Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH2:23][CH3:24])[C:15]3[C:20]([C:21]=2[CH:22]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH2:23][CH3:24])[C:15]4[C:20]([C:21]=3[CH:22]=2)=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:5]=[CH:4][N:3]=1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: Clc1ccnc(Cl)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c2ccccc2c2cc(Nc3ccnc(Cl)n3)ccc21

Procedure:
Briefly, 2,4-dichloropyrimidine (1) was reacted with 3-amino-9-ethylcarbazole (2) by heating in iso-propanol in the presence of N,N-diisopropylethylamine. Separation of the regioisomers provided the pure 4-substituted pyrimidine derivative (3), which was reacted with 4-(3-Aminopropyl)morpholine (4) in sec-butanol under microwave heating in the presence of N,N-diisopropylethylamine to provide EHop-016 (5).
Reaction SMILES: C(O[C@@H:5]1[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:6]1[O:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.[CH:38]1[C:43]([N+:44]([O-:46])=[O:45])=[CH:42][CH:41]=[C:40]([OH:47])[CH:39]=1.B(F)(F)F.CCOCC>ClCCl>[C:8]([O:7][C@@H:6]1[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:27][C@H:5]1[O:47][C:40]1[CH:41]=[CH:42][C:43]([N+:44]([O-:46])=[O:45])=[CH:38][CH:39]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(OC[C@H]1O[C@@H](Oc2ccc([N+](=O)[O-])cc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 71.7 %

Procedure:
A solution of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (10 g), p-nitrophenol (5.6 g, 2 eq) and boron trifluoride diethyl etherate (1.2 ml, 0.5 eq) in dry dichloromethane (100 ml) was allowed to stand at room temperature overnight. Thin-layer chromatography on silica gel [Eluant EtOAc:CHCl3:Hexanes 1:2:4] then indicated essentially complete conversion to a slightly less polar material. The solution was washed with aq bicarbonate and processed conventionally. Flash chromatography on silica gel [eluant EtOAc:CHCl3:Hexanes 1:2:8] then afforded 8.29 g of title compound.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[C:33]([CH2:41]Br)[CH:32]=2)[O:11][C@H:10]1[CH2:43][O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:52]#[N:53].[K+]>CCO.O>[CH2:24]([O:23][C@@H:13]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@@H:10]([CH2:43][O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[O:11][C@H:12]1[C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[C:33]([CH2:41][C:52]#[N:53])[CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: [C-]#N
Reactant: BrCc1cc([C@@H]2O[C@@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c2ccccc2c1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c2ccccc2c1
Temperature: 25 °C
Yield: 46 %

Procedure:
To a solution of the (2S,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(3-(bromomethyl)naphthalen-1-yl)-tetrahydro-2H-pyran in EtOH (80 mL) and water (40 mL) was added potassium cyanide (4.24 g, 65.1 mmol). The reaction mixture was refluxed overnight. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The crude residue was purified by column chromatography to yield 2-(4-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxy-methyl)-tetrahydro-2H-pyran-2-yl)naphthalen-2-yl)acetonitrile (10.9 g, 46%) as a white solid.
Reaction SMILES: [C:1]([O:9][C:10]1[C:11]([C:29]([O:31][CH3:32])=[O:30])=[N:12][C:13]([CH:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[N:14][C:15]=1[OH:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33]I>C1COCC1.C([O-])([O-])=O.[Cs+].[Cs+]>[C:1]([O:9][C:10]1[C:15](=[O:16])[N:14]([CH3:33])[C:13]([CH:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])=[N:12][C:11]=1[C:29]([O:31][CH3:32])=[O:30])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(C2CCCN2C(=O)OC(C)(C)C)nc(O)c1OC(=O)c1ccccc1
Reactant: CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)c1nc(C2CCCN2C(=O)OC(C)(C)C)n(C)c(=O)c1OC(=O)c1ccccc1
Temperature: 40 °C

Procedure:
To a stirred solution of the product of Step 2 (1.0 eq.) in THF, Cs2CO3 was added (1.2 eq.) followed by the addition of CH3I (2.0 eq.). The reaction was stirred at 40° C. until the starting material was consumed as determined by MS analysis. The reaction was concentrated and the residue taken up with EtOAc, washed with 1 N HCl, saturated solution of NaHCO3 and brine. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. Reaction crude showed 3.4:1 ratio N (desired product) versus O methylation. The title product was purified by flash column chromatography (EtOAc:Petroleum Ether=1:1) and obtained as a 1:1 mixture of rotamers by NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH3:15][C:16]([CH3:18])=[O:17].[OH-].[Na+]>O.Cl>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1/[CH:5]=[CH:15]/[C:16](=[O:17])[CH3:18]
Reactant: COc1ccc(C=O)c(OC)c1OC
Reactant: CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(/C=C/C(C)=O)c(OC)c1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 19.6 g (0.1 mol) of 2,3,4-trimethoxybenzaldehyde in 21 ml (0.28 mol) of acetone and 10.5 ml of water was treated with 2.5 ml of 3N sodium hydroxide solution, whereby the temperature of the reaction mixture should not exceed 30°. The mixture was stirred at room temperature for 20 hours, diluted with water, and 3N hydrochloric acid was added to produce a strongly acidic reaction. The aqueous phase was extracted twice with methylene chloride. The combined organic phases were washed with water, dried over magnesium sulphate and concentrated. The residue was purified by flash chromatography on 1000 g of silica gel (elution agent ether/hexane 10:1). There was obtained (E)-4-(2,3,4-trimethoxyphenyl)but-3-en-2-one as a yellow oil. MS: 236 (M+), 205 (base peak) m/e.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[O:13][N:12]=[C:11]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[C:16]([CH3:22])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.O.[NH2:28][NH2:29]>Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[O:13][N:12]=[C:11]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=[N:28][NH2:29])=[C:16]([CH3:22])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NN
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C=O
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C=NN
Yield: 61 %

Procedure:
A solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzaldehyde (i.e. the product of Step 1, Example 1, 500 mg), concentrated hydrochloric acid (5 drops) and hydrazine hydrate (86 mg) in methanol (20 mL) were heated at reflux for 5 h. The mixture was concentrated and the residue was triturated with water. Filtration yielded the title compound (317 mg, 61%).
Reaction SMILES: [CH2:1]([NH:8][CH:9]([C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH3:24])[C:12]=4[CH:9]([NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:10][OH:11])=[CH:18][CH:19]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(CO)NCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(CO)NCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 2-benzylamino-2-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:10]O.P(Cl)(Cl)(Cl)(Cl)[Cl:13].O>C(Cl)(Cl)(Cl)Cl>[Cl:13][CH2:10][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[F:1]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COc1cccc(CO)c1F
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COc1cccc(CCl)c1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a solution of (2-fluoro-3-methoxyphenyl)methanol (13 g, 83.2 mmol) in CCl4 (75 mL), PCl5 (26 g, 128.7 mmol) was added. The resulting mixture was heated at 90° C. for 30 min and then stirred at room temperature for 1 h. The mixture was poured into water (160 mL) and extracted with dichloromethane (2×150 mL). The combined organic layers were washed with brine (200 mL), dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel column chromatography (1:15 EtOAc/petroleum ether) to give the title compound (11.5 g). 1H NMR (CDCl3): δ 7.10-6.91 (m, 3H), 4.63 (s, 2H), 3.89 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].C(=O)([O-])[O-].[K+].[K+].[CH:16]1[C:21]([C:22]#[N:23])=[CH:20][N:19]=[C:18](Cl)[CH:17]=1.O>CC(N(C)C)=O>[OH:6][CH2:5][C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][C:18]1[CH:17]=[CH:16][C:21]([C:22]#[N:23])=[CH:20][N:19]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: OCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: N#Cc1ccc(Oc2cccc(CO)c2)nc1
Temperature: 100 °C
Yield: 99.8 %

Procedure:
Add 3-hydroxybenzyl alcohol (0.99 g, 7.94 mmol) and potassium carbonate (1.50 g, 10.83 mmol) to 6-chloronicotinitrile (1.00 g, 7.22 mmol) in dimethylacetamide (25 mL) and stir. Heat to 100° C. for 4 hrs. Let cool to ambient temperature and pour into water (100 mL). Extract with diethyl ether (3×100 mL). Combine the organic layers and wash with 1N NaOH (2×50 mL) and dry over magnesium sulfate. Filter and concentrate under reduced pressure to give the product (1.63 g, 99%): 1H NMR (CDCl3) 8.49 (d, J=2.2 Hz, 1H), 7.95 (dd, J=2.2 Hz, 8.7 Hz, 1H), 7.47 (t, J=7.9 Hz, 1H), 7.29 (s, 1H), 7.21 (s, 1H), 7.10 (d, J=8.2 Hz, 1H), 7.06 (d, J=8.7 Hz, 1H), 4.77 (s, 2H).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([S:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH3:27].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.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>[CH2:25]([S:24][C:5]1[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7](=[O:8])[C:2]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:3]([CH3:27])[N:4]=1)[CH3:26]
Reactant: CCSc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OB(O)c1ccccc1
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: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCSc1nc(C)c(-c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 26.5 %

Procedure:
To a solution of 4′-{[5-bromo-2-(ethylthio)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.76 g) and phenylboronic acid (0.32 g) in 1,4-dioxane (10 mL) solution were added 2 M aqueous cesium carbonate solution (2 mL) and tetrakis(triphenylphosphine)palladium (0.1 g), and the mixture was stirred at 90° C. for 12 hr under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off through celite. The filtrate was washed successively with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.2 g, 26%) as a colorless solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][N:34]([CH3:39])[CH2:35][C:36](O)=[O:37].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][N:30]([C:36](=[O:37])[CH2:35][N:34]([CH3:39])[CH3:33])[CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 23.2 %

Procedure:
A mixture of 5-(2-benzyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (150 mg, 0.33 mmol), N,N-dimethylglycine (40 mg, 0.39 mmol), EDCl (69 mg, 0.36 mmol), HOBt (48 mg, 0.36 mmol), and N,N-diisopropylethylamine (227 μL, 1.30 mmol) in DMF (2 mL) was stirred at rt for 6 h. An additional 0.5 eq. of N,N-dimethylglycine was added and the mixture continued to stir at rt for 16 hr. The crude reaction mixture was purified via preparative HPLC using a gradient elution from 15% to 40% acetonitrile in water to provide 39 mg (24%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1 H), 7.92 (s, 1 H), 7.81 (d, 1 H), 7.66 (s, 1 H), 7.28-7.39 (m, 5 H), 7.15 (dd, 1 H), 6.60 (s, 1 H), 5.67 (s, 2 H), 4.32 (dd, 1 H) 3.33-3.46 (m, 1 H), 3.01-3.20 (m, 4 H), 2.66-2.78 (m, 1 H), 2.19 (s, 6 H), 2.05 (d, 2 H), 1.44-1.75 (m, 2 H); ES-MS m/z 509.23 [M+H]+, HPLC RT (min) 2.12.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH:5]1[CH2:10][N:9]([C:11](=[O:24])[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:8][CH2:7][NH:6]1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:35]2[S:36][CH:37]=[C:38]([C:40](O)=[O:41])[N:39]=2)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>CN(C)C=O>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:35]2[S:36][CH:37]=[C:38]([C:40]([N:6]3[CH2:7][CH2:8][N:9]([C:11](=[O:24])[C:12]4[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=4)[CH2:10][CH:5]3[CH2:4][O:3][CH3:2])=[O:41])[N:39]=2)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34]
Reactant: COCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1
Reactant: COc1ccc(-c2nc(C(=O)O)cs2)cc1OC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1C(=O)c1csc(-c2ccc(OC)c(OC)c2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-methoxymethyl-4-(3,4,5trimethoxybenzoyl) piperazine hydrochloride obtained in Reference Example 6 (0.50 g), 2-(3,4-dimethoxyphenyl)thiazol-4-carboxylic acid (0.37 g), triethylamine (0.42 g) and N,N-dimethylformamide (5 ml) is added dropwise, while stirring under icecooling, diethyl cyanophosphonate (0.46 g). The reaction mixture is stirred at 0° C. for one hour and there poured into ice-water, followed by extraction with ethyl acetate. The organic layer is washed with water, dried and concentrated under reduced pressure. The concentrate is purified by means of a silica gel column chromatography (eluent: AcOEt) to give 1-[2(3,4-dimethoxyphenyl) thiazol-4-ylcarbonyl]-2-methoxymethyl-4-(3,4,5-trimethoxybenzoyl)piperazine. Recrystallization from EtOH gives colorless needles, m.p. 149-151° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:19])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][C:16]([OH:18])=[O:17])([CH3:14])[CH2:6][CH2:5]2.N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>O1CCCC1>[C:26]([O:1][C:2]1[C:3]([CH3:19])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][C:16]([OH:18])=[O:17])([CH3:14])[CH2:6][CH2:5]2)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CC(=O)O)O2
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(CC(=O)O)O2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 66.1 g. (0.25 mol.) of (±)-(6-hydroxy-2,5, 7,8-tetramethylchroman-2-yl) acetic acid and 250 ml. each of pyridine and acetic anhydride was stirred at 25° C. under N 2 for 20 hours and stripped of solvent at 40° C. to give an orangebrown oil. To a suspension of this material in 500 ml. of H 2 O and 100 ml. of tetrahydrofuran was added 166 g. (2.0 mol.) of NaHCO 3. the suspension was stirred at 25° C. for 4.0 hours, washed with ether, acidified with 2N-aqueous HCl and extracted with ether. The ether solutions were washed with saturated brine, dried over sodium sulfate and stripped of solvent to give (±)-(6-acetoxy-2,5,7,8-tetramethylchroman-2-yl) acetic acid as and orangeish resin. Crystallization from diethyl ether petroleum ether (b.p. 30°-60° C.) gave (±)-(6-acetoxy-2,5,7,8 -tetramethylchroman-2-yl) acetic acid as a granular white solid.
Reaction SMILES: [C:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH2:16])=[O:15])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)(=[O:4])[CH:2]=[CH2:3].[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([NH:37][CH2:3][CH2:2][C:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH2:16])=[O:15])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:19][CH2:18]1)=[O:4])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NCc1ccccc1
Reactant: C=CC(=O)n1c(N2CCC(Cc3ccccc3)CC2)cc2cc(C(N)=O)ccc21
Product: NC(=O)c1ccc2c(c1)cc(N1CCC(Cc3ccccc3)CC1)n2C(=O)CCNCc1ccccc1

Procedure:
was prepared by reacting 1-acryloyl-(4-benzylpiperidinyl)-indole-5-carboxamide with benzylamine. M+ 479.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:59])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:56]=[CH:55][C:34]([C:35]([O:37][CH2:38][O:39][C:40](=[O:54])[NH:41][C@@H:42]([CH3:53])[C:43]([O:45]CC3C=CC=CC=3)=[O:44])=[O:36])=[CH:33][C:32]=2[O:57][CH3:58])=[O:29])[CH:5]=[CH:6][CH:7]=1.[H][H]>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[C:3]([F:59])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:56]=[CH:55][C:34]([C:35]([O:37][CH2:38][O:39][C:40]([NH:41][C@@H:42]([CH3:53])[C:43]([OH:45])=[O:44])=[O:54])=[O:36])=[CH:33][C:32]=2[O:57][CH3:58])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)OCOC(=O)N[C@@H](C)C(=O)OCc2ccccc2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)OCOC(=O)N[C@@H](C)C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 24, a solution of chiral ((S)-1-(benzyloxy)-1-oxopropan-2-ylcarbamoyloxy)methyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate in ethyl acetate was treated with 10% palladium on carbon under 1 atm of hydrogen to give chiral (S)-2-(((4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoyloxy)methoxy)carbonylamino)propanoic acid as a white solid. MS (ES+) m/z calcd. for C36H36Cl2F2N4O8: [(M+H)+]: 761, found: 761.
Reaction SMILES: Cl[C:2]1[C:3]([CH:8]2[CH2:11][N:10]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:22]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:23]1.C(N(CC)CC)C>CS(C)=O>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([CH:24]2[CH2:25][CH2:26][N:22]([C:2]3[C:3]([CH:8]4[CH2:11][N:10]([C:12]5[CH:21]=[CH:20][C:19]6[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=6)[N:13]=5)[CH2:9]4)=[N:4][CH:5]=[CH:6][N:7]=3)[CH2:23]2)[CH:28]=1
Reactant: c1cncc(C2CCNC2)c1
Reactant: Clc1nccnc1C1CN(c2ccc3ccccc3n2)C1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: c1cncc(C2CCN(c3nccnc3C3CN(c4ccc5ccccc5n4)C3)C2)c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a 3 mL vial was added 2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinoline (0.04000 g, 0.135 mmol), 3-(pyrrolidin-3-yl)pyridine (commerically available at Array Biopharma, 0.040 g, 0.270 mmol), and triethylamine (commerically available at Sigma Aldrich, 0.038 ml, 0.270 mmol) in DMSO (Solvent Volume: 0.449 ml) and the reaction was stirred at 110° C. overnight. Upon completion, the reaction was filtered into a 24 well plate and purified by reverse phase purification using the following conditions: (Instrumentation: MS—Waters SQ; UV—Waters 2487 or Waters PD; Solvents: A: Water w/0.1% NH4OH B: Acetonitrile w/0.1% NH4OH; Column: Phenomenex Gemini-NX C18 110A 5 um 21×100; Flow Rate: 44 mL/min. 10 min Method, variable gradient over 8 mins.)