Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=C(C=C(F)[CH:27]=1)C[C@@H]([C@@H](C1COCCN1C(OC(C)(C)C)=O)O)C(O)=O.[Si](O[C@H]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)[C@@H:38]([NH:48][C:49](=[O:61])[C:50]1[CH:55]=[C:54](C)[CH:53]=[C:52]([C:57]([O:59]C)=[O:58])[CH:51]=1)[CH2:39][C:40]1C=C(F)C=C(F)C=1)(C(C)(C)C)(C)C.BrC1C=C(C=C(C(OC)=O)C=1)C(N[C@@H](CC1C=C(F)C=C(F)C=1)[C@@H]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)O[Si](C(C)(C)C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>CN(C=O)C.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.C(OCC)(=O)C>[CH2:27]([N:48]([CH2:38][CH2:39][CH3:40])[C:49]([C:50]1[CH:51]=[C:52]([CH:53]=[CH:54][CH:55]=1)[C:57]([OH:59])=[O:58])=[O:61])[CH2:2][CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCOCC1[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C)cc(C(=O)OC)c2)N(C(=O)OC(C)(C)C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(Br)cc(C(=O)OC)c2)N(C(=O)OC(C)(C)C)C1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCN(CCC)C(=O)c1cccc(C(=O)O)c1
Temperature: 100 °C
Yield: 77 %

Procedure:
Step G (4): Preparation of (2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-(methoxycarbonyl)-5-methylbenzamido)propyl)-4-propoxypyrrolidine-1-carboxylate. To a solution of (2R,4R)-tert-butyl 2-((1S,2S)-2-(3-bromo-5-(methoxycarbonyl)benzamido)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylate (Step G (3). 163 mg, 0.21 mmol) in DMF (10 mL) were added potassium carbonate (87 mg, 0.63 mmol), Pd(PPh3)4 (24 mg, 0.021 mmol), and trimethylboroxine (53 mg, 0.42 mmol) and the reaction mixture was stirred at 100° C. with sealed cap for 5 h. Then another portion of trimethylboroxine (53 mg, 0.42 mmol) was added and the reaction was stirred at 60° C. overnight. Another portion of trimethylboroxine (53 mg, 0.42 mmol) was added and the reaction was stirred at 100° C. for 6 h. Ethyl acetate (100 mL) was added and the mixture was washed with H2O and concentrated under vacuum. The crude mixture was purified by silica gel Flash Chromatography (0% to 5% to 10% to 15% EtOAc/Hexane step gradient) to give 110 mg of the title compound (77% yield): 1H NMR (CDCl3, 500 MHz) δ ppm 0.02 (3H, s), 0.07 (3H, s), 0.85 (9H, s), 0.88 (3H, m), 1.45-1.52 (11H, m), 2.02-2.07 (1H, m), 2.20 (1H, d, J=15 Hz), 2.41 (3H, s), 2.66 (1H, dd, J=10, 15 Hz), 2.94 (1H, m), 3.28-3.37 (3H, m), 3.76 (1H, dd, J=5, 10 Hz), 3.90 (3H, s), 3.99 (1H, m), 4.07-4.13 (2H, m), 4.62 (1H, m), 6.59 (1H, m), 6.77 (1H, s), 6.79 (1H, s), 7.91 (1H, s), 7.94 (1H, s), 8.20 (1H, brd s), 8.34 (1H, s). MS (ESI) (M+H)+ 705.41.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[C:12]([C:22]3[CH:27]=[CH:26][C:25]([S:28](C)(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:32]>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[C:12]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH2:32])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Reactant: N
Product: CC(C)(C)COc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 384 substituting 2-(3,4-difluorophenyl)-4-(2,2-dimethylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 310 mg, 38%). mp 173-175° C. 1H NMR (300 MHz, DMSO-d6) δ 0.8 (s, 9H), 3.3 (s, 3H), 4.1 (s, 2H), 7.51 (m, 3H), 7.6 (m, 1H), 7.85 (m, 3H), 7.95 (d, J=9 Hz, 2H), 8.21 (s, 1H). MS (DCI/NH3) m/z 450 (M+H)+, 467 (M+NH4)+. Anal. calc. for C21H21F2N3O4S: C, 56.12; H, 4.71; N, 9.35. Found, C, 55.83; H, 4.73; N, 9.08.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:15][CH:16]([CH2:20][CH2:21][CH2:22]C)[C:17](Cl)=O>C1(C)C=CC=CC=1>[Cl:15][CH:16]([C:17]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([F:12])([F:13])[F:14])[C:2]=2[N:1]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCC(Cl)C(=O)Cl
Reactant: Nc1c(C(=O)O)cccc1C(F)(F)F
Solvent: Cc1ccccc1
Product: CCCC(Cl)c1nc2c(C(F)(F)F)cccc2c(=O)o1
Yield: 55 %

Procedure:
A mixture of 10.25 g of 2-amino-3-trifluoromethylbenzoic acid, 20 ml of toluene and 20.3 g of 2-chlorohexanoic acid chloride (prepared according to J. Org. CHem., Vol. 40 (1975), p. 23420) was refluxed for one hour and then toluene and excess acid chloride were removed by distillation. The residue was chromatographed over silica gel and eluted with methylene chloride and then by chromatography under pressure. Elution with a 1-1 ethyl acetate-petroleum ether (b.p.=60°-80° C.) mixture yielded 8.4 g of 2-(1-chlorobutyl)-8-trifluoromethyl-4H-3,1-benzoxazine-4-one in the form of an oil which was used as is for the next step.
Reaction SMILES: [C:1]([O:9][C:10]1[C:11]([C:21]([O:23][CH3:24])=[O:22])=[N:12][C:13](I)=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([Zn]C#N)#[N:26]>CN(C=O)C>[C:1]([O:9][C:10]1[C:11]([C:21]([O:23][CH3:24])=[O:22])=[N:12][C:13]([C:25]#[N:26])=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(I)c2cccnc2c1OC(=O)c1ccccc1
Reactant: N#C[Zn]C#N
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C#N)c2cccnc2c1OC(=O)c1ccccc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 8-(benzoyloxy)-5-iodo-1,6-naphthyridine-7-carboxylate (750 mg, 1.727 mmol) in anhydrous DMF (10 ml) was added dicyanozinc (142 mg, 1.21 mmol) and tetrakis(triphenylphospine)palladium(0) (299 mg, 0.26 mmol) and the solution was stirred at 85° C. overnight. The reaction was quenched with water and extracted with chloroform three times. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (17-55% EtOAc/Hexanes gradient elution) to provide a white solid.
Reaction SMILES: C(S([N:7]=[C:8]([C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[N:30]=[CH:29][CH:28]=[CH:27]2)[C:9]1[CH:21]=[CH:20][C:12]([C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1)=O)(C)(C)C.Cl.CCOCC>CO>[NH2:7][CH:8]([C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[N:30]=[CH:29][CH:28]=[CH:27]2)[C:9]1[CH:21]=[CH:20][C:12]([C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1
Reactant: CCN(CC)C(=O)c1ccc(C(=NS(=O)C(C)(C)C)c2cccc3cccnc23)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CCN(CC)C(=O)c1ccc(C(N)c2cccc3cccnc23)cc1

Procedure:
Treatment of 15 (135 mg, ˜0.30 mmol) with HCl in ether (0.3 mL, 0.6 mmol) in MeOH (2 mL) at 25° C., for 5 min. Concentration in vacuo, dilution with water, washing with EtOAc. The solution was then made basic with K2CO3(aq), extracted with and evaporated to give (+)-6 (53 mg, 53% from 14). 1H NMR (CDCl3): δ1.2 (m, 6H), 2.2 (s, 2H), 3.4 (m, 4H), 6.40 (s, 1H), 7.30-7.58 (m, 7H), 7.71 (m, 1H), 8.15 (m, 1 H), 8.92 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6](=O)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].[C:15]([O:19][C:20](=[O:27])[C:21](=[N:25]O)[C:22](=O)[CH3:23])([CH3:18])([CH3:17])[CH3:16].O>C(O)(=O)C.[Zn]>[CH2:1]([O:3][C:4]([C:5]1[C:22]([CH3:23])=[C:21]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:27])[NH:25][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:14])[CH3:2]
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Reactant: CC(=O)C(=NO)C(=O)OC(C)(C)C
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)Cc1[nH]c(C(=O)OC(C)(C)C)c(C)c1C(=O)OCC
Temperature: 75 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
A stirred solution of 3-oxo-butyric acid tert-butyl ester (32 g, 0.2 mol) in glacial acetic acid was added dropwise with an aqueous solution of sodium nitrite (13.8 g, 0.2 mol sodium nitrite in 20 ml of water) while maintaining the temperature at 0˜5° C. Upon completion of the addition, the reaction mixture was stirred in an ice-water bath for 1 hour and at room temperature for another 3 hours. The solution of 2-hydroxyimino-3-oxo-butyric acid tert-butyl ester was obtained which was used as such. A mixture of 3-oxo-glutaric acid diethyl ester (40 g, 0.2 mol) in 90 ml of glacial acetic acid was added with the above solution of 2-hydroxyimino-3-oxo-butyric acid tert-butyl ester and zinc dust (26 g, 0.4 mol) alternatively at a rate to maintain the reaction temperature below 65° C. Upon completion of the addition, the mixture was stirred at 75° C. for 2 hours, added with cold water (100 ml), and the mixture was stirred at room temperature for 1 hour. The zinc dust was removed by filtration and the filtrate was extracted with ethyl acetate (100 ml×3). The combined organic extracts were washed with water (100 ml×3), saturated sodium bicarbonate solution (100 ml×4), and brine (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 5-ethoxycarbonylmethyl-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester (60 g, 88.5%) as a yellow oil.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[N:11]=[C:12]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[S:13][C:14]=1[CH3:15].O>C(#N)C>[Cl:1][CH2:9][C:10]1[N:11]=[C:12]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[S:13][C:14]=1[CH3:15]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)sc1C
Solvent: O
Solvent: CC#N
Product: Cc1sc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1CCl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
N-Chlorosuccinimide (4.5 g) was added to a solution (100 ml) of tert-butyl 4-(4,5-dimethyl-1,3-thiazol-2-yl)piperazine-1-carboxylate (10 g) in acetonitrile at 0° C., and the mixture was stirred at 0° C. for 30 min. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (0:1-1:4-1:2, v/v) to give tert-butyl 4-(4-chloromethyl-5-methyl-1,3-thiazol-2-yl)piperazine-1-carboxylate as colorless crystals (6.2 g, yield 55%).
Reaction SMILES: [CH2:1]([C:4]1[NH:5][CH:6]=[C:7]([CH2:9][OH:10])[N:8]=1)[CH2:2][CH3:3].[N+]([O-])(O)=O.C([O-])([O-])=O.[Na+].[Na+]>[N+]([O-])(O)=O>[CH2:1]([C:4]1[NH:5][CH:6]=[C:7]([CH:9]=[O:10])[N:8]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc(CO)c[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Product: CCCc1nc(C=O)c[nH]1
Temperature: 0 °C

Procedure:
A 108.6 gm. portion of 2-n-propyl-4-imidazolemethanol and 107 ml. of concentrated HNO3 are heated on a steam bath for 2 1/2 hours. Three drops of fuming HNO3 are added during this time. The pH is adjusted to 8 with concentrated aqueous Na2CO3 and the mixture is cooled to 0° C. overnight. The solid is recovered, washed with water and recrystallized from a mixture of ethyl acetate and petroleum ether giving a yellow solid. Treatment of the mother liquor gives an additional tacky solid which is triturated with 2-propanol giving a second solid. These two solids are taken up in hot 2-propanol and recrystallized as a yellow solid. This solid is recrystallized from ethanol:water (1:1) giving yellow crystals, m.p. 103.5°-105.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15](=[O:16])[N:14]([C:17]3[S:18][C:19]([C:23]([NH:25][CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[O:24])=[C:20]([CH3:22])[N:21]=3)[CH:13]=[N:12]2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:36]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15](=[O:16])[N:14]([C:17]3[S:18][C:19]([C:23]([N:25]([CH3:36])[CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[O:24])=[C:20]([CH3:22])[N:21]=3)[CH:13]=[N:12]2)=[CH:6][CH:7]=1
Reactant: CI
Reactant: Cc1nc(-n2cnn(CCNc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(-n2cnn(CCNc3ccc(F)cc3)c2=O)sc1C(=O)N(C)Cc1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
A solution of 2-(1-(2-(4-fluorophenylamino)ethyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide (0.10 g, 0.40 mmol) in anhydrous tetrahydrofuran (10 mL) was treated with sodium hydride (60% suspension in mineral oil, 0.02 g, 0.47 mmol) at ambient temperature for 30 minutes, followed by the addition of iodomethane (0.015 mL, 0.24 mmol). The reaction mixture was stirred at ambient temperature for 1 hour, quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with ethyl acetate to afford the title compound as a white solid in 25% yield (0.03 g): 1H NMR (300 MHz, CDCl3) δ 8.60-8.49 (m, 2H), 8.24 (s, 1H), 7.69-7.59 (m, 1H), 7.35-7.27 (m, 1H), 6.91-6.77 (m, 2H), 6.59-6.49 (m, 2H), 4.69 (s, 2H), 4.15-4.04 (m, 2H), 3.99-3.87 (m, 1H), 3.54-3.44 (m, 2H), 2.98 (s, 3H), 2.39 (s, 3H); MS (ES+) m/z 468.18 (M+1).
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]1([CH:10]2[CH2:15][CH2:14][O:13][C:12](=[O:16])[CH2:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[OH:13][CH2:14][CH2:15][CH:10]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:11][C:12]([NH:2][NH2:3])=[O:16]
Reactant: O=C1CC(c2ccccc2)CCO1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)CC(CCO)c1ccccc1
Temperature: 25 °C

Procedure:
Hydrazine monohydrate (1.6 mL) was added to a solution of 4-phenyl-tetrahydropyran-2-one (573 mg; CAS No. 61949-75-5) in ethanol (3 mL) at room temperature, and the reaction solution was heated under reflux for three hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-methanol system) to obtain 492 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)(O)[O-].[Na+].[C:15]([N:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:20]([O:35][CH3:36])[CH2:19]1)(=[O:17])[NH2:16]>C1COCC1>[CH2:27]([O:26][C:25]([NH:24][C@H:21]1[CH2:22][CH2:23][N:18]([C:15]2[O:17][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:16]=2)[CH2:19][C@H:20]1[O:35][CH3:36])=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: CO[C@@H]1CN(C(N)=O)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1coc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)n1
Temperature: 70 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
Ethyl bromopyruvate (2.93 g, 15 mmol) and sodium bicarbonate (2.10 g, 25 mmol) were added to a solution of cis(±)-benzyl (1-carbamoyl-3-methoxypiperidin-4-yl)carbamate obtained in Example (103b) (1.4 g, 4.56 mmol) in THF (30 mL), and the mixture was stirred at 70° C. for three hours. The insoluble matter was filtered off, followed by dilution with ethyl acetate. This was washed with water and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 1/2, 1/1, 2/1, 4/1) to obtain 1.46 g of the title compound as a colorless solid (79%).
Reaction SMILES: [CH:1]1([N:7]([CH3:33])[C:8]([C:10]2[CH:32]=[CH:31][C:13]3[N:14]([CH2:25][CH2:26][CH2:27][C:28](O)=[O:29])[C:15]([NH:17][C:18]([C:20]4[S:21][CH:22]=[CH:23][CH:24]=4)=[O:19])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.O[N:36]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[OH-].[NH4+].Cl>CN(C=O)C>[CH:1]1([N:7]([CH3:33])[C:8]([C:10]2[CH:32]=[CH:31][C:13]3[N:14]([CH2:25][CH2:26][CH2:27][C:28](=[O:29])[NH2:36])[C:15]([NH:17][C:18]([C:20]4[S:21][CH:22]=[CH:23][CH:24]=4)=[O:19])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: On1nnc2ccccc21
Reactant: CN(C(=O)c1ccc2c(c1)nc(NC(=O)c1cccs1)n2CCCC(=O)O)C1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc2c(c1)nc(NC(=O)c1cccs1)n2CCCC(N)=O)C1CCCCC1
Reaction time: 1 h
Yield: 0.4 %

Procedure:
To a solution of 4-{5-(N-cyclohexyl-N-methyl-carbamoyl)-2-[(thiophene-2-carbonyl)-amino]-benzoimidazol-1-yl}-butyric acid (Example 2) (0.05 g, 11 mmol) in DMF (5 mL) was added 1-hydroxybenzotriazole hydrate (0.02 g, 16 mmol) followed by 1-[3-(dimethylamino)propyl]-3-ethylcarbodimide hydrochloride (0.03 g, 16 mmol). The mixture was stirred for 1 h., and ammonium hydroxide (5 mL) was added. Stirring was continued for 48 h. The solution was neutralized with 1M HCl, and partitioned between EtOAc (10 mL) and water (10 mL). The organic layer was washed with saturated sodium carbonate (10 mL) and water (3×10 mL). The solvent was evaporated and the resulting oil was purified by flash chromatography with 5% MeOH/dichloromethane to give the title compound (0.02 g, 40%), m.p. 112-115° C.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[CH3:17])=[C:10]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:9]=2)[C:6]2[CH:24]=[CH:25][CH:26]=[CH:27][C:5]=2[N:4]=1)[CH3:2].CN(CCN(C)C)C.[Li]CCCC.[C:41]([O:45][C:46]([N:48]1[CH2:51][C:50](=[O:52])[CH2:49]1)=[O:47])([CH3:44])([CH3:43])[CH3:42]>C1COCC1>[C:41]([O:45][C:46]([N:48]1[CH2:51][C:50]([C:13]2[N:14]([CH3:17])[C:15]3[C:11]([N:12]=2)=[C:10]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:9]=[C:8]([N:7]2[C:6]4[CH:24]=[CH:25][CH:26]=[CH:27][C:5]=4[N:4]=[C:3]2[CH2:1][CH3:2])[N:16]=3)([OH:52])[CH2:49]1)=[O:47])([CH3:44])([CH3:42])[CH3:43]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2ncn(C)c2n1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Temperature: -40 °C
Yield: 65.3 %

Procedure:
To a mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (2.5 g, 6.88 mmol) and TMEDA (1.6 mL, 10.33 mmol) in THF (40 mL) at −78° C. was added n-BuLi (4.1 mL, 2.5 M in hexanes, 10.33 mmol). The resulting mixture was allowed to warm to −40° C. over 30 min then cooled back to −78° C. before the addition of a solution of 3-oxoazetidine-1-carboxylic acid tert-butyl ester (1.8 g, 10.33 mmol) in THF (10 mL). The reaction mixture was warmed to −10° C. over 2 h then quenched with sat, aq. NH4Cl and extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-5%) then recrystallised from iPrOAc and pentane affording 3-[2-(2-Ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester as a cream solid (2.4 g, 64%). LCMS (method A): RT 2.83 min [M+H]+ 535.4
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[C:23]([F:26])([F:25])[F:24]>>[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:18][C:17]=1[C:23]([F:24])([F:25])[F:26]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: COc1ccc(CCCC(=O)O)cc1
Product: COc1ccc(CCCC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
N-[4-chloro-3-(trifluoromethyl)phenyl]-4-(4-methoxyphenyl)butanamide was prepared as described in Example 5, Step 1 using 4-(4-methoxyphenyl)butyric acid and 4-chloro-3-(trifluoromethyl)aniline. LCMS, AA: Rt=2.17 min, [MH− 370.1].
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH:12]([CH2:14][N:15]3[CH2:20][CH2:19][C:18](OS(C)(=O)=O)([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][CH2:16]3)[O:11][C:10]2=[O:32])=[CH:5][CH:4]=1)#[N:2].CS(Cl)(=O)=O.[N:38]1C=CC=CC=1>N.C(O)C.C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH:12]([CH2:14][N:15]3[CH2:20][CH2:19][C:18]([NH2:38])([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][CH2:16]3)[O:11][C:10]2=[O:32])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)CC1(OS(C)(=O)=O)CCN(CC2CN(c3ccc(C#N)cc3)C(=O)O2)CC1
Reactant: c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CC1(N)CCN(CC2CN(c3ccc(C#N)cc3)C(=O)O2)CC1
Reaction time: 2 h

Procedure:
1 g of ethyl 1-(3-(4-cyanophenyl)-2-oxo-5-oxazolidinylmethyl)-4-methanesulfonyloxypiperidine-4-acetate (obtainable from the 4-hydroxy compound (see Example 13) with methanesulfonyl chloride/pyridine) is dissolved in a 2% NH3 solution in 10 ml of a 1:1 mixture of ethanol and THF, and the solution is left to stand at 20° for 2 hours. The solution is concentrated by evaporation and subjected to conventional work-up to give ethyl 1-(3-(4-cyanophenyl)-2-oxo-5-oxazolidinylmethyl)-4-aminopiperidine-4-acetate, FAB 387.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:20]1([S:26]([CH:29]2[CH:39]([C:40]3[CH:45]=[C:44](Br)[CH:43]=[C:42]([CH3:47])[N:41]=3)[NH:38][C:31]3([CH2:35][CH2:34][N:33]([CH3:36])[C:32]3=[O:37])[CH2:30]2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>COCCOC.O.O.CCOC(C)=O>[C:20]1([S:26]([CH:29]2[CH2:30][C:31]3([CH2:35][CH2:34][N:33]([CH3:36])[C:32]3=[O:37])[NH:38][CH:39]2[C:40]2[CH:45]=[C:44]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=3)[CH:43]=[C:42]([CH3:47])[N:41]=2)(=[O:28])=[O:27])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(Br)cc(C2NC3(CCN(C)C3=O)CC2S(=O)(=O)c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(C2NC3(CCN(C)C3=O)CC2S(=O)(=O)c2ccccc2)n1
Temperature: 120 °C
Yield: 103.2 %

Procedure:
PdCl2(Ph3P)2 (128.4 mg, 0.1800 mmol) was added to a degassed mixture of 4-trifluoromethylphenyl-boronic acid (365.03 mg, 1.92 mmol), sodium carbonate (582.01 mg, 5.49 mmol) and 7-(benzene-sulfonyl)-8-(4-bromo-6-methyl-2-pyridyl)-3-methyl-3,9-diazaspiro[4.4]nonan-4-one (which may be prepared as described in Description 12) (850 mg, 1.83 mmol) in DME (12 mL) and water (4 mL) under N2 in a microwave vial and the reaction was heated in the microwave at 120° C. for 1 hour. The mixture was diluted with water/EtOAc, filtered, and the phases separated. The organic layer was dried (Na2SO4) and the solvent evaporated to afford a light brown solid. This was purified using a Biotage SP4, 25 g SNAP cartridge, eluting with 0 to 10% MeOH/EtOAc to afford the 3-(benzenesulfonyl)-7-methyl-2-[6-methyl-4-[4-(trifluoromethyl)-phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]nonan-6-one (D16) (1 g, 1.8883 mmol) as an off-white solid (with traces of impurities);