Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCCCC.C([Li])CCC.[C:12]1(=[O:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CCOCC.[Cl-].[Na+].O.CCCCCC.C1C=CC=CC=1>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][CH:13]1[CH2:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]1=[O:21])[CH3:28]
Reactant: CCOC(=O)CBr
Reactant: O=C1CCc2ccccc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCCCCC
Solvent: O
Product: CCOC(=O)CC1Cc2ccccc2C1=O

Procedure:
A hexane solution containing 0.41 mole of butyllithium is diluted with 1 l. of dry ether. A solution of 1-indanone (50.3 g, 0.38 mole) in 500 ml of dry ether is added dropwise at -10° C with stirring. After the addition is completed, the reaction mixture is stirred for 30 min. A solution of ethyl bromoacetate (63 g) in ether (100 ml) is added slowly from a dropping funnel. The reaction is stopped immediately by careful addition of saturated brine solution. The organic layer is separated and washed several times with fresh portions of the same brine solution. Removal of the ether gives a viscous product which is subjected to chromatography on silica gel using hexane and hexane-benzene (1:1) as eluting solvents. A homogeneous fraction is identified by spectral features. The title compound is more polar than 1-indanone on tlc plate (silica-chloroform), Rf values being 0.65 and 0.55 respectively, νmaxCHCl3 broad peaks at 1765 and 1725 cm-1 , 1640, 1615, 1505 and 1495 cm-1.
Reaction SMILES: C(C1C=C(NC(=O)CCCC2C=CC([B:25]([OH:27])[OH:26])=CC=2)C=CC=1S(CC)(=O)=O)#N.[C:29]([C:31]1[CH:32]=[C:33]([NH:42][C:43](=[O:56])[O:44][CH2:45][CH2:46][C:47]2[C:52]([CH3:53])=[CH:51][C:50](Br)=[CH:49][C:48]=2[CH3:55])[CH:34]=[CH:35][C:36]=1[S:37]([CH2:40][CH3:41])(=[O:39])=[O:38])#[N:30]>>[C:29]([C:31]1[CH:32]=[C:33]([NH:42][C:43]([O:44][CH2:45][CH2:46][C:47]2[C:52]([CH3:53])=[CH:51][C:50]([B:25]([OH:27])[OH:26])=[CH:49][C:48]=2[CH3:55])=[O:56])[CH:34]=[CH:35][C:36]=1[S:37]([CH2:40][CH3:41])(=[O:39])=[O:38])#[N:30]
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Reactant: CCS(=O)(=O)c1ccc(NC(=O)OCCc2c(C)cc(Br)cc2C)cc1C#N
Product: CCS(=O)(=O)c1ccc(NC(=O)OCCc2c(C)cc(B(O)O)cc2C)cc1C#N
Yield: 54 %

Procedure:
Using a procedure analogous to that used to prepare 6D, 32C (480 mg, 1.0 mmol) was reacted with 5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 32D (240 mg, 54%) as a tan solid. MS (ESI) m/z 453.12 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[C:4]([C:6]1[C:7]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:8]=2[O:9][C:10]=1[CH3:11])=[O:5]>O1CCCC1>[Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[CH:4]([OH:5])[C:6]1[C:7]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:8]=2[O:9][C:10]=1[CH3:11]
Reactant: COC(=O)c1ccc2oc(C)c(C(=O)c3ccc(Cl)cc3Cl)c2c1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2oc(C)c(C(O)c3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
3-(2,4-Dichlorobenzoyl)-5-(methoxycarbonyl)-2-methylbenzo[b]furan (0.84 g, 2.31 mmol) was dissolved in tetrahydrofuran (20 ml) and a solution (1.0 M, 5 ml, 5 mmol) of a borane-tetrahydrofuran complex in tetrahydrofuran was added. The mixture was stirred at room temperature for 30 min and then at 50° C. for 2 hr. The reaction mixture was concentrated under reduced pressure and a saturated aqueous ammonium chloride solution was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure to give the objective compound (0.8 g) as a colorless oil. This crude product was used in the next reaction as it was.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([N:11]=[C:12]=[O:13])([CH3:10])[CH3:9])[CH:3]=1.[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C:12](=[O:13])[O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH3:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccccc1
Reactant: CC(C)(N=C=O)c1cccc(Br)c1
Solvent: c1ccncc1
Product: CC(C)(NC(=O)OCc1ccccc1)c1cccc(Br)c1
Temperature: 100 °C

Procedure:
To solution of A6.1c (11 g, 0.045 mol) in dichloromethane (110 ml) was added triethylamine (5.85 g, 0.057 mol) and cooled to 0° C. under N2. Ethylchloroformate (5.65 g, 0.05 mol) was added drop wise and stirred at 0° C. for 1 h. Sodium azide (3.24 g, 0.049 mol) was added and the mixture was stirred at RT over night. Reaction mixture was filtered to remove triethylamine-hydrochloride salt. The organic layer was concentrated to provide 1-azido-2-(3-bromophenyl)-2-methylpropan-1-one which was dissolved in toluene (60 mL) and heated to 100° C. for 30 min. The toluene was removed under vacuum to provide 1-bromo-3-(2-isocyanatopropan-2-yl)benzene. A mixture of 1-bromo-3-(2-isocyanatopropan-2-yl)benzene, pyridine (30 ml) and benzyl alcohol (12.2 g, 0.113 mol) was heated to 100° C. for 2 h under nitrogen. The reaction mixture was cooled to RT, quenched with 1.5 N HCl and extracted with ethyl acetate (3×50 ml). The combined organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated. Product was purified by column chromatography to give 7 g (45%) of A6.1d. 1H NMR (300 MHz, CDCl3) 1.65 (s, 6H), 5.03 (s, 2H), 5.1 (bs, 1H), 7.2 (dd, 1H), 7.35 (m, 6H), 7.54 (s, 1H). LCMS (M−H)+=350.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:16])=[CH:4][C:5]([O:14][CH3:15])=[C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([OH:12])=O)[CH:7]=1.[N:17]1([CH:23]2[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24]2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C>[Br:1][C:2]1[C:3]([Cl:16])=[CH:4][C:5]([O:14][CH3:15])=[C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([N:20]2[CH2:21][CH2:22][N:17]([CH:23]3[CH2:24][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26]3)[CH2:18][CH2:19]2)=[O:12])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCNCC2)C1
Reactant: COc1cc(Cl)c(Br)cc1N[C@@H](C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(Br)cc1N[C@@H](C)C(=O)N1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.8 %

Procedure:
To a solution of (S)-2-(5-bromo-4-chloro-2-methoxyphenylamino)propanoic acid (1.6 g, 5.21 mmol), tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (1.88 g, 7.82 mmol), EDCI.HCl (2.0 g, 10.42 mmol), HOBt (1.41 g, 10.42 mmol) in DMF (20 mL) at 0° C., Et3N (1.58 g, 15.63 mmol) was added. The resulting mixture was stirred at RT for 16 h and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (methanol/dichloroethane=1:50) to afford the desired product (2.1 g, 76% yield). ESI-MS m/z: 531.3[M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([F:26])([F:25])[F:24])[C:12]1=[O:27])[C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]([CH3:29])([CH3:28])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([F:26])([F:25])[F:24])[C:12]1=[O:27])[C:4]([OH:6])=[O:5]
Reactant: CC(C)(C)OC(=O)[C@@H](N1CCN(Cc2ccccc2C(F)(F)F)C1=O)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[C@@H](C(=O)O)N1CCN(Cc2ccccc2C(F)(F)F)C1=O
Yield: 73 %

Procedure:
A solution of Example 138B in dichloromethane (1.5 mL) was treated with trifluoroacetic acid (1.5 mL) at 25° C. for 16 h. The solvents were evaporated, and the crude residue was purified using reverse phase chromatography eluting with a gradient of 95% water (0.1% trifluoroacetic acid)/5% acetonitrile to 100% acetonitrile to give the title compound (0.121 g, 73%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].ClCCl.C([O-])(O)=O.[Na+].Cl.[CH2:23]([O:30][NH2:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O.O1CCCC1>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:31][O:30][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:11])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Reactant: NOCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C(=O)NOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
To a suspension of 4-(acetyloxy)benzoic acid (17) (10.0 g, 55.5 mmol) in dichloromethane (200 ml) oxalyl chloride (15 ml, 172 mmol) and dimethylformamide (0.1 ml) were added. The reaction mixture was stirred at ambient temperature for 30 minutes and at reflux temperature for 1 hour. The volatiles were evaporated in vacuo, the residue was dissolved in benzene (100 ml) and the solvent was evaporated again. The procedure was repeated several times until the poignant smell disappeared after drying in vacuo. The viscous oil was dissolved in tetrahydrofuran (100 ml) and this solution slowly over 10 minutes was added to a prearranged mixture consisting of saturated NaHCO3 solution (100 ml), solid NaHCO3 (11 g), O-benzylhydroxylamine hydrochloride (9.90 g, 62 mmol), and tetrahydrofuran (150 ml). The resulting mixture was stirred at ambient temperature for 1 hour and the volume of the reaction mixture was decreased ca. twice by evaporating the mixture on vacuum rotary evaporator. The residue was extracted with ethyl acetate (3×100 ml), the combined organic extracts were successively washed with 2N HCl (100 ml), water (100 ml), brine (100 ml), and dried (Na2SO4). The solvents were evaporated and the residue was crystallized from toluene to give the title compound (14.275 g, 90%) as white crystals, m.p. 120-122° C. 1H NMR (CDCl3, HMDSO) δ: 2.30 (3H, s); 5.02 (2H, s); 7.14 (2H, d, J=8.6 Hz); 7.26-7.54 (5H, m); 7.69 (2H, d, J=8.6 Hz); 8.56 (1H, br s).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][S:40]([CH2:43][CH2:44][NH2:45])(=[O:42])=[O:41].O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:26])[F:27])=[N:20][C:21]([C:22](=[O:23])[NH:45][CH2:44][CH2:43][S:40]([CH3:39])(=[O:42])=[O:41])=[C:15]2[CH2:14]1)=[O:12])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: CS(=O)(=O)CCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)NCCS(C)(=O)=O)c2C1)Cc1cc(F)c(F)cc1F
Yield: 33.9 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.15 g, 0.27 mmol), 2-methanesulfonyl-ethylamine (65.5 mg, 0.41 mmol) and bis (2-oxo-3-oxazolidinyl)phosphonic chloride (0.104 g, 0.41 mmol) were dissolved in 5 mL of dichloromethane under stirring, and triethylamine (0.25 mL, 1.62 mmol) was then added to the solution. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-[1-(2-methanesulfonyl-ethylcarbamoyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 2b (60 mg, yield 34%) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3](=O)[C:4](=[O:18])[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)(=O)C([O-])=O>C(OCC)C.C(#N)C>[CH3:1][N:2]([CH3:20])[CH2:3][CH:4]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:6]=1)[OH:18]
Reactant: CN(C)C(=O)C(=O)C1=CC2(CCCC2)c2ccccc21
Agent: O=C([O-])C(=O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: CC#N
Product: CN(C)CC(O)C1=CC2(CCCC2)c2ccccc21

Procedure:
The oxoamide from step (a) (2.69) in anhydrous diethyl ether (200 ml) is stirred for 24 hours at about 20° C. with lithium aluminium hydride (2 g) in diethyl ether (100 ml). The excess of hydride is destroyed with saturated aqueous sodium sulphate solution. The ether phase is separated, washed, dried and concentrated to an oil which contains 2-dimethylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol contaminated by much of the corresponding indanyl analogue. The two compounds are separated by chromatography on aluminium oxide with diethyl ether/methanol as eluent. The product so obtained is converted into the hydrogen oxalate of the title compound in acetonitrile solution. M.p. 133°-134° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[C:8](=[NH:15])(OC)[CH2:9][CH2:10][CH2:11][CH3:12]>CO.O.C1(C)C=CC=CC=1>[C:8]([NH:1][CH2:2][C:3]([OH:5])=[O:4])(=[NH:15])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: NCC(=O)O
Reactant: CCCCC(=N)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCCC(=N)NCC(=O)O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A stirred suspension of glycine (18.77 g, 0.25 mol) in methanol (80 ml) and water (4.5 ml) was cooled to 0° C. and adjusted to pH 9.6 by adding 30 percent strength sodium hydroxide solution. Methyl pentanimidate (68.81 g of a 42 percent strength solution in toluene=0.25 mol) was added to this suspension over the course of 5 minutes. After stirring for 18 hours at room temperature, the suspension was filtered, and the filter cake was washed with toluene (75 ml) and dried. The yield of the title compound was 25.45 g (purity>95 percent by H-NMR), 64 percent based on glycine. Other data concerning the title compound was:
Reaction SMILES: [CH3:1][CH:2]([C:13]1[CH:32]=[CH:31][C:16]2[N:17]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][C:21](=[O:30])[N:20]=[C:18]3[S:19][C:15]=2[CH:14]=1)[C:3]([O:5][C:6]1([CH3:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4].NC1S[C:36]2[CH:42]=C(C(C)C(OC34CC5CC(CC(C5)C3)C4)=O)C=C[C:37]=2N=1>>[CH3:1][CH:2]([C:13]1[CH:32]=[CH:31][C:16]2[N:17]3[C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][C:21](=[O:30])[N:20]=[C:18]3[S:19][C:15]=2[CH:14]=1)[C:3]([O:5][C:6]12[CH2:12][CH:36]3[CH2:42][CH:8]([CH2:9][CH:10]([CH2:37]3)[CH2:11]1)[CH2:7]2)=[O:4]
Reactant: CC(C(=O)OC1(C)CCCCC1)c1ccc2c(c1)sc1nc(=O)cc(-c3ccccc3)n12
Reactant: CC(C(=O)OC12CC3CC(CC(C3)C1)C2)c1ccc2nc(N)sc2c1
Product: CC(C(=O)OC12CC3CC(CC(C3)C1)C2)c1ccc2c(c1)sc1nc(=O)cc(-c3ccccc3)n12
Temperature: 160 °C
Yield: 39 %

Procedure:
Using a method similar to that used in the preparation of 1-methylcyclohexyl α-methyl-2-oxo-4-phenyl-2H-pyrimido[2,1-b]benzothiazole-8-acetate, 8.9 g of 1-adamantyl 2-amino-α-methylbenzothiazole-6-acetate were reacted with heating at 160° C. for 1 hour to obtain 4.73 g (39% yield) of 1-adamantyl α-methyl-2-oxo-4-phenyl-2H-pyrimido[2,1-b]benzothiazole-8-acetate as a yellow solid after crystallization from ethyl acetate/petroleum ether melting at 188°-190° C.
Reaction SMILES: [CH3:1][Mg]Br.[CH:4]([C:6]1[N:10]([CH3:11])[CH:9]=[N:8][CH:7]=1)=[O:5].O>C(OCC)C.C1COCC1>[OH:5][CH:4]([C:6]1[N:10]([CH3:11])[CH:9]=[N:8][CH:7]=1)[CH3:1]
Reactant: Cn1cncc1C=O
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(O)c1cncn1C
Temperature: -20 °C
Yield: 88 %

Procedure:
Methyl magnesium bromide (100 ml of a 3M solution in diethyl ether, 0.30 mol) was added dropwise to a solution of 5-formyl-1-methylimidazole (14.5 g, 0.13 mol) in THF (750 ml) cooled to −20° C. such that the reaction temperature was kept below 3° C. The mixture was allowed to warm to ambient temperature and water (150 ml) was carefully added. The aqueous mixture was continuously extracted with EtOAc. The EtOAc extract was dried, and the volatiles removed by evaporation to give the title compound 14.4 g, (88%) as a solid product. NMR: 1.41 (d, 3H), 4.65-4.77 (m, 1H), 4.96-5.11 (m, 1H), 6.72 (s, 1H), 7.47 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:22][CH3:23])[C:12]1[N:17]=[C:16]([CH:18]([OH:20])[CH3:19])[CH:15]=[C:14]([CH3:21])[N:13]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:9])[CH3:10])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:22][CH3:23])[C:12]1[N:17]=[C:16]([CH:18]([O:20][S:32]([CH3:31])(=[O:34])=[O:33])[CH3:19])[CH:15]=[C:14]([CH3:21])[N:13]=1
Reactant: CCN(c1nc(C)cc(C(C)O)n1)c1ccc(C(C)C)cc1Br
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(c1nc(C)cc(C(C)OS(C)(=O)=O)n1)c1ccc(C(C)C)cc1Br
Temperature: 0 °C
Yield: 81.2 %

Procedure:
A mixture of N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(1-hydroxyethyl)-6-methylpyrimidinamine (1.1 g, 2.7 mmol), triethylamine (1.5 mL, 11 mmol) and dichloromethane (15 mL) was stirred at 0° C. under a nitrogen atmosphere. Methanesulfonylchloride (364 mg, 3.2 mmol) was added dropwise and the reaction mixture was then stirred for 1.5 h. The resulting turbid solution was washed successively with an ice-cold 1 N HCl solution, a saturated NaHCO3 solution and a saturated NaCl solution. Drying over MgSO4, filtration and removal of solvent in vacuo gave N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(1-methanesulfonyloxyethyl)-6-methylpyrimidinamine as a clear colorless oil (1.0 g): NMR (CDCl3, 300 MHz): 7.5 (d, 1H, J=1), 7.25-7.1 (m, 2H), 6.55 (s, 1H), 4.3-4.05 (m, 1H), 3.85-3.6 (m, 1H), 3.0-2.5 (m, 4H), 2.5-2.05 (br m, 3H), 1.3 (d, 6H, J=8), 1.2 (t, 3H, J=8); CI-MS, 456, 458 (M+H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[C:36]4[CH:43]([CH3:44])[CH2:42][CH2:41][C:37]=4[N:38]=[CH:39][N:40]=3)=[CH:31][CH:30]=2)[CH2:16][N:17]([CH:25]([CH3:27])[CH3:26])C(=O)OC(C)(C)C)=[CH:11][CH:10]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[C:36]4[CH:43]([CH3:44])[CH2:42][CH2:41][C:37]=4[N:38]=[CH:39][N:40]=3)=[CH:31][CH:30]=2)[CH2:16][NH:17][CH:25]([CH3:27])[CH3:26])=[CH:11][CH:10]=1.[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4]
Reactant: CC1CCc2ncnc(-c3ccc(O[C@@H](CN(C(=O)OC(C)(C)C)C(C)C)c4ccc(Cl)cc4)cc3)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)NC[C@H](Oc1ccc(-c2ncnc3c2C(C)CC3)cc1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of (R)-tert-butyl 2-(4-chlorophenyl)-2-(4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenoxy)ethyl(isopropyl)carbamate (26 mg, 0.0498 mmol) in methylene chloride (1.0 mL) at 0° C. The mixture was stirred at 0° C. for 10 minutes and then at room temperature for 2 hours. The contents were concentrated. The resulting residue was purified by reverse-phase HPLC to give (R)-N-(2-(4-chlorophenyl)-2-(4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenoxy)ethyl)propan-2-amine as TFA salt (7.5 mg, 23%). 1H NMR (d6-DMSO, 500 MHz) δ□(ppm): 8.9 (s, 1H), 8.7 (s, br, 2H), 7.8 (t, 2H), 7.5 (m, 4H), 7.1 (d, 2H), 5.7 (d, 1H), 3.8 (m, 1H), 3.4-3.5 (m, 2H), 3.3-3.4 (m, 1H), 3.0-3.1 (m, 1H), 2.9 (m, 1H), 2.3 (m, 1H), 1.7 (m, 1H), 1.3 (dd, 6H), 0.9 (dd, 3H). MS (422.3, M+1).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[NH:10][C@@H:11]([CH3:29])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C@@H:26]3C[O:27]3)[C:20]=2C=O)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C([C:38](OO)=[O:39])C=1.CC(C)=O.ClCCl>ClCCl>[CH2:1]([O:8][C:9](=[O:30])[NH:10][C@@H:11]([CH3:29])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][CH2:25][C@@H:26]([CH2:38][OH:39])[O:27][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](Cn1ncc2ccc(OC[C@@H]3CO3)c(C=O)c21)NC(=O)OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CC(C)=O
Product: C[C@@H](Cn1ncc2ccc3c(c21)O[C@H](CO)CO3)NC(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 59.9 %

Procedure:
To a stirred solution of the epoxide from Step A (0.86 g, 2.10 mmol) in dichloromethane (100 mL) was added m-chloroperbenzoic acid (70%, 0.62 g, 2.52 mmol) in portions under nitrogen atmosphere. After the addition completed the reaction mixture was stirred overnight. The reaction was quenched by a saturated aqueous solution of sodium thiosulfate (20 mL) and dichloromethane was evaporated. To the aqueous residue was added potassium carbonate (1.0 g) and methanol (200 mL), the resulting mixture was stirred for ½ h and organic solvent was evaporated. The residue was extracted with ethyl acetate (50 mL×3), dried and evaporated to dryness to afford an oil. Chromatography on silica eluting with a gradient of 0% to 10% acetone/dichloromethane gave an oil (0.50 g, 60%). LCMS (+APCI) m/z 397 (M+H), 1H NMR (600 MHz, CDCl3) δ 7.82 (s, 1H), 7.33-7.13 (m, 5H), 7.14 (d, J=8.4 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 5.04-4.97 (m, 3H), 4.65 (ddd, J=6.6, 13.4, 51.6 Hz, 2H), 4.32 (m, 3H), 4.08 (m, 2H), 3.91 (m, 2H), 1.18(d, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:33])=[C:10]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([C:23]4[CH:28]=[CH:27][C:26]([NH:29]C(=O)C)=[CH:25][CH:24]=4)(=[O:22])=[O:21])[CH2:16][CH2:15]3)[C:11]=2[F:13])[C:6](=[O:34])[C:5]([C:35]([OH:37])=[O:36])=[CH:4]1)[CH3:2].Cl>C(O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:33])=[C:10]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([C:23]4[CH:24]=[CH:25][C:26]([NH2:29])=[CH:27][CH:28]=4)(=[O:22])=[O:21])[CH2:16][CH2:15]3)[C:11]=2[F:13])[C:6](=[O:34])[C:5]([C:35]([OH:37])=[O:36])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(S(=O)(=O)c4ccc(NC(C)=O)cc4)CC3)c(F)c21
Agent: Cl
Solvent: CCO
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(S(=O)(=O)c4ccc(N)cc4)CC3)c(F)c21

Procedure:
A mixture of 2.15 g of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-[4-(4-acetamidobenzenesulfonyl)-1-piperazinyl]-3-quinolinecarboxylic acid obtained in Example 1, 100 ml of 2N hydrochloric acid and 50 ml of ethanol is refluxed for 2 hours while stirring. The reaction mixture is then concentrated under reduced pressure. To the residue is added 1N sodium hydroxide solution to dissolve. The pH of the solution is adjusted to 7.0 with acetic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16](N(CC)CC)[CH3:17].C(OC(ON=C(C#N)C(N)=O)=O)C>C(OCC)(=O)C.O1CCCC1>[CH2:16]([O:14][C:13](=[O:15])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:17]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CCN(CC)CC
Agent: CCOC(=O)ON=C(C#N)C(N)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CNC(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of N-benzyloxycarbonylglycine (1.05 g) and triethylamine (0.73 ml) in ethyl acetate (10 ml) and tetrahydrofuran (10 ml), 2-ethoxycarbonyloxyimino-2-cyanoacetic acid amide (1.11 g) is added, and the resulting mixture is stirred for 2 hours. The reaction mixture is treated as in Example A to give N-benzyloxycarbonylglycine ethyl ester (1.2 g) as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([NH2:13])[CH3:12].O>C1COCC1>[CH2:11]([NH:13][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:12]
Reactant: CCN
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: C1CCOC1
Solvent: O
Product: CCNc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-3-nitropyridine (51 g, 325 mmol) in THF (650 mL) was added a 2 M solution of ethylamine in THF (365 mL, 731 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was poured into water (˜1.5 L) and the resulting solid was filtered and dried under reduced pressure to give the title compound (52 g).