Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][NH:6][C:7]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:11]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)[C:10](=[O:28])[N:9]([CH2:29][C:30]2[C:31]([CH3:40])=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=2)[N:8]=1)=O.O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]1[N:8]2[N:9]([CH2:29][C:30]3[C:31]([CH3:40])=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=3)[C:10](=[O:28])[C:11]([C:20]3[CH:21]=[CH:22][C:23]([C:26]#[N:27])=[CH:24][CH:25]=3)=[C:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[C:7]2=[N:6][N:5]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc(NNC(=O)CCl)c(-c2ccc(Cl)cc2)c(-c2ccc(C#N)cc2)c1=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1nc(C(F)(F)F)ccc1Cn1c(=O)c(-c2ccc(C#N)cc2)c(-c2ccc(Cl)cc2)c2nnc(CCl)n21
Temperature: 120 °C
Reaction time: 6 h
Yield: 54.2 %

Procedure:
To a round bottom flask was added 2-chloro-N′-(4-(4-chlorophenyl)-5-(4-cyanophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-1,6-dihydropyridazin-3-yl)acetohydrazide (400 mg, 0.681 mmol) and toluene (10 ml). The mixture was heated at 120° C. for 5 min. After this time, POCl3(1.5 ml) was added and the reaction was stirred at 120° C. for an additional 6 hr. The reaction mixture was then cooled to room temperature and concentrated to dryness under reduced pressure. The resulting residue was dissolved in EtOAc (50 ml) and washed with saturated NaHCO3(20 ml), water (20 ml), and saturated NaCl (20 ml). The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified using an ISCO automated chromatography system (12 g silica gel, 20%-40% EtOAc/Hex) to give the product 4-(3-(chloromethyl)-8-(4-chlorophenyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)benzonitrile (210 mg) as an off-white solid (54% yield). HPLC retention time 3.148 min (Method A); LCMS (M+1)=569.0.
Reaction SMILES: [CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=O)[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21].C([O-])(=O)C.[Na+]>C(O)C.O>[CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=[N:20][OH:21])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1C(=O)N(Cc2ccccc2)c2ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1C(=NO)c2ccccc2N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
To a suspension of 7.11 g of N-benzylisatin in 75 ml of ethanol was added a solution of 3.84 g of hydroxylamine hydrochloride and 3.84 g of sodium acetate in 500 ml of water. The mixture was stirred at room temperature for 1 hour, followed by concentration. The residue was washed with water and recrystallized from ethanol to give 6.11 g (81%) of the title compound as yellow crystals.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][N:13]=[C:14]([Cl:17])[CH:15]=2)[N:10]=[CH:9][CH:8]=1)(=O)=O.[CH3:20][C:21]1[N:26]=[C:25]([NH2:27])[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.COCCOC>[C:16]([C:24]1[C:25]([NH2:27])=[N:26][C:21]([CH3:20])=[CH:22][C:23]=1[C:7]1[C:16]2[C:11](=[CH:12][N:13]=[C:14]([Cl:17])[CH:15]=2)[N:10]=[CH:9][CH:8]=1)([CH3:11])([CH3:7])[CH3:15]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(N)n1
Reactant: O=S(=O)(Oc1ccnc2cnc(Cl)cc12)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: COCCOC
Solvent: ClCCl
Product: Cc1cc(-c2ccnc3cnc(Cl)cc23)c(C(C)(C)C)c(N)n1
Yield: 17 %

Procedure:
A solution of 6-chloro-1,7-naphthyridin-4-yl trifluoromethanesulfonate (1.0 equiv.), 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (1.0 equiv.) and Pd(dppf)Cl2—CH2Cl2 (0.1 equiv.) in 3:1 DME/2M Na2CO3 was heated in a microwave at 100° C. for 15 minutes. Upon cooling, the solution was partitioned between EtOAc and Na2CO3(sat.) washed further with NaCl(sat.), dried over MgSO4, concentrated and purified by silica gel chromatography (2-4% MeOH/CH2Cl2 w/0.1% DIEA eluant) to yield tert-butyl 4-(6-chloro-1,7-naphthyridin-4-yl)-6-methylpyridin-2-amine (17%). LC/MS=271.0 (M+H), LC=1.81 min.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([CH:16]=[O:17])=[CH:9][C:8]=1[O:18][CH2:19][CH3:20])(=O)=O.[I-:23].[Na+].CCOC(C)=O>CS(C)=O>[CH2:19]([O:18][C:8]1[CH:9]=[C:10]([CH:11]=[C:12]([N+:13]([O-:15])=[O:14])[C:7]=1[I:23])[CH:16]=[O:17])[CH3:20]
Reactant: [I-]
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1OS(=O)(=O)C(F)(F)F
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOc1cc(C=O)cc([N+](=O)[O-])c1I
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of 2-ethoxy-4-formyl-6-nitrophenyl trifluoromethanesulfonate (4.7 g, 13.7 mmol) in DMSO (10 mL) was added sodium iodide (6.2 g, 41.1 mmol). The mixture was stirred under N2 atmosphere at 3˜10° C. overnight. EtOAc/aqueous workup. Purified by silica gel column chromatography (PE:EtOAc=50:1 to PE:EtOAc=10:1) (4.0 g, yield 91%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:25]3[N:8]([N:9]([CH3:26])[CH2:10][O:11][C:12]=3[C:13]=1[N:14]1[CH2:18][CH2:17][C@@H:16]([NH:19][C:20]3[S:21][CH:22]=[CH:23][N:24]=3)[CH2:15]1)[CH:7]=[C:6]([C:27]([OH:29])=[O:28])[C:5]2=[O:30].F[C:32](F)(F)[C:33](OC(=O)C(F)(F)F)=[O:34]>>[C:33]([N:19]([C:20]1[S:21][CH:22]=[CH:23][N:24]=1)[C@@H:16]1[CH2:17][CH2:18][N:14]([C:13]2[C:12]3=[C:25]4[C:4]([C:5](=[O:30])[C:6]([C:27]([OH:29])=[O:28])=[CH:7][N:8]4[N:9]([CH3:26])[CH2:10][O:11]3)=[CH:3][C:2]=2[F:1])[CH2:15]1)(=[O:34])[CH3:32]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CN1COc2c(N3CC[C@@H](Nc4nccs4)C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Product: CC(=O)N(c1nccs1)[C@@H]1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2OCN4C)C1
Temperature: 25 °C

Procedure:
A solution of product 36b (200 mg, 0.46 mmol, 1.0 eq.) in trifluoroacetic anhydride (5 mL) is heated to 90° C. for 6 hours. The reaction medium is cooled down to room temperature, the mixture is filtered and the filtrate is concentrated under reduced pressure. The obtained residue is re-crystallized from methanol and then purified by preparative HPLC (acetonitrile/H2O gradient). The expected product is obtained as a beige solid (25 mg, 88%).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=O)(C)(C)C.C(N(CC)CC)C.[F:22][C:23]([F:35])([F:34])[C@@:24]([O:29][Si](C)(C)C)([CH3:28])[C:25](Cl)=[O:26]>C(Cl)Cl>[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:25](=[O:26])[C@:24]([OH:29])([CH3:28])[C:23]([F:35])([F:34])[F:22])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: C[C@@](O[Si](C)(C)C)(C(=O)Cl)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@](O)(C(=O)N1CCC(N)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-t-butyloxycarbonylaminopiperidine (Method C, 8.0 g, 40.0 mmol) and triethylamine (8.5 ml), 60 mmol) in DCM (200 ml) was added a solution of (S)-3,3,3-trifluoro-2-trimethylsilyloxy-2-methylpropanoyl chloride (J. Med. Chem., 1999, 42, 2741-2746) (10.0 g, 41.3 mmol) in DCM (5 ml). The resultant mixture was stirred at ambient temperature overnight, the DCM evaporated, the residue taken up in EtOAc (150 ml), washed with saturated citric acid solution, saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was dissolved in methanol (25 ml), treated with saturated hydrogen chloride in methanol (100 ml), stirred at ambient temperature overnight and evaporated to dryness. The residue was recrystallized from methanol/EtOAc to give the title compound as the hydrochloride salt (7.5 g, 27.2 mmol). Mp: 245-246° C.; NMR: 1.45 (m, 2H), 1.5 (s, 3H), 1.95 (m, 2H), 3.25 (m, 1H), 4.4 (m, 2H), 4.65 (m, 2H), 7.15 (s, 1H), 8.2 (s, 3H); m/z (+ve ESP) 241 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10]CC2C=CC(OC)=CC=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]2[CH:31]=[N:32][C:33]([C:40]([CH3:44])([CH3:43])[CH2:41][OH:42])=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=2)=[O:28])=[C:22]([F:45])[CH:21]=1)[CH3:2].C(Cl)Cl>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]1[C:5]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]3[CH:31]=[N:32][C:33]([C:40]([CH3:44])([CH3:43])[CH2:41][OH:42])=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:35]=3)=[O:28])=[C:22]([F:45])[CH:21]=2)=[CH:6][NH:7][C:8](=[O:10])[CH:9]=1)[CH3:2]
Reactant: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)Nc2cnc(C(C)(C)CO)c(C(F)(F)F)c2)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc(=O)[nH]cc1-c1ccc(CC(=O)Nc2cnc(C(C)(C)CO)c(C(F)(F)F)c2)c(F)c1
Yield: 53.1 %

Procedure:
A solution of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(6-(1-hydroxy-2-methylpropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide (20 mg, 0.032 mmol) in TFA in DCM (5 mL, 3.72 mmol) was stirred at 25° C. After LCMS analysis showed the starting material was consumed, the solvent was removed in vacuo to give the crude product, which was purified by preparative HPLC (under neutral condition) to yield a white solid of 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(6-(1-hydroxy-2-methylpropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide (8.8 mg, 0.017 mmol, 54% yield): 1H NMR (400 MHz, CD3OD) δ 8.91 (s, 1H), 8.46 (d, J=2.0 Hz, 1H), 7.40-7.35 (m, 2H), 7.24-7.21 (m, 2H), 5.98 (s, 1H), 4.13-4.08 (m, 2H), 3.82 (s, 4H), 1.37 (t, J=7.0 Hz, 9H); ES-LCMS m/z: 508.2 (M+H).
Reaction SMILES: CO[C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[CH2:22]([CH2:24][NH2:25])[OH:23]>CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-].[Ti+4]>[CH3:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]/[CH:12]=[CH:11]\[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([NH:25][CH2:24][CH2:22][OH:23])=[O:21]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Reactant: NCCO
Agent: [Ti+4]
Agent: CCCC[O-]
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCCO

Procedure:
As in Example 1, 445.7 g (1.5 mol) of technical grade oleic acid methyl ester (sunflower oil fatty acid, oleic acid content approx. 85%, saponification value 188.8, iodine value 85), 184.2 g (3 mol) of ethanolamine and 5.1 g (0.015 mol, 1 mol-%) of titanium tetrabutylate were reacted under nitrogen and normal pressure at 140° to 150° C. to form oleic acid ethanolamide with removal of methanol by distillation. The excess ethanolamine was then distilled off at 4 hPa/120°-125° C. The temperature was then increased to 220°-265° C. at 0.08-0.1 hPa, the product and water distilling over. 2-(8-Heptadecen-1-yl)-2-oxazoline was obtained in a yield of 394.1 g (86% of the theoretical). n20 : 1.4700.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=1.Br[C:22]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:23]=1[CH:24]=[O:25]>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:6]=[C:7]([C:22]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:23]=2[CH:24]=[O:25])[CH:8]=[CH:9][CH:10]=1
Reactant: O=Cc1cc(C(F)(F)F)ccc1Br
Reactant: COC(=O)Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Product: COC(=O)Cc1cccc(-c2ccc(C(F)(F)F)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: [3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester and 2-bromo-5-(trifluoromethy)benzaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[C:16]([C:18]2[NH:19][C:20]([C:23]3[S:24][CH:25]=[CH:26][N:27]=3)=[CH:21][CH:22]=2)[CH:15]=[C:14]([O:28][C@@H:29]([CH3:33])[CH2:30][O:31][CH3:32])[CH:13]=1)[C:5]([OH:7])=O.[C:34]([NH:37][NH2:38])(=[O:36])[CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[C:34]([NH:37][NH:38][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([O:11][C:12]2[CH:17]=[C:16]([C:18]3[NH:19][C:20]([C:23]4[S:24][CH:25]=[CH:26][N:27]=4)=[CH:21][CH:22]=3)[CH:15]=[C:14]([O:28][C@@H:29]([CH3:33])[CH2:30][O:31][CH3:32])[CH:13]=2)=[C:2]([F:1])[CH:3]=1)(=[O:36])[CH3:35]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)O)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Reactant: CC(=O)NN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)NNC(C)=O)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 117.1 %

Procedure:
3-Fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}benzoic acid (84 mg, 0.179 mmol) synthesized in Example (44a) was dissolved in dichloromethane (5.0 mL), and acetohydrazide (40 mg, 0.540 mmol), HATU (200 mg, 0.526 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.861 mmol) were added, followed by stirring at room temperature overnight under nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate) to afford the desired compound (110 mg, yield ˜100%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=1.[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:7][NH:6][C:5]1[CH:8]=[CH:9][C:2]([C:15]#[C:14][Si:11]([CH3:13])([CH3:12])[CH3:10])=[CH:3][CH:4]=1
Reactant: CNc1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CNc1ccc(C#C[Si](C)(C)C)cc1
Yield: 36.4 %

Procedure:
To a suspension of 4-bromo-N-methylaniline (500 mg, 2.7 mmol), trimethylsilyl acetylene (527 mg, 5.4 mmol), CuI (92 mg, 0.5 mmol) and PPh3 (233 mg, 0.9 mmol) in TEA (20 mL) was added PdCl2(PPh3)2 (94 mg, 0.1 mmol) at r.t. under N2. The reaction was stirred at reflux overnight. The reaction was filtered, concentrated, and purified by silica gel chromatography (PE:EtOAc=20:1) to give 200 mg (37%) of the title compound as a yellow oil. [M+H] Calc'd for C12H17NSi, 204. Found, 204.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:4]([CH2:19][N:20]([CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:21][CH2:22][CH3:23])[CH2:3]1.CCN(CC)CC.[C:41](Cl)(=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43]>C(Cl)Cl>[F:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][CH2:25][CH2:24][N:20]([CH2:19][C@@H:4]2[CH2:3][C@H:2]([NH:1][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:7][CH2:6][C@H:5]2[NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:21][CH2:22][CH3:23])=[CH:32][CH:31]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCCN(CCCc1ccc(F)cc1)C[C@@H]1C[C@H](N)CC[C@H]1NC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(CCCc1ccc(F)cc1)C[C@@H]1C[C@H](NC(=O)C(C)(C)C)CC[C@H]1NC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
A solution of benzyl(1R,2S,4R)-4-amino-2-(((3-(4-fluorophenyl)propyl)(propyl)-amino)methyl)-cyclohexylcarbamate (1.1 g, 2.4 mmol) and Et3N (0.3 g, 3 mmol) in CH2Cl2 (50 ml) was cooled in an ice bath and treated drop-wise with pivaloyl chloride (0.32 g, 2.6 mmol). The solution is stirred for 30 minutes and then washed successively with saturated sodium bicarbonate, 0.5 N NaOH, and brine. The solution was dried over sodium sulfate, filtered and the solvent removed on a rotary evaporator. This chromatographed on silica gel to (0.3:2.7:97 NH4OH/MeOH/CH2Cl2) to give 0.85 g of white solid. MS: (M+H)+=540.38.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl>O>[Br:12][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(CC(=O)O)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: O=C(O)Cc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 50 g (0.33 mol) of 4-methylphenyl acetic acid, 62 g (0.35mol) of N-bromosuccinimide, 200 ml of carbon tetrachloride and 0.1 g of 2,2-azobis(isobutyronitrile) are placed in a 500 ml flask and heated to reflux with stirring for 4 hours. After the reaction mixture is cooled to room temperature, it is poured into 500 ml of water. The obtained precipitate is filtered off, and then washed with water. After drying under an atmosphere of reduced pressure, 55 g of a white powder are obtained (72%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:19]O>>[OH:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:19])=[O:8]
Reactant: CO
Reactant: Cc1c(C(=O)O)cc(O)cc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(O)cc([N+](=O)[O-])c1C
Yield: 80 %

Procedure:
To a stirred solution of 5-hydroxy-2-methyl-3-nitrobenzoic acid (3.50 g, 17.8 mmol) in methanol (40 mL), was added thionyl chloride (3.9 mL, 53 mmol) at 0° C. The mixture was heated under reflux for 3 hours and concentrated under reduced pressure. Aqueous sodium bicarbonate was added to the residue which was extracted with ethyl acetate. The combined organic layers were washed with water, dried and concentrated under reduced pressure. The crude material was purified by column chromatography to afford the title compound (3.0 g, 80%).
Reaction SMILES: [Na].Br[C:3]1[C:8]([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=2)=[C:7]([C:17](=[O:19])[CH3:18])[CH:6]=[C:5]([Cl:20])[C:4]=1[CH3:21].[CH2:22]([O:24][CH:25]([N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1)[CH3:26])[CH3:23]>O.C1(C)C=CC=CC=1.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>[Cl:20][C:5]1[C:4]([CH3:21])=[C:3]([C:30]2[CH:29]=[N:28][N:27]([CH:25]([O:24][CH2:22][CH3:23])[CH3:26])[CH:31]=2)[C:8]([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=2)=[C:7]([C:17](=[O:19])[CH3:18])[CH:6]=1
Reactant: CC(=O)c1cc(Cl)c(C)c(Br)c1-c1cc(F)cc(F)c1
Reactant: CCOC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(C)n1cc(-c2c(C)c(Cl)cc(C(C)=O)c2-c2cc(F)cc(F)c2)cn1
Temperature: 90 °C
Yield: 40.1 %

Procedure:
To a solution of sodium hydrogenecarbonate (0.093 g, 1.1 mmol) in water (2 mL) was added a solution of 1-(6-bromo-4-chloro-3′,5′-difluoro-5-methylbiphenyl-2-yl)ethanone (0.20 g, 0.56 mmol) in toluene (2 mL) followed by 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.18 g, 0.67 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.064 g, 0.056 mmol). The mixture was bubbled with N2 for 5 min and then heated at 90° C. overnight. The organic layer was concentrated and flashed on silica gel (eluting with 0-20% of ethyl acetate in hexanes) to afford the desired product (94 mg, 40%). LCMS calculated for C22H22ClF2N2O2 (M+H)+: m/z=419.1. found: 419.1.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:17]([CH:28]=O)=[N:18][CH:19]=[C:20]([N:22]([CH:24]2[CH2:27][CH2:26][CH2:25]2)[CH3:23])[N:21]=1.[CH2:30]([NH:37][CH2:38][CH2:39][OH:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:30]([N:37]([CH2:28][C:17]1[C:16]([Cl:15])=[N:21][C:20]([N:22]([CH:24]2[CH2:25][CH2:26][CH2:27]2)[CH3:23])=[CH:19][N:18]=1)[CH2:38][CH2:39][OH:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CN(c1cnc(C=O)c(Cl)n1)C1CCC1
Reactant: OCCNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN(c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1)C1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
Sodium triacetoxyborohydride (0.71 g) was added to a solution of 3-chloro-5-[cyclobutyl(methyl)amino]pyrazine-2-carbaldehyde (0.50 g), N-benzylethanolamine (0.40 g) and acetic acid (0.38 mL) in acetonitrile (8 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was basified with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 10-*60% ethyl acetate/hexane) to give the title compound (0.74 g, 92%) as a pale-yellow oil.
Reaction SMILES: [CH:1]1([C:5]([OH:7])=O)[CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:41][C:42]1[C:43](=[O:50])[N:44]([CH3:49])[CH:45]=[C:46]([Br:48])[CH:47]=1>C(Cl)Cl>[Br:48][C:46]1[CH:47]=[C:42]([NH:41][C:5]([CH:1]2[CH2:2][CH2:3][CH2:4]2)=[O:7])[C:43](=[O:50])[N:44]([CH3:49])[CH:45]=1
Reactant: O=C(O)C1CCC1
Reactant: Cn1cc(Br)cc(N)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1cc(Br)cc(NC(=O)C2CCC2)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 49.8 %

Procedure:
To a mixture or cyclobutanecarboxylic acid (200 mg, 2.0 mmol), HATU (1.14 g, 3.0 mmol) and DIPEA (516 mg, 4.0 mmol) in DCM (8 mL) was added 3-amino-5-bromo-1-methylpyridin-2(1H)-one (330 mg, 1.62 mmol). The reaction mixture was stirred at 25° C. for 5 hours. The resulting mixture was evaporated under reduced pressure and the residue was purified on a silica-gel column eluting with 20:1 DCM/methanol to afford 101a (230 mg, 54%). MS-ESI: [M+H]+ 285.1
Reaction SMILES: O[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[O:28])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:15]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1.O>[CH:23]1([O:22][C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=2[O:20][CH3:21])[CH2:13][C:12]2[O:28][C:2]3[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=3[N:11]=2)[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: COc1ccc(CC(=O)Nc2cccc([N+](=O)[O-])c2O)cc1OC1CCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: COc1ccc(Cc2nc3cccc([N+](=O)[O-])c3o2)cc1OC1CCCC1
Temperature: 25 °C
Yield: 58.1 %

Procedure:
A solution of N-(2-hydroxy-3-nitrophenyl)-3-cyclopentyloxy-4-methoxyphenylacetamide (2.0 g) and pyridinium p-toluene-sulphonate (500 mg) in xylene (140 ml) was refluxed, under nitrogen, overnight. The reaction mixture was cooled to room temperature, diluted with water (100 ml) and extracted with dichloromethane (3×75 ml). The combined organic extracts were washed with water (3×100 ml), brine (100 ml), dried (CaSO4) and evaporated in-vacuo to yield an orange oil. The oil was purified by flash chromatography (SiO2 ;dichloromethane;ethanol;ammonia (50:1:0.1)) to yield the title compound (1.107 g, 58%) as an orange solid (top 95°-98.5° C.). δH (250 MHz;d6DMSO) 1.45-1.95 (8H,m,4×CH2), 3.70 (3H,s,OMe), 4.36 (2H, s,CH2), 4.74 (1H,m,CH), 6.89 (2H,bs,ArH), 7.02 (1H,bs,ArH), 7.56 (1H,t,ArH), 8.15 (1H,dd,ArH), 8.17 (1H,dd,ArH). m/z 368 (M+), 338 (M--NO), 300 (M--C5H8), 285, 270, 253, 149, 137, 123, 100.