Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][OH:53]>CN(C)C=O>[OH:53][CH2:52][CH2:51][O:50][CH2:49][CH2:48][NH:47][C:8]([C:7]1[CH:6]=[C:5]([CH:13]=[CH:12][CH:11]=1)[C:3]([O:2][CH3:1])=[O:4])=[O:10]
Reactant: NCCOCCO
Reactant: COC(=O)c1cccc(C(=O)O)c1
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: CN(C)C=O
Product: COC(=O)c1cccc(C(=O)NCCOCCO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 1000-mL round bottom flask, was placed a solution of 3-(methoxycarbonyl)benzoic acid (20 g, 111.11 mmol, 1.00 equiv) in N,N-dimethylformamide (500 mL), HATU (63.2 g, 166.32 mmol, 1.50 equiv), N,N-diisopropylethylamine (21.5 g, 166.67 mmol, 1.50 equiv), and 2-(2-aminoethoxyl)ethanol (23.3 g, 221.90 mmol, 2.00 equiv). The resulting solution was stirred overnight at 25° C. The resulting mixture was concentrated under vacuum. The resulting solution was dissolved in 200 mL of ethyl acetate. The resulting mixture was washed with 10×200 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane:methanol (100:1). This resulted in 15 g (51%) of methyl 3-((2-(2-hydroxyethoxyl)ethyl)carbamoyl)benzoate as red oil.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[O:6][CH2:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=O)=[O:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:20][C:18]1[CH:19]=[C:3]([CH2:1][OH:2])[CH:4]=[C:5]([O:6][CH2:7][CH2:8][NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:17]=1
Reactant: Cc1cc(C=O)cc(OCC(=O)Nc2ccncc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(CO)cc(OCCNc2ccncc2)c1
Temperature: 1 °C
Reaction time: 0.25 h

Procedure:
A suspension of 2-(3-formyl-5-methyl-phenoxy)-N-pyridin-4-yl-acetamide (0.30 g) in anhydrous tetahydrofuran (1 ml), stirring under a nitrogen atmosphere, was cooled to about 1° C. and treated with a 1M tetrahydrofuran solution of lithium aluminium hydnde (5.47 ml) over a period of 3 min. After 15 min the mixture was allowed to warm to room temperature. After stirring for a further 22 h the mixture was cooled to about 2° C. and the excess reagent was quenched with cautious dropwise addition of wet tetrahydrofuran and then water. The resulting aqueous mixture was partitioned between ethyl acetate and dilute sodium hydroxide solution saturated with sodium chloride and ammonium sulphate. The organic phase was dried with magnesium sulphate and concentrated under reduced pressure and the resulting gum was triturated with diethyl ether giving, after drying, the title compound as an off-white solid (0.13 g).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:30][C:31]#[N:32])[CH2:11][CH2:10][CH:9]([O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)=O)C.O.[BH4-].[Na+].[OH-].[NH4+]>C1COCC1.O.O.O.O.O.O.[Co](Cl)Cl>[C:26]([Si:13]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[O:12][CH:9]1[CH2:10][CH2:11][C:6]2([C:4](=[O:3])[NH:32][CH2:31][CH2:30]2)[CH2:7][CH2:8]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CCOC(=O)C1(CC#N)CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](OC1CCC2(CCNC2=O)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.5 %

Procedure:
Treat a 0° C. mixture of 4-(tert-butyl-diphenyl-silanyloxy)-1-cyanomethyl-cyclohexanecarboxylic acid ethyl ester (7.19 g, 15.9 mmol), cobalt (II) chloride hexahydrate (1.90 g, 7.98 mmol) in THF (130 mL), and water (65 mL) portion-wise with sodium borohydride (3.02 g, 7.98 mmol). Warm to room temperature and stir for 16 hours under N2. Heat the reaction to 50° C. for 8 hours, cool to room temperature and stir 16 hours under N2. Treat the reaction with 28% ammonium hydroxide (2 mL) and filter through hyflo. Remove the solvent from the filtrate in vacuo and dilute the residue with minimal water and brine and extract three times with 3:1 chloroform:isopropanol. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford crude product. Purify with a 0 to 10% methanol in CH2Cl2 gradient on silica gel to afford 1.20 g (18%) of the titled product. Rf=0.48 and 0.61 (9/1 CH2Cl2/methanol). MS (m/z): 408 (M+).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])([CH3:16])([CH3:15])[CH3:14].[Br:23][C:24]1[CH:29]=[C:28]([CH2:30]Br)[CH:27]=[CH:26][C:25]=1[Cl:32].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Br:23][C:24]1[CH:29]=[C:28]([CH2:30][C:19]([CH3:21])([CH3:20])[C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:22])[CH:27]=[CH:26][C:25]=1[Cl:32]
Reactant: Clc1ccc(CBr)cc1Br
Reactant: CC(C)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)C(C)(C)Cc1ccc(Cl)c(Br)c1
Temperature: -30 °C
Reaction time: 4 h

Procedure:
Under argon, 4.0 ml (28.8 mmol) of diisopropylamine were dissolved in 50 ml of dry THF, and the mixture was cooled to −30° C. 11.5 ml (28.8 mmol) of n-butyllithium solution (2.5 M in hexane) were added dropwise. The resulting mixture was warmed to 0° C. and then cooled to −70° C. A solution of 2.77 g (19.2 mmol) of tert-butyl-2-methylpropanoate in 20 ml of THF was then added, the temperature being kept below −60° C. After 4 h of stirring at −60° C., a solution of 6.0 g (21.1 mmol) of 2-bromo-4-(bromomethyl)-1-chlorobenzene in 30 ml of THF was added, the reaction temperature once more being kept below −60° C. The reaction mixture was stirred overnight slowly warming to RT, and saturated aqueous ammonium chloride solution and ethyl acetate were then added. After phase separation, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1→4:1). This gave 5.6 g (84% of theory) of the title compound.
Reaction SMILES: C([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)=O)[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.Cl>>[Cl:26][C:21]1[CH:20]=[C:19]([CH2:17][CH2:16][CH2:15][CH:12]2[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]2)[CH:24]=[CH:23][C:22]=1[Cl:25]
Reactant: O=C(CCC1CCN(C(=O)c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Agent: Cl
Product: Clc1ccc(CCCC2CCNCC2)cc1Cl
Yield: 42.9 %

Procedure:
The procedure is as in Example 6 starting from 51.1 g of 3-(1-benzoyl 4-piperidyl) 1-(3,4-dichlorophenyl) 1-propanone. 15.3 g of 4-[3-(3,4-dichlorophenyl)1-propyl]piperidine in the form of the hydrochloride melting at 150° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[C:13](=[O:17])[CH2:14][CH2:15][CH2:16][C:11]=2[O:10][N:9]=1.C([N-]C(C)C)(C)C.[Li+].[Cl:26][CH2:27][CH2:28][CH2:29]I.O>C1COCC1.CCCCCC.ClCCl.CCOCC>[Cl:26][CH2:27][CH2:28][CH2:29][CH:14]1[C:13](=[O:17])[C:12]2[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[N:9][O:10][C:11]=2[CH2:16][CH2:15]1
Reactant: O=C1CCCc2onc(-c3ccccc3F)c21
Reactant: ClCCCI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: O=C1c2c(-c3ccccc3F)noc2CCC1CCCCl
Temperature: -78 °C

Procedure:
In 500 ml anhydrous THF was dissolved 15.0 g 6,7-dihydro-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-one under nitrogen atmosphere with stirring. The solution was cooled to -78° C. and 65.0 ml lithium diisopropylamide (1.5 molar in cyclohexane) was added dropwise. The resulting solution was stirred for ten minutes at -78° C. and 9.10 ml 1-chloro-3-iodopropane was added. Upon warming to room temperature, the reaction mixture was poured into water and ether. The layers were separated and the aqueous phase was extracted three times with dichloromethane and once with ether. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave the crude product as an oil. Column chromatography on silica gel (start with 10% dichloromethane in hexane and gradually increase polarity to 100% dichloromethane) gave 5.30 g of 5-(3-chloropropyl)-6,7-dihydro-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-one as an oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C)C1C=CC=CC=1>CO.Cl.[OH-].[Pd+2].[OH-]>[CH3:1][NH:8][CH2:10][CH2:11][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CN(CCC(c1ccccc1)c1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CNCCC(c1ccccc1)c1ccccc1
Reaction time: 18 h

Procedure:
A solution of N-benzyl-N-methyl-3,3-diphenylpropylamine (1.03 g, 3.27 mmol) in methanol (35 ml) and aq. HCl (0.27 ml, of a 12.1M aq. solution, 3.3 mmol) was purged with argon and palladium hydroxide (405 mg) added. The flask was evacuated and shaken under an atmosphere of hydrogen (50 psi) for 18 hrs. The hydrogen was replaced by argon and the catalyst removed by filtration. The filtrate was treated with aq. NaOH (100 ml of a 1 M solution) and extracted into Et2O. The organic extracts were dried (Na2SO4) and evaporated in vacuo to afford the title compound as an oil.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]#[N:9])[CH:5]=[CH:4][N:3]=[CH:2]1.N>C(O)C.[Ni]>[N:1]1([C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: N#Cc1ccccc1-n1ccnc1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NCc1ccccc1-n1ccnc1

Procedure:
A solution of 2-imidazol-1-yl-benzonitrile (200 mg, 1.2 mmol) in ethanol saturated with ammonia (20 ml) was stirred in the presence of Raney nickel (50% slurry in water, washed with ethanol, catalytic amount) under a hydrogen atmosphere for 4 h. The reaction mixture was filtered over celite and concentrated to give 2-Imidazol-1-yl-benzylamine; 1H NMR (CDCl3, 400 MHz) δ 7.69 (bs, 1H), 7.57 (m, 1H), 7.47 (m, 1H), 7.38 (m, 1H), 7.27 (m, 1H), 7.22 (bs, 1H), 7.16 (m, 1H), 3.73 (s, 2H).
Reaction SMILES: C1(C2N(C)C3C=C(N4C=CC(OCC5SC(F)=C(F)C=5)=CC4=O)C=CC=3N=2)CC1.[Br:30][C:31]1[CH:32]=[C:33]([CH2:37][O:38][C:39]2[CH:44]=[CH:43][N:42]([C:45]3[CH:46]=[CH:47][C:48]4[N:52]=[C:51]([CH:53]5[CH2:55][CH2:54]5)[N:50]([CH3:56])[C:49]=4[CH:57]=3)[C:41](=[O:58])[CH:40]=2)[S:34][C:35]=1F>>[Br:30][C:31]1[CH:32]=[C:33]([CH2:37][O:38][C:39]2[CH:44]=[CH:43][N:42]([C:45]3[CH:46]=[CH:47][C:48]4[N:52]=[C:51]([CH:53]5[CH2:54][CH2:55]5)[N:50]([CH3:56])[C:49]=4[CH:57]=3)[C:41](=[O:58])[CH:40]=2)[S:34][CH:35]=1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4cc(Br)c(F)s4)cc3=O)cc21
Agent: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4cc(F)c(F)s4)cc3=O)cc21
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4cc(Br)cs4)cc3=O)cc21

Procedure:
A mixture of the title compound, 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((4,5-difluoro-2-thienyl)methoxy)pyridin-2(1H)-one and 4-((4-bromo-5-fluoro-2-thienyl)methoxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one obtained in step D in example 219 was subjected to HPLC separation (C18, mobile phase: H2O/CH3CN (0.1% TFA included)). The solution was neutralized with saturated Na2CO3 solution and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO4, filtered through a plug of silica gel, and concentrated in vacuo. The residual solid was recrystallized from EtOH to give the title compound (30.0 mg) as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][N:6]([CH2:17][C:18]([N:20]([N:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([F:31])[CH:28]=2)[CH2:23]1)[CH3:21])=[O:19])[C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[N:12][NH:13]2)=[CH:9][C:8]=1[CH3:16])[CH3:2].FC(F)(F)S(O[CH2:39][CH:40]([F:42])[F:41])(=O)=O>>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][N:6]([C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[N:12][N:13]2[CH2:39][CH:40]([F:42])[F:41])=[CH:9][C:8]=1[CH3:16])[CH2:17][C:18]([N:20]([N:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([F:31])[CH:28]=2)[CH2:23]1)[CH3:21])=[O:19])[CH3:2]
Reactant: CCOC(=O)CN(CC(=O)N(C)N1Cc2ccc(F)cc2C1)c1cc2[nH]ncc2cc1C
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Product: CCOC(=O)CN(CC(=O)N(C)N1Cc2ccc(F)cc2C1)c1cc2c(cnn2CC(F)F)cc1C
Yield: 65.2 %

Procedure:
Using the compound (1.46 g, 3.32 mmol) of Example 259, step B, and 2,2-difluoroethyl trifluoromethanesulfonate (957 mg, 4.47 mmol), and according to the method of Example 241, step C, the title compound (1.09 g, yield 65%) was obtained as a colorless amorphous solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28](=[O:32])[N:29]([CH3:31])C)[CH:25]=[C:24]([Br:33])[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:2].BrC1C=C(C=C(OCCCCCCC2C=CC=C(OCCCC(=O)NOCC)C=2CCC(OCC)=O)C=1)C(O)=O.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[F:106][CH:107]([F:117])[O:108][C:109]1[CH:116]=[CH:115][CH:114]=[CH:113][C:110]=1CN.CCN(C(C)C)C(C)C>ClCCl>[CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28](=[O:32])[NH:29][CH2:31][C:110]3[CH:113]=[CH:114][CH:115]=[CH:116][C:109]=3[O:108][CH:107]([F:117])[F:106])[CH:25]=[C:24]([Br:33])[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:2]
Reactant: NCc1ccccc1OC(F)F
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)N(C)C)c2)c1CCC(=O)OCC
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CCONC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)O)c2)c1CCC(=O)OCC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)NCc3ccccc3OC(F)F)c2)c1CCC(=O)OCC
Yield: 85 %

Procedure:
The title compound was prepared by the same method as 4-{3-[6-(3-bromo-5-dimethylcarbamoyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester starting from 3-bromo-5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbamoyl-propoxy)-phenyl]-hexyloxy}-benzoic acid (900 mg, 1.48 mmol), PyBroP (828 mg, 1.77 mmol), 2-(difluoromethoxy)-benzylamine (306 mg, 1.77 mmol) and DIPEA (515 uL, 2.96 mmol) in dichloromethane (30 mL) to obtain 4-[3-{6-[3-bromo-5-(2-difluoromethoxy-benzylcarbamoyl)-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (960 mg, 85%) as a colorless oil
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([O:10][C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([OH:21])=[CH:18]3)=[CH:13][CH:12]=2)=[CH:8][CH:7]=[CH:6][N:5]=1.CC1C=CC(S(O[CH2:33][C:34]([F:37])([F:36])[F:35])(=O)=O)=CC=1.[Cl-].[NH4+]>CS(C)=O.C1COCC1>[F:35][C:34]([F:37])([F:36])[CH2:33][O:21][C:17]1[CH:18]=[C:19]2[C:14]([CH:13]=[CH:12][C:11]([O:10][C:9]3[C:4]([NH2:3])=[N:5][CH:6]=[CH:7][CH:8]=3)=[CH:20]2)=[CH:15][CH:16]=1
Reactant: Nc1ncccc1Oc1ccc2ccc(O)cc2c1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Nc1ncccc1Oc1ccc2ccc(OCC(F)(F)F)cc2c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 16.9 %

Procedure:
To a mixture of sodium hydride (60%, 116 mg), 7-[(2-aminopyridin-3-yl)oxy]naphthalen-2-ol (477 mg) and dehydrated THF (10 mL) was added a mixture of 2,2,2-trifluoroethyl 4-methylbenzenesulfonate (370 mg) and dehydrated THF (5 mL) at room temperature. The reaction mixture was stirred at 70° C. over the weekend, DMSO (10.00 mL) was added and the mixture was stirred at 120° C. for 1 hr. The reaction mixture was added to a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (82 mg) as a pale-yellow viscous product.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:14][CH:13]([C:15]([F:18])([F:17])[F:16])[C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][C:10]=2[CH:24]=1)=O.C([O-])(=O)C.[Na+].C(O)C>O.C(OCC)C>[OH:3][N:2]=[CH:4][C:6]1[CH:7]=[CH:8][C:9]2[O:14][CH:13]([C:15]([F:18])([F:17])[F:16])[C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][C:10]=2[CH:24]=1
Reactant: CCOC(=O)C1=Cc2cc(C=O)ccc2OC1C(F)(F)F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C1=Cc2cc(C=NO)ccc2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.9 %

Procedure:
A 50 mL round bottom flask was charged with hydroxylamine HCl (0.255 g, 3.67 mmol), ethyl 6-formyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 75, Step 1) (1.00 g, 3.34 mmol), sodium acetate (0.301 g, 3.67 mmol), ethanol (10 mL), and H2O (2 mL). The reaction was stirred at room temperature for 18 hours, then diluted with H2O and diethyl ether. The layers were separated and the organic phase washed with H2O, brine, dried over MgSO4, filtered, and concentrated in vacuo yielding an orange semi-crystalline mass. Recrystallization of this solid from hot ethyl acetate and isooctane yielded the oxime (0.578 g, 55%): mp 113.0–116.2° C. 1H NMR (acetone-d6/300 MHz) 10.46 (s, ca. 1 exch.), 8.11 (s, 2H), 7.92 (s, 1H), 7.72 (d, 1H, J=2 Hz)), 7.68 (dd, 1H, J=8.5, 2.0 Hz), 7.07 (d, 1H, J=8.5 Hz), 5.89 (q, 1H, J=7.1 Hz), 4.43–4.22 (m, 2H), 1.34 9t, 3H, J=7.3 Hz). FABLRMS m/z 316 (M+H). EIHRMS m/z 315.0719 (M+, Calc'd 315.0733). Anal. Calc'd for C14H12F3N1O4: C, 53.34; H, 3.84; N 4.44. Found: C, 53.85; H, 3.90; N, 4.19.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O1C=CC=C1[Zn]>C1COCC1.[Cl-].[Zn+2].[Cl-].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>[C:12]1([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Brc1ccccc1
Reactant: c1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: c1ccc(-c2ccco2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 83.9 %

Procedure:
To a 0° C. solution of furan (10.2 g, 0.15 mol) in 100 mL of THF was added 2.5 M n-butyllithium (60 mL, 0.15 mol). The solution was stirred 3 h and the suspension was then added to a solution of zinc chloride (20 g, 0.15 mol) in 100 mL of THF at room temperature and stirred 1 h. In another flask bromobenzene (10.5 mL, 0.10 mol) was added to a solution of tetrakis(triphenylphosphine)palladium(0) (0.57 g, catalytic) in 300 ml THF and to this mixture was added the furyl zinc solution via cannula. The mixture was heated at 50° C. and stirred for 24 h. The reaction was cooled and quenched with 10% aqueous HCl solution (100 mL). The aqueous layer was washed with ether (2×100 mL) and the combined organic extract was washed with saturated sodium bicarbonate solution (100 mL), brine (100 mL), dried over MgSO4, filtered and concentrated. Distillation at 10 torr (b.p. 94° C.) yielded 12.1 g (81%) of 2-phenylfuran.
Reaction SMILES: Br[C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:25][C:26]1([CH3:42])[CH2:35][CH2:34][C:33]([CH3:37])([CH3:36])[C:32]2[CH:31]=[C:30]([C:38](=C)[CH2:39]O)[CH:29]=[CH:28][C:27]1=2.O>C(OCC)C.CCCCCCC.C(OCC)(=O)C>[Br:5][CH2:2][C:38]([C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[C:26]([CH3:42])([CH3:25])[CH2:35][CH2:34][C:33]2([CH3:37])[CH3:36])=[CH2:39]
Reactant: C=C(CO)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOCC
Solvent: CCCCCCC
Product: C=C(CBr)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reaction time: 24 h

Procedure:
Tetrabromomethane (1.21 g, 3.8 mmol) is added to a mixture of triphenylphosphine (970 mg, 3.8 mmol) in ethyl ether (20 ml). A solution of 2-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)prop-2-en-1-ol (300 mg, 1.2 mmol) in ethyl ether (2 ml) is added. Stirring is continued for 24 h, then the reaction mixture is treated with water and ethyl acetate. The organic phase is washed with water and then concentrated in vacuo in a rotary evaporator. The oil obtained is taken up in heptane and filtered through silica. The filtrate is concentrated in vacuo in a rotary evaporator.
Reaction SMILES: [P:1]([Cl:12])(Cl)([O:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:2].Cl.[CH2:14]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH2:19])[CH3:15].CCN(CC)CC>C(Cl)Cl>[Cl:12][P:1]([NH:19][C@H:18]([C:17]([O:16][CH2:14][CH3:15])=[O:21])[CH3:20])([O:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:10])=[CH:8][CH:9]=1)=[O:2]
Reactant: O=P(Cl)(Cl)Oc1ccc(Cl)cc1
Reactant: CCOC(=O)[C@H](C)N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)NP(=O)(Cl)Oc1ccc(Cl)cc1

Procedure:
Following the procedure described for Example 1, step 2, treatment of a solution in DCM (0.090 M) of 4-chlorophenyl dichlorophosphate with L-alanine ethyl ester hydrochloride (1.0 eq.) and Et3N (2.0 eq.) provided the title compound as a colorless oil as a 1:1* mixture of diastereoisomers.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[N+:22]([O-])=O)[C@H:10]([OH:25])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>C(O)C.[Pd]>[C:1]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[NH2:22])[C@H:10]([OH:25])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: Cc1ccc(N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2O)c(N)c1
Reaction time: 17 h

Procedure:
A mixture of racemic 1-Boc-trans-3-hydroxy-4-(4-methyl-2-nitro-phenylamino)-piperidine (15.0 g, 42.6 mmol) and 10% Pd on carbon (1.5 g, 10% by weight) in ethanol (280 mL) was stirred under 1 atm of H2 gas for 17 h. The solid catalyst was then removed by filtration through Celite and all volatiles were removed under reduced pressure to yield the product, racemic 1-Boc-trans-4-(2-amino-4-methyl-phenylamino)-3-hydroxy-piperidine as a heavy oil (14.1 g, quant).