Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:21]2[S:25][C:24]([C:26]3([O:30][CH2:31][O:32][CH3:33])[CH2:29][CH2:28][CH2:27]3)=[N:23][CH:22]=2)=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[I:42]I>O1CCCC1>[Cl:1][C:2]1[C:3]([C:21]2[S:25][C:24]([C:26]3([O:30][CH2:31][O:32][CH3:33])[CH2:29][CH2:28][CH2:27]3)=[N:23][CH:22]=2)=[C:4]2[CH:10]=[C:9]([I:42])[N:8]([S:11]([C:14]3[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=3)(=[O:12])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: II
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4c3ccn4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(I)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cold (−78° C.) solution of 5-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(1-(methoxymethoxy)cyclobutyl)thiazole (Example 1E) (5.0 g, 9.92 mmol) in tetrahydrofuran (50 mL) was added a solution of lithium diisopropylamide (13.9 mmol) in tetrahydrofuran (15 mL). The reaction was stirred at −78° C. for 1 hour, and a solution of iodine (3.52 g, 13.89 mmol) in tetrahydrofuran (10 mL) was added. The cold bath was removed, and, after 15 minutes, the reaction was quenched by the addition of saturated aqueous sodium thiosulfate and ethyl acetate. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate (2×). The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 30% ethyl acetate in hexane, to give the title compound. MS ESI(+) m/z 586 [M+H]+;
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]([CH3:9])[C:6](Cl)=[O:7])=[O:4].[CH3:10][C:11]([S:16]([CH3:19])(=[O:18])=[O:17])([CH3:15])[CH:12]=[N:13][OH:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:10][C:11]([S:16]([CH3:19])(=[O:18])=[O:17])([CH3:15])[CH:12]=[N:13][OH:14].[Cl:1][CH2:2][C:3]([N:5]([CH3:9])[C:6](=[O:14])[O-:7])=[O:4]
Reactant: CN(C(=O)Cl)C(=O)CCl
Agent: CC(C)(C=NO)S(C)(=O)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(C(=O)[O-])C(=O)CCl
Reaction time: 72 h

Procedure:
To a solution of 5.0 g (0.029 m) of N-chloroacetyl-N-methylcarbamoyl chloride dissolved in 40 ml of toluene was added 4.74 g (0.029 m) of 2-methyl-2-methylsulfonylpropionaldoxime dissolved in 35 ml. of toluene followed by a slow addition of 2.9 g (0.029 m) of triethylamine. The reaction mixture was stirred at ambient temperatures over a period of 3 days. The solid product was filtered. The filter cake was washed with water and hexane and air dried to afford 5.7 g of a white solid with a melting point of 120°-121° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][CH2:24][C:25]([NH2:27])=[O:26])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C@:13]2([CH2:23][CH2:24][C:25]([NH2:27])=[O:26])[O:12][C:11](=[O:28])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:17][CH:18]=1
Reactant: OB(O)c1ccccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCC(N)=O)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccccn2)cc1)N1CC[C@](CCC(N)=O)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanamide and pyridine-2-boronic acid following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=0.976 min, m/z=448; 1H NMR (CDCl3) 1.50 (d, 3H), 1.91 (m, 1H), 2.17-2.23 (m, 5H), 2.41 (m, 1H), 2.86 (m, 1H), 5.18 (m, 1H), 5.32 (m, 1H), 5.66 (m, 1H), 7.00 (m, 4H), 7.18 (m, 3H), 7.57 (d, 1H), 7.69 (m, 3H), 8.58 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5](I)=[CH:4][N:3]=1.[C:9]([Si:11]([CH3:14])([CH3:13])[CH3:12])#[CH:10]>[Pd].[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C.CCN(CC)CC>[Br:1][C:2]1[CH:7]=[N:6][C:5]([C:10]#[C:9][Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][N:3]=1
Reactant: Brc1cnc(I)cn1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cnc(Br)cn1

Procedure:
Reaction of a mixture of 2-bromo-5-iodo-pyrazine and copper (I) iodide under inert conditions in an appropriate solvent and base e.g. DMF/Et3N with ethynyl-trimethyl-silane using a palladium catalyst e.g. Pd(PPh3)4 at room temperature gives 2-Bromo-5-trimethylsilanylethynyl-pyrazine. This material can be used without further purification and reacted to form 6-bromo-2-trimethylsilanyl-pyrazolo[1,5-a]pyrazine using 0-(mesitylenesulfonyl)hydroxylamine to form the N-amino adduct. This can then be cyclised by reacting with base e.g. K2CO3 to form pyrazolopyrazine core (Scheme 6).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:29])([CH3:28])[O:6][CH2:7][C@@H:8]([O:10][C:11]1[CH:12]=[C:13]([CH:24]=[C:25]([OH:27])[CH:26]=1)[C:14]([NH:16][C:17]1[CH:22]=[N:21][C:20]([CH3:23])=[CH:19][N:18]=1)=[O:15])[CH3:9])([CH3:4])[CH3:3].[N:30]1([C:34]([C:36]2[CH:41]=[N:40][C:39](Cl)=[CH:38][N:37]=2)=[O:35])[CH2:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[N:30]1([C:34]([C:36]2[N:37]=[CH:38][C:39]([O:27][C:25]3[CH:24]=[C:13]([CH:12]=[C:11]([O:10][C@@H:8]([CH3:9])[CH2:7][O:6][Si:5]([C:2]([CH3:3])([CH3:4])[CH3:1])([CH3:28])[CH3:29])[CH:26]=3)[C:14]([NH:16][C:17]3[CH:22]=[N:21][C:20]([CH3:23])=[CH:19][N:18]=3)=[O:15])=[N:40][CH:41]=2)=[O:35])[CH2:33][CH2:32][CH2:31]1
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)cn1
Reactant: O=C(c1cnc(Cl)cn1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cnc(NC(=O)c2cc(Oc3cnc(C(=O)N4CCC4)cn3)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)cn1
Temperature: 140 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
A mixture of 3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-hydroxy-N-(5-methylpyrazin-2-yl)benzamide (0.12 g, 0.29 mmol), 2-(azetidin-1-ylcarbonyl)-5-chloropyrazine (57 mg, 0.29 mmol) and potassium carbonate (80 mg, 0.57 mmol) in acetonitrile (5 mL) was stirred in a microwave reactor at 140° C. for 1 hour. The mixture was reduced in vacuo and ethyl acetate (50 mL) added. The mixture was washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and reduced in vacuo to give a brown oil which was chromatographed on silica, eluting with 50 to 100% ethyl acetate in isohexane, to give the desired compound as a colourless oil (90 mg). 1H NMR δ (CDCl3): −0.03 (s, 3H), 0.00 (s, 3H), 0.81 (s, 9H), 1.26 (d, 3H), 2.32 (quin, 2H), 2.49 (s, 3H), 3.61-3.76 (m, 2H), 4.20 (t, 2H), 4.46 (sextet, 1H), 4.62 (t, 2H), 6.91 (t, 1H), 7.21 (t, 1H), 7.32 (t, 1H), 8.07 (s, 1H), 8.28 (d, 1H), 8.30 (s, 1H), 8.79 (d, 1H), 9.48 (d, 1H). m/z 579 (M+H)+
Reaction SMILES: C([O:8][NH:9][C:10](=[O:43])[CH:11]([CH2:30][NH:31][S:32]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)(=[O:34])=[O:33])[C:12]1([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]1=[O:25])C1C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[OH:8][NH:9][C:10](=[O:43])[CH:11]([CH2:30][NH:31][S:32]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)(=[O:34])=[O:33])[C:12]1([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]1=[O:25]
Reactant: COc1ccc(S(=O)(=O)NCC(C(=O)NOCc2ccccc2)C2(CC(C)C)CCN(CCc3ccccc3)C2=O)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)NCC(C(=O)NO)C2(CC(C)C)CCN(CCc3ccccc3)C2=O)cc1
Reaction time: 6.5 h
Yield: 97.9 %

Procedure:
A solution of N-benzyloxy-α-[[[(4-methoxyphenyl)sulfonyl]amino]methyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide (218 mg, 0.359 mmol) in EtOH (7 mL) is treated with palladium hydroxide on carbon (55 mg) and placed under a H2 atmosphere via a balloon. After 6.5 hours, the mixture is filtered, rinsing the residual solids with MeOH and CHCl3. The filtrate is concentrated to give 182 mg of a white solid. The material is crystallized from hot EtOAc with a trace of MeOH, eventually diluting with hexane, to provide 136 mg of the title compound as a solid (mp 195°-196° C.):
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=[O:5])#[N:2].[CH3:7][Si:8]([CH2:11]O)([CH3:10])[CH3:9].[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[C:1]([CH2:3][C:4]([O:6][CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9])=[O:5])#[N:2]
Reactant: N#CCC(=O)O
Reactant: C[Si](C)(C)CO
Agent: C[n+]1ccccc1Cl
Agent: O=S([O-])([O-])=S
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)COC(=O)CC#N
Yield: 85.2 %

Procedure:
8.5 g (0.1 mole) of cyanoacetic acid, 10.43 g (0.1 mole) of trimethylsilylmethanol, 30.66 g (0.12 mole) of 2-chloro-1-methylpyridinium iodide, 24.3 g (0.24 mole) of triethylamine and 200 ml of tetrahydrofuran were placed in a reaction vessel and reaction was allowed to take place at 50° C. for 3 hours in an argon atmosphere. Thereafter, a 10% aqueous sodium thiosulfate solution was added, followed by extraction with ether. An organic layer obtained was washed with a 10% aqueous sodium thiosulfate solution and then with water, then dried overnight with anhydrous magnesium. Thereafter, the desiccant was filtered off and the solvent was removed under a reduced pressure, followed by vacuum distillation to afford 14.6 g of trimethylsilylmethyl α-cyanoacetate (NCCH2CO2CH2SiMe3) (b.p. 81°-82° C./2 mmHg, yield 85%).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6](O)[CH:7]=[CH:8][CH:9]=1)=[N+:2]=[N-:3].NC1C=CC([OH:18])=CC=1>>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:18])=[CH:8][CH:9]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1cccc(O)c1
Reactant: Nc1ccc(O)cc1
Product: [N-]=[N+]=Nc1ccc(O)cc1

Procedure:
4-Azidophenol was prepared similarly to 3-azidophenol, using 4-aminophenol (5.0 g) instead of 3-aminophenol. This gave 5.27 g (85% yield) of a dark red oil. 1H NMR (acetone-d6, 300 MHz, ppm): 8.48 (s, 1H, Ar—OH), 6.94 (m, 4H, Ar—H). 13C NMR (MeOD-d4, 75 MHz, ppm): 156.4, 132.4, 121.1, 117.7. FT-IR (cm−1): 3372, 2113, 2072.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[CH2:11][S:12][CH3:13].[CH:14]([Mg]Br)=[CH2:15].[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1>[F:1][C:2]1[C:3]([CH2:11][S:12][CH3:13])=[C:4]2[C:5]([CH:14]=[CH:15][NH:8]2)=[CH:6][CH:7]=1
Reactant: CSCc1c(F)cccc1[N+](=O)[O-]
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSCc1c(F)ccc2cc[nH]c12
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of 11.42 g (56.7 mmol) of the compound from Example 2A in 127 ml of tetrahydrofuran was slowly added dropwise to 284 ml (283.7 mmol) of a 0.7N solution of vinylmagnesium bromide in tetrahydrofuran under argon at −78° C., and the solution was then stirred at −78° C. for 2 h. The reaction mixture was added to an ice-cold, saturated aqueous ammonium chloride solution, some ethyl acetate was added, the phases were separated, and the aqueous phase was extracted three times with ethyl acetate. Washing of the combined organic phases with saturated aqueous sodium chloride solution was followed by drying over sodium sulfate, filtration and removal of the solvents in vacuo. Purification of the residue by flash chromatography (mobile phase: cyclohexane/toluene/dichloromethane 10/10/1) afforded 6.31 g (57% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:31]=[CH:30][C:17]([C:18]([NH:20][CH2:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[O:19])=[CH:16][CH:15]=3)[N:11]=[C:10]([C:32]3[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[CH:33]=3)[CH:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([NH:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:19])=[CH:30][CH:31]=3)[N:11]=[C:10]([C:32]3[CH:33]=[C:34]([Cl:39])[CH:35]=[C:36]([Cl:38])[CH:37]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1ccc(Cn2nc(-c3cc(Cl)cc(Cl)c3)cc2-c2ccc(Br)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCNC(=O)c1ccc(Cn2nc(-c3cc(Cl)cc(Cl)c3)cc2-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the intermediate from step F (30 mg, 0.047 mmol) in DCM (2 mL) was added trifluroacetic acid (2 mL). The reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and lyophilized from acetonitrile-water to give the title compound. 1H NMR (DMSO, 500 MHz): δ 8.49(t, J=5.5 Hz, 1H), 7.89 (d, J=1.8 Hz, 2H), 7.75 (d, J=8.2 Hz, 2H), 7.7 (d, J=8.5 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 7.22 (s, 1H), 7.11 (d, J=8.2 Hz, 2H), 5.5 (s, 2H), 3.45 (q, J=7.1 Hz, 2H), 2.49 (t, J=6.8 Hz, 2H). LC-MS: 2.59 min; (M+H)=571.9.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O>[Br:11][C:8]1[CH:9]=[N:10][C:2]2[N:1]=[C:16]([C:15]3[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=3)[NH:6][C:4](=[O:5])[C:3]=2[CH:7]=1
Reactant: O=Cc1cccc(F)c1
Reactant: NC(=O)c1cc(Br)cnc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=c1[nH]c(-c2cccc(F)c2)nc2ncc(Br)cc12
Temperature: 115 °C
Reaction time: 1.5 h
Yield: 47.5 %

Procedure:
A mixture of 2-amino-5-bromonicotinamide (100 mg, 0.46 mmol), 3-fluorobenzaldehyde (69 mg, 0.56 mmol), NaHSO3 (40 mg, 0.38 mmol), 4-methylbenzene sulfonic acid (15 mg, 0.05 mmol) in DMAc (3 mL) was stirred at 115° C. for 1.5 h, then additional NaHSO3 (40 mg, 0.38 mmol) was added to the mixture. After 1.5 h, the third portion of NaHSO3 (40 mg, 0.38 mmol) was added to the mixture. After being stirred overnight at 115° C., the reaction mixture was concentrated in vacuo, suspended in water and filtered to give the product of 6-bromo-2-(3-fluorophenyl)pyrido[2,3-d]pyrimidin-4(3H)-one (70 mg, yield: 47%), which was used for the next step without further purification. 1H-NMR (DMSO-d6, 400 MHz) δ 13.04 (br s, 1H), 9.07 (d, J=2.8 Hz, 1H), 8.65 (d, J=2.8 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 8.02 (dd, J=9.6, 1.6 Hz, 1H), 7.60˜7.68 (m, 1H), 7.45˜7.54 (m, 1H). MS (M+H)+: 320/322.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=1)[CH2:8][N:9]1[C@@H:17]2[C@H:12]([C@H:13]([CH2:20][C:21]3[CH:26]=[C:25]([CH2:27][C@H:28]([OH:33])[C:29]([F:32])([F:31])[F:30])[C:24]([N:34]=CN(C)C)=[C:23]([F:39])[CH:22]=3)[CH2:14][S:15](=[O:19])(=[O:18])[CH2:16]2)[O:11]C1=O)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[NH2:34][C:24]1[C:25]([CH2:27][C@H:28]([OH:33])[C:29]([F:32])([F:30])[F:31])=[CH:26][C:21]([CH2:20][C@H:13]2[C@H:12]([OH:11])[C@@H:17]([NH:9][CH2:8][C:7]3[CH:41]=[CH:42][CH:43]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH:6]=3)[CH2:16][S:15](=[O:19])(=[O:18])[CH2:14]2)=[CH:22][C:23]=1[F:39]
Reactant: CN(C)C=Nc1c(F)cc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc1C[C@H](O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cccc(CN[C@H]2CS(=O)(=O)C[C@@H](Cc3cc(F)c(N)c(C[C@H](O)C(F)(F)F)c3)[C@@H]2O)c1
Temperature: 60 °C

Procedure:
To a solution of N′-[4-[(3aR*,7S*,7aS*)-3-(3-tert-butyl-benzyl)-2,5,5-trioxo-octahydro-1-oxa-5lambda*6*-thia-3-aza-inden-7-ylmethyl]-2-fluoro-6-((S)-3,3,3-trifluoro-2-hydroxy-propyl)-phenyl]-N,N-dimethyl-formamidine (0.1 g, 0.16 mmol) in anhydrous THF was added KOSi(CH3)4 (0.11 g, 0.8 mmol) and the reaction mixture was heated for 16 h at 60° C. The reaction mixture was added to cold 10% aq. K2CO3 solution and extracted with EtOAc. The combined organic layers were washed with 10% aq. K2CO3 solution and brine, dried over MgSO4, filtered and evaporated. The residue was converted into the hydrochloride salt with 1N HCl in Et2O and the precipitated salt was dried under reduced pressure to yield the title compound as a light yellow solid: TLC (CH2Cl2-MeOH-AcOH-H2O 180:20:2:1) Rf=0.46; HPLC RtA=1.79 min; ESIMS [M+H]+=547; HPLC RtA=1.22 min; ESIMS [M+H]+=337; 1H NMR (400 MHz, CDCl3+1% D2O): δ 7.34 (m, 3H), 7.12 (d, 1H), 6.79 (dd, 1H), 6.66 (s, 1H), 4.14 (m, 1H), 3.87 (dd, 1H), 3.74 (dd, 1H), 3.38 (dt, 1H), 2.8-3.2 (m, 6H), 2.72 (dd, 1H), 2.63 (t, 1H), 2.55 (dd, 1H), 2.29 (m, 1H), 1.34 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[CH:10]([O:13][C:14]1[CH:15]=[C:16]([CH:25]=[C:26]([O:28][CH:29]([CH3:31])[CH3:30])[CH:27]=1)[CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1)([CH3:12])[CH3:11]>C(N(C(C)C)C(C)C)C.C(#N)C>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:24][CH:21]2[CH2:22][CH2:23][N:18]([CH2:17][C:16]3[CH:15]=[C:14]([O:13][CH:10]([CH3:11])[CH3:12])[CH:27]=[C:26]([O:28][CH:29]([CH3:31])[CH3:30])[CH:25]=3)[CH2:19][CH2:20]2)[C:7]=1[NH2:8]
Reactant: CC(C)Oc1cc(CN2CCC(N)CC2)cc(OC(C)C)c1
Reactant: Nc1c(Cl)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)Oc1cc(CN2CCC(Nc3ncnc(Cl)c3N)CC2)cc(OC(C)C)c1
Yield: 20 %

Procedure:
A solution of 4,6-dichloro-pyrimidin-5-ylamine (19.7 mg, 0.12 mmol, 1.0 equiv; commercially available) and 1-(3,5-diisopropoxy-benzyl)-piperidin-4-ylamine (46.0 mg, 0.15 mmol, 1.25 equiv; intermediate A3) in N-ethyl diisopropylamine (1.0 mL) and acetonitril (1.0 mL) was heated by microwave irradiation to 160° C. for 20 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 10.6 mg (20%) of the title compound. MS (ISP): 434.3 [M+H]+.
Reaction SMILES: [CH3:1][CH:2](O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]CC.CCC([OH:34])CCCCCCCCCCCCC.CCCC(O)CCCCCCCCCCCC>>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([OH:34])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCC(O)CC
Reactant: CCCCCCCCCCCCCCC(C)O
Agent: CCCCCCCCCCCCC(O)CCC
Product: CCCCCCCC(O)CCCCCC

Procedure:
2-hexadecanol; 3-hexadecanol; 4-hexadecanol;
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]([OH:24])[CH:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:8]([O:10]CC)=[O:9])=[CH:2]1.[OH-].[Na+].Cl>CO>[O:1]1[CH:5]=[CH:4][C:3]([CH:6]([OH:24])[CH:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][CH:15]=2)[C:8]([OH:10])=[O:9])=[CH:2]1
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccoc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccoc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
To a solution of ethyl (2RS,3RS)-3-(3-furanyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionate (19.0 g, 55.5 mmol) in methanol (100 ml) was added 2N aqueous sodium hydroxide solution (55.5 ml, 111 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to give (2RS,3RS)-3-(3-furanyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionic acid (15.1 g, 86%).
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)(=O)C>[N:19]1(/[C:1](/[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:9]2\[C:10](=[O:18])[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[S:13]\2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Reactant: C1CCNC1
Solvent: CC(=O)O
Product: O=C1/C(=C(/c2ccccc2)N2CCCC2)Sc2ccccc21
Yield: 5 %

Procedure:
Prepared as in Example 31 from 2-benzoyl-benzo[b]thiophen-3-ol and pyrrolidine in glacial acetic acid with a yield of 5% of theory. Egg-yellow crystals, m.p. 157° C. (ethyl acetate/petroleum ether 1:3).
Reaction SMILES: NCCC[N:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]1=O.C(NCCN)C1C=CC=CC=1.C(OC(OCC)OCC)C>>[CH2:10]([N:7]1[CH2:8][CH2:9][N:5]=[CH:6]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: NCCCN1CCN(Cc2ccccc2)C1=O
Agent: NCCNCc1ccccc1
Solvent: CCOC(OCC)OCC
Product: C1=NCCN1Cc1ccccc1

Procedure:
As shown in FIG. 9B (Scheme 4), the synthesis of 1-(3-aminopropyl)-3-benzylimidazolidin-2-one (35) will be performed by treating the starting material N1-benzylethane-1,2-diamine with diethoxymethoxyethane to form 1-benzyl-4,5-dihydro-1H-imidazole. The imidazole intermediate will be treated with BuLi (forming a lithiate) followed by quenching with water to form the final intermediate 1-benzylimidazolidin-2-one. Treating the imidazolidinone with NaH followed by Br—(CH2)3—N(SiMe3)2 under reducing conditions will afford the intermediate 35.
Reaction SMILES: [CH2:1]([C:5]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:8]2[CH:9]([C:13]([O:15][CH3:16])=[O:14])[NH:10][CH2:11][CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[C:43](Cl)(=[O:45])[CH3:44]>C(Cl)(Cl)Cl>[C:43]([N:10]1[CH2:11][CH2:12][C:7]2[N:6]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[NH:35][N:34]=[N:33][N:32]=4)=[CH:21][CH:20]=3)[C:8]=2[CH:9]1[C:13]([O:15][CH3:16])=[O:14])(=[O:45])[CH3:44]
Reactant: CC(=O)Cl
Reactant: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OC)NCC2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OC)N(C(C)=O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
To a mixture of the compound obtained in Example 3 (296 mg), triethylamine (317 mg) and chloroform (10 ml) is added dropwise a solution of acetyl chloride (148 mg) in chloroform (1 ml) under ice-cooling. The mixture is stirred at room temperature for two hours, and the reaction solution is washed, dried and evaporated to remove the solvent. The resulting residue is purified by silica gel column chromatography (solvent; chloroform/methanol=30:1) to give methyl 5-acetyl-2-n-butyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (158 mg).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][N:6]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18])[CH3:7])C>Br.C(#N)C>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][N:6]([CH2:5][C:4]([OH:20])=[O:3])[CH3:7])=[C:11]([N+:17]([O-:19])=[O:18])[CH:12]=1
Reactant: CCOC(=O)CN(C)CCc1ccc(F)cc1[N+](=O)[O-]
Agent: Br
Solvent: CC#N
Product: CN(CCc1ccc(F)cc1[N+](=O)[O-])CC(=O)O
Temperature: 70 °C
Reaction time: 8 h

Procedure:
{[2-(4-Fluoro-2-nitro-phenyl)-ethyl]-methylamino}-acetic acid ethyl ester (10.0 g, 0.035 mole) dissolved in concentrated hydrobromic acid (48 wt. % in water, 200 mL) was allowed to stir at 70° C. overnight and then reduced to a small volume in vacuo. The residue oil was taken up in acetonitrile and the solution was evaporated in vacuo. This procedure was repeated until the water was removed and a crystalline residue remained. This material was used in the next step without further purification. 1H NMR (DMSO): 8.00 δ (dd, 1H); 7.65 δ (m, 2H); 4.20 δ (s, 2H); 3.40 δ (large water peak obscure some aliphatic resonances); 3.20 δ (t, 2H); 2.90 δ (s, 3H).