Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]([C@@H:5]1[CH2:10][CH2:9][C@@H:8]([CH3:11])[CH2:7][C@H:6]1[OH:12])[CH3:4].[H-].[Na+].[CH:15](I)([CH3:17])[CH3:16].O>C(COC)OC>[CH:15]([O:1][CH2:2][CH:3]([C@@H:5]1[CH2:10][CH2:9][C@@H:8]([CH3:11])[CH2:7][C@H:6]1[OH:12])[CH3:4])([CH3:17])[CH3:16]
Reactant: CC(C)I
Reactant: CC(CO)[C@@H]1CC[C@@H](C)C[C@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)OCC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
20.0 g (0.12 mol) of (1R, 2S, 5R)-2-(2-hydroxy-1-methylethyl)-5-methylcyclohexanol was dissolved in 100 ml of dimethoxyethane, and 3.3 g (0.14 mol) of sodium hydride was added to the solution. The mixture was agitated for 30 min, and 23.7 g (0.14 mol) of isopropyl iodide was dropped thereinto and continued to agitate at room temperature for 24 hr. After the completion of the reaction, 300 ml of water was added to the reaction fluid and agitated. The reaction product was extracted with ether. The resultant ether phase was dried over anhydrous magnesium sulfate, and the solvent was distilled off, thereby obtaining 18.3 g (yield: 73.6%) of (1R, 2S, 5R)-2-(2-isopropoxy-1-methylethyl)-5-methylcyclohexanol in the form of a colorless liquid. The mass spectrometry and NMR data of the obtained compound are as follows:
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[CH:3]([NH:11][C@@H:12]([CH2:17][S:18]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:13]([O:15][CH3:16])=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[SH:18][CH2:17][C@H:12]([NH:11][CH:3]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1)[C:2]([F:1])([F:38])[F:39])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(c1ccc(F)cc1)C(F)(F)F
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](CS)NC(c1ccc(F)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
To a stirred solution of (2R)-methyl 2-((2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)amino)-3-(tritylthio)propanoate (24.8 g; 44.8 mmol) in anhydrous dichloromethane (200 mL), previously cooled to in an ice-water bath under nitrogen, was added trifluoroacetic acid (14 mL; 20.7 g; 182 mmol; 405 mole %), followed by triethylsilane (14.4 mL; 10.5 g; 90.1 mmol; 200 mole %). The reaction mixture was stirred at ambient temperature for 2 h then concentrated in vacuo. The residue was redistilled from dichloromethane and the residue absorbed onto silica gel (30 g). The absorbed sample was applied to a column of SiO2 (660 g) and eluted with 2% ethyl acetate in hexane, gradually increased to 10% EtOAc in hexane to give 11.74 g (84.5%) of (2R)-methyl 3-mercapto-2-((2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)amino)propanoate which was used directly in the next step. LC-MS, negative ion mode: m/z=310 [M−H]− (100%).
Reaction SMILES: CN1CC[O:5][CH2:4][CH2:3]1.Cl.[NH2:9][CH:10]([C:16](=[O:18])[CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(OC(=O)C)(=O)C.O>CN(C=O)C.C1COCC1>[C:4]([NH:9][CH:10]([C:16](=[O:18])[CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:5])[CH3:3]
Reactant: CCOC(=O)C(N)C(C)=O
Reactant: CN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(NC(C)=O)C(C)=O
Reaction time: 1 h
Yield: 12.5 %

Procedure:
4-Methylmorpholine (0.41 mL, 3.7 mmol) was added dropwise via a syringe pump to a mixture of ethyl 2-amino-3-oxobutanoate hydrochloride (565 mg, 3.12 mmol) and acetic anhydride (0.35 mL, 3.7 mmol) in DMF (2 mL) and THF (4 mL) at RT under N2 over a period of 30 min. The reaction was stirred for 1 h and water was then added. It was extracted with EtOAc. The organic layer was washed with saturated sodium bicarbonate, HCl (1 N) and brine, dried over sodium sulfate and concentrated. The residue was purified by ISCO FC with 0-40% EtOAc in hexane to give the title compound (73 mg, 13%) as a light-yellow crystalline solid. 1H NMR (400 MHz, CDCl3-d) δ ppm 6.60 (s, 1H) 5.22 (d, J=6.59 Hz, 1H) 4.25 (q, J=6.90 Hz, 2H) 2.36 (s, 3H) 2.04 (s, 3H) 1.28 (t, J=7.14 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:11]([N+:17]([O-:19])=[O:18])=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][OH:9])=[O:5].[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[Cl:1][C:2]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:11]([N+:17]([O-:19])=[O:18])=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][O:9][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][O:20]1)=[O:5]
Reactant: O=C(NCCO)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: O=C(NCCOC1CCCCO1)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of 12b (0.6 g, 2.14 mmol) in CH2Cl2 was cooled in an ice-bath, and 3,4-dihydro-2H-pyran (2.0 mL) and p-toluenesulfonic acid (0.1 g) were added. The reaction mixture was stirred for 2 h, then concentrated under reduced pressure. Chromatography of the residue on silica gel, eluting with EtOAc/petroleum ether (from 1:2 to 2:1), gave 2-chloro-3,5-dinitro-N-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]benzamide (12c) (0.8 g, 100%): as an oil;
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](N2CCOCC2)=[O:9])=[CH:4][C:3]=1[F:16].[CH3:17][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:9])[CH3:17])=[CH:4][C:3]=1[F:16]
Reactant: C[Mg]Br
Reactant: O=C(c1ccc(Br)c(F)c1)N1CCOCC1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Br)c(F)c1
Temperature: 25 °C
Yield: 36.9 %

Procedure:
To a 0° C. solution containing 8.62 g of 4-[(4-bromo-3-fluorophenyl)carbonyl]morpholine (30 mmols) in 150 mL THF was added 15 mL of methylmagnesium bromide (45 mmols, 3M solution in Et2O). The reaction mixture was allowed to warm slowly to ambient temperature. After 18 h the reaction mixture was quenched with 20 mL saturated aqueous NH4Cl solution. The layers were separated, and the organic layer was dried over MgSO4, filtered through a frit, and concentrated. The crude product was purified by silica gel chromatography (120 g redisep column, silica 40 um, 60A, 85 ml/min, A: EtOAc, B: hexanes, A: 8% for 14 min) to give 2.40 g (37%) of title compound as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])O)[OH:4].S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1>[CH2:11]1[O:12][CH:5]([CH:3]([OH:4])[CH2:2][OH:1])[C@@H:7]([OH:8])[CH:9]1[OH:10]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: OCC(O)C1OCC(O)[C@@H]1O

Procedure:
364 g sorbitol (2 moles), 600 ml toluene and 1 g concentrated sulfuric acid were placed into the equipment described above. The reaction mixture was heated to reflux temperature and 40 ml water (2.2 moles) was collected by azeotropic distillation within 6 hours. The toluene phase was decanted and the sorbitan formed was dissolved in 300 ml DMSO and placed into the reactor together with 3 ml 50% sodium hydroxide.
Reaction SMILES: N[N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:5][CH2:4][CH2:3]1.[ClH:19].[NH:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1>>[ClH:19].[C:13]1([CH:6]2[C:7]3[CH:12]=[CH:11][CH:10]=[C:9]4[C:22]5[CH2:21][NH:20][CH2:25][CH2:24][C:23]=5[N:2]([C:8]=34)[CH2:3][CH2:4][O:5]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NN1CCOC(c2ccccc2)c2ccccc21
Reactant: O=C1CCNCC1
Agent: Cl
Product: c1ccc(C2OCCn3c4c(c5cccc2c53)CNCC4)cc1

Procedure:
1-Amino-1,2,3,5-tetrahydro-5-phenyl-4,1-benzoxazepine [Testa and Fontanella, Il Farmaco, 18, 815 (1963)] is reacted with 4-piperidone hydrochloride as described in Example 110 to yield the title compound, m.p. 297°-299° .
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:20]#[N:21])=[C:4]2[N:9]([C:10]=1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:8][CH2:7][C:6](Cl)(Cl)[C:5]2=[O:19].C(O)(=O)C>C(O)C.[Pd]>[Cl:1][C:2]1[C:3]([C:20]#[N:21])=[C:4]2[N:9]([C:10]=1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:8][CH2:7][CH2:6][C:5]2=[O:19]
Reactant: N#Cc1c(Cl)c(-c2cccnc2)n2c1C(=O)C(Cl)(Cl)CC2
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: N#Cc1c(Cl)c(-c2cccnc2)n2c1C(=O)CCC2
Yield: 87.5 %

Procedure:
A suspension of 10.14 g of 2,7,7-trichloro-8-oxo-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carbonitrile and 300 cm3 of acetic acid in 1000 cm3 of ethanol is stirred under argon, and 3.06 g of 10% palladium on carbon in 50 cm3 of ethanol are added. The reaction mixture is bubbled with hydrogen for 2 hours at room temperature, and then filtered on No. 3 sintered glass covered with Celite. The cake is washed with twice 50 cm3 of ethanol and the filtrate is then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature close to 55° C. An oily residue is taken up in 150 cm3 of water and the pH is brought to 8-9 by addition of sodium hydrogen carbonate. 7.08 g of 2-chloro-8-oxo-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carbonitrile are obtained in the form of a white solid melting at a temperature greater than 260° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S@@:8](=[O:34])[C@@H:9]2[C@H:20]([NH:21][C:22](=[O:32])[C:23]([C:27]3[O:28][CH:29]=[CH:30][CH:31]=3)=[N:24][O:25][CH3:26])[C:19](=[O:33])[N:10]2[C:11]=1[C:12]([O:14]C(C)(C)C)=[O:13])(=[O:3])[NH2:2]>FC(F)(F)C(O)=O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S@@:8](=[O:34])[C@@H:9]2[C@H:20]([NH:21][C:22](=[O:32])[C:23]([C:27]3[O:28][CH:29]=[CH:30][CH:31]=3)=[N:24][O:25][CH3:26])[C:19](=[O:33])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[NH2:2]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)(C)C)=C(COC(N)=O)C[S@@](=O)[C@H]12)c1ccco1
Solvent: O=C(O)C(F)(F)F
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)C[S@@](=O)[C@H]12)c1ccco1
Temperature: 25 °C
Reaction time: 0.13 h
Yield: 40.3 %

Procedure:
t-Butyl (1R,6R,7R)-3-carbamoyloxymethyl-7-[2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylate 1-oxide (syn isomer) (0.42g) was dissolved in trifluoroacetic acid (5ml) and stirred at room temperature for 8 minutes. The solution was evaporated to a red oil in vacuo, dissolved in ethyl acetate:acetone (1:1, 5ml) and added dropwise with stirring to petroleum ether (60°-80°, 50ml). The deposited solid was collected and dried in a desiccator. The crude product was slurried with ethyl acetate, and the liquid phase was decanted and added dropwise to petroleum ether (60°-80° , 50ml), yielding the title compound as a colourless solid (150mg, 40%), λmax (0.25N NaHCO3) 263.5 (ε 15,000) and 281nm (ε 13,700); νmax (Nujol) 1,799 (β-lactam), 1725 and 1716 (COOH and OCONH2), 1684 and 1538 (CONH) and 1060 and 1050cm-1 (S→O);τ(Me2SO-d6) values include 0.02 (d, J8Hz, CONH), 4.17(dd, J4 and 8Hz, 7-H), 4.99 (d, J4Hz, 6-H) and 6.09 (s, N-OCH3).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH2:18]O)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].Cl.[CH3:27][N:28]([CH3:37])[CH2:29][CH2:30][N:31]1[C:35]([SH:36])=[N:34][N:33]=[N:32]1.P(OC)(OC)OC.Cl>C(N)=O.O.CCOCC>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH2:18][S:36][C:35]4[N:31]([CH2:30][CH2:29][N:28]([CH3:37])[CH3:27])[N:32]=[N:33][N:34]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Nc1nc(CC(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(CO)CS[C@H]23)cs1
Reactant: CN(C)CCn1nnnc1S
Agent: COP(OC)OC
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: NC=O
Product: CN(C)CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3csc(N)n3)[C@H]2SC1
Reaction time: 1.5 h

Procedure:
In a mixture of 4 ml of formamide and 4 ml of acetonitrole was suspended 423 mg of sodium 7β-[2-(2-aminothiazol-4-yl)acetamido]-3-hydroxymethyl-3-cephem-4-carboxylate.dihydrate. To the suspension were added in sequence 315 mg of 1-(2-dimethylaminoethyl)-5-mercapto-1H-tetrazole hydrochloride, 0.45 ml of trimethyl phosphite and 0.20 ml of ether solution of hydrogen chloride (5 mol./l). The mixture was stirred at 20~25° C. for 1.5 hour, and there was added 5 ml of water, followed by concentration under reduced pressure at 20 to 25° C. To the concentrated solution was added 50 ml of water, whose pH was adjusted to 5.8 with 1N NaOH, followed by subjecting the resultant to an Amberlite XAD-2 column chromatography, eluting with a mixture of water and acetone (4:1,v/v). Fractions containing the end product were combined, concentrated under reduced pressure and then freeze-dried to give 7β-[ 2-(2-aminothiazol-4-yl) acetamido]-3-[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[Li]CCCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C>O1CCCC1>[O:9]1[C:5]2[CH:4]=[CH:3][C:2]([B:16]([OH:21])[OH:17])=[CH:10][C:6]=2[CH:7]=[CH:8]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccc2occc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2occc2c1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
The solution of 5-bromo-1-benzofuran (1.0 g, 5.08 mmol) in dry tetrahydrofuran (50 mL) was kept below −60° C. under nitrogen, while BuLi (6.09 mmol, 2.5M solution in hexane) was added dropwise. It was warmed to −30° C. during 45 min and stirred at this temperature for another 30 min. The mixture was cooled again below −60° C. followed by dropwise addition of triisopropyl borate (1.44 g, 7.66 mmol). After warming to room temperature the mixture was quenched with hydrochloric acid (30 mL, 2N) and stirred for 1 h. The alkaline aqueous layer was brought to pH 5 and extracted with ethyl acetate (3×80 mL). All organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give (1-benzofuran-5-yl)boronic acid (500 mg, crude), which was used for the next step without further purification.
Reaction SMILES: [NH2:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]3[S:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12.C(=O)([O-])O.[Na+].O.[CH2:28]=[C:29]1[O:33][C:31](=[O:32])[CH2:30]1>CC(C)=O>[C:31]([NH:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]3[S:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12)(=[O:32])[CH2:30][C:29]([CH3:28])=[O:33]
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Reactant: C=C1CC(=O)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)CC(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(C)s3)CS[C@H]12
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
While a mixture of 0.344 g. of 7-amino-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid, 0.42 g. of sodium hydrogen carbonate, 5 ml. of water and 5 ml. of acetone is stirred under cooling at 5° C, 0.2 g. of diketene is added and the mixture is further stirred at room temperature for 30 minutes. The acetone is removed from the reaction mixture by distillation under reduced pressure and the residual is washed with ethyl acetate. The water layer is separated, adjusted to pH 2 with 50 % phosphoric acid and extracted three times with ethyl acetate. The extracts are pooled, washed with a saturated aqueous solution of sodium chloride, dehydrated over magnesium sulfate, concentrated and allowed to stand under cooling with ice. With the addition of ether the resultant crystals are loosened and recovered by suction-filtration. The procedure gives 7-acetoacetamido-3(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid as crystals melting at 177°-180° C (decomp.). Yield 0.129 g. (30 %).
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(Cl)=C(Cl)C=1)C.C=O.[NH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27].[Cl:29][C:30]1[CH:31]=[C:32]([CH:46]=[CH:47][C:48]=1[Cl:49])[CH2:33][N:34]([CH3:45])[C:35]([C:37]1[CH2:38]N(C)[C:40](=[O:43])[C:41]=1[OH:42])=[O:36]>>[Cl:29][C:30]1[CH:31]=[C:32]([CH:46]=[CH:47][C:48]=1[Cl:49])[CH2:33][N:34]([CH3:45])[C:35]([C:37]1[CH2:38][N:23]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C:40](=[O:43])[C:41]=1[OH:42])=[O:36]
Reactant: NCCC(=O)O
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCC(=O)O)C1
Yield: 25 %

Procedure:
3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and β-alanine as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as an amber solid (48.5 mg, 25% yield). Mp=183–184° C. 1H NMR (500 MHz, DMSO) δ: 12.34 (s, 2H), 10.79 (s, 1H), 7.61 (d, 1H, J=8.54), 7.51 (s, 1H), 7.24 (bs, 1H), 4.57 (s, 2H), 4.06 (s, 2H), 3.58 (t, 2H, J=6.40), 2.96 (bs, 3H), 2.54 (t, 2H, J=7.02). HRMS (M−H) calcd for C16H15N2Cl2O5: 385.0358. found: 385.0364.
Reaction SMILES: O.[OH-].[Li+].[CH:4]1([N:8]([CH2:20][C@@H:21]2[C@@H:28]3[C@@H:24]([O:25][C:26]([CH3:30])([CH3:29])[O:27]3)[C@H:23]([N:31]3[C:35]4[N:36]=[CH:37][N:38]=[C:39]([NH:40][CH2:41][C:42]5[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][C:43]=5[O:50][CH3:51])[C:34]=4[CH:33]=[CH:32]3)[CH2:22]2)[CH:9]2[CH2:12][CH:11]([CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[CH2:10]2)[CH2:7][CH2:6][CH2:5]1.O1CCCC1.CO.Cl>>[CH:4]1([N:8]([CH2:20][C@@H:21]2[C@@H:28]3[C@@H:24]([O:25][C:26]([CH3:29])([CH3:30])[O:27]3)[C@H:23]([N:31]3[C:35]4[N:36]=[CH:37][N:38]=[C:39]([NH:40][CH2:41][C:42]5[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][C:43]=5[O:50][CH3:51])[C:34]=4[CH:33]=[CH:32]3)[CH2:22]2)[CH:9]2[CH2:10][CH:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:12]2)[CH2:7][CH2:6][CH2:5]1
Reactant: CCOC(=O)CCC1CC(N(C[C@H]2C[C@@H](n3ccc4c(NCc5ccc(OC)cc5OC)ncnc43)[C@@H]3OC(C)(C)O[C@H]23)C2CCC2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C3CCC3)C3CC(CCC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium hydroxide monohydrate (0.58 g, 14 mmol) added to a solution of ethyl 3-(3-(cyclobutyl(((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)amino)cyclobutyl)propanoate (0.91 g, 1.4 mmol) in Tetrahydrofuran (12 ml, 150 mmol) and Methanol (3 ml, 60 mmol). The reaction mixture was stirred overnight at RT, upon which it was acidified with 1 N HCl to pH=6. The volatiles were removed in vacuo and the remaining water removed by azeotropic distillation with ethanol followed by 18 hours on lyophilizer. The resulting off white solid was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:29][O:30][C:31](=[O:49])[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][NH:39][C:40](N2C=CN=C2)=[O:41])=[CH:34][C:33]=1[O:47][CH3:48]>C(Cl)Cl>[CH3:29][O:30][C:31](=[O:49])[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][NH:39][C:40]([N:9]2[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C@@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:41])=[CH:34][C:33]=1[O:47][CH3:48]
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)c1ccc(CNC(=O)n2ccnc2)cc1OC
Solvent: ClCCl
Product: COC(=O)c1ccc(CNC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.8 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (49.2 mg, 0.116 mmol) and 4-{[(imidazole-1-carbonyl)-amino]-methyl}-2-methoxy-benzoic acid methyl ester (224.3 mg, 0.775 mmol) in CH2Cl2 (8 mL) was stirred rt for 16 hrs. The reaction mixture was then purified by flash column to give rac-4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-methyl)-2-methoxy-benzoic acid methyl ester (61.9 mg, 82.8%). HRMS (ES+) m/z Calcd for C33H33Cl2F2N3O4: 644.1889; Found: 644.1888
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH2:7])[N:3]=1.[CH:8]1[C:21]2[CH:20]([C:22](Cl)=[O:23])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[O:13][C:12]=2[CH:11]=[CH:10][CH:9]=1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([NH:7][C:22]([CH:20]2[C:21]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[O:13][C:14]3[C:19]2=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:23])[N:3]=1
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Reactant: Cc1nc(N)no1
Product: Cc1nc(NC(=O)C2c3ccccc3Oc3ccccc32)no1

Procedure:
The title compound, white solid, m.p. 186° C. and MS: m/e=307 (M+) was prepared in accordance with the general method of example 44a from 5-methyl-[1,2,4]oxadiazol-3-ylamine and 9H-xanthene-carboxylic acid chloride.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:9]([CH3:12])([O-:11])=[O:10].[OH-].[Na+].Cl>CO>[C:2]1([CH:1]=[CH:12][N+:9]([O-:11])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=[N+]([O-])C=Cc1ccccc1
Temperature: -18 °C
Reaction time: 2 h
Yield: 36.7 %

Procedure:
Benzaldehyde (10.0 g, 94.2 mmol) and nitromethane (5.1 mL, 94.2 mmol) were dissolved in MeOH, the solution was cooled to -18° C., and NaOH (3.9 g, 98.9 mmol) in aqueous solution (80 mL) was added while maintaining the temperature below -10° C. The mixture was stirred at 0° C. for 2 hours, then stored at 5° C. overnight. The solution was then poured into stirring acid (200 mL conc. HCl/300 mL H2O). The precipitate was collected, washed, and recrystallized from EtOH to afford the title compound as light orange needles (5.15 g, 37%).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].CCN(C(C)C)C(C)C.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[CH2:1]([NH:3][CH:23]1[CH2:24][CH2:25][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:21][CH2:22]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 111.1 %

Procedure:
Ethylamine (10 mL, 1 M in THF, 10 mmol) and DIEA (2.3 mL, 13.4 mmol) were dissolved in 100 mL of 1,2-dichloroethane under nitrogen. A solution of 1-tert-butoxycarbonyl-4-piperidone (1.3 g, 6.7 mmol) in 100 mL of 1,2-dichloroethane was added, followed by sodium triacetoxyborohydride (4.2 g, 20 mmol). The mixture was stirred at rt under nitrogen for 14 h, then diluted with CH2Cl2. The solution was washed twice with each of 1 N NaOH and brine, dried over Na2So4 and concentrated to afford 1.7 g (97%) of the title compound.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:20])[NH:12][C:11]1=[O:21])(=O)=O.[C:22]1([C:28]2[CH2:29][CH2:30][NH:31][CH2:32][CH:33]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C(OCC)(=O)C.O>[C:22]1([C:28]2[CH2:33][CH2:32][N:31]([CH2:6][CH2:7][CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13](=[O:20])[NH:12][C:11]3=[O:21])[CH2:30][CH:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: CS(=O)(=O)OCCCCn1c(=O)[nH]c(=O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1[nH]c(=O)n(CCCCN2CC=C(c3ccccc3)CC2)c2ccccc12
Yield: 30.4 %

Procedure:
A mixture of 1-(4-methanesulfonyloxybutyl)-2,4(1H,3H)-quinazolinedione (312 mg), 4-phenyl-1,2,3,6-tetrahydropyridine (200 mg) and triethylamine (303 mg) was refluxed for 1.5 hours. The reaction mixture was poured into ethyl acetate-water, extracted with ethyl acetate. Combined organic extract was washed in turn with water and brine, dried over magnesium sulfate, and evaporated. The crude residue was washed with hot methanol to give 1-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-2,4(1H,3H)-quinazolinedione (114 mg) as a powder.