Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([N:16]2[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]2=[O:26])[CH:6]=[CH:7][C:8]=1[C:9]1[CH2:14][CH2:13]S[C:11](=[O:15])[CH:10]=1)C.[OH:27]C1C=C(N2C[C@H](CNC(=O)C)OC2=O)C=CC=1C1CCNC(=O)C=1>>[O:27]=[C:11]1[CH:10]=[C:9]([C:8]2[CH:3]=[CH:4][C:5]([N:16]3[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]3=[O:26])=[CH:6][CH:7]=2)[CH2:14][CH2:13][O:15]1
Reactant: CCc1cc(N2C[C@H](CNC(C)=O)OC2=O)ccc1C1=CC(=O)SCC1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CC(=O)NCC3)c(O)c2)C(=O)O1
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CC(=O)OCC3)cc2)C(=O)O1

Procedure:
N-((5S)-3-(3-ethyl-4-(2-oxo-5,6-dihydrothiapyran-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide and N-((5S)-3-(3-hydroxy-4-(2-oxo-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide are excluded.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]1[C:19]3[C:14](=[N:15][CH:16]=[CH:17][C:18]=3[NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[N:13]([CH:30]3[CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]3)[CH:12]=1)[N:7]([CH3:41])[CH2:6][CH2:5]2.Cl.O1CCOCC1>C(Cl)Cl>[NH:32]1[CH2:31][CH:30]([N:13]2[C:14]3=[N:15][CH:16]=[CH:17][C:18]([NH:20][S:21]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)(=[O:23])=[O:22])=[C:19]3[C:11]([C:10]3[CH:9]=[C:8]4[C:4]([CH2:5][CH2:6][N:7]4[CH3:41])=[CH:3][C:2]=3[F:1])=[CH:12]2)[CH2:33]1
Reactant: CN1CCc2cc(F)c(-c3cn(C4CN(C(=O)OC(C)(C)C)C4)c4nccc(NS(=O)(=O)c5ccccc5)c34)cc21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN1CCc2cc(F)c(-c3cn(C4CNC4)c4nccc(NS(=O)(=O)c5ccccc5)c34)cc21
Yield: 97.4 %

Procedure:
To a solution of tert-butyl 3-(3-(5-fluoro-1-methylindolin-6-yl)-4-(phenylsulfonamido)-1H-pyrrolo[2,3-b]pyridin-1-yl)azetidine-1-carboxylate (D33) (489 mg, 0.847 mmol) in DCM (8 mL) was added 4M HCl in dioxane (4.23 mL, 16.93 mmol). The final mixture was stirred at RT for 6 hours. The mixture was concentrated in vacuo. The residue was dissolved in MeOH and passed through a SCX cartridge eluting with MeOH followed by 2M ammonia in MeOH to give the title compound (394 mg). LCMS (A): m/z (M+H)+ 478, C25H24FN5O2S requires 477 (acidic).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:20][O-:21].[Na+]>C1COCC1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[N:15][C:16]([O:21][CH3:20])=[CH:17][CH:18]=2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(NC(=O)c2ccc(Cl)nc2)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2ccc(C(C)C)cc2)cn1
Temperature: 50 °C
Reaction time: 24 h
Yield: 77.2 %

Procedure:
N-(4-Isopropylphenyl)-6-chloropyridine-3-carboxamide (1.00 g) was dissolved in THF (10 mL) and sodium methoxide (0.21 g) was added. The mixture was stirred at 50° C. for one day. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give N-(4-isopropylphenyl)-6-methoxypyridine-3-carboxamide (0.76 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:27](O)=[O:28])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:31]=[C:32]([NH2:34])[CH3:33]>>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:24])([F:26])[F:25])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:27]3[O:28][N:34]=[C:32]([CH3:33])[N:31]=3)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(N)=NO
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Product: Cc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCC(O)CC3)C2)n1

Procedure:
200 mg (0.480 mmol) of the compound from Example 63A and 71 mg (0.961 mmol) of N′-hydroxyethanimidamide were reacted according to the General Method 2. Yield: 144 mg (62% of theory)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1/[C:15](=[CH:20]\[O:21][CH3:22])/[C:16]([O:18][CH3:19])=[O:17].[OH:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH:27]=[O:28]>C(#N)C>[CH:27]([C:26]1[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:24]([CH:25]=1)[O:23][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1/[C:15](=[CH:20]\[O:21][CH3:22])/[C:16]([O:18][CH3:19])=[O:17])=[O:28]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1CBr
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CO/C=C(/C(=O)OC)c1ccccc1COc1cc(C=O)ccc1OC
Reaction time: 6 h
Yield: 49.5 %

Procedure:
Potassium carbonate (0.35 g, 2.6 mmol) was added to a solution (E)-methyl 2-(2-(bromomethyl)phenyl)-3-methoxyacrylate (0.5 g, 1.7 mmol) and 3-hydroxy-4-methoxybenzaldehyde (0.32 g, 2.1 mmol) in 20 mL of acetonitrile (CH3CN) which was then stirred for 6 hours under reflux. The reaction solvent was removed by vacuum concentration. The residue was stirred in water (20 mL), and the aqueous layer was extracted twice with 20 mL of dichloromethane. The organic was dried over anhydrous magnesium sulfate, filtered and concentrated in a vacuum to remove the solvent. Purification through silica gel chromatography afforded the title compound as a white oil (0.3 g, yield 49%).
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12](I)[CH:11]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[CH:17]1([SH:22])[CH2:21][CH2:20][CH2:19][CH2:18]1>CN1CCCC1=O.C(N(CC)CC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([Si:5]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([S:22][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:11]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: SC1CCCC1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(I)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(SC2CCCC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
Tert-butyl[(3-iodobenzyl)oxy]dimethylsilane (WO9513095) (1.44 g) in dry 1-methyl-2-pyrrolidone (15 ml) and triethylamine (4 ml) was stirred at room temperature under nitrogen. 1-1′Bis(diphenylphosphino)ferrocene (110 mg) and tris(dibenzylideneacetone)dipalladium(0) (258 mg) were added and the mixture was stirred for 15 min. Cyclopentyl mercaptan (0.42 g) was then added, and the reaction mixture stirred at 60° C. for 2 h. The reaction mixture was cooled to room temperature, poured onto water and extracted with diethyl ether. The combined organic extracts were dried (MgSO4) and the solvent evaporated in vacuo. The residue was purified on a 50 g SPE, eluting with a stepped gradient of 10 to 100% dichloromethane-cyclohexane to give the title compound (1.09 g) LCMS RT=4.67 min
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][C:18]([OH:20])=O)=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22].[NH:25]1[CH2:30][CH2:29][CH2:28][CH:27]([OH:31])[CH2:26]1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][C:18]([N:25]2[CH2:30][CH2:29][CH2:28][CH:27]([OH:31])[CH2:26]2)=[O:20])=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22]
Reactant: O=C(O)CNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: OC1CCCNC1
Product: O=C(NCC(=O)N1CCCC(O)C1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 70 from 2-(5-((3,5-dichloropyridin-4-yl)thio)-4-nitrothiophene-2-carboxamido)acetic acid (200 mg, 0.49 mmol) from example 210 and piperidin-3-ol (59.0 mg, 0.59 mmol). The title compound was obtained as a solid (25.0 mg, 11% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (1H, m), 8.51 (1H, s), 4.87 (1H, m), 4.08 (2H, m), 3.58 (1H, m), 3.48 (1H, m), 3.38 (1H, m), 3.15 (1H, m), 2.60 (1H, m), 1.85 (1H, m), 1.75 (1H, m), 1.47 (1H, m), 1.33 (1H, m). MS m/z: 491.23, 493.26 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:15][CH3:16])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([CH:13]=O)[N:12]=2)[C:8]=1[CH3:9])[CH3:2].[NH2:17]OS(O)(=O)=O>O>[CH2:1]([C:3]1[C:4]([O:15][CH3:16])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13]#[N:17])[N:12]=2)[C:8]=1[CH3:9])[CH3:2]
Reactant: CCc1c(OC)nc2nc(C=O)cn2c1C
Reactant: NOS(=O)(=O)O
Solvent: O
Product: CCc1c(OC)nc2nc(C#N)cn2c1C
Yield: 82.7 %

Procedure:
To a rapidly stirred suspension of 19.84 g of 6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidine-2-carboxaldehyde in 300 ml of water at room temperature was added all at once a solution of 13.30 g of hydroxylamine-o-sulfonic acid in 250 ml of water. After 40 minutes when the intermediate had precipitated, 8 g of solid sodium hydroxide were added and the intermediate dissolved. After 1 hour when the product had precipitated, the mixture was filtered and the solid was washed with water, dried, then crystallized from ethyl acetate to obtain 16.18 g of 6-ethyl-7-methoxy-5-methylimidazo [1,2-a]pyrimidine-2-carbonitrile (83% yield) as a pale yellow solid melting at 166°-168° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[Br:9].[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O.O>[Br:9][C:3]1[C:2]([F:1])=[C:7]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:5][C:4]=1[F:8]
Reactant: Fc1cccc(F)c1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c(Br)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
A mixture of 2,6-difluorobromobenzene (125.5 g, 650 mmol) in 98% sulphuric acid (250 ml) was cooled in an ice-water bath and then treated with a 1:1 mixture of 98% sulphuric acid and fuming nitric acid (100 ml) added at such a rate that the internal temperature never exceeded 35° C. Once addition was complete the reaction was stirred at ambient temperature for 3 h then poured onto ice. This mixture was diluted with water (final volume 5 l), the resulting solid collected by filtration, washed with water, then dried under vacuum over phosphorus pentoxide, to afford 2-bromo-1,3-difluoro-4-nitrobenzene as a cream-coloured solid (145 g, 94%): δH (360 MHz, CDCl3) 7.10-7.15 (1H, m), 8.09-8.16 (1H, m).
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:8]=3[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]4)[CH2:2][CH2:3]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: Nc1nc(N)c2c(N3CCN(S(=O)(=O)c4ccc(F)cc4)CC3)cccc2n1
Yield: 41 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 4-fluorobenzene-sulfonyl chloride (79.8 mg; 0.41 mmol) to obtain 33.2 mg. (41% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.89 (m, 2H), 7.54 (t, J=8.5 Hz, 2H), 7.38 (t, J=7.5 Hz, 1H), 6.97 (d, J=8.5 Hz, 1H), 6.93 (s, 1H), 6.83 (d, J=8.0 Hz, 1H), 5.92 (br s, 2H), 3.73 (d, J=11.5 Hz, 2H), 3.11 (d, J=12.0 Hz, 2H), 2.85 (t, J=11.5 Hz, 1H), 2.59 (t, J=11.5 Hz, 2H). ESIMS+404.4.5 m/z
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][C:13]([CH3:15])=O.S(Cl)(Cl)=O>CN(C1C=CN=CC=1)C.COCCOC>[OH:11][C:9]1[CH:8]=[CH:7][C:3]2[C:4](=[O:6])[O:5][C:13]([CH3:15])([CH3:12])[O:1][C:2]=2[CH:10]=1
Reactant: CC(C)=O
Reactant: O=C(O)c1ccc(O)cc1O
Agent: CN(C)c1ccncc1
Solvent: COCCOC
Solvent: O=S(Cl)Cl
Product: CC1(C)OC(=O)c2ccc(O)cc2O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
To a cold mixture of 2,4-dihydroxybenzoic acid (25.9 g, 168.1 mmol), acetone (12.7 g, 218.5 mmol) and DMAP (1.03 g, 8.4 mmol) in 1,2-dimethoxyethane (DME) (96 mL) in an ice bath was added thionyl chloride (26.0 g, 218.5 mml) slowly. Resulting mixture was stirred at 0° C. for 1 h and then at rt for 23 h. Reaction mixture was quenched at 0° C. with saturated NaHCO3 solution (slowly with caution). After 200 mL of saturated NaHCO3 solution was added, NaHCO3 solid was added in small portion to the mixture until pH reaches 7-8. It was diluted with water (200 mL) and extracted with EtOAc (2×200 mL). Organic layers were combined and washed with brine, dried over MgSO4, filtered and concentrated. Crude residue was triturated with CH2Cl2 (100 mL). Solid was collected and dried to provide the title compound (10.4 g). 1H NMR (200 MHz, DMSO-d6): δ (ppm)=7.66 (d, J=7.8 Hz, 1H), 6.59 (d, J=7.8 Hz, 1H), 6.36 (s, 1H), 1.65 (s, 6H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([CH3:10])=[O:9].CC(C)=O.[N-:15]=[N+:16]=[N-:17].[Na+]>O>[N:15]([CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([CH3:10])=[O:9])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)c1sccc1CBr
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)c1sccc1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of methyl 3-bromomethyl-2-thienyl ketone (5 g., 0.023 mole) in 42 ml. of acetone and 4 ml. of water was added sodium azide (1.56 g., 0.024 mole) with caution (exothermic!). The resulting solution was stirred at room temperature for 2.5 hours, the acetone evaporated, the residue diluted with water and extracted with diethyl ether. The combined extracts were washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and the dried extracts evaporated to dryness to obtain 4.0 g. (97%) of yellow oil. 1H--NMR (CDCl3), ppm. (δ): 7.5 (d, J=5, aromatic-H), 7.2 (d, J=5, aromatic-H), 4.75 (s, CH2N3), 2.5 (s, CH3); IR spectrum (film, cm.-1 : 3100, 2100 (N3), 1660, 1525 and 1420.
Reaction SMILES: C(OP([CH2:9][C:10]1[S:11][C:12]([Br:15])=[CH:13][CH:14]=1)(=O)OCC)C.[H-].[Na+].[CH3:18][C:19]([CH3:21])=O.O>O1CCCC1>[Br:15][C:12]1[S:11][C:10]([CH:9]=[C:19]([CH3:21])[CH3:18])=[CH:14][CH:13]=1
Reactant: CCOP(=O)(Cc1ccc(Br)s1)OCC
Reactant: CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)=Cc1ccc(Br)s1
Temperature: 25 °C
Yield: 2.7 %

Procedure:
(5-Bromothiophen-2-ylmethyl)phosphonic acid diethyl ester described in Preparation Example 142 (3.13 g, 10 mmol) was dissolved in tetrahydrofuran (20 mL), sodium hydride (0.40 g, 10 mmol, 60% in oil) was added to this solution under stirring at room temperature. The solution was stirred for 30 minutes at 60° C., then, acetone (1 g, 17.2 mmol) was added, and the solution was further stirred for 30 minutes. Water (100 mL) was added to the reaction solution, which was then extracted with hexane (50 mL), the organic layer was washed with water, dried over anhydrous magnesium sulfate, then, the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane), and the title compound (60 mg, 0.27 mmol, 2.7%) was obtained as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[H-].[Na+].[CH3:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br>CN(C=O)C>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([O:1][CH2:15][C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[CH3:18])[CH:11]=[C:10]([OH:12])[CH:9]=1
Reactant: Cc1ccccc1CBr
Reactant: COC(=O)c1cc(O)cc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O)cc(OCc2ccccc2C)c1
Temperature: 15 °C
Reaction time: 0.33 h
Yield: 29.8 %

Procedure:
To a solution of methyl 3,5-dihydroxybenzoate (50 g, 0.30 mol) in DMF (500 ml) at 0° C. was added sodium hydride (10.8 g, 0.27 mol) portion wise. The reaction was allowed to warm to 15° C., and stirred for 20 minutes. The mixture was re-cooled to 0° C. and a solution of 2-methylbenzyl bromide (36 ml, 0.27 mol) in DMF (50 ml) was added over 30 minutes. The reaction was warmed to ambient temperature and concentrated in vacuo. The residual oil was partitioned between ethyl acetate (500 ml) and water (250 ml), and the ethyl acetate layer was separated, washed with water and evaporated. The residue was purified by column chromatograph on silica gel (gradient, 0-100% ethyl acetate in isohexane) to give the desired compound (21.9 g, 27%).
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([F:16])[CH:11]=1)[C:5](=O)[CH:6]([CH3:8])[CH3:7].[NH2:18]N>CO.CCOC(C)=O>[F:16][C:12]1[CH:11]=[C:10]([C:4]2[CH:3]=[N:2][NH:18][C:5]=2[CH:6]([CH3:8])[CH3:7])[CH:15]=[CH:14][N:13]=1
Reactant: NN
Reactant: CC(C)C(=O)C(=CN(C)C)c1ccnc(F)c1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)c1[nH]ncc1-c1ccnc(F)c1
Reaction time: 4 h
Yield: 69.9 %

Procedure:
To a solution of 1-dimethylamino-2-(2-fluoro-pyridin-4-yl)-4-methyl-pent-1-en-3-one (crude, 26.5 mmol) in methanol (50 mL) is added hydrazine (0.84 mL, 26.5 mmol) at 0° C. The reaction mixture is stirred for 4 h, diluted with EtOAc, and washed with water. The organic layer is washed with brine, dried over sodium sulfate, and concentrated in vacuo. Purification by flash chromatography (SiO2, EtOAc/heptan 5:1) afforded 3.8 g of 2-fluoro-4-(5-isopropyl-1H-pyrazol-4-yl)-pyridine as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].CCN(CC)CC.[S:20](Cl)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:27][C:26]1[CH:28]=[CH:29][C:23]([S:20]([O:1][CH2:2][CH2:3][N:4]([C:5]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:11])[CH3:12])(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN(CCO)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCN(C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.5 %

Procedure:
To a mixture of 112a (9.0 g, 51 mmol), and Et3N (18.6 mL, 51 mmol) in DCM (100 mL) was added TsCl (9.77 g, 51 mmol). The mixture was stirred at rt for 4 h and concentrated. The residue was diluted with EA, washed with water. The organic layer was dried and concentrated to give 2-(tert-butoxycarbonyl(methyl)amino)ethyl 4-methylbenzenesulfonate 112b (10.0 g, 61%) as light yellow oil. ESI-LCMS: m/z=230.0
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]([F:36])([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:25][CH2:26][C:27]([F:36])([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][CH2:29]1)=[O:23]
Reactant: Cc1ccc(C)c(Nc2c(C(=O)N3CCC(F)(c4ccccc4)CC3)cnc3c(C(=O)O)cnn23)c1
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CCC(F)(c4ccccc4)CC3)cnc12
Yield: 34.6 %

Procedure:
In the same manner as in Example 1, step 6and using 7-(2,5-dimethylphenylamino)-6-(4-fluoro-4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (91 mg, 0.19 mmol) obtained in step 4 and ethanesulfonamide (100 mg, 0.95 mmol), the title compound (38 mg, 35%) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[O:5][CH2:6][CH2:7][N:8]([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].[NH:23]1[CH:27]=[N:26][CH:25]=[N:24]1>CN1C(=O)CCC1.ClCCl.[Cu]I>[CH3:9][N:8]([CH3:10])[CH2:7][CH2:6][O:5][C:4]1[CH:3]=[C:2]([N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=1
Reactant: c1nc[nH]n1
Reactant: CN(C)CCOc1cc(Br)cc([N+](=O)[O-])c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CN(C)CCOc1cc(-n2cncn2)cc([N+](=O)[O-])c1
Yield: 57 %

Procedure:
Intermediate 16A (200 mg, 0.69 mmol), copper(I) iodide (65.9 mg, 0.35 mmol), potassium carbonate (287 mg, 2.1 mmol) and 1H-1,2,4-triazole (143 mg, 2.075 mmol) in NMP (2 mL) were heated at 120° C. for 6 hours. The reaction mixture was diluted with dichloromethane, and filtered through a plug of silica gel and washed with ethyl acetate. The filtrate was concentrated, and the residue was purified by reverse phase HPLC to obtain Intermediate 16B (109 mg, 56.8% yield) as a yellow solid. HPLC: Rt=0.74 min. (PHENOMENEX® Luna 5 micron C18 4.6×30 mm, 10-90% aqueous methanol containing 0.1% TFA, 2 min. gradient, flow rate=5 mL/min, detection at 254 nm). MS (ES): m/z=278.08 [M+H]+.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([OH:23])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:39][C@H:40]([C:48]([OH:50])=[O:49])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([NH:39][C@H:40]([C:48]([OH:50])=[O:49])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:23])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Yield: 39.3 %

Procedure:
Starting from 3-hexadecanoyloxyoctadecanoic acid (1 g) prepared by the method described in Preparation 2 and L-phenylalanine (1 g), N-(3-hexadecanoyloxyoctadecanoyl)-L-phenylalanine (500 mg) was obtained as powders according to a similar manner to that of Example 6.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[C:7]([Cl:8])=[N:6][C:5](=[C:9]([Cl:11])[Cl:10])[N:4]=1>C1(C)C=CC=CC=1>[Cl:2][C:3]1[N:4]=[C:5]([C:9]([Cl:1])([Cl:11])[Cl:10])[NH:6][C:7]=1[Cl:8]
Reactant: ClC1=NC(=C(Cl)Cl)N=C1Cl
Reactant: Cl
Solvent: Cc1ccccc1
Product: Clc1nc(C(Cl)(Cl)Cl)[nH]c1Cl
Yield: 89 %

Procedure:
Dry hydrogen chloride was passed into a solution of 218 g (1.0 mol) of 4,5-dichloro-2-dichloromethyleneimidazole in about 2 liters of dry toluene until the formation of a precipitate had ended (at least 1 mol). After cooling (the HCl addition took place exothermically), filtering off and drying, 235 g (89% of theory) of 4,5-dichloro-2-trichloromethyl-imidazole of melting point 210° C. (with decomposition) were obtained.
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]2[CH:19]=[CH:18][C:13]([C:14](OC)=[O:15])=[CH:12][C:11]=2[C:20]2([CH:25]=[CH2:26])[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)C>C1COCC1>[F:1][C:2]1[C:3]([C:10]2[CH:19]=[CH:18][C:13]([CH2:14][OH:15])=[CH:12][C:11]=2[C:20]2([CH:25]=[CH2:26])[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: C=CC1(c2cc(C(=O)OC)ccc2-c2cc(OC)ncc2F)CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC1(c2cc(CO)ccc2-c2cc(OC)ncc2F)CCCC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 4-(5-fluoro-2-methoxypyridin-4-yl)-3-(1-vinylcyclopentyl)benzoate 26.5 (51.0 mg, 143 μmol) in THF (2.0 mL) was slowly added LAH, (1.0 M solution in diethyl ether (0.30 mL, 287 μmol)) at room temperature. The resulting mixture was stirred at 50° C. for 1 hour. The product was obtained after work up and solvent removal. The desired product was used in the next step without further purification. MS ESI (pos.) m/e: 328.2 (M+H)+.