Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OCC)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[CH3:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[NH:17])=[CH:14][CH:13]=1.O>C(Cl)(Cl)Cl>[OH:6][C:1]1[N:18]=[C:16]([C:15]2[CH:19]=[CH:20][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[N:17]=[C:3]([CH3:5])[CH:2]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1ccc(C(=N)N)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc(-c2nc(C)cc(O)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
Under N2, a solution of ethyl acetoacetate (7.15 g, 0.053 mol) in CHCl3 (200 ml) was added dropwise to a suspension of 4-methoxybenzamidine in CHCl3 (200 ml). After stirring at room temperature overnight, water was added to the solution. The aqueous phase was separated and extracted with CHCl3 and the organic layers were combined, dried (Na2SO4), filtered and concentrated to dryness. The residue was chromatographed on silica gel and the product was eluted with 2% CH3OH--CHCl3 to yield 8.58 g (75%) of product, m.p. 198°-199° C.
Reaction SMILES: [OH-].[Na+].Cl[CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[OH:15])=[O:7]>S(=O)(=O)(O)O>[OH:14][C:11]1[CH:10]=[C:9]2[C:8]([C:6](=[O:7])[CH2:5][CH2:4][O:15]2)=[CH:13][CH:12]=1
Reactant: O=C(CCCl)c1ccc(O)cc1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C1CCOc2cc(O)ccc21
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To a stirred 2 M solution of sodium hydroxide (500 mL, 1000 mmol) at 5° C. was added 3-chloro-1-(2,4-dihydroxyphenyl)propan-1-one (Preparation 2A, 13.6 g, 67.9 mmol) in one portion. The solution was warmed to room temperature over 2 h, re-cooled to 5° C., and the pH was adjusted to ˜2 with 6 M aqueous sulfuric acid (˜50 mL). An orange precipitant formed which was collected by vacuum filtration and dried under reduced pressure. The filtrate was extracted with ethyl acetate (3×100 mL), washed with brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave an orange solid. The two recovered solids were combined to give 7-hydroxychroman-4-one (9.0 g, 54.8 mmol, 81% yield). LC/MS M+1=165.0; 1H NMR (400 MHz, CDCl3) δ ppm 7.77 (1H, d, J=8.58 Hz), 6.45 (1H, dd, J=8.69, 2.31 Hz), 6.33 (1H, d, J=2.42 Hz), 5.62 (1H, br. s.), 4.33-4.66 (2H, m), and 2.58-2.90 (2H, m).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:25]([Si:29]([O:32][CH2:33][CH2:34]I)([CH3:31])[CH3:30])([CH3:28])([CH3:27])[CH3:26]>C1COCC1>[C:25]([Si:29]([CH3:31])([CH3:30])[O:32][CH2:33][CH2:34][CH:6]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: N#Cc1ccc(Cn2ccnc2)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCC(c1ccc(C#N)cc1)n1ccnc1
Temperature: -60 °C

Procedure:
4-Imidazol-1-ylmethyl-benzonitrile (5.5 gms, 30 mmol) was suspended in freshly distilled THF (150 mL) in dry glassware and stirred under argon in a -60° C. dry ice acetone bath then Lithium bis(trimethylsilyl)amide 1 molar in THF (33 mL) was added slowly. The mixture was stirred for 30 minutes and the temperature was reduced to -78° C. A suspension of tert-butyl-(2-iodo-ethoxy)-dimethyl-silane (9.5 gm, 33 mmol) in 20 mL of THF was cooled to -78° C. and added via cannula to the first solution and the resulting mixture was allowed to slowly warm to ambient temperature. After 16 hours the reaction was quenched by the addition of 10 mL of water and the solvent was removed in vacuo. The residue was suspended in ethyl acetate (200 mL) and extracted 2 times with saturated aqueous sodium bicarbonate (100 mL), then water (100 mL), then saturated sodium chloride solution (100 mL). The organic solvent was removed in vacuo and the residue was chromatographed on silica gel using 1:3 ethyl acatate: hexanes. The desired fractions were combined and the solvent was removed in vacuo to give the desired product.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:19][C:20]([C@@H:22](/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](=[O:51])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C@@:23]([OH:34])([CH2:31][CH2:32][OH:33])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:21])[C:14](=[O:18])[N:15]([CH3:17])[CH3:16])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].F[B-](F)(F)F.[CH3:57][O+](C)C.C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C>ClCCl>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C@H:13]([NH:19][C:20]([C@@H:22](/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](=[O:51])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C@@:23]([OH:34])([CH2:31][CH2:32][O:33][CH3:57])[C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])=[O:21])[C:14](=[O:18])[N:15]([CH3:17])[CH3:16])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: C[O+](C)C
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCO)C(=O)OC(C)(C)C)C(=O)N(C)C)cc1
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCOC)C(=O)OC(C)(C)C)C(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 22.4 %

Procedure:
tert-Butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-dimethylcarbamoyl-ethylcarbamoyl]-2-hydroxy-2-(2-hydroxy-ethyl)-12-oxo-nonadec-4-enoate (15.0 mg, 21.5 μmol) was dissolved in dichloromethane (0.5 mL), and trimethyloxonium tetrafluoroborate (6.7 mg, 45.1 μmol) and 2,6-di-tert-butyl-4-methylpyridine (9.3 mg, 45.1 μmol) were added at 0° C. The mixture was stirred at room temperature for 5 hours. The reaction mixture was purified by preparative HPLC to obtain the title compound (3.5 mg, 22% yield).
Reaction SMILES: [F:1][C:2]1[C:3]([CH:14]=[N:15][OH:16])=[CH:4][C:5]2[C:9]([CH3:11])([CH3:10])[O:8][B:7]([OH:12])[C:6]=2[CH:13]=1.C1C(=O)N([Cl:24])C(=O)C1>CN(C=O)C>[F:1][C:2]1[C:3]([C:14]([Cl:24])=[N:15][OH:16])=[CH:4][C:5]2[C:9]([CH3:11])([CH3:10])[O:8][B:7]([OH:12])[C:6]=2[CH:13]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC1(C)OB(O)c2cc(F)c(C=NO)cc21
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2cc(F)c(C(Cl)=NO)cc21
Temperature: 45 °C
Reaction time: 3 h

Procedure:
To a solution of the crude compound 6-fluoro-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde oxime (205 mg, 0.92 mmol) in DMF (4.0 mL) at rt was added NCS (147 mg, 1.1 mmol). The reaction mixture was stirred at 45° C. for 3 h. The mixture was cooled to rt, poured into ice-water and extracted with DCM (60 mL×3). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude compound 6-fluoro-N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride as colorless oil. It was used in next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][C:7](=[O:16])[C:6](=[O:17])[NH:5]2.CO[CH:20]1[CH2:24][CH2:23][CH:22](OC)O1>>[N:1]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[NH:8][C:7](=[O:16])[C:6](=[O:17])[NH:5]3)[CH:20]=[CH:24][CH:23]=[CH:22]1
Reactant: Nc1cc2[nH]c(=O)c(=O)[nH]c2cc1C(F)(F)F
Reactant: COC1CCC(OC)O1
Product: O=c1[nH]c2cc(-n3cccc3)c(C(F)(F)F)cc2[nH]c1=O

Procedure:
12.2 mmol of 6-amino-7-trifluoromethyl-2,3(1H,4H)-quinoxalinedione were reacted with 12.2 mmol of 2,5-dimethoxytetrahydrofuran by the method of Example 5d.
Reaction SMILES: Cl[C:2]1[N:29]=[CH:28][C:5]2[N:6]=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:14][CH:13]=3)[N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[CH:3]=1.[H][H]>C(OCC)(=O)C.[C].[Pd]>[CH3:11][N:8]1[C:9](=[O:10])[C:4]2[CH:3]=[CH:2][N:29]=[CH:28][C:5]=2[N:6]=[C:7]1[C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:16][CH:17]=1
Reactant: [H][H]
Reactant: Cn1c(-c2ccc(OCCCN3CCCCC3)cc2)nc2cnc(Cl)cc2c1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cn1c(-c2ccc(OCCCN3CCCCC3)cc2)nc2cnccc2c1=O
Yield: 43.7 %

Procedure:
6-Chloro-3-methyl-2-[4-(3-piperidin-1-ylpropoxy)phenyl]pyrido[3,4-d]pyrimidin-4(3H)-one (42.0 mg, 0.101 mmol) produced in Example 18 was dissolved in ethyl acetate (1 mL), and 10% palladium-carbon (11 mg, 0.0101 mmol) was added thereto and stirred in a hydrogen atmosphere at room temperature for 24 hours. The reaction solution was filtered through Celite, then the Celite was washed with ethyl acetate, and the mother liquid was concentrated. The residue was purified through silica gel column chromatography (chloroform/methanol=3/1) to obtain the intended compound (16.7 mg, 44%) as a colorless solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N:10]([O-])=[O:11].[Na+].Cl>C(O)(=O)C.O>[N:10]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)=[O:11]
Reactant: O=N[O-]
Reactant: c1ccc2c(c1)CCN2
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=NN1CCc2ccccc21
Yield: 42.3 %

Procedure:
To a solution of 2,3-dihydro-1H-indole (10.0 g, 84 mmol) in acetic acid (100 ml) at 0° C. was added dropwise a solution of sodium nitrite (6.08 g, 88 mmol) in water (25 ml) so that the temperature was maintained below 5° C. After 1 hour water (500 ml) and 1 M hydrochloric acid (500 ml) were added to the precipitate that formed. The mixture was stirred for another hour before the product was filtered off, washed with water (3×100 ml) and dried under vacuum to give 1-nitroso-2,3-dihydro-1H-indole as a brown solid (5.27 g). 400 MHz 1H NMR (DMSO-d6) δ: 7.8 (d, J=7.6 Hz 1H), 7.45 (d, J=7.6 Hz, 1H), 7.37 (t, J=7.6 Hz 1H), 7.29 (t, J=7.6 Hz, 1H), 4.09 (m, 2H), 3.19 (t, J=7.6 Hz, 2H); LCMS: 149 [M+H]
Reaction SMILES: OC1CC[N:5]([C:8]([NH:10][C:11]2[NH:15][C:14]3[CH:16]=[CH:17][C:18]([O:20][S:21]([C:24]4[CH:29]=[CH:28][C:27]([N:30]5[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]5)=[CH:26][CH:25]=4)(=[O:23])=[O:22])=[CH:19][C:13]=3[N:12]=2)=[O:9])[CH2:4][CH2:3]1.NC[CH:39]1[O:44][CH2:43][CH2:42][NH:41][CH2:40]1>O1CCCC1.CN1CCCC1=O>[N:41]1([CH2:3][CH2:4][NH:5][C:8](=[O:9])[NH:10][C:11]2[NH:15][C:14]3[CH:16]=[CH:17][C:18]([O:20][S:21]([C:24]4[CH:25]=[CH:26][C:27]([N:30]5[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]5)=[CH:28][CH:29]=4)(=[O:23])=[O:22])=[CH:19][C:13]=3[N:12]=2)[CH2:42][CH2:43][O:44][CH2:39][CH2:40]1
Reactant: O=C(Nc1nc2cc(OS(=O)(=O)c3ccc(N4CCC(O)CC4)cc3)ccc2[nH]1)N1CCC(O)CC1
Reactant: NCC1CNCCO1
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: O=C(NCCN1CCOCC1)Nc1nc2cc(OS(=O)(=O)c3ccc(N4CCC(O)CC4)cc3)ccc2[nH]1
Yield: 33.1 %

Procedure:
A solution of 4-(4-hydroxy-piperidin-1-yl)-benzenesulfonic acid 2-[(4-hydroxy-piperidine-1-carbonyl)-amino]-1H-benzoimidazol-5-yl ester (example 79, 20 mg) and 2-(aminomethyl)-morpholine (50 mg) in tetrahydrofuran (1 ml) and N-methylpyrrolidinone (0.2 ml) was heated at 95° C. for 22 hours. The reaction mixture was then evaporated and purified by triggered LC/MS to give 4-(4-hydroxy-piperidin-1-yl)-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)-ureido]-1H-benzoimidazol-5-yl ester as an off-white solid (7 mg). Mass spectrum: 545 [M+H]+; retention time=5.47 minutes.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:31])[C@H:11]([CH:28]([CH3:30])[CH3:29])[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[CH:16][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[C:41](Cl)(=[O:46])[CH2:42][CH2:43][CH2:44][CH3:45]>>[CH2:2]([O:9][C:10](=[O:31])[C@H:11]([CH:28]([CH3:29])[CH3:30])[N:12]([C:41](=[O:46])[CH2:42][CH2:43][CH2:44][CH3:45])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[CH:18][CH:19]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)[C@H](NCc1ccc(-c2ccccc2C#N)cc1)C(=O)OCc1ccccc1
Reactant: CCCCC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)[C@H](C(=O)OCc1ccccc1)C(C)C

Procedure:
5.5 g of N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester hydrochloride, 4.33 g of diisopropylethylamine and 3 ml of valeryl chloride are stirred at room temperature for 36 hours and the mixture is then evaporated to dryness. The residue is taken up in ether and washed with sodium bicarbonate and brine. The crude product is further processed without purification.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[C:7]([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15].O[ClH](O)(=O)=O>N1C=CC=CC=1>[C:14]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[C:7]([CH3:11])[C:8]([OH:10])=[O:9])=[CH:12][CH:13]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=Cc1ccc(O)cc1)C(=O)O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C=C(C)C(=O)O)cc1
Reaction time: 2 h
Yield: 89.9 %

Procedure:
In 100 ml of pyridine was dissolved 18 g of refined 4-hydroxy-α-methylcinnamic acid synthesized in Referential Example 1, 20 g of acetic anhydride was dropped into the solution, and the reaction was carried out at room temperature with stirring for 2 hours. Then, the liquid reaction mixture was dropped in a 1% by weight aqueous solution of hydroxychloric acid, and the precipitated reaction product was recovered by filtration, washed with water, and dried to obtain 20 g of 4-acetoxy-α-methylcinnamic acid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH3:5].C([NH2:26])C1C=CC=CC=1>CO>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]([CH:4]([CH3:5])[CH2:3][CH2:2][NH2:26])=[CH:7][CH:8]=2)=[CH:13][CH:14]=1
Reactant: NCc1ccccc1
Reactant: CC(CCCl)c1ccc(-c2ccc(F)cc2)cc1
Solvent: CO
Product: CC(CCN)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
A solution of 33.3 g of N-benzyl-3-(4'-fluoro-4-biphenylyl)-1-butylamine [obtainable by reacting 3-(4'-fluoro-4-biphenylyl)-butanol with SOCl2 ] to give 1-chloro-3-(4'-fluoro-4-biphenylyl)-butane and reaction with benzylamine in 500 ml of methanol is hydrogenated over 8 g of 5% Pd-on-charcoal at 20° and normal pressure. After filtration and evaporation, 3-(4'-fluoro-4-biphenylyl)-butylamine is obtained. Hydrochloride, m.p. 222°-224°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:12]([Mg]Cl)[CH2:13][CH3:14]>C1COCC1.[Cu]I>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](=[O:5])[CH2:12][CH2:13][CH3:14]
Reactant: CCC[Mg]Cl
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: [Cu]I
Solvent: C1CCOC1
Product: CCCC(=O)c1ccc(Cl)cc1Cl
Temperature: -20 °C
Reaction time: 1 h

Procedure:
A mixture of 2,4-dichlorobenzoyl chloride (4.5 g) and copper (I) iodide (200 mg) in dry THF (30 ml) was cooled to −20° C. under argon. Then a solution of n-propyl magnesium chloride (2 M in ether, 11.0 ml) was added dropwise. Ten minutes after addition was complete, the cooling bath was removed and the mixture stirred for 1 hour. Water was carefully added, followed by extraction with toluene. The toluene layer was washed with dilute HCl, water, saturated sodium bicarbonate solution, dried and concentrated in vacuo to give 1-(2,4-dichlorophenyl)butan-1-one (4.0 g).
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:13][O:12]2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH3:14][NH2:15]>CO>[CH3:14][NH:15][CH2:13][CH:11]([C:8]1[CH:9]=[CH:10][C:5]([S:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=1)[OH:12]
Reactant: CN
Reactant: CC(C)Sc1ccc(C2CO2)cc1
Solvent: CO
Product: CNCC(O)c1ccc(SC(C)C)cc1

Procedure:
A solution of 842 mg of 4-isopropylthiophenyloxirane in 30 ml of methanol which contained 20% of methylamine was reacted at 70° C. in a sealed tube for 41 hours. After allowing the reaction mixture to cool down, the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (eluent: a 10:1 mixture of chloroform and methanol) to give 428 mg of an oily substance.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([N:19]2[CH2:23][CH2:22][CH2:21][C@H:20]2[CH2:24][OH:25])[CH:18]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)=[O:6].B(O)(O)[C:27]1[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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>[OH:25][CH2:24][C@@H:20]1[CH2:21][CH2:22][CH2:23][N:19]1[C:17]1[CH:16]=[C:4]([C:5]([NH:7][CH2:8][C:9]2[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[O:6])[CH:3]=[C:2]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)[CH:18]=1
Reactant: Cc1ccc(CNC(=O)c2cc(Br)cc(N3CCC[C@H]3CO)c2)cn1
Reactant: Cc1ccc(B(O)O)cc1
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: O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(N3CCC[C@H]3CO)c2)cc1

Procedure:
To a mixture of (S)-3-bromo-5-(2-(hydroxymethyl)pyrrolidin-1-yl)-N-((6-methylpyridin-3-yl)methyl)benzamide (65 mg, 0.16 mmol), p-tolylboronic acid (24 mg, 0.18 mmol), toluene (4 mL), cesium carbonate (57 mg, 0.18 mmol), and water (0.2 mL) under argon was added tetrakis(triphenylphosphine)palladium(0) (9.2 mg, 0.0080 mmol). The reaction mixture was heated under reflux for 5 h. After cooling, the mixture was filtered through Celite and the filter cake was washed with EtOAc. The filtrate was washed with brine, dried (Na2SO4), and concentrated. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 30-80% CH3CN/water [10 mM Et2NH]) to afford a white foam.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH3:15])=[O:13])(OCC)=O)C.[Si:16]([O:23][CH:24]([C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=O)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C1COCC1>[Si:16]([O:23][CH:24]([C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:11][C:12]([O:14][CH3:15])=[O:13])([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCC=O)c1ccc2ccccc2c1
Reactant: CCOP(=O)(CC(=O)OC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C=CCCCCC(O[Si](C)(C)C(C)(C)C)c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 177 mg, 4.42 mmol) in THF (25 mL) at room temperature under nitrogen atmosphere was added dropwise neat methyl diethylphosphonoacetate (811 μL, 4.42 mmol). The resulting solution was stirred for 10 minutes while cooling down to 0° C. A solution of crude aldehyde 183 (1.05 g, 2.94 mmol) in THF (10 mL) was transferred via cannula. The resulting solution was stirred for 15 minutes at 0° C. and quenched with a saturated aqueous solution of ammonium chloride. The THF was evaporated in vacuo and the aqueous residue was partitioned between diethyl ether and water. The aqueous layer was extracted with diethyl ether and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude residue was purified by flash chromatography (5% ethyl acetate/hexane), affording the title compound 184 in 63% yield (1.30 g). 1H NMR: (300 MHz, CDCl3) δ: 7.83-7.78 (m, 3H), 7.69 (s, 1H), 7.49-7.41 (m, 3H), 6.94 (dt, J=15.4, 7.1 Hz, 1H), 5.79 (dt, J=15.7, 1.1 Hz, 1H), 4.79 (dd, J=7.1, 5.2 Hz, 1H), 3.71 (s, 3H), 2.16 (q, J=7.4 Hz, 2H), 1.81-1.62 (m, 2H), 1.48-1.29 (m, 4H), 0.90 (s, 9H), 0.04 (s, 3H), −0.15 (s, 3H). MS (ESI)=413 (MH+).
Reaction SMILES: [CH:1]1([C@@H:4]2[O:14][CH2:13][C@:7]3([C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=4[F:22])[NH:8][O:9][C@@H:10]([CH2:11][F:12])[C@@H:6]3[CH2:5]2)[CH2:3][CH2:2]1.N[C@@]1(C2C=CC(F)=CC=2F)CO[C@@H](COCC2C=CC=CC=2)C[C@H]1CO>>[NH2:8][C@@:7]1([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:13][O:14][C@@H:4]([CH:1]2[CH2:3][CH2:2]2)[CH2:5][C@H:6]1[C@@H:10]([OH:9])[CH2:11][F:12]
Reactant: FC[C@@H]1ON[C@@]2(c3ccc(F)cc3F)CO[C@@H](C3CC3)C[C@@H]12
Agent: N[C@@]1(c2ccc(F)cc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO
Product: N[C@@]1(c2ccc(F)cc2F)CO[C@@H](C2CC2)C[C@H]1[C@@H](O)CF

Procedure:
rel-(3R,3aR,5R,7aS)-5-Cyclopropyl-7a-(2,4-difluorophenyl)-3-(fluoromethyl)hexahydro-1H-pyrano[3,4-c][1,2]oxazole (C44) was converted to the product using the chemistry described for synthesis of [(2R,4R,5S)-5-amino-2-[(benzyloxy)methyl]-5-(2,4-difluorophenyl)tetrahydro-2H-pyran-4-yl]methanol (C6) in Preparation P1. The product was obtained as an oil. Yield: 0.17 g, 0.54 mmol, 99%. LCMS m/z 316.2 [M+H+].
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23](O)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[O:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH2:34][NH2:35])[CH2:28][CH2:27]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([NH:35][CH2:34][CH2:33][CH2:32][N:29]3[CH2:30][CH2:31][O:26][CH2:27][CH2:28]3)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NCCCN1CCOCC1
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)NCCCN3CCOCC3)cs2)c1-c1ccc(F)cc1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and 3-morpholinopropan-1-amine and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:37]CC1C2C=CC=CC=2C2C1=CC=CC=2)[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]=[CH:25][CH:24]=[CH:23]2)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCCCC1.CC(=O)OCC.CO>C(Cl)Cl>[NH2:37][C@H:13]([C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:30][CH2:31][CH3:32])[O:33][CH2:34][CH3:35])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]=[CH:25][CH:24]=[CH:23]2)=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
6-tert-butoxycarbonylamino-2-(S)-(9H-fluoren-9-yl)methylamino-N—((S)-1,1-diethoxypropan-2-yl)-N-(quinolin-8-ylmethyl)hexanamide (Compound III-14) 20.0 g (27 mmol) and piperidine 22.7 g (270 mmol) were added in DCM (90 ml). The mixture was stirred for 1.5 h at room temperature. The mixture was diluted with DCM (200 ml) and washed with water (150 ml×3). The solution was concentrated in vacuo. The residue was purified by column chromatography on silica gel with PE:EA=50:1 to DCM:MeOH=10:1 to give the title compound 11.3 g, (yield 81%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:5][CH:6]=1.[H-].[Na+].[CH3:15][O:16][CH2:17]Cl.O>CN(C=O)C>[CH3:15][O:16][CH2:17][N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[C:4]1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1c[nH]c(-c2ccccc2)n1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCn1cc(C)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 63.8 %

Procedure:
To a solution of 1.0 g (6.32 mmol) of 4-methyl-2-phenylimidazole in 25 mL of DMF at 0° C. was added 278 mg (6.95 mmol, 60% in oil) of NaH. After stirring for 5 min, 0.528 mL (6.95 mmol) of chloromethyl methyl ether was added, and the reaction was warmed to 25° C. and stirred 4 h. The reaction was poured into H2O, and the product was extracted with hexanes/EtOAc (1:1). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. Purification by silica gel flash column chromatography using hexanes/EtOAc (5:95) as eluent provided 816 mg (64%) of title compound: low resolution MS (ES) m/e 225 (MNa+), 203 (MH+).