Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@@H:4]([O:23][CH2:24][CH3:25])[C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:8]=1[CH2:21][CH3:22])O.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3](=[O:26])[C@@H:4]([O:23][CH2:24][CH3:25])[CH2:5][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:8]=1[CH2:21][CH3:22]
Reactant: CCO[C@H](C(=O)OC)[C@H](O)c1ccc(OCc2ccccc2)cc1CC
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCO[C@@H](Cc1ccc(OCc2ccccc2)cc1CC)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 c], (2S,3R)-3-(4-benzyloxy-2-ethyl-phenyl)-2-ethoxy-3-hydroxy-propionic acid methyl ester was treated with triethylsilane in trifluoroacetic acid to yield (2S)-3-(4-benzyloxy-2-ethyl-phenyl)-2-ethoxy-propionic acid methyl ester as colorless liquid.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[NH2:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:29]/[O:30][C:31]([C:34]([O:36]C(C)(C)C)=[O:35])([CH3:33])[CH3:32])/[C:15]([NH:17][C@H:18]2[C@H:21]([CH2:22][CH3:23])[N:20]([S:24]([OH:27])(=[O:26])=[O:25])[C:19]2=[O:28])=[O:16])[N:13]=1.FC(F)(F)C(O)=O>>[CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[NH2:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:29]/[O:30][C:31]([C:34]([OH:36])=[O:35])([CH3:32])[CH3:33])/[C:15]([NH:17][C@H:18]2[C@H:21]([CH2:22][CH3:23])[N:20]([S:24]([OH:27])(=[O:26])=[O:25])[C:19]2=[O:28])=[O:16])[N:13]=1
Reactant: CC[C@H]1[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c2csc(N)n2)C(=O)N1S(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H]1[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c2csc(N)n2)C(=O)N1S(=O)(=O)O
Reaction time: 20 h
Yield: 25.6 %

Procedure:
250 mg of (3S, 4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-(t-butoxycarbonyl)-1-methylethoxy]imino]acetamido]-4-ethyl-2-oxo-1-azetidinesulphonic acid triethylamine salt are added at -10° C. to 3 ml of trifluoroacetic acid. After 20 hours at -10° C., the mixture is evaporated and the residue is purified by DCCC [droplet counter current chromatography; rising droplets in the mixture chloroform/methanol/water (7:13:8)]. 58 mg of amorphous (3S, 4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(1-carboxy-1-methylethoxy)imino]acetamido]-4-ethyl-2-oxo-1-azetidinesulphonic acid triethylamine salt are obtained.
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH3:10]>CO>[N:1]1([C:7]([NH2:10])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: N
Reactant: O=C(Cl)N1CCOCC1
Solvent: CO
Product: NC(=O)N1CCOCC1

Procedure:
A solution of morpholine-4-carbonyl chloride (2.0 g) in methanol (10 mL) and 7 N NH3 in methanol (5 mL) was stirred at 45° C. overnight. The mixture was concentrated to give a solid, which was dried under vacuum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](F)=[O:6].[BH4-].[Na+].Cl>C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[CH2:5][OH:6]
Reactant: O=C(F)c1ccc(F)c(Br)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: OCc1ccc(F)c(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
221 g (1 mol) of 3-bromo-4-fluoro-benzoyl fluoride were added dropwise to a mixture of 30.4 g (0.8 mol) of sodium tetrahydridoborate and 840 ml of isopropanol at 20°-25° C. in the course of 3 hours. The reaction mixture was stirred for about a further 30 minutes and then poured into 2 liters of ice-water. The pH was adjusted to 1 by adding concentrated hydrochloric acid, and the organic layer was then separated off. The aqueous phase was subsequently extracted with 200 ml of methylene chloride. The combined organic phases were dried and filtered and the filtrate was distilled. 163 g (79.5% of theory) of 3-bromo-4-fluorobenzyl alcohol of boiling point 137° C./16 mbars and of refractive index nD20 =1.5623 were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[CH:4][C:3]=1[Cl:9].[H-].[Na+].[N+](C1C=CC([O:21][C:22]([C:24]2[C:25]3[CH:34]=[C:33]([C:35](=[O:37])[CH3:36])[O:32][C:26]=3[C:27]([O:30][CH3:31])=[N:28][CH:29]=2)=O)=CC=1)([O-])=O>CN(C)C=O>[Cl:9][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([Cl:8])[C:2]=1[NH:1][C:22]([C:24]1[C:25]2[CH:34]=[C:33]([C:35](=[O:37])[CH3:36])[O:32][C:26]=2[C:27]([O:30][CH3:31])=[N:28][CH:29]=1)=[O:21]
Reactant: COc1ncc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cc(C(C)=O)oc12
Reactant: Nc1c(Cl)cncc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ncc(C(=O)Nc2c(Cl)cncc2Cl)c2cc(C(C)=O)oc12
Reaction time: 0.75 h
Yield: 11.2 %

Procedure:
A solution of 4-amino-3,5-dichloropyridine (57 mg) in dry N,N-dimethylformamide (10 ml) was stirred at room temperature under an atmosphere of dry nitrogen. Sodium hydride (21 mg) was added and stirring continued for 45 minutes. 2-Acetyl-7-methoxyfuro[2,3-c]pyridine-4-carboxylic acid 4-nitrophenyl ester (100 mg) was added and the resulting mixture stirred overnight. The solvent was removed in vacuo, the residue taken up in water (100 ml) and extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with water (100 ml) then brine (50 ml), dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification by column chromatography on silica eluting with 50% hexane in ethyl acetate gave the title compound (12 mg) as a white solid.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([C:26]1[C:27]([Cl:36])=[N:28][C:29]3[C:34]([CH:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:13]2)(C(C)(C)C)(C)C.F.F.F.C(N(CC)CC)C>C(#N)C>[Cl:36][C:27]1[C:26]([C:14]2[N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:16]3[C:12]([CH:13]=2)=[CH:11][C:10]([CH2:9][OH:8])=[CH:18][CH:17]=3)=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(CO[Si](C)(C)C(C)(C)C)ccc21
Agent: F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(CO)ccc21

Procedure:
A solution of tert-butyl 5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-(2-chloro-3-quinolinyl)-1H-indole-1-carboxylate (7-1, 2.50 g, 4.78 mmol, 1 equiv) and triethylamine trihydrofluoride (3.89 mL, 23.9 mmol, 5.00 equiv) in acetonitrile (100 mL) was heated at 50° C. for 3 h. The reaction mixture was carefully partitioned between saturated sodium bicarbonate solution and ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated to give tert-butyl 2-(2-chloro-3-quinolinyl)-5-(hydroxymethyl)-1H-indole-1-carboxylate (7-2) as a tan foam. 1H NMR (500 MHz, CDCl3) δ 8.31 (d, 1H, J=8.5 Hz), 8.19 (s, 1H), 8.08 (d, 1H, J=8.5 Hz), 7.87 (d, 1H, J=8.1 Hz), 7.78 (br t, 1H, J=8.0 Hz), 7.63 (s, 1H), 7.62 (br t, 1H, J=8.0 Hz), 7.41 (d, 1H, J=8.5 Hz), 6.66 (s, 1H), 4.82 (d, 2H, J=4.9 Hz), 1.81 (br s, 1H), 1.27 (s, 9H).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([SH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:15](Cl)(=[O:26])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25]>C1(C)C=CC=CC=1>[C:15](=[O:26])([S:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25]
Reactant: Sc1ccccc1
Reactant: C=CCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CCCCCCCCCC(=O)Sc1ccccc1

Procedure:
A 50-mL, one-necked, round-bottomed flask was charged with 10 mL toluene, triethylamine (0.70 mL, 5.0 mmol) and thiophenol (0.51 mL, 5.0 mmol). A solution of 10-undecenoyl chloride (1.10 mL, 5.1 mmol) in 15 mL toluene was added by a pressure-equalizing dropping funnel over 30 min while stirring the solution with a magnetic stirrer.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]([C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)=[O:6]>C(O)(=O)C>[CH3:3][O:4][C:5]([C:7]1[C:16]2[C:11](=[C:12]([Br:1])[C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)=[O:6]
Reactant: BrBr
Reactant: COC(=O)c1cccc2cc(OC)ccc12
Solvent: CC(=O)O
Product: COC(=O)c1cccc2c(Br)c(OC)ccc12
Yield: 67.6 %

Procedure:
A solution of bromine (26.6 g, 0.167 mole) in glacial acetic acid (25 ml) was added dropwise to a cooled suspension of 6-methoxy-1-naphthalenecarboxylic acid methyl ester (30 g, 0.13 9 moles) in glacial acetic acid (2.75 ml). The precipitate was collected, washed with water and crystallized from ethanol to give 33.3 g of 5-bromo-6-methoxy-1-naphthalenecarboxylic acid methyl ester; mp 119° C.; NMR (CDCl3) δ 3.97 (s, 3H), 4.03 (s, 3H), 7.35 (d, J=9.25 Hz, 1H), 7.4 (m, 1H), 8.05 (d, J=6.75 Hz, 1H) 8.45 (d, J=8.25 Hz, 1H), 8.9 (d, J=9.25, 1H). The latter ester (10.1 g, 34 mmoles) and Cu2 (CN)2.H2O (3.4 g, 17 mmoles) in distilled dimethylformamide (75 ml) containing 15 drops of pyridine was heated at 180° C. for 5 hr. The hot mixture was poured into a mixture of ice (50 g) and conc. NH4OH (50 ml). The resulting precipitate was collected, washed with water, dried and recrystallized from chloroform-ethyl acetate to afford 5.6 g of 5-cyano-6-methoxy-1-naphthalenecarboxylic acid methyl ester: mp 210°-211° C., NMR (CDCl3)δ 3.95 (s, 3H), 4.15 (s, 3H). To a stirred solution of the latter ester (5.95 g, 24.66 mmoles) in 2-methoxyethanol (100 ml) at 20°-22° C., 4N aqueous NaOH solution (12.3 ml) was added. The reaction mixture was stirred at 20°-22° C. for 60 hr, diluted with water, cooled to 0° C. and rendered acidic with 1N aqueous HCl. The precipitate was collected and dried to yield 5.6 g of the title compound; mp>290° C.; NMR (DMSO-d 6) δ 4.1 (s, 3H), 8.1 (m, 5H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([N:6]2[C:14](=[O:15])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:16])=[N:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=1[C:36]([F:39])([F:38])[F:37]>C1COCC1>[I:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][N:1]2[CH:5]=[CH:4][C:3]([N:6]3[C:14](=[O:15])[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:7]3=[O:16])=[N:2]2)=[C:30]([C:36]([F:37])([F:38])[F:39])[CH:31]=1
Reactant: O=C1c2ccccc2C(=O)N1c1cc[nH]n1
Reactant: FC(F)(F)c1cc(I)ccc1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1c1ccn(Cc2ccc(I)cc2C(F)(F)F)n1
Reaction time: 0.5 h

Procedure:
To a solution of 2-(1H-pyrazol-3-yl)-1H-isoindole-1,3(2H)-dione (for a preparation see Intermediate 28)(0.72 g, 3.38 mmol) in THF (20 ml) was added 1.0 M lithium bis(trimethylsilyl)amide in THF (3.5 ml, 3.50 mmol, Aldrich). The slight suspension was stirred for 30 min. To the yellow solution was added a solution of 1-(bromomethyl)-4-iodo-2-(trifluoromethyl)benzene (for a preparation see within Example 73)(1.24 g, 3.40 mmol) in THF (10 ml). The resulting yellow solution was stirred at ambient temperature under nitrogen overnight. The solvent was removed in vacuo and the residue partitioned between DCM (100 ml) and water (100 ml). To aid the separation, brine (50 ml) and dilute hydrochloric acid (25 ml) were added. The phases were separated and the aqueous phase washed with dichloromethane (50 ml). The organic phases were combined, dried (MgSO4), filtered and the solvent removed in vacuo to leave 2-(1-{[4-iodo-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)-1H-isoindole-1,3(2H)-dione as an orange solid (1.7 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(O)c2cc(OCc3ccccc3)ccc2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)C=Cc2cc(OCc3ccccc3)ccc2O1
Reaction time: 1 h
Yield: 84.4 %

Procedure:
A solution of 9.6 g (33.8 mmol) of 6-benzyloxy-2,2-dimethylchroman-4-ol and 0.2 g of p-toluenesulfonic acid in 85 ml of toluene was heated under reflux on a water separator for 1 h. After cooling, the mixture was washed twice with sodium bicarbonate solution, dried over magnesium sulfate and concentrated i. vac., giving 7.6 g of 6-benzyloxy-2,2-dimethyl-2H-chromen.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C@@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]3[OH:18])=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:19].[C:20]([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[OH:18][C@@H:13]1[CH2:14][CH2:15][CH2:16][CH2:17][C@H:12]1[NH:11][C:8]1[S:9][C:10]2[C:2]([CH3:20])=[C:3]([OH:19])[CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1Br
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(O)ccc2nc(N[C@@H]3CCCC[C@H]3O)sc12
Temperature: 120 °C
Yield: 17 %

Procedure:
To the solution of 7-bromo-2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-ol (117 mg, 0.34 mmol, 1.0 eq) in 1 mL DMF in a microwave vial was added trimethylboraxine (128 mg, 1.02 mmol, 3.0 eq), Pd(Cl2)dPPf (27 mg, 0.034 mmol, 0.1 eq) and 1 mL of 2M Na2CO3 solution at room temperature. Thereafter, the reaction mixture was heated in the microwave at 120° C. for 15 minutes. The reaction was quenched with saturated NaHCO3 solution (25 ml) and the aqueous phase extracted with ethyl acetate (50 mL×3), combined organic layers dried over Na2SO4, filtered and condensed under reduced pressure. Purification over ISCO using a gradient of 0%-18% methanol-DCM gave 17 mg of product as brownish powder in 17% yield. LC/MS (m/z) [279.1] (MH+)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:17][CH2:16][CH2:15][CH:14]([OH:18])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:2].C1OCCOCCOCCOCCOCCOC1.[K].Br[CH2:40][C:41]1[C:42]([C:49]2[C:54]([Cl:55])=[CH:53][CH:52]=[CH:51][C:50]=2[Cl:56])=[N:43][O:44][C:45]=1[CH:46]1[CH2:48][CH2:47]1>C(O)(C)(C)C.O1CCCC1>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:17][CH2:16][CH2:15][CH:14]([O:18][CH2:40][C:41]3[C:42]([C:49]4[C:50]([Cl:56])=[CH:51][CH:52]=[CH:53][C:54]=4[Cl:55])=[N:43][O:44][C:45]=3[CH:46]3[CH2:48][CH2:47]3)[CH2:13][CH2:12]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: Clc1cccc(Cl)c1-c1noc(C2CC2)c1CBr
Reactant: CCOC(=O)c1ccc(N2CCCC(O)CC2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N2CCCC(OCc3c(-c4c(Cl)cccc4Cl)noc3C3CC3)CC2)cc1
Reaction time: 0.08 h

Procedure:
Anhydrous tetrahydrofuran (5 mL) is added at room temperature to a mixture of 4-(4-hydroxy-azepan-1-yl)-benzoic acid ethyl ester (364 mg, 1.38 mmol), 18-crown-6 (407 mg, 1.52 mmol) and tert-butyl alcohol, potassium derivative (178 mg, 1.52 mmol). The mixture is stirred for 5 minutes and then 4-bromomethyl-5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazole (480 mg, 1.38 mmol) is added. After 1.5 h, the solvent is removed and water is added. The aqueous phase is extracted with ethyl acetate. The organic layers are combined, dried over anhydrous sodium sulfate, filtered, and the solvent is removed under reduced pressure. The residue is purified via flash chromatography (40 g silica) eluting with a gradient of ethyl acetate/hexane (0% to 30%) to provide the title compound as a colorless waxy solid (203 mg, 28%). ES/MS m/z 529.0 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][C:14]=2[CH2:28][N:29]2[C@@H:33]([CH3:34])[C@@H:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:31][C:30]2=[O:41])[CH:7]=1)[CH3:2].[NH2:43][C:44]1[CH:45]=[CH:46][C:47](Cl)=[N:48][CH:49]=1>>[CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:47]3[CH:46]=[CH:45][C:44]([NH2:43])=[CH:49][N:48]=3)=[CH:15][C:14]=2[CH2:28][N:29]2[C@@H:33]([CH3:34])[C@@H:32]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[O:31][C:30]2=[O:41])[CH:7]=1)[CH3:2]
Reactant: Nc1ccc(Cl)nc1
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Product: CCOC(=O)Cc1cccc(Oc2ccc(-c3ccc(N)cn3)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 19, Step 3, using the following starting materials: {3-[2-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-phenyl}-acetic acid ethyl ester and 5-amino-2-chloropyridine.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:11](=[O:48])[NH:12][C@@H:13]([C:23]([N:25]1[CH2:30][CH2:29][N:28]2[C:31](=[O:40])[N:32]([CH2:35][C:36]([F:39])([F:38])[F:37])[C:33](=[O:34])[C@:27]2([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=2)[CH2:26]1)=[O:24])[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:10])[CH3:9])(C)(C)C.[ClH:50]>CCO>[ClH:50].[NH2:7][C:8]([CH3:10])([CH3:9])[C:11]([NH:12][C@@H:13]([C:23]([N:25]1[CH2:30][CH2:29][N:28]2[C:31](=[O:40])[N:32]([CH2:35][C:36]([F:37])([F:38])[F:39])[C:33](=[O:34])[C@:27]2([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=2)[CH2:26]1)=[O:24])[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:48]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](CCCc1ccccc1)C(=O)N1CCN2C(=O)N(CC(F)(F)F)C(=O)[C@]2(Cc2ccccn2)C1
Agent: Cl
Solvent: CCO
Product: CC(C)(N)C(=O)N[C@H](CCCc1ccccc1)C(=O)N1CCN2C(=O)N(CC(F)(F)F)C(=O)[C@]2(Cc2ccccn2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the compound of Example 199, Step D (73 mg) in EtOH (5 mL, 0° C.) was added conc. HCl (0.5 mL). The solution was stirred at 0° C. for 1 h and concentrated down to deliver 68 mg of Example 199, Step E: +APcI MS (M+1)+ 589; 1H NMR=400 MHz (CD3OD) δ: 8.36 (d, 1H), 4.86 (br m, 3H), 1.44 (s, 3H), 1.42 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:44][C:45]1[CH:65]=[CH:64][C:48]([O:49][C:50]2[C:55]([C:56]3[CH:61]=[CH:60][N:59]=[C:58]([NH:62][CH3:63])[N:57]=3)=[CH:54][CH:53]=[CH:52][N:51]=2)=[CH:47][CH:46]=1>C(Cl)(Cl)Cl>[F:1][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([NH:44][C:45]1[CH:46]=[CH:47][C:48]([O:49][C:50]2[C:55]([C:56]3[CH:61]=[CH:60][N:59]=[C:58]([NH:62][CH3:63])[N:57]=3)=[CH:54][CH:53]=[CH:52][N:51]=2)=[CH:64][CH:65]=1)=[O:10]
Reactant: O=C(O)c1cccnc1F
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(N)cc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)c3cccnc3F)cc2)n1
Reaction time: 16 h

Procedure:
To a mixture of 2-fluoro-3-pyridinecarboxylic acid (1.06 g, 7.50 mmol) and HATU (3.11 g, 8.18 mmol) in CHCl3 at ambient temperature under nitrogen was added n,n-diisopropylethylamine (2.38 ml, 13.6 mmol) via syringe. The mixture was allowed to stir for 5 min, at which point 4-(2-(4-aminophenoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine (2.00 g, 6.82 mmol) was added. The reaction was allowed to stir 16 h, resulting in the formation of a fine precipitate. The reaction was filtered, rinsing with 2× dichloromethane and the solid dried in vacuo to give 2-fluoro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)nicotinamide as a tan solid. MS m/z=417 [M+1]+. Calc'd for C22H17FN6O2: 416.41.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:14])([CH3:13])[C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.[CH3:15][O:16]C1C=CC(C(C2SCCS2)(C)C)=CC=1C=O>>[CH3:13][C:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:8]([CH:7]=1)[CH:15]=[O:16])([C:10](=[O:12])[CH3:11])[CH3:14]
Reactant: COc1ccc(C(C)(C)C2SCCS2)cc1C=O
Reactant: COc1ccc(C(C)(C)C(C)=O)cc1
Product: COc1ccc(C(C)(C)C(C)=O)cc1C=O

Procedure:
This compound was prepared from Compound 84 in the same manner of Compound 81.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[OH:10])=[O:4].[C:11](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][S:6][C:5]=1[C:3]([OH:2])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1sccc1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1ccsc1C(=O)O
Reaction time: 1 h

Procedure:
48.5 g (0.31 mmoles) of 3-hydroxy-2-thiophene carboxylic acid methyl ester (IV: R3 =H) are dissolved in 400 ml of acetone, 84.7 g (0.61 moles) of potassium carbonate, 77.3 g (0.61 moles) of dimethylsulfate are added, and the mixture is refluxed with stirring for 1 hour. The salt mass is aspirated, washed several times with acetone and the combined filtrate is concentrated in vacuo. 750 ml of aqueous 2N sodium hydroxide are added and boiled. The reaction solution is cooled, washed with ether and acidified with concentrated HCl. The precipitating colorless crystals are aspirated and recrystallized from ethanol. Yield: 43.1 g (89%), m.p. 184°-185° C.
Reaction SMILES: Cl[CH:2]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])=[CH:34][CH:33]=1)[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:5][CH:4]=1.[CH2:61]([NH2:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1.C(N(C(C)C)C(C)C)C>C(Cl)(Cl)Cl>[CH2:61]([NH:68][CH:2]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])=[CH:34][CH:33]=1)[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:5][CH:4]=1)[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1
Reactant: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(C(Cl)c2ccc(OCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Reactant: NCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(C(NCc2ccccc2)c2ccc(OCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
To chloro-bis(4-docosyloxyphenyl)methane (75.9 mg, 89.1 μmol) were added chloroform (1 ml), benzylamine (29.1 μl, 267 μmol) and N-ethyldiisopropylamine (45.7 μl, 267 μmol), and the mixture was stirred at room temperature overnight. The reaction mixture was warmed to 50° C. and stirred for 1 hr. The mixture was cooled to room temperature again, and washed successively with 0.5N hydrochloric acid, 10% aqueous sodium hydrogen carbonate and 20% brine. The organic layer was dehydrated with anhydrous sodium sulfate, chloroform was evaporated, and the residue was precipitated with methanol to give N-benzyl-[bis(4-docosyloxyphenyl)]methylamine (72 mg, 87%).
Reaction SMILES: [CH2:1]([N:4]1[CH2:11][CH:10]2[C:6]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=3)([NH:7][O:8][CH2:9]2)[CH2:5]1)[CH:2]=[CH2:3].C(OCC)(=O)C>C(O)(=O)C.[Zn]>[CH2:1]([N:4]1[CH2:5][C:6]([NH2:7])([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)[CH:10]([CH2:9][OH:8])[CH2:11]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CC2CONC2(c2cccc(Br)c2)C1
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C=CCN1CC(CO)C(N)(c2cccc(Br)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
A 22° C. solution of 5-allyl-6a-(3-bromophenyl)-3,3a,4,6-tetrahydro-1H-pyrrolo[3,4-c]isoxazole (40 g, 129.4 mmol) in acetic acid (400 mL) is treated with zinc dust (42.3 g, 646.8 mmol) in one portion. The reaction is stirred vigorously at room temperature for 1 hour. Ethyl acetate (400 mL) is added and the mixture is filtered through diatomaceous earth. The filtrate is evaporated and the residue dried under vacuum. The residue is partitioned in water (300 mL) and MTBE (300 mL). The pH is adjusted to 8 with sodium hydroxide 50% w/w and the organic layer is separated, dried over sodium sulfate, and filtered. The filtrate is evaporated and the residue dried under vacuum to give the title compound (41 g, 97%). ES/MS (m/e): 311 (M+1).