Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][O:12][CH2:11][C@H:10]1[NH2:14])(C(C)(C)C)(C)C.[Cl:15][C:16]1[C:23]([CH3:24])=[C:22](F)[CH:21]=[CH:20][C:17]=1[C:18]#[N:19].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[Cl:15][C:16]1[C:23]([CH3:24])=[C:22]([NH:14][C@H:10]2[C@@H:9]([OH:8])[CH2:13][O:12][CH2:11]2)[CH:21]=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1COC[C@H]1N
Reactant: Cc1c(F)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: Cc1c(N[C@@H]2COC[C@@H]2O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
The title compound is prepared by essentially following the procedure as described in Example 1 using (3R,4R)-4-(tert-butyl(dimethyl)silyl)oxytetrahydrofuran-3-amine (Preparation 36) and 2-chloro-4-fluoro-3-methyl-benzonitrile. The crude product is purified on silica gel using 40-70% EtOAc/hexanes. The isolated product is dissolved in THF to make a 0.5 M solution. TBAF (2.0 mL, 2 mmol, 1 M solution in THF) is added and stirred at room temperature for 16 h. The solution is concentrated in vacuo, EtOAc is added, and the solution is washed with water (2×). The organic portion is dried over magnesium sulfate, filtered, and concentrated. The residue is purified by reverse phase chromatography on silica-bound C18 using 15-95% acetonitrile/water+0.1% formic acid. Fractions containing the title compound are concentrated in vacuo to remove acetonitrile, then extracted with EtOAc. The organics are dried over magnesium sulfate and concentrated in vacuo to give the title compound as a white solid (134 mg, 19%). 1H-NMR (400 MHz, DMSO-d6) δ 7.53 (d, J=8.7 Hz, 1H), 6.73 (d, J=8.8 Hz, 1H), 5.60-5.56 (m, 1H), 5.53 (d, J=4.9 Hz, 1H), 4.33-4.29 (m, 1H), 4.05-3.99 (m, 2H), 3.92 (dd, J=4.6, 9.6 Hz, 1H), 3.63 (dd, J=2.4, 9.5 Hz, 1H), 3.53-3.50 (m, 1H), 2.19 (s, 3H). LC-ES/MS m/z 253 (M+1).
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[CH:20][C:19]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=3)[C@@H:12]([CH2:32][CH:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH2:11]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1>CCO.[Pd]>[F:30][C:27]([F:28])([F:29])[C:22]([C:19]1[CH:20]=[N:21][C:16]([N:13]2[CH2:14][CH2:15][N:10]([S:7]([C:5]3[S:6][CH:2]=[CH:3][CH:4]=3)(=[O:9])=[O:8])[CH2:11][C@@H:12]2[CH2:32][CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[N:17][CH:18]=1)([OH:31])[C:23]([F:24])([F:26])[F:25]
Reactant: O=S(=O)(c1ccc(Br)s1)N1CCN(c2ncc(C(O)(C(F)(F)F)C(F)(F)F)cn2)[C@@H](CC2CCOCC2)C1
Agent: [Pd]
Solvent: CCO
Product: O=S(=O)(c1cccs1)N1CCN(c2ncc(C(O)(C(F)(F)F)C(F)(F)F)cn2)[C@@H](CC2CCOCC2)C1
Reaction time: 8 h
Yield: 60.5 %

Procedure:
In a 50-mL round-bottomed flask a mixture of (S)-2-(2-(4-(5-bromothiophen-2-ylsulfonyl)-2-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)pyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (60 mg, 0.092 mmol) and 10% Pd/C (19.5 mg, 0.018 mmol) in EtOH (10 mL) stirred under 1 atm of H2 for 8 h. Afterwards, the mixture was filtered through a pad of Celite® (diatomaceous earth). The filtrate was concentrated and the crude product was purified by carefully filtering through a plug of silica gel using 5% MeOH in CH2Cl2 as the eluent. Concentration of the filtrate yielded 1,1,1,3,3,3-hexafluoro-2-(2-((2S)-2-(tetrahydro-2H-pyran-4-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol (32 mg).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([P:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:20][CH:19]=3)Cl)=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[CH2:47]Br>C1COCC1.CCOCC.CCCCCC>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([P:16]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[CH2:47][P:16]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[CH:22][CH:23]=3)[C:13]3[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:11][CH:12]=3)[C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClP(c1ccc(CCCc2ccccc2)cc1)c1ccc(CCCc2ccccc2)cc1
Reactant: BrCc1ccccc1-c1ccccc1CBr
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: c1ccc(CCCc2ccc(P(Cc3ccccc3-c3ccccc3CP(c3ccc(CCCc4ccccc4)cc3)c3ccc(CCCc4ccccc4)cc3)c3ccc(CCCc4ccccc4)cc3)cc2)cc1
Reaction time: 10 h
Yield: 34.6 %

Procedure:
Di[p-(3-phenylpropyl)phenyl]chlorophosphine 1 (6.0 g, 13.1 mmol) was dissolved in 150 ml THF and Li (0.185 g, 26.2 mmol) was chopped directly into the reaction flask under Ar. A deep red solution was resulted in 10 min and all the lithium was consumed in 4 h. The solution was then filtered and 2,2'-dibromomethyl-1,1'-biphenyl (2.23 g, 6.5 mmol) in 20 ml THF was added dropwise with an ice-water bath. The color of the solution was slowly changed to pale yellow. The mixture was stirred for additional 10 h before the solvent was removed by vacuum. 50 ml diethyl ether was added and it was washed with 3×10 ml H2O. The ether phase was dried over MgSO4 and the solvent was then removed by vacuum. The resulting pale yellow viscous oil was purified over silica gel column. 2.3 g (69% yield) of 11 was eluted with Et2O/hexane (1/10), 11 was characterized by 1H, 13C, 31P NMR and Mass spectrometry.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].[CH:13]([Mg]Br)=[CH2:14]>O1CCCC1>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[C:5]([CH:6]([OH:7])[CH:13]=[CH2:14])[CH:8]=[CH:9][CH:10]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(O)c1cccc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
3-(Trifluoromethyl)benzaldehyde (100 g) was added to a pre-cooled (0 to 5° C.) solution of vinyl magnesium bromide (862 mL; 1M) in tetrahydrofuran under the nitrogen atmosphere. The reaction mixture was stirred at room-temperature for one hour. After completion, the reaction was quenched with de-ionized water (500 mL) and dichloromethane (500 mL) was added. The dichloromethane layer was washed with sodium bicarbonate solution (7%; 500 mL), layers were separated and organic layer was concentrated under vacuum at 40° C. to 45° C. to give 1-[3-(trifluoromethyl)phenyl]prop-2-en-1-ol as oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][CH3:14])=[C:8]([B:10]([OH:12])[OH:11])[CH:9]=1)([OH:3])=O.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[N:15]1([C:1]([C:4]2[CH:5]=[CH:6][C:7]([O:13][CH3:14])=[C:8]([B:10]([OH:12])[OH:11])[CH:9]=2)=[O:3])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: C1COCCN1
Reactant: COc1ccc(C(=O)O)cc1B(O)O
Product: COc1ccc(C(=O)N2CCOCC2)cc1B(O)O

Procedure:
The title compound was prepared in analogy to the procedure described for intermediate K using 5-carboxy-2-methoxyphenyl boronic acid and morpholine; ESI-MS: 266.5 [M+H]+ (LC-MS 2); 1H-NMR (DMSO-d6, 400 MHz) δ 7.84 (s, 1H), 7.57 (d, 1H), 7.46 (d, 1H), 7.03 (d, 1H), 3.83 (s, 3H), 3.62-3.60 (m, 4H), 3.49-3.42 (m, 4H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.[CH3:25][CH:26]([O:28][CH2:29][C:30](O)=[O:31])[CH3:27].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C1COCC1.C(N(CC)CC)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4][C@H:3]2[CH2:2][NH:1][C:30](=[O:31])[CH2:29][O:28][CH:26]([CH3:27])[CH3:25])=[CH:11][C:12]=1[F:17]
Reactant: CC(C)OCC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)OCC(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate (300 mg), (1-methylethoxy)acetic acid (119 mg), 1H-benzotriazol-1-ol (136 mg) and triethylamine (0.291 ml) in THF (4.2 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (192 mg), and the mixture was stirred at room temperature overnight. To the reaction mixture was added distilled water, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (384 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:10][C:9]2[C:11]([Br:14])=[CH:12][S:13][C:8]=2[CH:7]=1)=[O:5])C.O[Li].O>>[Br:14][C:11]1[C:9]2[NH:10][C:6]([C:4]([OH:5])=[O:3])=[CH:7][C:8]=2[S:13][CH:12]=1
Reactant: CCOC(=O)c1cc2scc(Br)c2[nH]1
Agent: [Li]O
Solvent: O
Product: O=C(O)c1cc2scc(Br)c2[nH]1

Procedure:
3-Bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester was hydrolyzed according to Procedure F (7 equiv LiOH—H2O; room temperature overnight, then at 50° C. overnight again; acidified aqueous phase extracted with ethyl acetate; combined organic phases dried over MgSO4, concentrated).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C@@H:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([O:29][CH3:30])=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:19][CH:18]=1)[CH3:16])(C)(C)C>ClCCl>[CH3:30][O:29][C:24]1[C:23]([C:20]2[CH:21]=[CH:22][C:17]([C@H:15]([NH2:14])[CH3:16])=[CH:18][CH:19]=2)=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: COc1ncccc1-c1ccc([C@@H](C)NC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ncccc1-c1ccc([C@@H](C)N)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
2M Aqueous sodium carbonate solution (3.25 ml, 6.50 mmol) was added to a mixture of 2-methoxypyridine-3-boronic acid (994 mg, 6.50 mmol), (R)-[1-(4-bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (650 mg, 2.16 mmol) and tetrakis(triphenylphosphine)palladium (0) (125 mg, 0.108 mmol) in 1,2 dimethoxyethane (27 ml). The mixture was heated at 95° C. for 16 h under nitrogen atmosphere. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed twice with brine, dried over anhydrous magnesium sulfate and the solvent evaporated. The resulting gum was chromatographed over silica gel eluting with heptane/dichloromethane and the solvent evaporated to give (R)-{1-[4-(2-methoxy-pyridin-3-yl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (593 mg, 1.71 mmol, 83.5%) as a crystalline solid. Trifluoroacetic acid (6.45 ml, 86.8 mmol) was added dropwise to a solution of (R)-{1-[4-(2-methoxy-pyridin-3-yl)-phenyl]-ethyl}carbamic acid tert-butyl ester (645 mg, 1.97 mmol) in dichloromethane (6.45 ml) under a nitrogen atmosphere at 0° C. After stirring for 1 h at 0° C. the solvent was evaporated. Methanol (20 ml) was added and the mixture added to a Strata™ 5 g/20 ml SCX column. The intermediate amine was eluted with 2M ammonia in methanol. The solvent was evaporated to give (R)-1-[4-(2-methoxy-pyridin-3-yl)-phenyl]-ethylamine as a gum (425 mg, 1.86 mmol, 94.6%). The title compound was then prepared in a similar manner to (R)-2,5-dimethyl-furan-3-sulfonic acid [1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethyl]-amide (Example 10) using 4-bromo-3-thiophenesulfonyl chloride and 1-[4-(2-Methoxy-pyridin-3-yl)-phenyl]-ethylamine. Title compound: 1H NMR (400 MHz, CDCl3): δ 8.17 (d, 1H), 7.56 (d, 1H), 7.41, 7.20 (a/b, 4H), 7.38 (m, 1H), 6.99-6.92 (m, 2H), 5.27 (d, 1H), 4.60 (m, 1H), 3.97 (s, 3H), 1.54 (d, 3H) ppm; MS (ESI) m/z: 453 [M+H]+.
Reaction SMILES: C(O)C.Cl.[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15](=[NH:19])OCC)([O-:7])=[O:6].CO[CH:22](OC)[CH2:23][NH2:24].Cl>[OH-].[Na+]>[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]1[NH:19][CH:22]=[CH:23][N:24]=1)([O-:7])=[O:6]
Reactant: CCOC(=N)Cc1ccccc1[N+](=O)[O-]
Reactant: COC(CN)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1Cc1ncc[nH]1
Temperature: 25 °C

Procedure:
Ethanol (2,200 ml) and 5,156 g (8.81 moles) of ethyl 2-(2-nitrophenyl)acetimidate hydrochloride were charged into a 22 liter flask. The suspension was stirred under nitrogen at room temperature and 1022.9 g (9.73 moles) of aminoacetaldehyde dimethylacetal were added all at once. The mixture was stirred for 1 hour and 1,693 ml of 12N hydrochloric acid were added all at once to cause a gentle exotherm (to 40°). Heat was then applied and the temperature was maintained at 70°-80° for 30 minutes. The solution was cooled to 20° (ice-water bath) and diluted with 2,700 ml of 10N sodium hydroxide solution to precipitate the product. The suspension was stirred at 10° for 1 hour under nitrogen atmosphere, the solid collected by filtration and washed with 3×2,000 ml of water to give 2-(2-nitrobenzyl)-imidazole, m.p. 155°-7°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][C:8]=1F)#[N:2].C(O[CH2:24][CH3:25])(=O)C>CS(C)=O>[N:2]1([C:8]2[CH:7]=[CH:6][C:5]([C:10]3[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=3)[C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:3]=2[C:1]#[N:2])[CH2:25][CH2:24][CH2:7][CH2:8][CH2:3][CH2:1]1
Reactant: CCOC(C)=O
Reactant: COC(=O)c1ccnc(-c2ccc(F)c(C#N)c2)c1
Solvent: CS(C)=O
Product: COC(=O)c1ccnc(-c2ccc(N3CCCCCC3)c(C#N)c2)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
In 7 ml of DMSO was dissolved 2.22 g of methyl 2-(3-cyano-4-fluorophenyl)isonicotinate, and 2.44 ml of hexamethyleneimine was added thereto, followed by heating at 50° C. for 5 hours. After cooling, the reaction solution was diluted with ethyl acetate and was washed with 1M hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, and brine, successively. The organic layer was dried and then concentrated under reduced pressure and the resulting residue was dissolved in a mixed solvent of ethyl acetate and diisopropyl ether. Activated carbon was added thereto, followed by stirring for 1 hour. Then, the activated carbon was removed by filtration and washed with ethyl acetate. The resulting filtrate and washing liquid were combined and concentrated to obtain 2.58 g of methyl 2-(4-azepan-1-yl-3-cyanophenyl)isonicotinate. (2) Then, 2.49 g of the compound was dissolved in a mixed solvent of 15 ml of methanol and 30 ml of THF, and 11 ml of a 1M aqueous sodium hydroxide solution was added thereto, followed by heating at 80° C. for 1 hour.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[CH:4][C:3]=1[N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>Cl>[CH:15](=[N:9][NH:8][C:5]1[N:6]=[N:7][C:2]([Cl:1])=[C:3]([N:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)[CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccccc1
Reactant: NNc1cc(N2CCCC2)c(Cl)nn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Clc1nnc(NN=Cc2ccccc2)cc1N1CCCC1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 73.6 %

Procedure:
To a solution of 6-chloro-5-(pyrrolidin-1-yl)pyridazin-3-ylhydrazine (14 g, 0.063 mol) in 0.1 N hydrochloric acid (600 ml) was added benzaldehyde (6.4 ml, 0.063 mol) dropwise at room temperature. The mixture was stirred at 60° C. for 15 min, yielding a thick slurry. The pH of the solvent was adjusted to ˜11 with 4 N aqueous sodium hydroxide solution, and the precipitate filtered off. The residue was washed with water, ethanol and diethyl ether, yielding the title compound as a white solid (14 g, 73%). 1H NMR (360 MHz, DMSO) δ1.93 (4H, m), 3.58 (4H, m), 6.57 (1H, s), 7.35 (1H, m), 7.39 (2H, m), 7.66 (2H, d, J=7.1 Hz), 8.06 (1H, s), 11.16 (1H, s). MS (ES+) m/e 302 [MH]+, 304 [MH]+.
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:8]=[C:9]1[O:13][C:11](=[O:12])[CH2:10]1>CO.CCCCCC>[CH2:1]([NH:7][C:11](=[O:12])[CH2:10][C:9](=[O:13])[CH3:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C=C1CC(=O)O1
Reactant: CCCCCCN
Solvent: CCCCCC
Solvent: CO
Product: CCCCCCNC(=O)CC(C)=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 51.1 %

Procedure:
A solution of 27.83 g (0.28 mol) N-n-hexylamine was added dropwise to a solution of 20.00 g (0.24) diketene in 100 ml MeOH at 0° C. After stirring for 4 hours at 0° C., no starting material was detected anymore by thin-layer chromatography. The reaction mixture was spun off, and the obtained solid was taken up in 200 ml n-hexane, filtrated off and dried overnight under vacuum. 22.53 g of product was obtained as a white solid.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)([O-])=O.[F-:15].[K+]>>[F:15][C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: [F-]
Agent: [K+]
Product: O=C1OC(=O)c2cc(F)ccc21
Temperature: 100 °C
Reaction time: 4 h
Yield: 59.6 %

Procedure:
Into a reaction vessel were placed 290 grams (1.5 mol) 4-nitrophthalic anhydride and 91 grams (1.57 mol) of anhydrous potassium fluoride. The reaction vessel was closed and shaken to mix the reactants and was then attached to a distilling head, receiver, and nitrogen inlet. The mixture was heated, under a nitrogen blanket beginning at 100°C. while the temperature was raised to 230°C. over a 25 minute period and kept at a temperature of 230°-250°C. for about 4 hours. After 2 hours, the nitrogen line was replaced by a vacuum line and the system evacuated to about 160 mm. This resulted in the collection over the next 2 hours of 148.5 grams (60% yield) 4-fluorophthalic anhydride, which upon analysis indicated the material to be greater than 97% pure (melting point 72°-76°C.).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].CCN(C(C)C)C(C)C.[NH:21]1[CH2:26][CH2:25][O:24][C@H:23]([CH2:27][OH:28])[CH2:22]1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[OH:28][CH2:27][C@H:23]1[O:24][CH2:25][CH2:26][N:21]([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[CH2:22]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC[C@@H]1CNCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCO[C@H](CO)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.8 %

Procedure:
Benzyl chloroformate (0.598 mL, 0.956 mmol, 3.5 equiv) was added slowly to a solution of DIPEA (0.477 mL, 2.73 mmol, 10 equiv) and 2.20.1a (64 mg, 0.547 mmol) in DCM (2 mL). The resulting mixture was stirred at room temperature for 4 hours. EtOAc and saturated aqueous NaHCO3 solution were then added to the mixture. The phases were separated and the organic layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The remaining oil was purified by silica gel column chromatography (EtOAc/heptane, 40-100%) to give product 74 mg (54% yield). MS m/z (M+1) 252.2.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[C:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])[CH3:27]>>[C:26]([N:29]1[CH2:34][CH2:33][N:32]([C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][N:8]([C:12]4[CH:17]=[C:16]([N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)[N:15]=[C:14]([NH2:25])[N:13]=4)[CH2:9]3)=[CH:4][CH:3]=2)[CH2:31][CH2:30]1)(=[O:28])[CH3:27]
Reactant: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)CC3)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 30 starting from 4-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine and 1-acetylpiperazine (Aldrich Cat. No. 359513). LCMS (M+H)+: m/z=451.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH:16]([CH:20]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[OH:21])[C:17](O)=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:29]([O:36][C:37](=[O:50])[C@H:38]([CH2:40][C:41]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[NH:43][CH:42]=1)[NH2:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.CN1CCOCC1.Cl>CN(C)C=O.C(OCC)C>[CH2:29]([O:36][C:37](=[O:50])[C@H:38]([CH2:40][C:41]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[NH:43][CH:42]=1)[NH:39][C:17](=[O:18])[CH:16]([CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:20]([CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1)[OH:21])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(O)C(Cc1ccccc1OCc1ccccc1)C(O)C1CCCCC1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1)C(Cc1ccccc1OCc1ccccc1)C(O)C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
To a solution of (2RS,3RS)-2-(2-benzyloxyphenylmethyl)-3-cyclohexyl-3-hydroxypropionic acid (111 mg) in dimethylformamide (3 ml) were added L-tryptophan benzyl ester hydrochloride (198 mg), 1-hydroxybenzotriazole hydrate (60.8 mg), 1,3-dicyclohexylcarbodiimide (80.5 mg) and 4-methylmorpholine (91 mg) successively. After being stirred for 16 hours at ambient temperature, the mixture was poured into a mixture of diethyl ether and aqueous 1N hydrochloric acid solution. The organic layer was separated and the aqueous layer was extracted with diethyl ether. The combined organic layer was washed with aqueous bicarbonate solution and brine, dried and evaporated under reduced pressure. The residue was purified by chromatography to afford N-[(2RS,3RS)-2-(2-benzyloxyphenylmethyl)-3-cyclohexyl-3 hydroxypropionyl]-L-tryptophan benzyl ester (171 mg).
Reaction SMILES: [ClH:1].[C:2]([CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9](/[CH:12]=[C:13]2\[CH2:14][N:15]([CH:20]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[C:21]([CH:23]3[CH2:25][CH2:24]3)=[O:22])[CH2:16][CH2:17][C@H:18]\2[SH:19])=[N:8]1)([OH:4])=[O:3].N1C=CC=CC=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>ClCCl>[ClH:1].[C:39]([S:19][C@@H:18]1[CH2:17][CH2:16][N:15]([CH:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[C:21]([CH:23]2[CH2:25][CH2:24]2)=[O:22])[CH2:14]/[C:13]/1=[CH:12]\[C:9]1[CH:10]=[CH:11][N:7]([CH2:6][CH2:5][C:2]([OH:4])=[O:3])[N:8]=1)(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)CCn1ccc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CC[C@H]2S)n1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)S[C@@H]1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1ccn(CCC(=O)O)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of (4R)-(E)-3-{[1-(2-carboxyethyl)-1H-pyrazol-3-yl]methylidene}-1-[(1RS)-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-sulfanylpiperidine hydrochloride (249.4 mg) in dichloromethane (12 ml) were added pyridine (0.24 ml) and acetic anhydride (0.24 ml) at 0° C. After the mixture was stirred at room temperature for 2.5 hours, solvents were removed under reduced pressure and the residue was purified by silica gel chromatography using dichloromethane and methanol (99:1 to 93:7) as eluents to afford the free base of the title compound (75.5 mg), which was treated in acetonitrile (2 ml) with a 4N hydrogen chloride dioxane solution (120 μl). The solvent and excess hydrogen chloride were removed under reduced pressure to afford the title compound (79.4 mg, yield: 29%) as a pale yellow amorphous solid.