18 h
Yield: 96.5 %

Procedure:
4-Amino-6-hydroxy-2-mercaptopyrimidine hydrate (16.1 g) and powdered sodium hydroxide, (8.0 g) was stirred in dry DMF (100 ml) for 20 mins. 4-Chloromethyl-2-methylthiazole hydrochloride monohydrate (20 g) was added portionwise and the resulting suspension stirred 18 hrs. The mixture was poured onto water and the solid collected, washed with water and dried to afford the sub-title compound (24.3 g)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:8])[CH:7]=1.[Mg].C[O:12][B:13](OC)[O:14]C.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([B:13]([OH:14])[OH:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: OB(O)c1cc(F)cc(F)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
In a nitrogen atmosphere, a solution prepared by dissolving 100 g of 3,5-difluorobromobenzene in 150 mL of THF was added dropwise at a rate that caused gentle reflux to a mixed solution of 13.85 g of magnesium and 55 mL of THF. After dropwise addition, the mixture was stirred at 40° C. for 1 hour and cooled with ice. Then, a solution prepared by dissolving 64.59 g of trimethoxyborane in 130 mL of THF was slowly added dropwise under ice cooling, followed by stirring at room temperature for 1 hour. Then, 10% hydrochloric acid was added until the reaction system became acidic, and the mixture was stirred at room temperature for 30 minutes. Then, an organic layer was separated from the mixture, and an aqueous layer was subjected to extraction with hexane. The hexane extract was combined with the organic layer and washed with saturated brine. The resultant mixture was dried by adding sodium sulfate, and then the solvent was distilled off under reduced pressure to yield 71.65 g of 3,5-difluorophenylboronic acid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C>C(Cl)Cl>[CH3:21][S:22]([O:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC(O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 0.17 h
Yield: 62.4 %

Procedure:
To a solution of 4-hydroxy-1-(p-nitrobenzyloxycarbonyl)piperidine (2.96 g, 14.8 mmol) (obtained as described in Reference Example 51(1)) in methylene chloride (90 ml) were added methanesulfonyl chloride (1.15 ml, 14.8 mmol) and triethylamine (2.07 ml, 14.8 mmol) in an ice bath. The reaction mixture was brought to room temperature in 10 minutes, and then stirred for 6 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was recrystallized from a solution of n-hexane:ethyl acetate (1:1) to afford 4-methanesulfonyloxy-1-(p-nitrobenzyloxycarbonyl)piperidine (3.31 g, yield 87%) as pale yellow crystals.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Br[CH2:9][CH2:10][CH2:11][Cl:12]>CC(C)=O>[Cl:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClCCCBr
Reactant: C1CCNC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: ClCCCN1CCCC1
Yield: 56.6 %

Procedure:
Pyrrolidine (10 g, 0.14 mol), acetone (28 ml), 5M NaOH solution (21 ml) and 1-bromo-3-chloropropane (24.4 g, 0.15 mol) were stirred together under N2 for 8 hours. The organic layer was separated and concentrated in vacuo. The crude product was purified by vacuum distillation (b.p. 90° C./30 mbar) to give the title compound (11.7 g, 57%) as a colourless oil.