Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:31]([Cu])#[N:32].[OH-].[NH4+].Cl>CCOC(C)=O.CN1CCCC1=O>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:31]#[N:32])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2ccc(Oc3ccc(OCCC)cc3)cc2c1O
Reactant: N#C[Cu]
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccc(OCCC)cc3)cc2c1O
Temperature: 120 °C
Reaction time: 4 h
Yield: 73.8 %

Procedure:
A mixture of 1-bromo-4-hydroxy-6-(4-propoxy-phenoxy)-isoquinoline-3-carboxylic acid butyl ester (315 mg, 0.664 mmol), CuCN (66 mg, 0.730 mmol), and N-methylpyrrolidinone (2 mL) was stirred at 120° C. for 4 h. After cooling to room temperature the mixture was poured into EtOAc (20 mL) and saturated ammonium hydroxide solution (˜1 mL) was added. The mixture was rapidly stirred for 2 min. Then it was acidified with concentrated HCl, washed with water, and saturated NaCl solution before it was dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography to give title compound (206 mg). ESI MS (m/z): 421 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7])=[CH:4][CH:3]=1.C1COCC1.C(N(CC)CC)C.[CH3:26][O:27][C:28]([CH:30]([C:34]1[CH:43]=[CH:42][C:41]2[C:40]([CH3:45])([CH3:44])[CH2:39][CH2:38][C:37]([CH3:47])([CH3:46])[C:36]=2[CH:35]=1)[C:31](Cl)=[O:32])=[O:29]>O>[CH3:26][O:27][C:28]([CH:30]([C:34]1[CH:43]=[CH:42][C:41]2[C:40]([CH3:45])([CH3:44])[CH2:39][CH2:38][C:37]([CH3:47])([CH3:46])[C:36]=2[CH:35]=1)[C:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7])=[CH:12][CH:13]=1)=[O:32])=[O:29]
Reactant: COC(=O)C(C(=O)Cl)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: C=CCOC(=O)c1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)c1ccc(NC(=O)C(C(=O)OC)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.8 g (10 mmol) of allyl 4-aminobenzoate, 50 ml of THF and 1.7 ml (12 mmol) of triethylamine were introduced into a round-bottomed flask. A solution of 3.3 g (10 mmol) of α-methoxycarbonyl-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetic acid chloride in 25 ml of THP was added dropwise and the mixture was stirred at room temperature for 2 hours. The reaction medium was poured into water, and extracted with ethyl acetate. The organic phase was decanted off, dried over magnesium sulfate and evaporated. The residue obtained was recrystallized from ethanol; 3.3 g (69%) of the expected compound of melting point 155°-156° C. were recovered after filtration and drying.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:13]C)[C:11]=1[Cl:12])[C:5]([O:7]C)=[O:6].B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:13])[C:11]=1[Cl:12])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Cl)c(Cl)c(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1cc(O)c(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.7 %

Procedure:
Methyl 3,4-dichloro-5-methoxybenzoate (5) (518 mg, 2.34 mmol) was suspended in DCM (10 mL) under a reflux condenser fitted with a CaCl2 drying tube. BBr3 (554 μL, 5.86 mmol) was added and the reaction mixture was stirred at RT for 15 h. The reaction mixture was cautiously poured in to iced water (20 mL) and the mixture stirred for 10 min. The product was extracted with EtOAc (50 mL), then the organic solution was washed with brine (2×50 mL) and dried over MgSO4 and filtered. The solvent was removed in vacuo and the residue purified by silica gel chromatogrpahy (40 g, 0-100% EtOAc in isohexane) to afford 3,4-dichloro-5-hydroxybenzoic acid (6) (260 mg, 51% yield) as a white solid: m/z 205 [M−H]− (ES−).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[N:6][C:7]=1[NH:8][C:9]1([CH3:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[C:17](OC)(OC)(OC)[CH3:18]>>[CH3:17][C:18]1[N:8]([C:9]2([CH3:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:7]2=[N:6][C:5]([OH:16])=[CH:4][CH:3]=[C:2]2[N:1]=1
Reactant: CC1(Nc2nc(O)ccc2N)CCCCC1
Reactant: COC(C)(OC)OC
Product: Cc1nc2ccc(O)nc2n1C1(C)CCCCC1

Procedure:
From 5-amino-6-(1-methylcyclohexylamino)pyridin-2-ol and trimethyl orthoacetate, prepared in a similar manner as the one described in Example 1.127, Step D, the title compound was obtained. LCMS m/z=246.10 [M+H]+. 1H NMR (400 MHz, methanol-d4) δ ppm 1.52-1.58 (m, 1H), 1.67-1.78 (m, 5H), 1.90 (s, 3H), 2.48-2.52 (m, 2H), 2.75-2.82 (m, 2H), 3.02 (s, 3H), 6.91 (d, J=8.8 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[Br:13]Br>C(OCC)C>[CH2:11]([O:10][C:8]([C:3]1[CH2:4][CH2:5][CH2:6][CH:7]([Br:13])[C:2]=1[OH:1])=[O:9])[CH3:12]
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: BrBr
Solvent: CCOCC
Product: CCOC(=O)C1=C(O)C(Br)CCC1
Temperature: 0 °C
Yield: 94.4 %

Procedure:
Ethyl 2-oxocyclohexanecarboxylate (30 g, 176 mmol, 28 mL) was dissolved in diethyl ether (30 mL) and cooled to 0° C. under nitrogen. Bromine (28 g, 176 mmol, 9.0 mL) was added dropwise over 15 min and the reaction mixture was allowed to warm to RT over 90 min. The mixture was slowly poured into ice-cold saturated aqueous potassium carbonate (250 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were dried over magnesium sulfate, filtered, concentrated in vacuo and dried on the vacuum line for 18 h to afford 41.4 g (94%) of 3-Bromo-2-hydroxy-1-enecarboxylic acid ethyl ester (4) as a yellow oil. The structure was confirmed by 13C NMR (75 MHz, CDCl3): δC 14.1, 17.7, 21.8, 32.0, 60.0, 60.8, 99.7, 1663, and 172.8.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([O:13][C:14]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27]Cl)=[CH:23][C:22]=2[O:29][CH3:30])=[C:18]([CH3:31])[N:17]=[C:16]([NH2:32])[N:15]=1)(=[O:12])=[O:11].[NH:33]1[C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][N:35]=[CH:34]1>>[NH2:32][C:16]1[N:15]=[C:14]([O:13][S:10]([C:3]2[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=2[CH3:9])(=[O:12])=[O:11])[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:33]3[C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][N:35]=[CH:34]3)=[CH:23][C:22]=2[O:29][CH3:30])=[C:18]([CH3:31])[N:17]=1
Reactant: COC(=O)c1cnc[nH]1
Reactant: COc1cc(CCl)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Product: COC(=O)c1cncn1Cc1ccc(Cc2c(C)nc(N)nc2OS(=O)(=O)c2c(C)cc(C)cc2C)c(OC)c1
Yield: 15.1 %

Procedure:
The sub-title compound was synthesized by the method of example 1 step (vii) from the product of example 1 step (v) (500 mg) and Methyl 1H-imidazole-5-carboxylate (199 mg). The sub-title compound (90 mg) was obtained as a white solid; 1H NMR (300 MHz, CDCl3); 7.73 (1H, s), 7.61 (1H, s), 6.89 (2H, s), 6.83 (1H, d), 6.61 (1H, s), 6.55 (1H, d), 5.42 (2H, s), 3.78 (3H, s), 3.68 (5H, s), 2.46 (3H, s), 2.42 (6H, s), 2.26 (3H, s); LC-MS: m/z 566.
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])=[O:11])=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>O>[NH2:8][CH:9]([CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])=[O:11]
Reactant: COc1ccccc1CNC(=O)C(Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccccc1CNC(=O)C(N)Cc1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of the 2-t-butoxycarbonylamino-3-(1H-indol-3-yl)-N-(2-methoxybenzyl)propanamide prepared supra (25.1 g, 59.2 mmoles) and anisole (12 ml, 110.4 mmoles) at 0° C. was added dropwise an aqueous solution of trifluoroacetic acid (118 ml, 1.53 moles) in 50 ml of water. This mixture was stirred for one hour at 0° C., followed by stirring for about 2.5 hours at ambient temperature. The mixture was then refrigerated for about 16 hours.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].[C:22]([N:25]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38](Br)[N:37]=1)[CH2:26][C:27]([NH:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:28])(=[O:24])[CH3:23]>>[C:22]([N:25]([CH2:35][C:36]1[N:37]=[C:38]([NH:1][C:2]2[S:3][C:4]([C:10]3[C:11]([F:21])=[CH:12][C:13]([C:17]([OH:20])([CH3:18])[CH3:19])=[CH:14][C:15]=3[F:16])=[CH:5][C:6]=2[C:7]([NH2:9])=[O:8])[CH:39]=[CH:40][CH:41]=1)[CH2:26][C:27]([NH:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:28])(=[O:24])[CH3:23]
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CC(=O)N(CC(=O)NC1CCCC1)Cc1cccc(Br)n1
Product: CC(=O)N(CC(=O)NC1CCCC1)Cc1cccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)n1

Procedure:
The title compound was prepared using the procedure described in Example 1 with 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.12 g, 0.38 mmol) and N2-acetyl-N2-[(6-bromopyridin-2-yl)methyl]-N-cyclopentylglycinamide (0.14 g, 0.38 mmol) as the starting materials.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][N:18]=1)[C:13]([OH:15])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.O[N:26]=[C:27]([NH2:35])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.N1C=CC=CC=1.[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>ClCCl.CN(C)C=O.C(OCC)(=O)C>[CH2:28]([C:27]1[N:35]=[C:13]([C:12]2[CH:16]=[CH:17][N:18]=[C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:11]=2)[O:15][N:26]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NC(Cc1ccccc1)=NO
Reactant: O=C(O)c1ccnc(NC(=O)c2ccccc2)c1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Nc1cc(-c2nc(Cc3ccccc3)no2)ccn1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-benzamidoisonicotinic acid (0.35 g, 1.44 mmol) and N,N-dimethylformamide (0.1 mL) in dichloromethane (5 mL) was added oxalyl chloride (0.15 mL, 1.73 mmol) at ambient temperature. The resulting mixture was stirred at ambient temperature for 1 hour and concentrated in vacuo to dryness. The residue was dissolved in N,N-dimethylformamide (2 mL) and added to a solution of N′-hydroxy-2-phenylacetimidamide (0.24 g, 1.59 mmol) and pyridine (0.3 mL, 3.70 mmol) in N,N-dimethylformamide (1 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 3 hours, diluted with ethyl acetate (40 mL), washed with water (20 mL) and brine (20 mL). The organic solution was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was dissolved in toluene (10 mL), followed by the addition of (methoxycarbonylsulfamoyl)triethylammonium hydroxide (0.53 g, 2.16 mmol). The mixture was refluxed for 1 hour and concentrated in vacuo. The residue was purified by column chromatography to give N-[4-(3-benzyl-[1,2,4]oxadiazol-5-yl)-pyridin-2-yl]-benzamide as a colorless solid (0.06 g 12%): mp 150-151° C.; 1H NMR (300 MHz, CDCl3) δ 9.06 (s, 1H), 8.69 (s, 1H), 8.46 (d, J=4.9 Hz, 1H), 7.94-7.91 (m, 2H), 7.72-7.69 (m, 1H), 7.62-7.48 (m, 3H), 7.39-7.24 (m, 5H), 4.16 (s, 2H); MS (ES+) m/z 357.5 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](F)=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH:19]([CH3:21])[CH3:20])[N:3]=1.[N-:22]=[N+]=[N-].[Na+].O>CN1C(=O)CCC1>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:22])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH:19]([CH3:21])[CH3:20])[N:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)c1cc(-c2ccc(F)c3ccccc23)nc(N)n1
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)c1cc(-c2ccc(N)c3ccccc23)nc(N)n1
Reaction time: 16 h
Yield: 53 %

Procedure:
2-Amino-4-(4-fluoronaphth-1-yl)-6-isopropyl-pyrimidine (0.288 g) was dissolved in N-methyl pyrrolidinone (5 mL) and sodium azide (0.288 g) was added. The mixture was brought to a temperature of 160° C. under an inert atmosphere for 16 hours. After cooling the reaction mixture was poured into water (50 mL) and the reaction product was extracted with ethyl acetate (3×30 mL). The organic layer was dried over sodium sulfate and evaporated to dryness. The product was purified by column chromatography on silica gel, eluting with hexane/ethyl acetate, and recrystallized from tert-butyl methyl ether to give 2-amino-4-(4-aminonaphth-1-yl)-6-isopropyl-pyrimidine (0.151 g), m.p. 185°-186° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH3:10])=[N:6][CH:7]=1.[CH2:11](C([Sn])=C(CCCC)CCCC)[CH2:12]CC>CN(C=O)C.C1COCC1.O.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>[CH2:8]([C:5]1[CH:4]=[CH:3][C:2]([CH:11]=[CH2:12])=[CH:7][N:6]=1)[CH2:9][CH3:10]
Reactant: CCCc1ccc(Br)cn1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=Cc1ccc(CCC)nc1
Temperature: 100 °C
Yield: 40.8 %

Procedure:
The title compound was prepared by following general procedure 2. 5-Bromo-2-propyl-pyridine (0.5 g, 2.5 mmol) was dissolved in DMF:THF (3:1, 8 mL). To this solution, tributylvinyltin (1.3 mL, 3.7 mmol) and Pd(PPh3)4 (0.057 g, 0.05 mmol) was added at RT under nitrogen and was heated at 100° C. for 2 h. The reaction mixture was cooled to RT and diluted with water (80 mL) and extracted with DCM (3×100 mL), the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator below 40° C. The crude was purified through column chromatography (3% ethylacetate:hexane in silica 100-200 mesh, Diameter of column—2.5.0 cm, Height of silica—approx. 5 inch) to provide 2-propyl-5-vinylpyridine as a light yellow liquid (0.15 g, 41% yield).
Reaction SMILES: [CH2:1]([S:3][CH2:4][C:5]([C:9]1[N:10](S(C)(=O)=O)[C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=2)([O:7][CH3:8])[CH3:6])[CH3:2].[OH-].[Na+]>>[CH2:1]([S:3][CH2:4][C:5]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[C:13]([C:21]([F:23])([F:22])[F:24])[CH:12]=2)([O:7][CH3:8])[CH3:6])[CH3:2]
Reactant: CCSCC(C)(OC)c1cc2cc([N+](=O)[O-])c(C(F)(F)F)cc2n1S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Product: CCSCC(C)(OC)c1cc2cc([N+](=O)[O-])c(C(F)(F)F)cc2[nH]1

Procedure:
This compound was prepared using the general de-protection procedure, as described in General Procedures Example. The starting material used was 2-(2-ethylsulfanyl-1-methoxy-1-methyl-ethyl)-1-methanesulfonyl-5-nitro-6-trifluoromethyl-1H-indole (0.17 g, 0.39 mmol). The base used was 4N sodium hydroxide (0.19 mL, 0.77 mmol). The title compound was obtained as a yellow solid.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:24])=[N:5]1)([CH3:3])[CH3:2].Cl.[F:26][C:27]1([F:35])[CH2:31][NH:30][C@H:29]([C:32]([NH2:34])=[O:33])[CH2:28]1.CO>C(Cl)Cl>[F:26][C:27]1([F:35])[CH2:31][N:30]([C:21]2[N:20]=[CH:19][C:16]3[C:17]4[N:11]([CH:10]=[C:9]([C:8]5[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[C:6]([CH3:24])[N:7]=5)[N:18]=4)[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[C@H:29]([C:32]([NH2:34])=[O:33])[CH2:28]1
Reactant: NC(=O)[C@@H]1CC(F)(F)CN1
Reactant: Cc1nc(-c2cn3c(n2)-c2cnc(O)cc2OCC3)n(C(C)C)n1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2cnc(N4CC(F)(F)C[C@H]4C(N)=O)cc2OCC3)n(C(C)C)n1
Yield: 17 %

Procedure:
Following the procedures of Example 339, 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol and 4,4-difluoro-L-prolinamide hydrochloride with added TEA (2.5 eq.) were reacted and the crude product subjected to flash chromatography (SiO2, gradient 0 to 5% methanol in DCM) to give 383 as a white solid (29 mg, 17%). LCMS: RT=3.14 min, [M+H]+=459. 1H NMR 400 MHz (DMSO-d6) δ: 9.09 (1H, s), 7.85 (1H, d, J=0.64 Hz), 7.55 (1H, br), 7.15 (1H, br), 6.05 (1H, s), 5.93-5.81 (1H, m), 4.61 (1H, dd, J=9.53, 4.24 Hz), 4.58-4.49 (4H, m), 4.00-3.98 (2H, m), 2.91-2.90 (1H, m), 2.45 (1H, dd, J=13.51, 4.18 Hz), 2.25 (3H, s), 1.49 (6H, dd, J=6.59, 3.35 Hz)
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([CH3:20])=[C:15]([CH:19]=2)[C:16]([OH:18])=O)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[NH2:52][C:53]1[CH:58]=[CH:57][C:56]([NH2:59])=[CH:55][N:54]=1>C(Cl)Cl>[NH2:52][C:53]1[N:54]=[CH:55][C:56]([NH:59][C:16](=[O:18])[C:15]2[CH:19]=[C:11]([CH:12]=[CH:13][C:14]=2[CH3:20])[C:9]([NH:8][CH2:7][CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:10])=[CH:57][CH:58]=1
Reactant: Nc1ccc(N)nc1
Reactant: Cc1ccc(C(=O)NCCC2CCCC2)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NCCC2CCCC2)cc1C(=O)Nc1ccc(N)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a RBF was charged 5-((2-cyclopentylethyl)carbamoyl)-2-methylbenzoic acid (0.25 g, 0.91 mmol), DCM (3 ml), n,n-diisopropylethylamine (0.6 ml, 3.5 mmol), HOBt (0.14 g, 1.0 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.21 g, 1.1 mmol), and 2,5-diaminopyridine (0.1 g, 0.91 mmol) in that order. This mixture was stirred at RT under N2 for 18 h. The reaction was partitioned between DCM (30 ml) and brine (20 mL). The precipitate formed was collected, washed with water, dried in a vacuum oven overnight to give N3-(6-aminopyridin-3-yl)-N1-(2-cyclopentylethyl)-4-methylisophthalamide as a purple solid.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=2)[O:11][CH2:12][CH2:13][CH2:14][C:15](O)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.[NH2:25][C:26]1[N:30]([CH3:31])[N:29]=[C:28]([CH3:32])[N:27]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(Cl)Cl.CN(C)C=O.O1CCCC1>[CH3:31][N:30]1[C:26]([NH:25][CH2:15][CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:18]=[CH:19][CH:20]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:9]=2)=[N:27][C:28]([CH3:32])=[N:29]1
Reactant: Cc1nc(N)n(C)n1
Reactant: O=C(O)CCCOc1cccc(CN2CCCCC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1nc(NCCCCOc2cccc(CN3CCCCC3)c2)n(C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.1 %

Procedure:
A stirred suspension of 4-[3-(1-piperidinylmethyl)phenoxy]butanoic acid (4.0 g) in methylene chloride (100 ml) and dimethylformamide (24 drops) was treated with thionyl chloride (5.16 g). The solution was stirred at room temperature for 18 h and evaporated in vacuo, to give a pale yellow solid which was dissolved in methylene chloride (100 ml) and treated with 5-amino-1,3-dimethyl-1,2,4-triazole (1.61 g). The reaction mixture was stirred at room temperature for 24 h and evaporated in vacuo. The residue was dissolved in aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic extracts were dried and evaporated to give a brown oil which was dissolved in tetrahydrofuran (500 ml), treated with lithium aluminium hydride (3.04 g), stirred at room temperature for 18 h and refluxed for 3 h. The cooled reaction mixture was quenched with water (300 ml) and extracted with ethyl acetate. The combined extracts were washed with brine, dried and evaporated in vacuo to give an oil which was distilled to give the title compound (1.7 g) as a pale yellow oil, b.p. 230°/0.06 mm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].O.[C:25](=[O:28])([O-])[OH:26].[Na+]>C(#N)C.[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[C:15]([O:26][C:25]([N:21]1[CH2:22][CH2:23][CH:18]([CH:15]2[CH2:16][CH2:17][N:12]([C:5]3[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:13][CH2:14]2)[CH2:19][CH2:20]1)=[O:28])([CH3:18])([CH3:16])[CH3:14]
Reactant: O=C([O-])O
Reactant: COc1cc(N2CCC(C3CCNCC3)CC2)ccc1[N+](=O)[O-]
Agent: [Zr+4]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1cc(N2CCC(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a suspension of 1-(3-methoxy-4-nitro-phenyl)-[4,4′]bipiperidinyl (1.75 g, 5.48 mmol), di-tert-butyl-dicarboxylate (1.20 g, 5.48 mmol) in acetonitrile (55 mL), zirconium tetrachloride (128 mg, 0.55 mmol) is added and the mixture is stirred at ambient temperature for 30 min. After water and aqueous sodium hydrogen carbonate are added, the mixture is filtrated and dried to give 1′-(3-Methoxy-4-nitro-phenyl)-[4,4′]bipiperidinyl-1-carboxylic acid tert-butyl ester (5.11 g, 92% yield) as yellow solids.
Reaction SMILES: C(P(CC1C=CC=C(CP(C(C)(C)C)C(C)(C)C)N=1)C(C)(C)C)(C)(C)C.[C:27](#[N:31])[C:28]([CH3:30])=[CH2:29].[NH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1(C)C=CC=CC=1.C(O)(C(F)(F)F)=O.C(O)(C(F)(F)F)=O.[Pd]>[NH:32]([CH2:29][CH:28]([C:27]#[N:31])[CH3:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Nc1ccccc1
Reactant: C=C(C)C#N
Agent: [Pd]
Agent: CC(C)(C)P(Cc1cccc(CP(C(C)(C)C)C(C)(C)C)n1)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C#N)CNc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.6 %

Procedure:
Pd(TFA)2 (33.0 mg, 0.10 mmol) and 2,6-Bis[(di-tert-butylphosphino)methyl]pyridine (40.0 mg, 0.10 mmol) were suspended in 0.5 mL of toluene in a screw-capped vial. The vial was sealed with a cap containing a PTFE septum and removed from the dry box. Methacrylonitrile (270 mg, 4.00 mmol) and aniline (93.1 mg, 1.00 mmol) were added to the reaction mixture by syringe. The reaction mixture was stirred at room temperature for 24 h, after which time it was adsorbed onto silica gel. The product was isolated by eluting with 15% ethyl acetate/hexanes to give 142 mg (89%) of 2-anilino-1-methylethyl cyanide. 1H NMR: (CDCl3) δ 7.22 (t, J=7.6 Hz, 2H), 6.78 (t, J=7.6 Hz, 1H), 6.63 (d, J=7.6 Hz, 2H), 3.71 (brs, 1H) 3.43 (dd, J=13.8, 8.0 Hz, 1H), 3.37 (dd, J=13.8, 6.0 Hz, 1H), 2.99 (m, 1H), 1.38 (d, J=7.1 Hz, 3H). 13C{1H} NMR: (CDCl3) δ 146.52, 129.50, 121.81, 118.50, 113.04, 47.04, 25.98, 15.39. Anal. Calcd. for C10H12N2: C, 74.97; H, 7.55; N, 17.48. Found: C, 74.75; H, 7.35; N, 17.57.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].C(O)C.C([O-])([O-])=O.[K+].[K+].[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>[Na+].[I-].O>[CH2:21]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(C=O)cc1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C=O)cc1OCc1ccccc1
Reaction time: 2.5 h
Yield: 99.9 %

Procedure:
A mixture of 3-hydroxy-4-methoxy-benzaldehyde (100 g, 0.657 mole), ethanol (300 ml), K2CO3 (108.9 g, 0.788 mole), benzyl chloride (86.8 ml, 0.755 mole) and NaI (5 g) under N2 was refluxed under stirring for 2.5 hours, then cooled and added with water (900 ml). The precipitate was filtered, washed with water, and then with petrolatum, then dried under vacuum at 40° C. to give 159 g of the title compound which was used as such in the subsequent step.