Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:14][Mg]Br>C1COCC1.O>[F:1][C:2]1[C:7]([C:8]2[CH2:12][CH2:11][C:10]([CH3:14])([OH:13])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C[Mg]Br
Reactant: O=C1C=C(c2cccnc2F)CC1
Solvent: O
Solvent: C1CCOC1
Product: CC1(O)C=C(c2cccnc2F)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(2-fluoropyridin-3-yl)cyclopent-2-enone (1 g, 5.64 mmol) in THF (28.2 mL) was added methylmagnesium bromide (4.70 mL, 14.11 mmol) dropwise over 5 minutes. The dark brown solution was stirred for 3 h at room temperature before. slowly quenching with aqueous ammonium chloride. The crude reaction was diluted with water and extracted with ethyl acetate, drying over magnesium sulfate, filtering, and concentrating to a dark brown oil under reduced pressure. The crude compound was purified by column chromatography (ethyl acetate/dichloromethane) to afford 3-(2-fluoropyridin-3-yl)-1-methylcyclopent-2-enol as a clear oil. MS (ESI, pos. ion) m/z: 194.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([N:13]1[CH2:20][CH:19]2[CH:15]([CH2:16][NH:17][CH2:18]2)[CH2:14]1)=[O:12].Cl[C:22]1[N:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][N:23]=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([N:13]1[CH2:20][CH:19]2[CH:15]([CH2:16][N:17]([C:22]3[N:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][N:23]=3)[CH2:18]2)[CH2:14]1)=[O:12]
Reactant: COc1ccc(C(=O)N2CC3CNCC3C2)c(OC)c1
Reactant: COc1ccnc(Cl)n1
Product: COc1ccc(C(=O)N2CC3CN(c4nccc(OC)n4)CC3C2)c(OC)c1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 38 and 2-chloro-4-methoxypyrimidine. MS (ESI): mass calculated for C20H24N4O4, 384.43; m/z found 385.2 [M+H]+.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][O:25][C:26]([C:28]1[C:37]2[O:36][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[C:34]([CH3:44])[C:33](=[O:45])[C:32]=2[CH:31]=[CH:30][CH:29]=1)=[O:27].O>CN(C)C=O>[ClH:2].[ClH:1].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:22][CH2:23][CH2:24][O:25][C:26]([C:28]2[C:37]3[O:36][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[C:34]([CH3:44])[C:33](=[O:45])[C:32]=3[CH:31]=[CH:30][CH:29]=2)=[O:27])[CH2:11][CH2:10]1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)OCCCBr)cccc2c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2ccccc2)oc2c(C(=O)OCCCN3CCN(c4ccccc4Cl)CC3)cccc2c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2.8 g of 1-(2-chlorophenyl)-piperazine hydrochloride and 4.2 g of anhydrous potassium carbonate in 25 ml of dimethylformamide was stirred at ambient temperature for 15 minutes. 4.81 g of Intermediate I was added, and stirring was continued for 2 days. The reaction mixture was then poured into 200 ml of cold water, and extracted with diethyl ether and ethyl acetate. The organic extracts were washed in turn with aqueous sodium chloride solution, 0.1N aqueous acetic acid solution, aqueous sodium chloride solution, aqueous 4% sodium carbonate solution and water, and were then dried on anhydrous sodium sulfate. After evaporation to dryness in vacuo, the residue was dissolved in 160 ml of acetonitrile and excess hydrogen chloride in diethyl ether was added. The insoluble title compound was recrystallized from acetonitrile. Yield 3.6 g, m.p. 138°-143° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O:24]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20]I)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[CH3:43][N:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1>C(OCC)(=O)C.C(OC(C)C)(C)C>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O-:24])=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20][N+:44]4([CH3:43])[CH2:48][CH2:47][CH2:46][CH2:45]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCI)CS[C@H]12)c1nsc(N)n1
Reactant: CN1CCCC1
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C=CC[N+]3(C)CCCC3)CS[C@H]12)c1nsc(N)n1
Reaction time: 1 h
Yield: 12.2 %

Procedure:
To a solution of diphenylmethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(3-iodo-1-propen-1-yl)-3-cephem-4-carboxylate (IX-1) (Z/E=2/1, 150 mg, 0.21 mmole) in ethyl acetate (2 ml) was added a solution of 1-methylpyrrolidine (36 mg, 0.42 mmole) in ethyl acetate (1 ml) in one portion with stirring. The mixture was stirred for 15 minutes and diluted with isopropyl ether (10 ml) to form a precipitate, which was collected by filtration. A mixture of the solid (130 mg), formic acid (1 ml) and concentrated HCl (0.1 ml) was stirred at room temperature. After 1 hour, the reaction mixture was concentrated under reduced pressure, diluted with water (20 ml) and filtered. The aqueous solution was passed through a reverse phase column (the packing of PrepPAK-500/C18 cartridge, 100 ml), eluting with water and 10% CH3OH. The desired fractions were collected, and concentrated in vacuo to a small volume and freeze-dried to give 13 mg (12%) of the title compound (I-1A) (Z/E=1/1), melting at >280° C. (dec.).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][NH:9][CH2:10][CH2:11][Br:12].Br.[P:14](Cl)([Cl:17])([Cl:16])=[O:15]>C(Cl)Cl>[CH3:8][N:9]([CH2:10][CH2:11][Br:12])[P:14]([Cl:17])([Cl:16])=[O:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CNCCBr
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCBr)P(=O)(Cl)Cl
Reaction time: 8 h
Yield: 93 %

Procedure:
Triethylamine (12.24 g, 121 mmol) was added dropwise to a stirred solution of N-methyl-N-bromoethylamine.HBr (12.04 g, 55 mmol) and phosphorus oxychloride (8.44 g, 55 mmol) in CH2Cl2 (100 ml) at 0° C. under N2. The mixture was allowed to stir overnight and then poured over ice. The layers were separated, and the aqueous layer was extracted with CH2Cl2 (3×100 ml). The organic layers were combined and dried (MgSO4). The filtrate was concentrated under reduced pressure and the residue purified by chromatography (1:4 EtOAc:hexanes) to give N-methyl-N-(2-bromoethyl)phosphoramidic dichloride as an oil (13 g, 93%): Rf 0.67 (1:4 EtOAc:hexanes); 1H NMR (CDCl3) 3.65(dt, 2H, J=14.10 Hz), 3.50(t, 2H, J=6.52 Hz), 2.93(d, 3H, J=15.46 Hz)ppm; 31P NMR (CDCl3) -6.57 ppm; IR (neat) 2980, 2940, 2880, 1740, 1450, 1370, 1340, 1280, 1250, 1210, 1105, 1050, 1005, 980, 975, 940, 915, 865, 755, 700 cm-1.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:8]([C:9]([OH:11])=O)=[N:7][CH:6]=[CH:5][N:4]=1.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH2:22][CH:23]([NH2:25])[CH3:24].Cl.C(N=C=NCCCN(C)C)C.O>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH2:22][CH:23]([NH:25][C:9]([C:8]1[C:3]([C:2]([F:1])([F:13])[F:12])=[N:4][CH:5]=[CH:6][N:7]=1)=[O:11])[CH3:24]
Reactant: CC(N)Cc1ccc(Cl)cc1Cl
Reactant: O=C(O)c1nccnc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(Cc1ccc(Cl)cc1Cl)NC(=O)c1nccnc1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 63.1 %

Procedure:
To a solution of 2-trifluoromethylpyrazine-3-carboxylic acid (0.25 g, 1.3 mmol), [2-(2,4-dichlorophenyl)-1-methylethyl]amine (0.27 g, 1.3 mmol) and 4-dimethylaminopyridine (0.19 g, 1.6 mmol) in chloroform (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.3 g, 1.6 mmol) and the mixture was stirred at room temperature for 12 hrs. After adding water and chloroform, the mixture was partitioned, and the organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give a desired compound (yield; 0.31 g, 63%).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH3:29])[CH:9]=[C:10]2[C:15]=1[N:14](C(OCC(C)C)=O)[CH:13]=[C:12]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:11]2=[O:28])(=O)C.BrN1C(=O)CCC1=O.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C(O)C>ClCCl>[CH:5]([C:6]1[CH:7]=[C:8]([CH2:29][N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[CH:9]=[C:10]2[C:15]=1[N:14]=[CH:13][C:12]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:11]2[OH:28])=[O:4]
Reactant: CCOC(=O)c1cn(C(=O)OCC(C)C)c2c(COC(C)=O)cc(C)cc2c1=O
Reactant: C1COCCN1
Agent: O=C1CCC(=O)N1Br
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1cnc2c(C=O)cc(CN3CCOCC3)cc2c1O
Reaction time: 0.17 h

Procedure:
A stirred solution of 3-ethyl 1-isobutyl 8-((acetyloxy)methyl)-6-methyl-4-oxo-1,3-(4H)-quinolinedicarboxylate (Preparation 26, 3.0 g) and N-bromosuccinimide (3.0 g) in dichloromethane (300 mL) is irradiated with a 650 watt sun lamp for 20 min. Morpholine (15 mL) is added to the solution. After 10 min, ethanol (20 mL) is added, and the solvents are removed at 50° C./20 mm. The reaction is repeated on the same scale. The reaction mixtures are combined and partitioned between chloroform (250 mL) and water (150 mL). The chloroform layer is washed twice with water, and the chloroform is evaporated. The residual oil is chromatographed on silica gel (1% methanol/chloroform) to give 2.15 g of the title compound. Physical characteristics: M.p. 202-204° C.; 1H NMR (CDCl3) δ1.43, 2.50, 3.69, 3.74, 4.42, 8.19, 8.59, 8.67, 10.18, 11.8. Anal. Found: C, 62.42; H, 5.92; N, 8.03.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH:8]([S:29][CH2:30][CH2:31][C:32]([O:34]C)=[O:33])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:4]([O:6]C)=[O:5].[OH-].[Na+]>CO>[CH3:1][O:2][CH:3]([CH:8]([S:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:4]([OH:6])=[O:5]
Reactant: COC(=O)CCSC(c1ccccc1CCCCCCCCc1ccccc1)C(OC)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(C(=O)O)C(SCCC(=O)O)c1ccccc1CCCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
A solution of methyl 2-methoxy-3-(2-carbomethoxyethylthio)-3-[2-(8-phenyloctyl)phenyl]propanoate (0.5807 g, 1.2 mmoles) in methanol (5 ml) under argon was cooled to 0° C., after which 10% sodium hydroxide (1.5 ml, 3.5 mmoles) was added. The mixture was permitted to warm to room temperature and stirred for 2 hours. The methanol was evaporated and the mixture diluted with water. The pH of the aqueous layer was adjusted to 2 with dilute hydrochloric acid and extracted with ether. The organic phase was dried over magnesium sulfate, filtered and evaporated. The diastereomeric mixture of products was separated on a silica column using 23% ethyl acetate in hexane plus 0.5% formic acid. Five runs were made and the fractions analyzed on an analytical column. The separation provided both diastereomers in greater than 99% purity. The erythro isomer was obtained in 28% yield and the threo isomer in 22%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9](OC(=O)C)=[CH2:10].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]=[CH2:10])=[CH:4][CH:3]=1
Reactant: C=COC(C)=O
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=COc1ccc(Br)cc1
Temperature: 100 °C
Yield: 73.6 %

Procedure:
To a mixture of 4-bromophenol (75 g, 433.5 mmol), acetic acid ethenyl ester (80.5 mL, 867.0 mmol) and sodium carbonate (27.6 g, 260.10 mmol) in toluene (430 mL) add di-mu-chlorobis((1,2,5,6-eta)-1,5-cyclooctadiene)diiridium (2.9 g, 4.34 mmol) and the heat the mixture at 100° C. for 2.5 hours. Cool the mixture to ambient temperature, dilute with ethyl acetate (EtOAc) (300 mL) and wash once with water (400 mL). Separate the organic portion and wash once with brine (250 mL). Dry the material over sodium sulfate, filter, and concentrate under reduced pressure. Purify the crude mixture by flash chromatography (0% to 5% EtOAc/Hex) to give the title compound (63.5 g, 74%): GCMS: 198.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:20]([O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O)[CH:21]=[CH2:22]>>[CH2:20]([O:23][C:24]1[CH:25]=[C:26]([CH2:27][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[CH:29]=[CH:30][CH:31]=1)[CH:21]=[CH2:22]
Reactant: C=CCOc1cccc(C=O)c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: C=CCOc1cccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-prop-2-enoxybenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(3-prop-2-enoxyphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].CC(C)([O-])C.[K+].C(S[C:18]1[N:23]2[CH:24]=[CH:25][N:26]=[C:22]2[CH:21]=[C:20]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)[N:19]=1)C>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:18]2[N:23]3[CH:24]=[CH:25][N:26]=[C:22]3[CH:21]=[C:20]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=3)[N:19]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(F)c1
Reactant: CCSc1nc(-c2ccc(OC)c(OC)c2)cc2nccn12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(-c2cc3nccn3c(Nc3cccc(F)c3)n2)cc1OC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To the solution of m-fluoroaniline (88.90 mg, 0.8 mmol) in 1.5 ml of dry DMSO was added, potassium tert-butoxide (94.26 mg, 0.84 mmol), and 5-ethylsulfenyl-7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidin (126.16 mg, 0.4 mmol). The resulting solution was stirred overnight and 3 ml of ice water was added. The produced precipitate was collected by filtration, and washed with water, 2-propanol, and ether to give crude product of (3-fluorophenyl)-[7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-yl]amine. The crude product was purified by preparative TLC to give the pure product (127.000 mg, 87.1%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:13][C@H:14]1[C:18]2[N:19]=[CH:20][N:21]=[C:22]([N:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)[C:17]=2[C@H:16]([CH3:36])[CH2:15]1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:36][C@H:16]1[C:17]2[C:22]([N:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:20]=[N:19][C:18]=2[C@H:14]([O:13][C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH2:15]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
4-Nitrobenzoyl chloride (4.27 g, 23.0 mmol) was added to a 0° C. solution of tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (7.0 g, 20.9 mmol) and triethylamine (4.38 ml, 31.4 mmol) in DCM (110 mL) The reaction mixture was stirred at room temperature overnight, after which saturated NaHCO3 was added. The mixture was stirred 10 minutes, and then extracted with DCM. The combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was flashed on Biotage 65M (3:1 hexanes:ethyl acetate loaded crude, then 2:1 hexanes:ethyl acetate eluted tert-butyl 4-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate and a few mixed fractions). Then tert-butyl 4-((5R,7S)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate was eluted using 1:2 hexanes:ethyl acetate. The fractions with product were concentrated by rotary evaporation to give tert-butyl 4-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (8.55 g, 84.5% yield) as a yellow foam. LC/MS (APCI+) m/z 484 [M+H]+. 1H NMR (CDCl3) shows single diastereomer). The fractions with other diastereomer were concentrated by rotary evaporation to give tert-butyl 4-((5R,7S)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.356 g, 3.52% yield) as a brown foam. LC/MS (APCI+) m/z 484 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]#[C:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[Br:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:9]2[CH2:8][CH2:7][C:6]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]#[C:32][CH2:33][N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[CH:25][CH:24]=3)(=[O:22])=[O:21])([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OCC#CCN3CCOCC3)cc2)CCN(Cc2ccc(Br)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1(S(=O)(=O)c2ccc(OCC#CCN3CCOCC3)cc2)CCN(Cc2ccc(Br)cc2)CC1

Procedure:
1-(4-Bromo-benzyl)-4-[4-(4-morpholin-4-yl-but-2-ynyloxy)-benzenesulfonyl]-piperidine-4-carboxylic acid was prepared starting from 1-(4-bromo-benzyl)-4-[4-(4-morpholin-4-yl-but-2-ynyloxy)-benzenesulfonyl]-piperidine-4-carboxylic acid ethyl ester (2.87 g, 4.6 mmol) dissolved in THF:methanol (3:1, 150 ml) and 10 N NaOH (10 ml). The resulting reaction mixture was worked up as outlined in Example 1 (Step 7). Yield 2.26 g (83%); white powder; mp 198° C.; MS: 593.1 (M+H)+.
Reaction SMILES: CO[C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([N:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([CH3:20])[CH3:19])[C:12]2=[O:35])[CH:5]=1.[CH:37]1([NH2:40])[CH2:39][CH2:38]1.C([Mg]Cl)(C)C>C1COCC1.[Cl-].[NH4+]>[CH2:28]([O:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]([NH:17][C:13]1[C:12](=[O:35])[N:11]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=2[Cl:10])[C:3]([NH:40][CH:37]2[CH2:39][CH2:38]2)=[O:36])[CH:16]=[CH:15][N:14]=1)([CH3:20])[CH3:19])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(Cl)c(-n2ccnc(NC(C)(C)c3ccccc3OCc3ccccc3)c2=O)c1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(Nc1nccn(-c2cc(C(=O)NC3CC3)ccc2Cl)c1=O)c1ccccc1OCc1ccccc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A solution of methyl-3-[3-({1-[2-(benzyloxy)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1(2H)-yl]-4-chlorobenzoate (Example 330f, 2.23 g) dissolved in THF (30 mL) was treated with cyclopropylamine (2.261 mL) and 2.0M Isopropylmagnesium chloride (11.06 mL) under nitrogen. The resulting solution was stirred at 20° C. for 2 h. The reaction mixture was diluted with aqueous ammonium chloride (150 mL), and extracted with dichloromethane (250 mL). The organic was dried (MgSO4), filtered and evaporated to afford the subtitle compound (2.40 g).
Reaction SMILES: [CH2:1]1[CH2:20][O:19][C:3]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)([CH2:4][CH2:5][CH2:6][C:7](=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[O:2]1.[C:21]([O:25][C:26](=[O:37])[C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[C:32](=[O:36])[C@H:33]([CH3:35])[NH2:34])([CH3:24])([CH3:23])[CH3:22].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[C:21]([O:25][C:26](=[O:37])[C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[C:32](=[O:36])[C@H:33]([CH3:35])[NH:34][CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][C:3]1([O:19][CH2:20][CH2:1][O:2]1)[C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)([CH3:23])([CH3:22])[CH3:24]
Reactant: CCOC(=O)C(=O)CCCC1(c2cccs2)OCCO1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(CCCC1(c2cccs2)OCCO1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
Ethyl 6,6-ethylenedioxy-2-oxo-6-(2-thienyl)-hexanoate (3 g.) and L-alanyl-L-proline t-butyl ester (2.5 g.) were added to a suspension of freshly activated 4 Å molecular sieve (15 g.) in ethanol (35 ml.) and the mixture was stirred at laboratory temperature for 1 hour. Acetic acid (1.25 ml.) was added, and sodium cyanoborohydride (0.625 g.) was then added in portions during 1 hour. The mixture was stirred at laboratory temperature for 48 hours and then filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was purified by flash chromatography on a silica gel column using a 40:1 v/v mixture of dichloromethane and methanol as eluant. There was thus obtained as an oil N-[1-ethoxycarbonyl-5,5-ethylenedioxy-5-(2-thienyl)pentyl]-L-alanyl-L-proline t-butyl ester.
Reaction SMILES: [BrH:1].[Br:2][C:3]([CH3:28])([CH3:27])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:20])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=[O:5].[Br-]>ClCCl>[Br:2][C:3]([CH3:28])([CH3:27])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([C:21]3([Br:1])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:20])=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)=[O:5]
Reactant: CC(C)(Br)C(=O)c1ccc(Oc2ccc(C(=O)C3CCCCC3)cc2)cc1
Reactant: Br
Agent: [Br-]
Solvent: ClCCl
Product: CC(C)(Br)C(=O)c1ccc(Oc2ccc(C(=O)C3(Br)CCCCC3)cc2)cc1
Reaction time: 3 h

Procedure:
A drop of 48% HBr was added to a solution of 2.7 g (6.29 mmol) of 2-bromo-1-[4-(4-cyclohexancarbonyl-phenoxy)-phenyl]-2-methyl-propan-1-one dissolved in 60 ml of dichloromethane; 0.322 ml (6.29 mmol) of bromide dissolved in 5 ml of dichloromethane were added drop wise, in 15′. After 3 h, the organic phase was washed with water and with a sodium metabisulphite solution, separated, dried on sodium sulphate and evaporated in vacuum obtaining 3.2 g of product as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[F:13][C:14]1[CH:26]=[CH:25][C:17]([CH2:18][NH:19][O:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:16][CH:15]=1>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:19]([CH2:18][C:17]2[CH:16]=[CH:15][C:14]([F:13])=[CH:26][CH:25]=2)[O:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CC(C)CONCc1ccc(F)cc1
Product: CC(C)CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 91 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(4-fluorobenzyl)-O-isobutyl-hydroxylamine as described in the preparation of Compound 44-C gave the title amide as white crystals (91% yield): mp 105–106° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 0.98 (3H, d, J=6.45 Hz, CH3), 1.77 (6H, s, CH3), 1.95 (1H, m, CH), 3.64 (2H, d, J=6.63 Hz, OCH2), 4.80 (2H, s, NCH2), 6.41 (1H, s, CH), 7.03 (2H, m, aromatics), 7.36 (2H, m, aromatics). Anal. calcd for C18H22FNO5: C, 61.53; H, 6.31; H, 3.98. Found: C, 61.47; H, 6.39; N, 3.97.