Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[Na+].[Na+].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](OB(O)O)=[CH:22][CH:21]=1.N>C1(C)C=CC=CC=1.CO.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(Cl)Cl>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=2)[C:7]([O:9][CH3:10])=[O:8])=[CH:22][CH:21]=1
Reactant: COC(=O)c1cncc(Br)c1
Reactant: COc1ccc(OB(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1cncc(-c2ccc(OC)cc2)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 24.7 %

Procedure:
2.16 g of methyl 5-bromonicotinate and 350 mg of tetrakis(triphenylphosphine)palladium were dissolved in 20 ml of toluene, and under a nitrogen current, 10 ml of a 2M aqueous solution of sodium carbonate and a suspension of 1.82 g of (4-methoxyphenyl)boric acid in 5 ml of methanol were added. The mixture was stirred at a bath temperature of 80° C. for 12 hours. To the reaction solution were added 100 ml of methylene chloride, 50 ml of a 2M aqueous solution of sodium carbonate and 5 ml of conc. aqueous ammonia to perform extraction. The organic layer was separated, and the solvent was evaporated. The residue was subjected to silica gel column chromatography. The column was eluted with a 3:7 mixture of ethyl acetate and hexane. The solvent was evaporated from the eluate to give 600 mg (yield 24.7%) of methyl 5-(4-methoxyphenyl)nicotinate as colorless needles having a melting point of 99° to 101° C.
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][N:4]([N:6]=[N:7][C:8]1[C:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C:11]=2[Se:10][C:9]=1[C:17]([O-:19])=O)[CH3:5].O>C1COCC1>[CH3:3][N:4]([N:6]=[N:7][C:8]1[C:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C:11]=2[Se:10][C:9]=1[C:17]([NH2:2])=[O:19])[CH3:5]
Reactant: CN(C)N=Nc1c(C(=O)[O-])[se]c2c1CCCC2
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)N=Nc1c(C(N)=O)[se]c2c1CCCC2
Temperature: 25 °C
Reaction time: 66 h
Yield: 18 %

Procedure:
To an ice cold (0-5° C.) solution of ammonium hydroxide (60 mL) was added a mixture of ethyl and methyl esters of 3-[(dimethylamino)diazenyl]-4,5,6,7-tetrahydrobenzo[2,1-d]selenophene-2-carboxylate (600 mg) in THF (6 mL) for 5 min. A catalytic amount of PEG-400 was added and stirred at rt for 66 h. The solution was poured into ice cooled water and extracted with chloroform (3×150 mL). The combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (98:2) as eluents to give the product as a pale brown color solid (100 mg, 18%), which was recrystallized from chloroform-hexane (70 mg), mp 198-202° C. IR (Neat) νmax 3347, 3163, 2932, 2860, 1631, 1342, 1313, 1220, 1103, 1020, 878 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.21 (1H, s, —CONH2), 6.07 (1H, s, —CONH2), 3.51 (3H, br s, —NCH3), 3.14 (3H, br s, —NCH3), 2.80-2.82 (2H, m, H-4), 2.64-2.65 (2H, m, H-7), 1.72-1.80 (4H, m, H-5,6); 13C NMR (100 MHz, CDCl3): δ 165.9, 149.5, 145.9, 132.6, 129.5, 29.0, 28.6, 23.1, 22.7; LC-MS (positive ion mode): m/z 321, 323 (M+Na)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=[O:4].Br[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[CH2:20]Br)[CH:13]=[CH:12][CH:11]=1.[H-].[Na+]>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([N:5]1[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:19]=2[C:18](=[CH:17][CH:16]=[CH:15]3)[CH2:20]1)=[O:4]
Reactant: NC(=O)C(F)(F)F
Reactant: BrCc1cccc2cccc(CBr)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(N1Cc2cccc3cccc(c23)C1)C(F)(F)F

Procedure:
Trifluoroacetamide (10 mmol) is reacted with 1,8-bis(bromomethyl)naphthalene (10 mmol) and sodium hydride (10 mmol) in DMF according to the procedure of Wright et al (Biochim. Biophys. Acta 1990, 1040, 95-101) to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][CH2:14][CH2:15][N:16]3[CH:21]4[CH2:22][CH2:23][CH:17]3[CH2:18][C:19](=O)[CH2:20]4)[O:12]CCO2)=[CH:4][CH:3]=1.[O:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.O.Cl>CC(C)=O.C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:28]([C:29]([CH:19]2[CH2:18][CH:17]3[N:16]([CH2:15][CH2:14][CH2:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[O:12])[CH:21]([CH2:22][CH2:23]3)[CH2:20]2)=[O:25])=[CH:27][CH:26]=1
Reactant: C1CCOC1
Reactant: O=C1CC2CCC(C1)N2CCCC1(c2ccc(F)cc2)OCCO1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: O
Product: O=C(CCCN1C2CCC1CC(C(=O)c1ccc(F)cc1)C2)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To the resulting suspension is added dropwise with stirring, a solution of 3.33 g. (0.01 mol) 8-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-8-azabicyclo[3.2.1]octan-3-one in 50 ml. dry tetrahydrofuran over 20 minutes while the reaction temperature is maintained between -65° C. to -75° C. The cold reaction mixture is then permitted to stir for 11/2 hours, then allowed to warm to room temperature, after which it is placed in an oil bath at +60° to 65° for 4 hours. After standing for about 16 hours, 50 ml. of water and 100 ml. of diethyl ether is added and following agitation the layers are partitioned. The aqueous solution is extracted two additional times with diethyl ether and all ethereal extracts are combined, dried over anhydrous sodium sulfate and concentrated to afford a viscous oil. The oil is dissolved in 300 ml. of acetone, 20 ml. of 1.2 N hydrochloric acid is added and the solution stirred for 4 hours. The solution is concentrated in vacuo, 100 ml. of 3 N hydrochloric acid is added and the solution is extracted with 150 ml. of diethyl ether. The hydrochloric acid solution is made basic with 15% sodium hydroxide aqueous solution, then extracted three times with 100 ml. portions of diethyl ether.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:18]([OH:21])([CH3:20])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24]I.O>C1COCC1>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:18]([O:21][CH3:24])([CH3:19])[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(O)C1c2ccccc2CCN1Cc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(C)(C)C1c2ccccc2CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
With cooling in an ice-MeOH bath under an argon atmosphere, a solution of 2-(2-benzyl-1,2,3,4-tetrahydroisoquinolin-1-yl)propan-2-ol (1.27 g) in THF (7 mL) was added dropwise to a solution of sodium hydride (60%, 199 mg) in THF (5 mL), followed by stirring at room temperature for 0.5 hours. Then, the reaction liquid was cooled in ice and methyl iodide (0.42 mL) was added thereto. The mixture was stirred at room temperature for 8 hours. To the mixture were added sodium hydride (60%, 199 mg) and methyl iodide (0.42 mL), followed by stirring at room temperature for 12 hours. Water was added to the reaction solution, followed by extraction with EtOAc. The extract was washed with saturated brine, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain 2-benzyl-1-(1-methoxy-1-methylethyl)-1,2,3,4-tetrahydroisoquinoline (1.17 g).
Reaction SMILES: [C:1]([C:3]1([C:9](OCC)=[O:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:2][CH2:1][C:3]1([CH2:9][OH:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: CCOC(=O)C1(C#N)CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC1(CO)CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.8 %

Procedure:
A solution of ethyl 4-cyanotetrahydro-2H-pyran-4-carboxylate (10 g, 54.64 mmol) in THF (50 mL) is added dropwise to a suspension of lithium aluminum hydride (8.26 g, 218.5 mmol) in THF (100 mL) at 0° C. The reaction mixture is warmed to room temperature and stirred for 4 h. The mixture is cooled to 0° C. and ice cold water (30 mL) is added slowly. The mixture is extracted with EtOAc (2×200 mL) and the organic layers are combined, dried (Na2SO4) and concentrated to afford the title crude compound (8 g, >99%) which is used in the next step without purification.
Reaction SMILES: CS(C)=O.Cl[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([N:14]([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])=[O:13])[C:7]=1[CH2:21][CH3:22].[H-].[Na+].[CH3:25][C:26]1([CH3:34])[O:31][CH2:30][CH:29]([CH2:32][OH:33])[CH2:28][O:27]1>C(OCC)(=O)C>[CH3:25][C:26]1([CH3:34])[O:31][CH2:30][CH:29]([CH2:32][O:33][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([C:12]([N:14]([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])=[O:13])[C:7]=2[CH2:21][CH3:22])[CH2:28][O:27]1
Reactant: CCc1c(Cl)ccnc1C(=O)N(C(C)C)C(C)C
Reactant: CC1(C)OCC(CO)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCc1c(OCC2COC(C)(C)OC2)ccnc1C(=O)N(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 36.9 %

Procedure:
To a dimethylsulfoxide (20 ml) solution of the 4-chloro-3-ethyl-N,N-diisopropylpyridine-2-carboxamide (1 g, 3.72 mmol) obtained in the step (92b) above, oily sodium hydride, in oil (195 mg, 4.46 mmol as the content was regarded as 55%) was added at room temperature. To the mixture, the (2,2-dimethyl-1,3-dioxan-5-yl)methanol (598 mg, 4.09 mmol) obtained in Example (11a) was added and the mixture was stirred at room temperature for 16.5 hours. Ethyl acetate was added to the reaction mixture. The mixture was washed twice with a saturate saline solution. The organic layer was dried over anhydrous magnesium sulfate, filtrated, and concentrated. The residue was washed with diethyl ether to obtain the title compound (520 mg, yield: 36.9%) as a light yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[F:20][C:21]([F:32])([F:33])[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Product: O=C(O)c1cccc(COc2ccc(-c3ccccc3OC(F)(F)F)cc2)c1

Procedure:
3-(2′-Trifluoromethoxy-biphenyl-4-yloxymethyl)-benzoic acid was prepared using general procedure 1 from 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (of Intermediate 1) and 2-(trifluoromethoxy)benzeneboronic acid (ASDI Incorporated, Newark, Del.). Mass spectrum MH+=389.
Reaction SMILES: [OH:1][CH:2]([P:13](=[O:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH3:10])=[C:5]([Cl:11])[C:4]=1[CH3:12].C/C(/[O-])=C/C(C)=O.C(OO)(C)(C)C>ClC1C=CC=CC=1>[Cl:11][C:5]1[C:4]([CH3:12])=[C:3]([C:8]([CH3:9])=[CH:7][C:6]=1[CH3:10])[C:2]([P:13](=[O:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:1]
Reactant: Cc1cc(C)c(C(O)P(=O)(c2ccccc2)c2ccccc2)c(C)c1Cl
Agent: CC(=O)/C=C(/C)[O-]
Agent: CC(C)(C)OO
Solvent: Clc1ccccc1
Product: Cc1cc(C)c(C(=O)P(=O)(c2ccccc2)c2ccccc2)c(C)c1Cl
Reaction time: 20 h
Yield: 81 %

Procedure:
To 15.4 g (0.04 mol) of α-hydroxy-(3-chloro-2,4,6-trimethylbenzyl)-diphenyl phosphine oxide and 0.4 g (1.5 mmol) of vanadyl(IV) bis-acetylacetonate in 100 g of chlorobenzene there were added 8.2 g (0.06 mol) of 70 wt % strength aqueous tert-butylhydroperoxide and isolated by crystallization following a period of 20 h. Yield: 81%, mp 125°-126° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[C:21](=[NH:34])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:22]1([C:21](=[N:34][C:2]2[N:7]=[CH:6][C:5]([CH:8]3[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]3)=[CH:4][CH:3]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)nc2)C1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(N=C(c3ccccc3)c3ccccc3)nc2)C1
Temperature: 100 °C
Yield: 22 %

Procedure:
To a stirred solution of tert-butyl (RS)-2-(6-chloropyridin-3-yl)morpholine-4-carboxylate (1.16 g) and benzophenone imine (977 μl) in toluene (35 ml) was added sodium tert-butoxide (597 mg). The reaction mixture was purged with argon for 10 min. (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (242 mg) and tris(dibenzylideneacetone)dipalladium(0) (107 mg) were added and the reaction mixture was heated at 100° C. overnight. The reaction mixture was then cooled to room temperature, poured into water and extracted twice with EtOAc. The organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 30% EtOAc in hexanes) to afford tert-butyl (RS)-2-(6-(diphenylmethyleneamino)pyridin-3-yl)morpholine-4-carboxylate (374 mg, 22%) as a yellow oil. MS (ISP): 444.2 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]([NH:16][CH:17]([CH3:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[N:7][C:8]3[C:9](I)=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.C1([Mg]Cl)C=CC=CC=1.C([Mg]Cl)(C)C.[CH:38]1([CH:41]=[O:42])[CH2:40][CH2:39]1>C1COCC1>[Br:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]([NH:16][CH:17]([CH3:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[N:7][C:8]3[C:9]([CH:41]([CH:38]4[CH2:40][CH2:39]4)[OH:42])=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1
Reactant: CC(Nc1nc2c(I)c[nH]c(=O)c2c2cc(Br)ccc12)C(C)(C)C
Reactant: O=CC1CC1
Agent: CC(C)[Mg]Cl
Agent: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CC(Nc1nc2c(C(O)C3CC3)c[nH]c(=O)c2c2cc(Br)ccc12)C(C)(C)C
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
9-bromo-4-iodo-6-[(1,2,2-trimethylpropyl)amino]benzo[c]-1,6-naphthyridin-1(2H)-one (50 mg, 0.100 mmol) was dissolved in THF and cooled to −30° C. Phenylmagnesium chloride (2M in THF) (105 μl, 0.210 mmol) was added dropwise, then stirred for 30 minutes before allowing to warm to room temperature by removing cooling baths and stirring an additional 30 minutes. Then, isopropylmagnesium chloride (2M in ether) (60.0 μl, 0.120 mmol) was added dropwise and stirred for 1 h. Then, cyclopropanecarboxaldehyde (29.9 μl, 0.400 mmol) was added and the reaction mixture was stirred for 30 minutes before quenching with saturated NH4Cl (10 mL). The reaction was then diluted with brine and extracted with ethyl acetate. The organic extract was then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Then, the residue was purified by preparative HPLC reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA, to give the title compound as a pale yellow solid as an approximate 1:1 mixture of diastereomers. LRMS (ESI) calc'd for (C22H27BrN3O2) [M+H]+ 444.1; found 444.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([NH:12][C@@H:13]([C:18]([OH:20])=[O:19])[C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C>[CH2:27]([O:19][C:18](=[O:20])[C@@H:13]([C:14]([CH3:16])([CH3:17])[CH3:15])[NH:12][S:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:11])=[O:10])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: COc1cccc(S(=O)(=O)N[C@@H](C(=O)O)C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(S(=O)(=O)N[C@@H](C(=O)OCc2ccccc2)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.1 %

Procedure:
N-(3 Methoxyphenylsulfonyl)D-tert-leucine (3.03 g, 10.1 mmol) is dissolved in DMF (30 ml). Potassium Carbonate (2.81 g, 20.1 mmol) is added followed by Benzyl Bromide (1.21 ml, 9.95 mmol) and the reaction is stirred at ambient temperature for 18 hours. The reaction mixture is partitioned between Ethyl Acetate and 1 N HCl. The organics are separated and washed with brine, dried over MgSO4 and concentrated. The residue is purified by column chromatography eluting with a gradient of 5-60% (Hex-EtOAc) to give the title compound (3.08 g, 78% yield). Mass spectrum (392.2; M+1, 390.2; M−1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2OC)[N:3]=1.C(OP(CC1C=CC(N)=CC=1)(=O)OCC)C>>[Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Agent: CCOP(=O)(Cc1ccc(N)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC

Procedure:
Prepared in a manner analogous to that for diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate using commercially available diethyl(4-aminobenzyl)phosphonate in place of diethyl (4-amino-3-methoxybenzyl)phosphonate. Following chromatography, the semi-pure product was crystallized from ethyl acetate to afford the title compound. 1H NMR (400 MHz, METHANOL-d4) d ppm 1.22-1.32 (m, 6 H), 3.17-3.28 (m, 2 H), 3.98-4.10 (m, 4 H), 7.30 (dd, J=8.72, 2.65 Hz, 2 H), 7.65 (d, J=7.83 Hz, 2 H), 8.63 (s, 1 H).
Reaction SMILES: [CH2:1]([C@H:8]([NH:32][C:33](=[O:43])[O:34][C@@H:35]1[C@H:42]2[C@H:38]([O:39][CH2:40][CH2:41]2)[O:37][CH2:36]1)[C@H:9]([OH:31])[CH2:10][N:11]([CH2:23][C:24]([CH3:30])([CH3:29])[CH2:25][CH2:26][C:27]#[N:28])[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH3:22])[CH:16]=1)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Ni].N.CO>[NH2:28][CH2:27][CH2:26][CH2:25][C:24]([CH3:30])([CH3:29])[CH2:23][N:11]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH3:22])[CH:16]=1)(=[O:14])=[O:13])[CH2:10][C@@H:9]([OH:31])[C@@H:8]([NH:32][C:33](=[O:43])[O:34][C@@H:35]1[C@H:42]2[C@H:38]([O:39][CH2:40][CH2:41]2)[O:37][CH2:36]1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNc1cccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCC#N)c1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CNc1cccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCCN)c1
Yield: 77.3 %

Procedure:
A mixture of 0.29 g (0.46 mmol) of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-[(1S,2R)-1-benzyl-3-((4-cyano-2,2-dimethylbutyl) [3-(methylamino)phenyl]sulfonylamino)-2-hydroxypropyl]carbamate and approximately 50 mg of Raney nickel (washed with water and MeOH) in 60 mL of 2M NH3/MeOH was subjected to hydrogenation at 45 psi. After 1.5 hours the reaction vessel was purged with nitrogen, catalyst-removed by filtration through celite and the filtrate concentrated in vacuo. The residue was subjected to flash chromatography (SiO2, 9:1 CH2Cl2/2M NH3 in MeOH) to afford 0.22 g (76%) of the desired amine as a white foam. NMR (CDCl3): 7.39-7.19 (m, 6H), 7.10 (d, 1H), 7.04-6.92 (m, 2H), 6.81 (dd, 1H), 5.63 (d, 1H), 5.05 (q, 1H), 4.16 (br s, 1H), 4.09-3.80 (m, 4H), 3.70 (m, 2H), 3.31 (m, 2H), 3.21-3.00 (m, 3H), 2.99-2.58 (m, 5H), 2.90 (s, 3H), 2.57-2.10 (br, 2H), 1.82-1.07 (m, 6H), 1.04 (s, 3H), 0.92 (s, 3H). MS(ESI): 619(M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15](N1C=CN=C1)(N1C=CN=C1)=[S:16]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]=[C:15]=[S:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N=C=S)CC1
Temperature: -15 °C
Reaction time: 14 h
Yield: 94.1 %

Procedure:
4-Aminopiperidine-1-carboxylic acid tert-butyl ester (5.0 g, 25 mmol) (Astatech, Inc) was dissolved in dimethylformamide (120 mL) and cooled to −15° C. Thiocarbonyidiimidazole (4.8 g, 27 mmol) (Aldrich) in dimethylformamide (100 mL) was added slowly at below −10° C. The mixture was stirred at room temperature for 14 h. All solvent was removed under vacuum and the residue was dissolved in methylene chloride (200 mL) and washed 2× water. The solvent was removed and the residue was triturated with hexane. This was filtered and the solution treated with Norite and filtered through celite. Removal of solvent gave 4-isothiocyanatopiperidine-1-carboxylic acid tert-butyl ester (5.7 g, 94% yield) as oil. LR-MS-EI(+): Compatible with 242 MW.
Reaction SMILES: [S:1]([C:4]1[S:8][C:7]([NH:9][C:10]2[N:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:12][CH:11]=2)=[N:6][CH:5]=1)[C:2]#N.SC[C@H]([C@@H](CS)O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].ClC1[CH:47]=[CH:46][N:45]=[C:44]([C:48]([O:50][CH3:51])=[O:49])[C:43]=1[F:52]>CO.CN(C=O)C>[C:20]([O:19][C:18]([NH:17][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([NH:9][C:7]2[S:8][C:4]([S:1][C:2]3[CH:47]=[CH:46][N:45]=[C:44]([C:48]([O:50][CH3:51])=[O:49])[C:43]=3[F:52])=[CH:5][N:6]=2)=[N:15][CH:14]=1)=[O:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Nc2ncc(SC#N)s2)nc1
Reactant: COC(=O)c1nccc(Cl)c1F
Agent: O=P([O-])([O-])[O-]
Agent: O[C@H](CS)[C@H](O)CS
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1nccc(Sc2cnc(Nc3ccc(CNC(=O)OC(C)(C)C)cn3)s2)c1F
Temperature: 23 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
Tert-butyl (6-(5-thiocyanatothiazol-2-ylamino)pyridin-3-yl)methylcarbamate (1.5 g, 4.13 mmol) was dissolved in methanol (30 mL) and treated with dithiothreitol (0.637 g, 4.13 mmol). The reaction was stirred at 23° C. for 1 hour. DMF (30 mL) was then added, followed by K3PO4 (0.351 g, 1.65 mmol) and methyl 4-chloro-3-fluoropicolinate (0.861 g, 4.53 mmol). The reaction was stirred at 23° C. for 1 hour, then methanol was evaporated. The title material was precipitated by adding water (˜200 mL), collected by filtration and dried under high vacuum to give the title material (1.875 g, 92%) as a solid. The compound was purified by silica gel chromatography (Biotage, dichloromethane/methanol) to give the title material as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 1.38 (9H, s) 3.91 (3H, s), 4.08 (2H, d, J=5.81 Hz), 7.09 (1H, d, J=8.34 Hz), 7.14 (1H, t, J=5.31 Hz), 7.41 (1H, t, J=5.94 Hz), 7.66 (1H, dd, J=8.46, 2.15 Hz), 7.82-7.85 (1H, m), 8.17 (1H, d, J=1.77 Hz), 8.33 (1H, d, J=5.05 Hz), 11.89 (1H, s). HPLC ret. time: 5.868 min. (Condition B).
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:16]=[CH:15][S:14][C:4]=2[S:5](=[O:13])(=[O:12])[CH2:6][C:7]=1[C:8]([O:10]C)=O.[NH2:17][C:18]1[S:19][CH:20]=[CH:21][N:22]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:3]2[CH:16]=[CH:15][S:14][C:4]=2[S:5](=[O:13])(=[O:12])[CH2:6][C:7]=1[C:8]([NH:17][C:18]1[S:19][CH:20]=[CH:21][N:22]=1)=[O:10]
Reactant: COC(=O)C1=C(O)c2ccsc2S(=O)(=O)C1
Reactant: Nc1nccs1
Solvent: Cc1ccccc1C
Product: O=C(Nc1nccs1)C1=C(O)c2ccsc2S(=O)(=O)C1
Temperature: 5 °C
Yield: 21.3 %

Procedure:
A mixture of methyl 4-hydroxy-6H-thieno[2,3-b]thiopyran-5-carboxylate 7,7-dioxide (5.2 g, 0.02 mole), 2-aminothiazole (3.0 g, 0.03 mole) and xylene (175 ml) is warmed and filtered from the polymeric products. The filtrate is refluxed for 30 min. when some more polymeric product is formed. It is filtered again, and the filtrate refluxed for 1.5 hrs. The mixture is cooled to 5° C. in an ice-bath, and the resulting crystalline product is collected. It is dissolved in THF, treated with charcoal and filtered. The filtrate is concentrated to give the desired product (1.4 g, 21%), m.p. 215°-216° C. IR (Nujol) 3100 (broad, NH and OH); 1590 (CONH); 1155 (SO2) cm-1. NMR (DMSO) δ 11.0 (b, ~2, NH and OH); 8.1 (d, 1, C3 '); 7.5 (m, 2, C2 -C3); 7.15 (d, 1, C4 '); 4.6 (s, 2, CH2). λmaxEtOH 360 (14,600), 267 (12,400), 246 (11,600) mμ; mol. ion. 328.