Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)[N:10]=[C:9]([N:22]3[CH:27]4[CH2:28][CH2:29][CH:23]3[CH2:24][O:25][CH2:26]4)[CH:8]=2)[CH2:3][CH2:2]1>ClCCl.CC(O)C.[Pd]>[CH:23]12[N:22]([C:9]3[CH:8]=[C:7]([CH:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[N:12]=[C:11]([C:13]4[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=4)[N:10]=3)[CH:27]([CH2:28][CH2:29]1)[CH2:26][O:25][CH2:24]2
Reactant: O=[N+]([O-])c1ccc(-c2nc(C3=CCOCC3)cc(N3C4CCC3COC4)n2)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CC(C)O
Product: Nc1ccc(-c2nc(C3CCOCC3)cc(N3C4CCC3COC4)n2)cc1
Reaction time: 72 h
Yield: 98.8 %

Procedure:
In a 250 mL round-bottomed flask was placed 8-(6-(3,6-dihydro-2H-pyran-4-yl)-2-(4-nitrophenyl)pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane (74, 353 mg, 0.895 mmol) in dichloromethane (10 mL) and 2-propanol (10 mL) to give a yellow solution. Pd—C (95 mg, 0.089 mmol) was added. The reaction mixture was stirred for 72 hours under an atmosphere of hydrogen. The reaction mixture was diluted with dichloromethane, filtered through Celite™ and washed with dichloromethane. The mixture was concentrated under reduced pressure to give 324 mg of a yellow solid. HRMS: 367.2130 [M+H+. For [M+H]+ mass error=0.3 mDa or 0.7 ppm.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[SH:16].C(N(CC)CC)C>O1CCCC1.CO>[Cl:8][C:7]1[C:2]([S:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH2:9])=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Nc1ccccc1S
Reactant: Clc1nccnc1Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: Nc1ccccc1Sc1nccnc1Cl

Procedure:
To a solution of 2,3-dichloropyrazine (7.45 g, 50 mmoles) and ortho-aminothiophenol (6.25 g, 50 mmoles) in tetrahydrofuran (50 ml) was added dropwise a solution of triethylamine (6 g) in THF (25 ml) over a period of 10 minutes. A cold water bath was used to control the modest exotherm and maintain the temperature below 20°. The triethylamine chloride was removed by filtration and the filtrate was evaporated to yield a solid that was slurried for 1 hour in methanol (75 ml). The solid thus obtained was recrystallized from methanol to yield the title compound, m.p. 130°-135° (dec.).
Reaction SMILES: [CH2:1]([SnH:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[F:14][C:15]([C:17]([O:25][Si:26]([CH3:29])([CH3:28])[CH3:27])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:18][C:19]#[CH:20])=[CH2:16].N(C(C)(C)C#N)=NC(C)(C)C#N>>[F:14][C:15]([C:17]([O:25][Si:26]([CH3:29])([CH3:27])[CH3:28])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:18]/[CH:19]=[CH:20]/[Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:1][CH2:2][CH2:3][CH3:4])=[CH2:16]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CCC(CCCC)(O[Si](C)(C)C)C(=C)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: C=C(F)C(C/C=C/[Sn](CCCC)(CCCC)CCCC)(CCCC)O[Si](C)(C)C
Temperature: 140 °C

Procedure:
A mixture of 21.4 ml. of tributylstannane, 18.3 g. of 4-(1'-fluorovinyl)-4-trimethylsilyloxy-1-octyne and azobisisobutyronitrile is heated under an inert atmosphere on an oil bath. Upon reaching 85° C. a rapid exotherm occurs which is moderated to maintain 140° C. using a water bath. After the exotherm the mixture is heated at 135° C. for one hour, then cooled to room temperature. The resulting oil is distilled via a Kugelrohr to give the desired product as 33.68 g. of a light yellow liquid (air bath 160° C., 0.15 mm.).
Reaction SMILES: [CH:1]1(Br)[CH2:3][CH2:2]1.[C:5]([C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])#[CH:6].[N-:25]=[N+:26]=[N-:27].[Na+].C(O)(C)(C)C>C(OCC)(=O)C.N.[Cu]I.O>[CH2:2]([N:25]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=2)[CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[N:27]=[N:26]1)[CH:1]=[CH2:3]
Reactant: [N-]=[N+]=[N-]
Reactant: C#Cc1cccc(CCOCCC(=O)OC(C)(C)C)c1
Reactant: BrC1CC1
Agent: [Cu]I
Agent: N
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCn1cc(-c2cccc(CCOCCC(=O)OC(C)(C)C)c2)nn1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
Cyclopropyl bromide (0.177 mL) was added in one portion to a mixture tert-butyl 3-(3-ethynylphenethoxy)propanoate [Example 4, Step ii)] (506 mg), sodium azid e (144 mg), tert-butanol (0.5 mL), water (2 mL) and copper(I) iodide (35.1 mg) and sealed into a microwave tube. The reaction was heated to 70° C., over a period of 3 h in the microwave reactor. The reaction mixture was diluted with ethyl acetate and 35% ammonia (1 mL) and ethyl acetate (2 mL) were added. The mixture was stirred for 30 min. and extracted into ethyl acetate. The organic was evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 20 to 100% ethyl acetate in isohexane to afford the titled compound (470 mg) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.70 (s, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.33 (t, J=7.7 Hz, 1H), 7.19 (d, J=7.7 Hz, 1H), 6.08 (ddt, J=5.9, 10.3 and 16.9 Hz, 1H), 5.41-5.32 (m, 2H), 5.03 (dt, J=6.2, 1.3 Hz, 2H), 3.70 (t, J=6.3 Hz, 2H), 3.69 (t, J=7.1 Hz, 2H), 2.92 (t, J=7.0 Hz, 2H), 2.48 (t, J=6.5 Hz, 2H), 1.43 (s, 9H)
Reaction SMILES: [CH2:1]=[C:2]([O:5][Si](C)(C)C)[CH:3]=[CH2:4].[Br:10][C:11]1[CH:19]=[C:18]2[C:14]([CH2:15][C:16](=[CH2:21])[C:17]2=[O:20])=[CH:13][C:12]=1[F:22].B(F)(F)F.CCOCC>C(Cl)Cl>[Br:10][C:11]1[CH:19]=[C:18]2[C:14]([CH2:15][C:16]3([CH2:4][CH2:3][C:2](=[O:5])[CH2:1][CH2:21]3)[C:17]2=[O:20])=[CH:13][C:12]=1[F:22]
Reactant: C=CC(=C)O[Si](C)(C)C
Reactant: C=C1Cc2cc(F)c(Br)cc2C1=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1CCC2(CC1)Cc1cc(F)c(Br)cc1C2=O
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
To a cold (0° C.) solution of (buta-1,3-dien-2-yloxy)trimethylsilane (1.86 mL, 10.6 mmol) in DCM (80 mL) was 6-bromo-5-fluoro-2-methylene-2,3-dihydro-1H-inden-1-one (Intermediate 5, 2.32 g, 9.62 mmol) added. Boron trifluoride diethyl etherate (0.594 mL, 4.81 mmol) was added at 0° C. The reaction was stirred for 30 min., and then quenched with MeOH (1.0 mL). The reaction mixture was acidified with aq. 2 M HCl solution, and extracted with DCM. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The product was purified by flash column chromatography using a stepwise gradient of heptane/EtOAc (7:1-3.5:1-1:1), to give the title compound (1.60 g, 53% yield). 1H NMR (500 MHz, CDCl3) δ ppm 1.83-1.94 (m, 2 H) 2.17-2.27 (m, 2 H) 2.38-2.51 (m, 2 H) 2.72 (dt, 2 H) 3.18 (s, 2 H) 7.25 (d, 1 H) 8.01 (d, 1 H); MS (ES+) m/z 311,313 [M+H]+.
Reaction SMILES: N[C:2]1[C:11]2[N:10]=[CH:9][C:8](=[O:12])[NH:7][C:6]=2[N:5]=[C:4]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])[N:3]=1.C(Br)(Br)[Br:24].C(ON=O)CC(C)C.C(#N)C>CS(C)=O.CCOCC>[Br:24][C:2]1[C:11]2[N:10]=[CH:9][C:8](=[O:12])[NH:7][C:6]=2[N:5]=[C:4]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])[N:3]=1
Reactant: Nc1nc(SCc2cccc(F)c2F)nc2[nH]c(=O)cnc12
Reactant: BrC(Br)Br
Agent: CC(C)CCON=O
Solvent: CC#N
Solvent: CS(C)=O
Solvent: CCOCC
Product: O=c1cnc2c(Br)nc(SCc3cccc(F)c3F)nc2[nH]1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
The product of step (d) (6.0 g) was suspended in DMSO (90 ml) and bromoform (60 ml) was added and the mixture was heated to 100° C. Isopentylnitrite (25 ml) was added and the mixture stirred for 5 min. The mixture was quickly cooled in an ice bath then evaporated to leave an oil. This was repeated three times. Acetonitrile (200 ml) was added and the solid which separated was removed by filtration. The solvent was evaporated and the residue was purified by flash chromatography, eluting with dichloromethane and then 5% ethyl acetate in dichloromethane to give a yellow solid which was slurried with ether then collected. The solid was washed with ether and dried to give the subtitled compound as a colourless solid (8.74 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.Br[CH2:14][C@H:15]([CH3:25])[CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C([O-])([O-])=O.[Cs+].[Cs+]>CCCCCCC.CCOC(C)=O>[Si:18]([O:17][CH2:16][C@@H:15]([CH3:25])[CH2:14][N:7]1[C:6]2[CH:12]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11])([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:19])[CH3:20]
Reactant: C[C@@H](CBr)CO[Si](C)(C)C(C)(C)C
Reactant: O=C1COc2ccc(F)cc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)CN1C(=O)COc2ccc(F)cc21
Yield: 76.1 %

Procedure:
6-Fluoro-4H-benzo[1,4]oxazin-3-one (95MF88) (2.54 g, 15.2 mmol), (R)-3-bromo-2-methylpropoxy-tert-butyldimethylsilane (4.07 g, 15.2 mmol) and Cs2CO3 (12.38 g, 38 mmol) were mixed according to GP7. CC (SiO2; Heptane/EtOAc 9:1) gave the title compound (111MF01) (4.09 g, 76%). 1H NMR (CDCl3) δ 6.93-6.87 (m, 1H), 6.92-6.88 (m, 1H), 6.68-6.63 (m, 1H), 4.56 (m, 2H), 4.01 (m, 1H), 3.78 (m, 1H), 3.58 (m, 1H), 3.45 (m, 1H), 2.11 (m, 1H), 0.92 (s, 12H), 0.06 (d, J=0.8 Hz, 6H); 13C NMR (CDCl3) δ 164.8, 158.5 (d, J=239.9 Hz), 141.6 (d, J=2.7 Hz), 130.1 (d, J=10.7 Hz), 117.6 (d, J=9.3 Hz), 109.6 (d, J=23.1 Hz), 103.6 (d, J=28.8 Hz), 67.8, 65.9, 44.2, 34.5, 26.0, 18.4, 14.9, −5.4, −5.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]2[C:21]3[N:28]([CH2:29][CH2:30]SCCO)[CH:27]=[CH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.CO.[C:37]([O:41]O)(C)(C)[CH3:38].[S:43]([O-:47])([O-])(=[O:45])=S.[Na+].[Na+]>ClCCl.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]2[C:21]3[N:28]([CH2:29][CH2:30][S:43]([CH2:38][CH2:37][OH:41])(=[O:47])=[O:45])[CH:27]=[CH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1
Reactant: O=S([O-])([O-])=S
Reactant: OCCSCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Reactant: CC(C)(C)OO
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: O=S(=O)(CCO)CCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2-({2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}thio)ethanol (150 mg), titanium tetraisopropoxide (43 μL), methanol (24 μL) and water (10 μL) in dichloromethane was stirred at room temperature for 30 min. 70% Aqueous tert-butyl hydroperoxide solution (0.12 mL) was added to the reaction system, and the mixture was stirred at room temperature for 2 days. An aqueous sodium thiosulfate solution was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate→ethyl acetate:methanol=4:1) to give the title compound (118 mg) as colorless crystals.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([OH:43])=O)=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[CH3:48][C:49]1[CH:50]=[C:51]([CH2:54][NH2:55])[S:52][CH:53]=1>>[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([NH:55][CH2:54][C:51]4[S:52][CH:53]=[C:49]([CH3:48])[CH:50]=4)=[O:43])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1
Reactant: Cc1csc(CN)c1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1csc(CNC(=O)c2sc(N3CCN(Cc4ccc(F)cc4)C3=O)cc2C)c1
Yield: 80 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (4-methylthiophen-2-yl)methanamine, the title compound was obtained as a colorless solid in 80% yield: 1H NMR (300 MHz, CDCl3) δ 7.30-7.24 (m, 2H), 7.08-6.98 (m, 2H), 6.82 (s, 1H), 6.78 (s, 1H), 6.09 (s, 1H), 5.96 (t, J=5.2 Hz, 1H), 4.66 (d, J=5.2 Hz, 2H), 4.42 (s, 2H), 3.83-3.75 (m, 2H), 3.47-3.39 (m, 2H), 2.49 (s, 3H), 2.22 (s, 3H); MS (ES+) m/z 444.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][C:24]([C:28]#[N:29])=[C:25]([F:27])[CH:26]=3)=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:31])[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C(N(C(C)C)CC)(C)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>CO.Cl[Ni]Cl>[F:27][C:25]1[CH:26]=[C:21]([C:18]2[CH:17]=[CH:16][C:15]([C@H:11]3[O:10][C:9]([CH3:31])([CH3:30])[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@@H:12]3[CH2:13][F:14])=[CH:20][CH:19]=2)[CH:22]=[N:23][C:24]=1[CH2:28][NH:29][S:44]([CH3:43])(=[O:46])=[O:45]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cnc(C#N)c(F)c3)cc2)OC1(C)C
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cnc(CNS(C)(=O)=O)c(F)c3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(4S,5R)-tert-butyl-5-(4-(6-cyano-5-fluoropyridin-3-yl)phenyl)-4-(fluoromethyl)-2,2-dimethyloxazolidine-3-carboxylate (1440 mg, 3.4 mmol) in methanol (25 mL) at 5° C. is treated with NiCl2 (80 mg, 0.34 mmol) and then sodium borohydride (380 mg, 10 mmol) is added in portions. The mixture is stirred for 1 hour at room temperature, concentrated to remove the methanol, quenched with aqueous sodium bicarbonate and extracted with ethyl acetate. The organics are dried over anhydrous sodium sulfate, filtered, and concentrated to an oil. The oil is dissolved in dichloromethane (5 mL), cooled to 5° C. and treated with diisopropylethylamine (0.88 mL, 5.0 mmol) and methanesulfonyl chloride (0.30 mL, 3.7 mmol) and stirred for 2 hours at room temperature. The mixture is concentrated and chromatographed on silica eluting with ethyl acetate in heptane to give the title compound. 1H NMR (400 MHz, CDCl3) 1.53 (s, 9H), 1.63 (s, 3H), 1.75 (s, 3H), 3.80-4.00 (m, 1H), 4.40-4.50 (m, 0.5H), 4.55-4.65 (m, 2.5H), 5.22 (d, 1H, J=7.33 Hz), 5.72 (bs, 1H), 7.60-7.70 (m, 5H), 8.63 (s, 1H). m/z (C1) M+H 512.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[N:9]=1)(=[O:3])[CH3:2].[C:16](OC)(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[SH:19].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[S:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[C:16](=[O:24])[N:15]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccccc1S
Reactant: CC(=O)OCCCc1cccc(C#N)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)OCCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 56.3 %

Procedure:
3-(6-Cyano-2-pyridyl)propyl acetate (1.5 g, 7.3 mmol) and methyl thiosalicylate (1.9 g, 11.0 mmol) were dissolved in toluene (5 ml), and triethylamine (2.1 ml, 15.1 mmol) was added thereto. The reaction mixture was refluxed for 16 hrs and kept at room temperature to precipitate crystals. The crystals were washed with toluene and recrystallized from ethanol to give the titled compound (1.4 g, 56%) as white crystals.
Reaction SMILES: [Na].[C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)#N.C(C1C=CC=CN=1)#N>C1(C)C(C)=CC=CC=1.O>[N:21]1[CH:22]=[CH:23][C:18]([C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[OH:9])=[CH:19][CH:20]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccncc1
Agent: [Na]
Solvent: N#Cc1ccccn1
Solvent: Cc1ccccc1C
Solvent: O
Product: OC(c1ccccc1)(c1ccccc1)c1ccncc1
Yield: 95 %

Procedure:
Sodium (16.6 grams, 0.72 mole) metal and xylene (150 ml) were charged into a 1 liter round bottom three-neck flask equipped with a mechanical stirrer, reflux condenser and two dropping funnels. The mixture was brought to reflux and the addition of benzophenone (54.6 grams, 0.3 mole) was begun. When about 1/4 to 1/3 of the benzophenone had added during 15-30 minutes, the addition of a solution of 4-cyanopyridine (38.2 grams, 0.37 mole) in xylene (200 mL) was begun at a rate so that about 1/2 of the cyanopyridine solution had been added when the addition of benzophenone was complete. The remaining cyanopyridine solution was added during another 30 minutes. Upon work-up with water (300 mL), 4-pyridyl diphenyl carbinol was obtained in about 95% yield.
Reaction SMILES: Br[CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1.CC(C)=[O:19]>[B-](F)(F)(F)F.[Ag+].O>[C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:4]1[C:5](=[O:7])[CH2:6][CH:2]([OH:19])[CH:3]=1)([OH:16])=[O:15]
Reactant: O=C(O)CCCCCCC1=CC(Br)CC1=O
Reactant: CC(C)=O
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: O
Product: O=C(O)CCCCCCC1=CC(O)CC1=O
Reaction time: 1.5 h

Procedure:
To a stirred solution of 10.6 g. (ca. 34 mmoles) of crude 4-bromo-2-(6-carboxyhexyl)cyclopent-2-en-1-one (Example 93) in 100 ml. of acetone and 65 ml. of water is added 8.80 g. (45.2 mmoles) of silver fluoborate during 2 minutes. The temperature is maintained at 25°-30°C. by external cooling. The mixture is stirred for 90 minutes, filtered, saturated with sodium chloride, and extracted with ether. The extract is extracted with half saturated sodium bicarbonate solutions. The basic solutions is reacidified with dilute hydrochloric acid, saturated with sodium chloride, and extracted with ether. the extract is washed with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The crude product is purified by partition chromatography on Celite to give an oil; λMeOHmax. = 233 mμ. (7360); νmax. = 3380 (hydroxyl groups), 1710 (carbonyl groups), and 1632 cm-1 (olefin group).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[C:14]([C:21]([F:24])([F:23])[F:22])[CH:13]=1.Cl>CN(C=O)C>[CH2:3]([O:10][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[C:14]([C:21]([F:22])([F:24])[F:23])[CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1ccc(F)cc1C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(OCc2ccccc2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 5.2 g portion of 60% sodium hydride oil dispersion was suspended in 50 ml of DMF, and 6.73 ml of benzyl alcohol was added thereto under ice-cooling. After warming up to room temperature, 12.3 g of 4-fluoro-2-trifluoromethylbenzoic acid was added thereto and stirred at room temperature for 6 hours. A 1 M hydrochloric acid aqueous solution was added to the reaction mixture, and the thus precipitated crystals were collected by filtration to obtain 16.39 g of 4-(benzyloxy)-2-(trifluoromethyl)benzoic acid.
Reaction SMILES: CN1C=CN=C1.[CH:7]1([CH2:12][C@H:13]([CH2:34][N:35]([CH:44]=[O:45])[O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:14]([N:16]2[C@H:20]([C:21](O)=[O:22])[CH2:19][CH2:18][N:17]2[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]1.CS(Cl)(=O)=O.[N:51]1[CH:56]=[CH:55][C:54]([NH2:57])=[N:53][CH:52]=1>ClCCl.C(OCC)(=O)C.C(#N)C>[CH:7]1([CH2:12][C@H:13]([CH2:34][N:35]([CH:44]=[O:45])[O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:14]([N:16]2[C@H:20]([C:21]([NH:57][C:54]3[CH:55]=[CH:56][N:51]=[CH:52][N:53]=3)=[O:22])[CH2:19][CH2:18][N:17]2[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: Nc1ccncn1
Agent: CS(=O)(=O)Cl
Agent: Cn1ccnc1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)Nc2ccncn2)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 92.8 %

Procedure:
1-Methylimidazole (1.78 mL, 22.3 mmol) was added into a solution of (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (4 g, 7.4 mmol) in dichloromethane (50.8 mL). The resulting solution was cooled to 0° C., and then methanesulfonyl chloride (0.6 mL, 7.8 mmol) was added dropwise at 0° C. To the reaction mixture was added 4-pyrimidinamine (849 mg, 8.9 mmol) and stirring continued for 1.5 h at ambient temperature. The reaction solution was filtered to remove unreacted 4-pyrimidinamine, and the filtrate was concentrated to provide a residue. The residue was dissolved in a mixed solution of ethyl acetate and acetonitrile, and was purified by silica gel chromatography (CombiFlash; Column: 220 g; 0-85% ethyl acetate in hexane; 60 min). The solvent was removed under reduced pressure to yield the desired product, phenylmethyl (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-3-[(4-pyrimidinylamino)carbonyl]-1-pyrazolidinecarboxylate (4.22 g, 92% yield). (ES+) m/z 615.2 (MH+).
Reaction SMILES: [C:1]1([C:7]2[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH:10]=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](Cl)(=[O:19])[CH3:18].C([O-])(O)=O.[Na+]>C1COCC1>[C:1]1([C:7]2[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH:10]=[N:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Cl
Reactant: NCCCCn1cncc1-c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)NCCCCn1cncc1-c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 41.9 %

Procedure:
To a stirred solution of 4-(5-phenyl-1H-imidazol-1-yl)butan-1-amine (0.278 mmol) in THF (3 mL) at 0° C. was added acetyl chloride (0.306 mmol) drop wise and the resulting white suspension was allowed to warm to rt and stir for 5 h. Saturated NaHCO3 (2 mL) was added and the aqueous phase was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo to afford a yellowish oil. Preparative thin layer chromatography afforded the pure product as colorless oil (30 mg, 43% yield). 1H NMR: 1.36 (m, 2H), 1.60 (m, 2H), 1.91 (s, 3H), 2.38 (br s, 1H), 3.12 (m, 2H), 4.00 (t, 2H, J=7.1 Hz), 5.80 (br s, 1H), 7.04 (s, 1H), 7.32-7.46 (m, 5H), 7.55 (s, 1H).
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C@H:6]([NH:9][CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:7][CH3:8].C([O-])(O)=O.[Na+].[Cl:20][C:21]1[N:26]=[C:25](Cl)[C:24]([N+:28]([O-:30])=[O:29])=[CH:23][N:22]=1>C1COCC1.CCOC(C)=O.[Cl-].[Na+].O>[Cl:20][C:21]1[N:26]=[C:25]([N:9]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[C@@H:6]([C:2]2[O:1][CH:5]=[N:4][N:3]=2)[CH2:7][CH3:8])[C:24]([N+:28]([O-:30])=[O:29])=[CH:23][N:22]=1
Reactant: CC[C@@H](NC1CCCC1)c1nnco1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC[C@H](c1nnco1)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
17 N-[(1R)-1-(1,3,4-oxadiazol-2-yl)propyl]cyclopentanamine (199 mg, 1.019 mmol) in anhydrous THF (3.980 mL) was treated with NaHCO3 (342.4 mg, 4.076 mmol) then 2,4-dichloro-5-nitro-pyrimidine (197.7 mg, 1.019 mmol). The reaction was stirred overnight at ambient temperature. The reaction was further stirred at 45° C. for 10 hours, diluted with EtOAc/Brine and extracted EtOAc (×3). The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc/petrol) to give the sub-tilte compound as a pale yellow oil (107 mg, 30%); 1H NMR (400.0 MHz, CDCl3) d 1.03 (3H, t), 1.45-2.80 (10H, m), 3.55 (1H, m), 4.39 (1H, m), 8.31 (1H, s), 8.60 (1H, s); MS ES (+) 353.1.