Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl.[CH2:14]([C:16]1[C:21]([CH2:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH3:15]>C(N(CC)CC)C>[CH2:14]([C:16]1[C:21]([CH2:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=1[N:24]1[CH2:29][CH2:28][N:27]([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:26][CH2:25]1)[CH3:15]
Reactant: CCc1cccc(N2CCNCC2)c1CC
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CCc1cccc(N2CCN(Cc3ccc([N+](=O)[O-])cc3)CC2)c1CC

Procedure:
In the manner given in Example 1A, p-nitrobenzyl chloride is reacted with (2,3-diethylphenyl)piperazine dihydrochloride in the presence of triethylamine to give 1-(2,3-diethylphenyl)-4-(p-nitrobenzyl)piperazine.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([C:34]([O:36]CC)=[O:35])[CH:28]=[C:27]4[CH3:39])=[CH:20][CH:19]=2)=[C:14]([CH:40]([CH3:42])[CH3:41])[O:13][N:12]=1.Cl.O>O1CCCC1.CO>[Cl:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[C:5]=1[C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([C:34]([OH:36])=[O:35])[CH:28]=[C:27]4[CH3:39])=[CH:20][CH:19]=2)=[C:14]([CH:40]([CH3:42])[CH3:41])[O:13][N:12]=1
Reactant: CCOC(=O)c1cc(C)c2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(C(=O)O)nc2ccc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)cc12
Temperature: 90 °C
Yield: 90.6 %

Procedure:
A 1 N solution of sodium hydroxide (93.1 μL, 93.1 μmol) was added to ethyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-4-methyl-2-quinolinecarboxylate (26.8 mg, 46.6 μmol) in tetrahydrofuran and methanol (1:1, 931.4 μL) and the mixture was heated in the microwave at 90° C. for 10 minutes. After cooling, the mixture was neutralized with 1 N hydrochloric acid (93.1 μL), water was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, then dried over anhydrous magnesium sulfate, filtered and concentrated to give 23.1 mg (91%) of 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-4-methyl-2-quinolinecarboxylic acid as a solid. 1H NMR (400 MHz, d6-DMSO): δ 13.29 (br s, 1H), 8.24 (d, J=2 Hz, 1H), 8.16 (d, J=9 Hz, 1H), 8.10 (dd, J=9, 2 Hz, 1H), 7.98 (s, 1H), 7.77 (d, J=9 Hz, 2H), 7.65-7.62 (m, 2H), 7.55 (dd, J=9, 7 Hz, 1H), 6.94 (d, J=9 Hz, 2H), 4.89 (s, 2H), 3.48 (septet, J=7 Hz, 1H), 2.81 (s, 3H), 1.35 (d, J=7 Hz, 6H). HRMS C30H24Cl2N2O4 m/z 547.1191 (M+H)+Cal; 547.1199 (M+H)+Obs.
Reaction SMILES: [N+:1]1([O-])[C:2]([CH3:8])=[CH:3][CH:4]=[CH:5][C:6]=1[CH3:7].F[B-](F)(F)F.[CH3:15][O+:16](C)C>C(Cl)Cl>[OH:16][CH2:15][C:4]1[CH:3]=[C:2]([CH3:8])[N:1]=[C:6]([CH3:7])[CH:5]=1
Reactant: Cc1cccc(C)[n+]1[O-]
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1cc(CO)cc(C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 168.7 %

Procedure:
A solution of 2,6-lutidine N-oxide (41.6 g, 0.337 mol, 1.0 equiv.) in dry DCM (650 mL) was added to a flask containing trimethyloxonium tetrafluoroborate (50.0 g, 0.337 mol, 1.0 equiv.) at room temperature. under a nitrogen atmosphere. The mixture was stirred at room temperature for 3.0 hours, then concentrated in vacuo to give 78 g of crude 4-hydroxymethyl-2,6-dimethylpyridine. The crude product was dissolved in methanol (500 mL) and the solution was heated to reflux under a nitrogen atmosphere, then a solution of ammonium persulfate (24.6 g, 0.101 mol) in water (100 mL) was added dropwise. The mixture was stirred at reflux for 16 hours; TLC indicated complete reaction. Half of the solvents were removed in vacuo, then quenched with 10% NaOH solution to pH approximately 7, and evaporated to dryness. The residue was dissolved in methanol and filtered, the filtrate was concentrated in vacuum, and purified by column chromatography (eluting with methanol: DCM=5-15%) to give the title compound as a white solid. Yield: 24.7 g (52%).
Reaction SMILES: [CH:1]1([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH4-].[Na+].O>C(O)C.C1(C)C=CC=CC=1>[CH:1]1([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH2:12][NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Nc1ccccc1
Reactant: O=Cc1ccccc1C1C=Cc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: C1=CC(c2ccccc2CNc2ccccc2)c2ccccc21
Temperature: 25 °C
Yield: 71.1 %

Procedure:
To a solution of 2-(1-indenyl)benzaldehyde (7.0 mmol) in ethanol (19.4 mL) was added dropwise aniline (7.3 mmol) under a nitrogen atmosphere. The mixture was stirred at room temperature. After disappearance of the aldehyde was confirmed by gas chromatography, The solvent was distilled off under reduced pressure. After addition of ethanol (19.4 mL), sodium borohydride (4.5 mmol) was added to the solution and the mixture was reacted at room temperature for 3 hrs. Water and toluene were then added to the reaction mixture. The organic layer was dried and concentrated. The obtained oily substance was purified by silica gel column chromatography to give N-[2-(1-indenyl)phenylmethyl]-N-phenylamine (1.48 g, yield 24.0%) as a yellow oily substance.
Reaction SMILES: C1(C)C=CC=CC=1.C(#N)C.[Cl:11][C:12]1[CH:13]=[C:14]([OH:19])[CH:15]=[N:16][C:17]=1[Cl:18].[C:20]([O:23][C@@H:24]1[C@@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:28]([O:34][C:35](=[O:37])[CH3:36])[CH2:27][S:26][C@@H:25]1Br)(=[O:22])[CH3:21]>[Cl-].[Zn+2].[Cl-].C(N(CC)CC)C>[C:20]([O:23][C@@H:24]1[C@@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:28]([O:34][C:35](=[O:37])[CH3:36])[CH2:27][S:26][C@H:25]1[O:19][C:14]1[CH:15]=[N:16][C:17]([Cl:18])=[C:12]([Cl:11])[CH:13]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Reactant: Oc1cnc(Cl)c(Cl)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cnc(Cl)c(Cl)c1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 50 %

Procedure:
5.1 g (37.5 mM) of zinc chloride are melted under reduced pressure, the melt is cooled under an inert atmosphere and then 12 ml of toluene, 12 ml of acetonitrile, 3 g of 4 Å molecular sieve and 2.45 g (15 mM) of 5,6-dichloro-3-pyridinol are added. The temperature of the mixture is brought to 90° C. and 3.78 g (37.5 mM) of triethylamine and 5.86 g (16.5 mM) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide are added. The reaction medium is stirred at 90° C. for 20 minutes and is then cooled and filtered to remove the inorganic salts, which are washed with ethyl acetate. The combined organic phases are washed with a 0.5 N sodium hydroxide solution and then the pH is brought to a value of 3 using a 0.1 N hydrochloric acid solution. The organic phase is subsequently washed with a saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The product is crystallized from ethyl ether and the desired product is obtained in the form of a light brown solid with a yield of 50%.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:18][CH:19]=[C:20]([CH2:22][CH2:23]O)[N:21]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.[CH3:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:18][CH:19]=[C:20]([CH2:22][CH2:23][N:28]4[CH2:29][CH2:30][CH2:31][C@H:27]4[CH3:26])[N:21]=3)=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: C[C@@H]1CCCN1
Reactant: CS(=O)(=O)c1ccc(-c2ccc(-c3nc(CCO)co3)cc2)cc1
Agent: Cl
Product: C[C@@H]1CCCN1CCc1coc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)n1

Procedure:
The title compound is prepared in a manner substantially similar to Example 53 from 2-[2-(4′-Methanesulfonyl-biphenyl-4-yl)-oxazol-4-yl]-ethanol (See Intermediate 71) and (R)-2-methylpyrrolidine hydrochloride [CAS 41720-98-3]. MS (m/e): 411.2 (M+1)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[NH:14][C:13](=O)[C:12]=2[CH2:11][CH2:10]1.[CH2:28]([N:30](CC)CC)C.CS(Cl)(=O)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:25])([F:24])[F:26])[C:15]=3[N:14]=[C:13]([NH:30][CH3:28])[C:12]=2[CH2:11][CH2:10]1
Reactant: Cc1cc(O)ccc1N1CCc2c1c1cccc(OC(F)(F)F)c1[nH]c2=O
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CNc1nc2c(OC(F)(F)F)cccc2c2c1CCN2c1ccc(O)cc1C
Temperature: -78 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
1-(2-Methyl-4-hydroxyphenyl)-4-oxo-6-trifluoromethoxy-2,3,4,5-tetra-hydropyrrolo[3,2-c]quinoline(2.3g, 6.1 mmol) was dissolved in dichloromethane. Triethylamine(2.6 ml, 18.0 mmol) was added and methanesulfonyl chloride(1.0 ml, 12.8 mmol) were added, and then the reaction mixture was stirred at -78° C. for 3 hours. The reaction mixture was slowly warmed up to -10° C., and stirred for 1 hours. After extracting the reaction mixture with dichloromethane, the organic layer was washed with water for 3 times. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized in dichloromethane/hexane to obtain 2.3 g of desired compound as solid in 72% of yield.
Reaction SMILES: [Br:1]N1C(C)(C)C(=O)N(Br)C1=O.[OH:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]([C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=2[CH3:30])[C:23]([O:25][CH3:26])=[O:24])[C:15](=[O:31])[CH:14]=1>C(#N)C>[Br:1][C:14]1[C:15](=[O:31])[N:16]([C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=2[CH3:30])[C:23]([O:25][CH3:26])=[O:24])[C:17]([CH3:19])=[CH:18][C:13]=1[OH:12]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: COC(=O)c1ccc(C)c(-n2c(C)cc(O)cc2=O)c1
Solvent: CC#N
Product: COC(=O)c1ccc(C)c(-n2c(C)cc(O)c(Br)c2=O)c1
Yield: 171.2 %

Procedure:
A solution of 1,3-dibromo-5,5-dimethylhydantoin (1.375 kg. 4.81 moles) in acetonitrile (11.5 L) was added to a solution of methyl 3-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-4-methylbenzoate (5) (2.50 kg, 9.15 mol) in acetonitrile (4.8 L). The solution was added at a rate that maintained the temperature less than −10° C. for 90 to 180 minutes. A portion of the acetonitrile (approximately 6 L) was removed after completion of the reaction via distillation. The product was precipitated by the addition of water (7.9 L) and filtered to yield 2.90 kg (90%) of methyl 3-(3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-4-methylbenzoate (4)
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:18])[NH:12][C:13]1[S:14][CH:15]=[CH:16][N:17]=1)(=O)C.Cl>>[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([NH:12][C:13]1[S:14][CH:15]=[CH:16][N:17]=1)=[O:18]
Reactant: CC(=O)Oc1ccccc1C(=O)Nc1nccs1
Agent: Cl
Product: O=C(Nc1nccs1)c1ccccc1O
Temperature: 50 °C
Yield: 86.4 %

Procedure:
2-(1,3-thiazol-2-ylcarbamoyl)phenyl acetate (501, 663.3 mg, 2.53 mmol) was added to a 25 mL round bottom flask equipped with a stirbar and a water-jacketed condenser. The headspace was replaced with dry nitrogen, and concentrated hydrochloric acid (15.0 mL) was added in a single portion. The suspension was heated to 50° C., and stirred well. The suspended solids dissolved to form a clear colorless solution before solids precipitate from the reaction mixture, which was then cooled in an ice bath, and the solids were filtered on a medium frit and washed with a large portion of water. The filter cake wash washed through the frit with methanol, collected, and the solvent was removed in vacuo to give 502 (481.5 mg, 86%) as a colorless solid.
Reaction SMILES: [CH:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([OH:12])[C:6]2=[N:5][C:4]=1[CH3:13])=[O:2].C(N([CH2:19][CH3:20])CC)C>CO>[CH:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][C@H:6]3[C:19]4[C:20](=[CH:1][CH:3]=[CH:4][CH:13]=4)[CH2:9][CH2:10][C@@H:11]3[OH:12])[C:6]2=[N:5][C:4]=1[CH3:13])=[O:2]
Reactant: CCN(CC)CC
Reactant: Cc1nc2c(O)cccn2c1C=O
Solvent: CO
Product: Cc1nc2c(O[C@H]3c4ccccc4CC[C@@H]3O)cccn2c1C=O
Reaction time: 8 h
Yield: 47.1 %

Procedure:
580 mg of 3-formyl-8-hydroxy-2-methyl-imidazo[1,2-a]pyridine and 580 mg of (+)-1R,2S-1,2,3,4-tetrahydro-naphthaline-1,2-oxide are reacted, analogously to the method described in Example 21, with 340 mg triethylamine in 43 ml of aqueous methanol (35 ml methanol+8 ml water) at 60° C. After 8 hours the mixture is worked up as described in Example 41. After stirring with petroleum ether and drying in high vacuum, 250 mg of the title compound is isolated. [α]D22 =+38° (c=1, chloroform).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[O:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16]=1[C:17](=[O:22])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH:6]=[CH:5]2.[Br:27]Br.C([O-])(=O)C.[K+]>C(O)(=O)C>[Br:27][C:10]1[CH:11]=[C:2]([OH:1])[CH:3]=[C:4]2[C:9]=1[CH:8]=[C:7]([C:12]1[O:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16]=1[C:17](=[O:22])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH:6]=[CH:5]2
Reactant: CC(C)CC(=O)c1c(-c2ccc3cc(O)ccc3c2)oc2ccccc12
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)CC(=O)c1c(-c2ccc3cc(O)cc(Br)c3c2)oc2ccccc12
Yield: 58.6 %

Procedure:
Following the procedure described in Step 4 of Example 1, 1-[2-(6-hydroxy-2-naphthyl)-1-benzofuran-3-yl]-3-methyl-1-butanone (0.863 g, 2.51 mmol) was brominated using bromine (0.15 mL, 2.9 mmol), and potassium acetate (2.45 g. 25.0 mmol) in glacial acetic acid (25 mL). Purification by flash chromatography using 15-100% chloroform in hexane as an eluant followed by chromatography on a Biotage apparatus using 15-20% chloroform in hexane as an eluant furnished 1-[2-(8-bromo-6-hydroxy-2-naphthyl)-1-benzofuran-3-yl]-3-methyl-1-butanone as an orange solid (0.623 g), mp 160-161° C. 1HNMR (200 MHz, DMSO-d6): δ10.95 (s,1H), 8.4 (s, 1H), 8.2 (d, 1H, J=8.6 Hz), 7.9-8.1 (m, 3H), 7.7-7.8 (d, 1H, J=6.8 Hz), 7.3-7.55 (m, 3H), 2.8 (d, 1H, J=6.8 Hz), 2.0-2.2 (m, 1H), and 0.75 ppm (d, 6H, J=6.3 Hz).
Reaction SMILES: Cl[P:2]1[N:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[P:4](Cl)[N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].[C:15]([C:19]1[CH:20]=[C:21]([CH:45]=[C:46]([C:49]([CH3:52])([CH3:51])[CH3:50])[C:47]=1[OH:48])[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[O:25])([CH3:18])([CH3:17])[CH3:16]>C(N(CC)CC)C>[C:15]([C:19]1[CH:20]=[C:21]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[O:25])[CH:45]=[C:46]([C:49]([CH3:51])([CH3:50])[CH3:52])[C:47]=1[O:48][P:2]1[N:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[P:4]([O:48][C:47]2[C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:20][C:21]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[O:25])=[CH:45][C:46]=2[C:49]([CH3:50])([CH3:52])[CH3:51])[N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:16])([CH3:17])[CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC(C)(C)N1P(Cl)N(C(C)(C)C)P1Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCc1cc(C(C)(C)C)c(OP2N(C(C)(C)C)P(Oc3c(C(C)(C)C)cc(CCC(=O)OCCCCCCCCCCCCCCCCCC)cc3C(C)(C)C)N2C(C)(C)C)c(C(C)(C)C)c1

Procedure:
The procedure of Example 1 is repeated using 2,4-dichloro-1,3-di-tert-butyl-1,3,2,4-diazadiphosphetidine, n-octadecyl 3,5-di-tert-butyl-4-hydroxyhydrocinnamate and triethylamine to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]=[O:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: OCc1cc(Cl)c2cn[nH]c2c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Product: O=Cc1cc(Cl)c2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4-chloro-1H-indazol-6-yl)methanol (30 mg, 0.18 mmol) in acetone (5 mL) was added PDC (100 mg, 0.27 mmol). The mixture was stirred overnight at rt. The mixture was filtered through celite, the filter cake was washed with ethyl acetate. The solution was washed with water (2×10 mL), brine (10 mL), dried over MgSO4 and concentrated to a brown solid (30 mg, 100%). 1H NMR (400 MHz, CD3OD) δ 10.1 (s, 1H), 8.21 (s, 1H), 8.08 (s, 1H), 7.62 (s, 1H).
Reaction SMILES: NC(=O)[C@@H:3]([NH:8][C:9](=[O:37])[C@@H:10]([NH:15][C:16]([N:18]1[C:26]2[CH2:25][CH2:24][N:23]([CH3:27])[CH2:22][C:21]=2[C:20]([C:28]2[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=2[F:36])=[N:19]1)=[O:17])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4]C(C)C.[N:39]1([C:45]([O:47][CH2:48][CH3:49])=[O:46])CCN[CH2:41][CH2:40]1>>[CH3:14][C:11]([CH3:12])([CH3:13])[C@H:10]([NH:15][C:16]([N:18]1[C:26]2[CH2:25][CH2:24][N:23]([CH3:27])[CH2:22][C:21]=2[C:20]([C:28]2[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=2[F:36])=[N:19]1)=[O:17])[C:9]([N:8]1[CH2:41][CH2:40][N:39]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:4][CH2:3]1)=[O:37]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C)C(N)=O
Reactant: CCOC(=O)N1CCNCC1
Product: CCOC(=O)N1CCN(C(=O)[C@@H](NC(=O)n2nc(-c3cc(F)c(F)cc3F)c3c2CCN(C)C3)C(C)(C)C)CC1

Procedure:
Compound 77 was prepared according to the procedure described for the synthesis of compound 72 by replacing leucine amide with ethyl piperazine-1-carboxylate. LCMS (+ESI) m/z=565.4 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([OH:13])=O.[CH3:16][N:17]1[C:25]2([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:31]>>[CH3:16][N:17]1[C:25]2([CH2:30][CH2:29][N:28]([C:11](=[O:13])[CH2:10][CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:1])([F:15])[F:14])[CH2:27][CH2:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:31]
Reactant: O=C(O)CCc1ccccc1C(F)(F)F
Reactant: CN1C(=O)c2ccccc2C12CCNCC2
Product: CN1C(=O)c2ccccc2C12CCN(C(=O)CCc1ccccc1C(F)(F)F)CC2

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 1 using 3-(2-(trifluoromethyl)phenyl)propanoic acid and 2-methylspiro[isoindoline-1,4′-piperidin]-3-one. LC-MS Method 1 tR=1.65, min, m/z=417, 415.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[C:11]([CH3:16])[N:12]=[CH:13][CH:14]=3)[CH2:9][O:8][C:6]=2[CH:7]=1.[C:17]([O:21][C:22]([NH:24][CH:25]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:26][OH:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CCOC(C)=O.O.CC([O-])=O.CC([O-])=O.[Pd+2].C(P(C(C)(C)C)C1C=CC=CC=1C1C(CCC)=CC(CCC)=CC=1CCC)(C)(C)C>[C:17]([O:21][C:22](=[O:23])[NH:24][C@@H:25]([CH2:28][CH:29]([CH3:30])[CH3:31])[CH2:26][O:27][C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[C:11]([CH3:16])[N:12]=[CH:13][CH:14]=3)[CH2:9][O:8][C:6]=2[CH:7]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)CC(CO)NC(=O)OC(C)(C)C
Reactant: Cc1nccc2c1COc1cc(Cl)ccc1-2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCc1cc(CCC)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(CCC)c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nccc2c1COc1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc1-2
Temperature: 25 °C
Yield: 187.3 %

Procedure:
A mixture of 8-chloro-4-methyl-5H-chromeno[3,4-c]pyridine (60 mg, 0.259 mmol), (S)-(+2-(tert-butoxycarbonylamino)-4-methyl-1-pentanol (113 mg, 0.518 mmol), 2-di-t-butylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl (6.60 mg, 0.016 mmol), Cs2CO3 (127 mg, 0.388 mmol) and Pd(OAc)2 (1.744 mg, 7.77 μmol) in toluene (5 mL) was heated at 80° C. for 16 h. After cooling to rt, the mixture was diluted with EtOAc (10 mL) and water (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford (S)-tert-butyl(4-methyl-1-((4-methyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)pentan-2-yl)carbamate, (0.2 g, 0.485 mmol, 30% yield) as a yellow solid. LCMS (ESI) m/e 413.39 [(M+H)+, calcd for C24H33N2O4 413.24]; LC/MS retention time (Method F): tR=0.97 min.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([OH:23])[C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:21])[C@@H:7]1[OH:22])=[O:4].[CH2:24](O)[CH2:25][CH2:26]C>>[CH2:1]([O:2][C:3]([CH:5]([OH:23])[C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:21])[C@@H:7]1[OH:22])=[O:4])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCO
Reactant: COC(=O)C(O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Product: CCCCOC(=O)C(O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Yield: 87 %

Procedure:
5 g of adenosine-5'-carboxylic acid methyl ester are dissolved in 200 ml of n-butanol and, together with 3 g of D-benzedrine, boiled under reflux for 3 hours. The reaction mixture is filtered and the filtrate evaporated in a vacuum. The evaporation residue is triturated with ether, filtered off with suction, again washed with ether and dried. There are thus obtained 5.6 g of adenosine-5'-carboxylic acid n-butyl ester, which has a melting point of 166°-167° C. The yield is 87% of theory. The crude product obtained can be recrystallized from water.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[C:33]([OH:40])[CH:32]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[C:16]4[S:17][CH:18]=[CH:19][N:20]=4)(=[O:14])=[O:13])=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[C:33]([OH:40])[CH:32]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Reactant: OB(O)c1ccc(Cl)cc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(Cl)cc4O)nccc3c2)cc1

Procedure:
To a microwave vial charged with 1-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate JJJ) (80 mg, 0.179 mmol), (4-chloro-2-hydroxyphenyl)boronic acid (30.9 mg, 0.179 mmol), potassium carbonate (124 mg, 0.897 mmol) and Pd(Ph3P)4 (20.73 mg, 0.018 mmol) was added dioxane (897 μl) and Water (299 μl) and irradiated at 100° C. for 30 min affording conversion to desired product as the primary species. The organic layer was decanted, the aqueous rinsed with EtOAc and the combined organics dried under reduced pressure. m/z (ESI) 537.9 (M+H)+.