Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]2[CH:21]=[N:20][N:19]=[N:18]2)=[C:6]([CH:16]=1)[CH2:7][NH:8][C:9](=[O:15])[C@@H:10]1[CH2:14][CH2:13][CH2:12][NH:11]1.C(OC([NH:29][C@@H:30]([C:35](O)=[O:36])[CH2:31][CH:32]1[CH2:34][CH2:33]1)=O)(C)(C)C.Cl.CCOC(C)=O>>[CH:32]1([CH2:31][C@H:30]([C:35]([N:11]2[CH2:12][CH2:13][CH2:14][C@H:10]2[C:9]([NH:8][CH2:7][C:6]2[CH:16]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[N:17]2[CH:21]=[N:20][N:19]=[N:18]2)=[O:15])=[O:36])[NH2:29])[CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CC1)C(=O)O
Reactant: O=C(NCc1cc(F)ccc1-n1cnnn1)[C@@H]1CCCN1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@H](CC1CC1)C(=O)N1CCC[C@H]1C(=O)NCc1cc(F)ccc1-n1cnnn1

Procedure:
The title compound was prepared from N-[5-fluoro-2-(1H-tetraazol-1-yl)benzyl]-L-prolinamide and N-(tert-butoxycarbonyl)-3-cyclopropyl-D-alanine (Example 31, Step C) followed by deprotection with HCl-EtOAc essentially according to the procedures described in Example 31, Steps D and E. HPLC RT=0.93 min (Method B); LCMS (M+H): 402; 1H NMR (400 MHz, DMSO-d6): δ 9.86 (s, 1H), 8.66 (t, J=6 Hz, 1H), 8.22–8.35 (m, 2H), 7.64–7.67 (m, 1H), 7.38–7.39 (m, 2H), 4.18–4.30 (m, 1H), 4.00–4.22 (m, 3H), 3.73–3.82 (m, 1H), 3.52–3.58 (m, 1H), 2.0–2.13 (m, 1H), 1.77–1.94 (m, 3H), 1.65–1.74 (m, 1H), 1.52–1.61 (m, 1H), 0.77–0.85 (m, 1H), 0.44–0.48 (m, 2H), 0.05–0.17 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:48])[N:10]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:47])[C:26]2[CH:31]=[CH:30][C:29]([CH2:32][N:33](C(OC(C)(C)C)=O)[CH2:34][C:35]3[NH:36][CH:37]=[CH:38][N:39]=3)=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1>CO>[CH2:1]([O:8][C:9](=[O:48])[N:10]([CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:47])[C:26]2[CH:31]=[CH:30][C:29]([CH2:32][NH:33][CH2:34][C:35]3[NH:39][CH:38]=[CH:37][N:36]=3)=[CH:28][CH:27]=2)=[CH:22][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(=O)Nc2ccc(CN(C(=O)OCc3ccccc3)C3CCCCC3)cc2)cc1)Cc1ncc[nH]1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(Nc1ccc(CN(C(=O)OCc2ccccc2)C2CCCCC2)cc1)c1ccc(CNCc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
The compound (1.82 g) obtained in Example 87-3 was dissolved in methanol (18 ml) and then added with a 4 mol/l hydrogen chloride/dioxane solution (18 ml), followed by stirring at room temperature for 2 hours. After the reaction, the solvent was distilled off. Then, the residue was adjusted to pH 11 with a 1 mol/l sodium hydroxide aqueous solution and extracted with chloroform, followed by drying with anhydrous magnesium sulfate. Subsequently, the solvent was distilled off, thereby obtaining the subject compound (1.48 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].Br[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C>C(O)(C)C.O.C(O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:9][C:6]1[CH:5]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:3]=[C:2]([Cl:1])[C:7]=1[CH3:8]
Reactant: Fc1ccc(Br)cc1
Reactant: Cc1c(Cl)cc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Solvent: O
Solvent: CCO
Product: Cc1c(Cl)cc(-c2ccc(F)cc2)cc1Cl
Temperature: 25 °C
Yield: 85.9 %

Procedure:
Alternate Step 2) Stir a slurry of 2-(3,5-dichloro-4-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (300 g, 1.05 moles) in 2 L of isopropanol under a blanket of nitrogen. Add p-bromofluorobenzene 61619 (150 mL; 1.36 moles) followed by an aqueous solution of potassium carbonate (160.5 g; 1.15 moles) in 300 mL water. Rinse the addition funnel with 400 mL isopropanol. Add triphenylphosphine (12.3 g; 46.89 mmoles) and Pd(OAc)2 (2.35 g; 10.47 mmoles) and heat the mixture at 75° C. for 8 h. Add water (300 mL) and allow the mixture to cool to room temperature to afford a slurry. Cool the slurry in an ice bath, collect the solid by filtration and rinse with 350 mL of 6:1 IPA-water. Dry the solid in a vacuum oven at room temperature overnight to afford 345 g of crude product. Suspend the crude product in 2.2 L of ethanol and heat at 70° C. to afford a solution. Add Darco (35 g) and stir for 30 min. Filter the mixture through a pad of Hyflo (Celite) and allow the solution to cool to room temperature to afford a slurry. Cool the slurry to 5° C., collect the solid by filtration, and rinse with cold ethanol (530 mL). Dry the solid under vacuum to afford 230 g of 3,5-dichloro-4′-fluoro-4-methyl-biphenyl as an off-white solid (86% yield).
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]1[C:12]2[CH:11]=[C:10]([C:13]([OH:15])=[O:14])[C:9]([F:16])=[CH:8][C:7]=2[CH2:6][CH2:5][CH2:4]1.Cl.[CH3:18]O>>[ClH:1].[NH2:2][C@H:3]1[C:12]2[CH:11]=[C:10]([C:13]([O:15][CH3:18])=[O:14])[C:9]([F:16])=[CH:8][C:7]=2[CH2:6][CH2:5][CH2:4]1
Reactant: N[C@@H]1CCCc2cc(F)c(C(=O)O)cc21
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc2c(cc1F)CCC[C@H]2N
Yield: 95 %

Procedure:
Step-1: (R)-8-Amino-3-fluoro-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid hydrochloride (commercially obtainable from NetChem Company (order no. 573545)) (2.035 mmol, 1 eq.) was added to a solution of HCl in methanol (1.25 M, 15 eq.) and the resulting mixture was heated to reflux for 16 h. The solvent was concentrated in vacuo, and the residue was dissolved in acetone (5 ml) and diethyl ether (30 ml) was added. The white solid was collected by filtration, washed with diethyl ether and dried in vacuo. Yield: 95%
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][N:10]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)[C:9]1=[O:13]
Reactant: Cc1cc(Br)ccn1
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(N2CCN(c3cnccc3C)C2=O)ccn1
Yield: 87.1 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 100 mg, 0.5649 mmol) was reacted with 4-bromo-2-methyl-pyridine (97 mg, 0.5649 mmol), 1,4-dioxane (5 mL), copper iodide (10.76 mg, 0.05649 mmol), trans-1,2-diamino cyclohexane (19.4 mg, 0.1694 mmol) and potassium phosphate (359.58 mg, 1.694 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3) afforded 132 mg of the product (88.0% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[N:14]1([CH2:20][CH2:21][O:22][C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[CH2:25][NH2:26])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.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]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:26][CH2:25][C:24]3[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=3[O:22][CH2:21][CH2:20][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: NCc1ccccc1OCCN1CCOCC1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=c1[nH]nc(Cl)c2cc(NCc3ccccc3OCCN3CCOCC3)ccc12

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (70 mg, 0.27 mmol), 2-(2-morpholin-4-yl-ethoxy)-benzylamine (83 mg, 0.35 mmol), Pd2(dba)3 (25 mg, 0.027 mmol), rac-BINAP (51 mg, 0.081 mmol) and NaOt-Bu (76 mg, 0.81 mmol) in DMA (6 mL) was heated at 80° C. for 1 h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-[2-(2-morpholin-4-yl-ethoxy)-benzylamino]-2H-phthalazin-1-one: 28 mg (25.0%): m/z (M+H)=415. 1H-NMR (DMSO-d6) δ: 12.33 (s, 1H), 7.91 (d, 1H), 7.45 (m, 1H), 7.24 (m, 2H), 7.13 (m, 1H), 7.04 (m, 1H), 6.90 (m, 1H), 6.79 (s, 1H), 4.36 (d, 2H), 4.15 (t, 2H), 3.51 (t, 4H), 2.72 (t, 2H), 2.45 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([CH:13]=[CH2:14])[N:10]=[C:9]([N:15]([CH3:17])[CH3:16])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[N:10]=[C:9]([N:15]([CH3:16])[CH3:17])[CH:8]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C=Cc1cc(C(=O)OC(C)(C)C)cc(N(C)C)n1
Agent: [Pd]
Solvent: CO
Product: CCc1cc(C(=O)OC(C)(C)C)cc(N(C)C)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-dimethylamino-6-vinyl-isonicotinic acid tert-butyl ester (877 mg), 3.53 mmol) in methanol (15 mL), Pd/C (150 mg, 10% Pd) is added and the mixture is stirred under 2 atm of H2 at rt for 3 h. The catalyst is filtered off and the filtrate is evaporated to give crude 2-dimethylamino-6-ethyl-isonicotinic acid tert-butyl ester; LC-MS: tR=0.76 min, [M+1]+=251.10. This material is dissolved in 6 N aq. HCl (60 mL) and the mixture is stirred at 80° C. for 72 h before the solvent is evaporated. The crude product is purified by MPLC on RP-C18-silica gel to give 2-dimethylamino-6-ethyl-isonicotinic acid (332 mg) as an orange oil, LC-MS: tR=0.51 min, [M+1]+=195.10.
Reaction SMILES: [C:1]([C:3]([O:5][CH3:6])=[O:4])#[N:2].[NH2:7][C:8]1[C:12]([C:13]#[N:14])=[C:11]([N:15]2[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:21]C(OC(C)(C)C)=O)[CH2:16]2)[N:10]([CH2:29][C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[Cl:37])[C:9]=1[C:38](OCC)=[O:39]>Cl.CO>[NH2:21][C@@H:17]1[CH2:18][CH2:19][CH2:20][N:15]([C:11]2[N:10]([CH2:29][C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[Cl:37])[C:9]3[C:38](=[O:39])[NH:2][C:1]([C:3]([O:5][CH3:6])=[O:4])=[N:7][C:8]=3[C:12]=2[C:13]#[N:14])[CH2:16]1
Reactant: COC(=O)C#N
Reactant: CCOC(=O)c1c(N)c(C#N)c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n1Cc1cc(F)ccc1Cl
Agent: Cl
Solvent: CO
Product: COC(=O)c1nc2c(C#N)c(N3CCC[C@@H](N)C3)n(Cc3cc(F)ccc3Cl)c2c(=O)[nH]1
Temperature: 90 °C

Procedure:
Methyl cyanoformate (170 μl) was added to a solution of ethyl 3-amino-5-{(3R)-3-[(tertbutoxycarbonyl)amino]piperidin-1-yl}-1-(2-chloro-5-fluorobenzyl)-4-cyano-1H-pyrrole-2-carboxylate (104 mg) in hydrochloric acid-methanol reagent 10 (4 ml), and the resulting mixture was stirred with heating at 90° C. in a sealed tube for 15 hours. The reaction solution was concentrated under reduced pressure and chloroform was added to the residue. The solid precipitated was removed by filtration and the filtrate was concentrated under reduced pressure. To the resulting residue was added diethyl ether, and the solid precipitated was collected by filtration to obtain a crude product of the title compound (107 mg).
Reaction SMILES: ClC1C=C[C:5]2[N:6]([C:8]([C:11]([C:13]3C=C4C(=CC=3)N=CC=C4)=O)=CN=2)[N:7]=1.Cl[C:24]1[CH:25]=[CH:26][C:27]2[N:28]([C:30]([C:33]([C:39]3[CH:40]=[C:41]4[C:46](=[CH:47][CH:48]=3)[N:45]=[CH:44][CH:43]=[CH:42]4)([OH:38])[C:34]([F:37])([F:36])[F:35])=[CH:31][N:32]=2)[N:29]=1.CN(C=O)C.FC([Si](C)(C)C)(F)F.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:35][C:34]([F:37])([F:36])[C:33]([C:30]1[N:28]2[N:29]=[C:24]([C:11]3[CH:13]=[N:7][N:6]([CH3:5])[CH:8]=3)[CH:25]=[CH:26][C:27]2=[N:32][CH:31]=1)([C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][CH:48]=1)[N:45]=[CH:44][CH:43]=[CH:42]2)[OH:38]
Reactant: O=C(c1ccc2ncccc2c1)c1cnc2ccc(Cl)nn12
Reactant: OC(c1ccc2ncccc2c1)(c1cnc2ccc(Cl)nn12)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)C(F)(F)F
Agent: [F-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc3ncc(C(O)(c4ccc5ncccc5c4)C(F)(F)F)n3n2)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(rac)-1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-2,2,2-trifluoro-1-quinolin-6-yl-ethanol (6-chloro-imidazo[1,2-b]pyridazin-3-yl)-quinolin-6-yl-methanone (Stage 1.2, 411 mg, 1.331 mmol) was dissolved in THF (1.5 mL) and DMF (1.5 mL) together with (trifluoromethyl)trimethylsilane (0.255 mL, 1.598 mmol) and the mixture was cooled down to 0° C. TBAF solution (1 M, 0.067 mL) was then added slowly. After 5 min, the RM was allowed to warm up to rt. After 24 h of stirring, it was warmed up to 50° C. and stirred for 24 h more. The reaction was then quenched with 1 N HCl. The precipitate formed was filtered off and identified as remaining pure starting material The solution was basified with pellets of NaOH. The second precipitate formed and filtered off was starting material as well. The aqueous layer was extracted twice with EtOAc and then the joined organics were washed with brine and dried over Na2SO4. After removing the solvent, the residue was purified by MPLC with DCM and MeOH to give the title compound as a brown solid (tR 0.8 min (conditions 2), MH+=379).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9](/[CH:12]=[CH:13]/[CH2:14][OH:15])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9](/[CH:12]=[CH:13]/[CH2:14][O:15][C:21]2[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](/C=C/CO)CC1
Reactant: COc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](/C=C/COc2ccc(OC)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.5 g of (E)-3-(trans-4-pentylcyclohexyl)allyl alcohol, 0.3 g of 4-methoxyphenol, 0.4 g of diethyl azodicarboxylate, 0.6 g of triphenylphosphine and 25 ml of absolute tetrahydrofuran was stirred at room temperature overnight and then concentrated. The residue was suspended with 50 ml of hot hexane and filtered. The filtrate was concentrated. Chromatography of the residue on silica gel with toluene/hexane (vol. 1:1) and recrystallization from methanol gave pure 4-methoxyphenyl (E)-3-(trans-4-pentylcyclohexyl)allyl ether with m.p. (C-N) 45° C. and cl.p. (N-I) 46° C.
Reaction SMILES: [CH2:1]1[N:6]([CH2:7][C:8]([NH:10][CH:11]2[CH:16]3[CH2:17][C:18]4(O)[CH2:20][CH:12]2[CH2:13][CH:14]([CH2:19]4)[CH2:15]3)=[O:9])[CH2:5][CH2:4][N:3]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)[CH2:2]1.CCN(S(F)(F)[F:38])CC>C(Cl)Cl>[CH2:1]1[N:6]([CH2:7][C:8]([NH:10][CH:11]2[CH:16]3[CH2:17][C:18]4([F:38])[CH2:20][CH:12]2[CH2:13][CH:14]([CH2:19]4)[CH2:15]3)=[O:9])[CH2:5][CH2:4][N:3]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)[CH2:2]1
Reactant: O=C(CN1CCN(c2ccc(C(F)(F)F)cn2)CC1)NC1C2CC3CC1CC(O)(C3)C2
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: O=C(CN1CCN(c2ccc(C(F)(F)F)cn2)CC1)NC1C2CC3CC1CC(F)(C3)C2
Temperature: 25 °C

Procedure:
A solution of N-[(Z)-5-hydroxy-2-adamantyl]-2-{4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}acetamide (66 mg, 0.15 mmoles) from Example 1D in DCM (0.5 mL) was cooled to −78° C., treated with DAST (0.020 mL, 0.16 mmoles) and slowly warmed to room temperature for 6 hours. The mixture was quenched by the addition of aqueous saturated sodium bicarbonate (0.1 mL), filtered through a Celite cartridge and purified (silica gel, 10-15% acetone in hexane) to provide the title compound as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.42 (s, 1H), 7.67 (m, 2H), 6.67 (d, J=9.1 Hz, 1H), 3.97 (s, 1H), 3.7 (s, 4H), 3.1 (s, 2H), 2.68 (s, 4H), 2.29-2.24 (m, 3H), 1.91-1.7 (m, 10H); MS (APCI+) m/z 441 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@@H:13]2[CH3:25])(=[O:11])=[O:10])=[C:5]([CH3:26])[CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:26][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[S:9]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]1[CH3:25])(=[O:10])=[O:11])[C:1]#[N:2]
Reactant: Cc1cc(C#N)ccc1S(=O)(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)ccc1S(=O)(=O)N1CCNC[C@@H]1C
Yield: 91.5 %

Procedure:
A solution of 1,1-dimethylethyl (3S)-4-[(4-cyano-2-methylphenyl)sulfonyl]-3-methyl-1-piperazinecarboxylate (may be prepared as described in Description 16) (3.71 g, 9.78 mmol) and TFA (5.00 ml, 64.9 mmol) in dry DCM (15 ml) was stirred at rt for 1 h, then concentrated under vacuum, azeotroping with toluene (25 ml). The residue was dissolved in MeOH (20 ml) and added to an SCX-2 cartridge (50 g), washing with MeOH. The product was eluted with 2M NH3 in MeOH; concentration under vacuum gave the title compound as a white solid (2.50 g).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][CH3:14])[CH:6]=[CH:5][CH:4]=1.[CH:15](=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[CH3:14][N:13]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[N:2]([CH3:1])[CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCC=O
Reactant: CNc1cccc2cccc(NC)c12
Product: CCCCCCCCCCCCC1N(C)c2cccc3cccc(c23)N1C

Procedure:
N,N'-dimethyl-1,8-naphthalene diamine was first prepared and condensed with tridecanal to give 2,3-dihydro-1,3-dimethyl-2-dodecylperimidine. The 2,3-dihydroperimidine was coupled with the his diazonium salt prepared in Example 12 to give the above blue dye.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:26])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[O:27]=[C:28]1[C@H:32]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:31][C:30](=[O:41])[O:29]1.C(O)(=O)C>C1C=CC=CC=1>[C:36]([O:35][C:34]([NH:33][C@@H:32]([C:28]([NH:26][C:4]1[CH:5]=[CH:6][C:7]([C:8]2[S:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][CH2:19]2)[N:11]=3)=[C:2]([F:1])[CH:3]=1)=[O:27])[CH2:31][C:30]([OH:41])=[O:29])=[O:40])([CH3:38])([CH3:39])[CH3:37]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC(=O)OC1=O
Reactant: Nc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@H](CC(=O)O)C(=O)Nc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzenamine (206 mg, 0.570 mmol) and (R)-tert-butyl 2,5-dioxo-tetrahydrofuran-3-ylcarbamate (123 mg, 0.570 mmol) was added benzene (5.7 mL) and acetic acid (163 μl, 2.85 mmol) before it was stirred at 80° C. for 1 h. The two regioisomers were separated via SFC (Column: Princeton Pyridine, Mobile Phase: 60:40 liquid CO2/MeOH) to give (3R)-3-(tert-butoxycarbonylamino)-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenylamino)-4-oxobutanoic acid and its regioisomer. MS (ESI) m/z: Calculated: 576.2; Observed: 577.1 (M++H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[N:19]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH3:16])[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Brc1ccnc(-c2ccncc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(CC1CCN(C(=O)OC(C)(C)C)CC1)c1ccnc(-c2ccncc2)n1
Temperature: 86 °C

Procedure:
To a solution of 4-methylaminomethylpiperidine-1-carboxylic acid tert-butyl ester (41 mg, 0.18 mmol) in anhydrous DMF (3 mL) was added 4-bromo-2-pyridin-4-yl-pyrimidine (Preparation 1, 42 mg, 0.18 mmol) and DIPEA (63 μL, 0.36 mmol), then the resulting solution was heated to 86° C. (bath) for 6 h. The reaction mixture was cooled to 20° C., then H2O (20 mL) and EtOAc (10 mL) were added. The layers were separated then the aqueous phase was extracted with EtOAc (2×30 mL). The combined organics were washed with brine (30 mL), dried (MgSO4), filtered and concentrated in vacuo. Flash column chromatography (EtOAc) gave the title compound: RT=2.87 nm in; m/z (ES+)=384 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([O:31]COC)[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([I:11])[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.O1CCCC1.Cl>CO>[Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([I:11])[N:8]([S:12]([C:15]3[CH:16]=[CH:17][C:18]([CH3:19])=[CH:20][CH:21]=3)(=[O:13])=[O:14])[C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(I)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc32)cc1
Temperature: 65 °C

Procedure:
To a solution of 5-(5-chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(1-(methoxymethoxy)cyclobutyl)thiazole (Example 1F) (1.5 g, 2.381 mmol) in a solvent mixture of tetrahydrofuran (24 mL) and methanol (10 mL) was added 10% aqueous HCl solution (7.24 ml, 23.81 mmol). The reaction was heated to 65° C. for 8 hours and was then cooled to room temperature. The reaction was partitioned between ethyl acetate (50 mL) and water (50 mL), and the layers were separated. The aqueous layer was extracted with additional ethyl acetate (2×50 mL). The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used without further purification. MS ESI(+) m/z 586.2 [M+H]+.
Reaction SMILES: [Cl:1]/[C:2](=[C:6](\[Cl:10])/[C:7]([O-])=[O:8])/[C:3]([O-])=[O:4].[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH3+:16])=[CH:14][CH:13]=1.FC1C=CC([NH3+])=CC=1>O>[F:11][C:12]1[CH:18]=[CH:17][C:15]([N:16]2[C:3](=[O:4])[C:2]([Cl:1])=[C:6]([Cl:10])[C:7]2=[O:8])=[CH:14][CH:13]=1
Reactant: [NH3+]c1ccc(F)cc1
Reactant: O=C([O-])/C(Cl)=C(/Cl)C(=O)[O-]
Solvent: O
Product: O=C1C(Cl)=C(Cl)C(=O)N1c1ccc(F)cc1
Yield: 95 %

Procedure:
5.56g of the thusly resulted 4-fluoroanilinium 2,3-dichloromaleate was suspended in 40 ml of water and allowed to react for 2 hours at reflux temperatures. Upon cooling the reaction mixture, precipitated crystal was separated by filtration to obtain 4.8g of N-(4-fluorophenyl)-2,3-dichloromaleimide melting at 240°-242° C (not corrected) at a yield of 95.0%. An analysis by gas chromatography showed the product had a purity of 99.2%.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)([OH:10])[C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[O-][CH2:21]C.[Na+].[Na].CI>C(O)C.O>[CH3:17][C:14]1[CH:13]=[CH:12][C:11]([C:6]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:19][CH:18]=2)([OH:10])[C:7]([O:9][CH3:21])=[O:8])=[CH:16][CH:15]=1
Reactant: CC[O-]
Reactant: Cc1ccc(C(O)(C(=O)O)c2ccc(C)cc2)cc1
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: O
Solvent: CI
Product: COC(=O)C(O)(c1ccc(C)cc1)c1ccc(C)cc1
Reaction time: 0.5 h

Procedure:
At 20° C., 12.43 g (0.048 mol) of 4,4′-dimethylbenzilic acid in 50 ml ethanol is added dropwise to freshly prepared sodium ethoxide solution containing 1.1 g (0.045 mol) of sodium and 100 ml of ethanol and the mixture is stirred for 30 minutes. The solution is evaporated to dryness, the residue dissolved in 50 ml of DMF, 9.08 g (0.064 mol) of methyl iodide is added dropwise at 20° C., and stirring is continued for a further 24 hours. 300 ml of water are added dropwise to the resulting suspension while cooling with ice, the mixture is extracted with diethylether; the organic phase is washed with water, dried over Na2SO4, and evaporated to dryness. Yield: 8.6 g (99% of theory); melting point: 83° C.-84° C.