Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH2:10])=[N:7][C:6]=1[CH3:11])([CH3:4])([CH3:3])[CH3:2].Cl[C:13](OCC(Cl)(Cl)Cl)=[O:14].C(N(CC)C(C)C)(C)C.[N:30]1([C:37]([CH:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:38])[CH2:36][CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>C(Cl)Cl.ClCCCl>[C:1]([C:5]1[S:9][C:8]([NH:10][C:13]([N:33]2[CH2:34][CH2:35][CH2:36][N:30]([C:37]([CH:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[O:38])[CH2:31][CH2:32]2)=[O:14])=[N:7][C:6]=1[CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cc1nc(N)sc1C(C)(C)C
Reactant: O=C(C1CCOCC1)N1CCCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1nc(NC(=O)N2CCCN(C(=O)C3CCOCC3)CC2)sc1C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.4 %

Procedure:
To a solution of 137.8 mg (0.8 mmol) of 5-tert-butyl-4-methyl-thiazol-2-ylamine in DCM (4 mL) were added 169.5 mg (0.8 mmol) of 2,2,2-trichloroethyl chloroformate and 0.21 mL (1.2 mmol) of N,N-diisopropylethylamine. The reaction was stirred for 18 h at room temperature. The reaction mixture was washed with saturated aqueous NaHCO3 solution and the aqueous layer was back-extracted with DCM (2×2 mL). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCE (4 mL) and a solution of 443 mg (0.8 mmol) of [1,4]diazepan-1-yl-(tetrahydro-pyran-4-yl)-methanone (triple trifluoroacetic acid salt, prepared according to Method L, step 1-2) in DCE (2 mL) and 0.42 mL (2.4 mmol) of N,N-diisopropylethylamine were added. The reaction was stirred for 18 h at 80° C. The reaction mixture was washed with 10% aqueous citric acid solution (3 mL). The aqueous layer was back-extracted with DCM (2×2 mL). The combined organic extracts were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by mass-triggered preparative LCMS to afford 92.7 mg of 4-(tetrahydro-pyran-4-carbonyl)-[1,4]diazepane-1-carboxylic acid (5-tert-butyl-4-methyl-thiazol-2-yl)-amide.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[NH:6]2.[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1.[H-].[Na+].O>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[N:6]2[CH2:18][C:17]1[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C1Nc2cccc(Br)c2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1C(=O)N(Cc2ccc(F)cc2)c2cccc(Br)c21
Yield: 90.8 %

Procedure:
To 4-bromoindoline-2,3-dione (200 mg, 0.89 mmol) in 5 ml DMF was added 4-Fluorobenzylbromide (0.120 ml, 0.98 mmol) then add NaH (35 mg, 0.89 mmol) and stir at room temperature overnight. Work up by adding water and EtOAc and extract three times with EtOAc. Pool all organics and wash one time with brine then dry over sodium sulfate, filter and concentrate to dryness. The residue was purified by chromatography over silica gel (eluted with Hexanes/EtOAc 99:1 to 50:50) to provide 270 mg (90%) of product.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([N+:14]([O-])=O)=[CH:9][CH:10]=2)[CH:5]=1)([O-:3])=[O:2].[SH-].[Na+]>CO.O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11]([CH:10]=[CH:9][C:8]([NH2:14])=[CH:7]2)=[CH:12][CH:13]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2ccc([N+](=O)[O-])cc2c1
Agent: [Na+]
Agent: [SH-]
Solvent: O
Solvent: CO
Product: Nc1ccc2ccc([N+](=O)[O-])cc2c1
Temperature: 0 °C

Procedure:
To a solution of 2,7-dinitronaphthalene (500 mg, 2.29 mmol) in methanol (5 mL) heated to reflux, is added over 15 minutes, a solution of sodium hydrosulfide (196 mg, 3.44 mmol) in methanol (5 mL) and water (10 mL). The reaction mixture is heated at reflux for 30 minutes and then poured into ice-water and filtered to give an orange solid. After washing the solid with boiling 10% aqueous HCl, the filtrate is basified with solid NaOH and extracted with EtOAc. The organic layer is dried (Na2SO4) and the solvents are evaporated to give 7-nitro-2-aminonaphthalene as a bright orange solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH2:9].C(O[C:13]([SH:15])=[S:14])C.[K]>CN(C=O)C>[SH:15][C:13]1[S:14][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=2[N:9]=1
Reactant: CCOC(=S)S
Reactant: Cc1ccc(Br)c(N)c1
Agent: [K]
Solvent: CN(C)C=O
Product: Cc1ccc2sc(S)nc2c1

Procedure:
The title compound was prepared using the method of example 239, starting with 2-bromo-5-methyl-phenylamine (244) (4.48 g, 24.0 mmol), O-ethylxanthic acid, potassium salt (Lancaster, 8.70 g, 54 mmol) in DMF (35 mL). The mercaptobenzothiazole 245 was obtained as an pale brown solid (2.31 g, 53%).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4]3=[C:5]([CH2:25][CH2:26][N:3]13)[CH:6]=[C:7]([C:12]([C@H:14]1[CH2:19][CH2:18][C@H:17]([CH2:20][NH:21]C(=O)C)[CH2:16][CH2:15]1)=[O:13])[CH:8]=2.[ClH:27]>>[ClH:27].[NH2:21][CH2:20][C@H:17]1[CH2:18][CH2:19][C@H:14]([C:12]([C:7]2[CH:8]=[C:9]3[C:4]4=[C:5]([CH2:25][CH2:26][N:3]4[C:2](=[O:1])[CH2:11][CH2:10]3)[CH:6]=2)=[O:13])[CH2:15][CH2:16]1
Reactant: CC(=O)NC[C@H]1CC[C@H](C(=O)c2cc3c4c(c2)CCN4C(=O)CC3)CC1
Agent: Cl
Product: NC[C@H]1CC[C@H](C(=O)c2cc3c4c(c2)CCN4C(=O)CC3)CC1
Temperature: 140 °C
Reaction time: 12 h

Procedure:
Concentrated hydrochloric acid (100 ml) was added to trans-N-({4-[(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)carbonyl]cyclohexyl}methyl)acetamide (12.0 g) obtained in Reference Example 77, and the mixture was stirred at 140° C. for 12 hours. Hydrochloric acid was evaporated under reduced pressure to give white powders. Further recrystallization from water-isopropyl ether afforded the title compound as colorless crystals (9.40 g) having a melting point, of 255 to 257° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([C@@H:17]1[CH2:21][O:20][C:19](=[O:22])[N:18]1[C:23](=[O:29])[CH2:24]P(=O)([O-])[O-])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[Li+].[CH2:32]([O:39][CH2:40][CH:41]=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(#N)C>[CH2:10]([C@@H:17]1[CH2:21][O:20][C:19](=[O:22])[N:18]1[C:23](=[O:29])/[CH:24]=[CH:41]/[CH2:40][O:39][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(CP(=O)([O-])[O-])N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: O=CCOCc1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(/C=C/COCc1ccccc1)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 0 °C

Procedure:
Diisopropylethylamine (51 mL, 290 mmol) was added slowly to a mechanically stirred, 0° C. slurry composed of {2-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-oxoethyl}phosphonate (94.8 g, 267 mmol; see Shapiro, G; Chengzhi, C. Tetrahedron Lett. 1992, 33, 2447) and dry lithium chloride (12.5 g, 280 mmol) in acetonitrile (260 mL). After stirring for 10 min, a solution of 2-benzyloxyacetaldehyde (40.0 g, 267 mmol) in acetonitrile (20 mL) was added dropwise over 10 min. The cooling bath was then removed and the reaction mixture was stirred at rt for 12 h before being partitioned between ether and water and the layers separated The aqueous phase was extracted with additional ether and the combined organic phases (700 mL total) were stirred at rt with 2M HCl (350 mL) for 1 h. The organic phase was then washed with saturated NaCl and NaHCO3 aqueous solutions, followed by drying over a mixture of Na2SO4 and MgSO4, and concentration in vacuo. Flash chromatography of the residue on silica gel eluting with 10/90 acetone/benzene yielded (4R)-4-benzyl-3-[(2E)-4-(benzyloxy)but-2-enoyl]-1,3-oxazolidin-2-one as a colorless solid upon trituration with ether. 1H NMR (500 MHz, d6-acetone) δ 7.57 (1H, d, J= 15.6 Hz), 7.43-7.27 (10H, m), 7.21-7.15 (1H, m), 4.84 (1H, t, J= 8.2 Hz), 4.64 (2H, s), 4.43 (1H, t, J= 8.5 Hz), 4.32 (2H, m), 4.29 (1H, dd, J= 2.9, 8.9 Hz), 3.24 (1H, dd, J= 3.1, 13.5 Hz), 3.03 (1H, dd, J= 8.4, 13.5 Hz).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Br:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)=[O:14].O>C(O)C>[BrH:11].[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)=[O:14]
Reactant: Sc1nc2ccccc2s1
Reactant: Cc1ccc(C(=O)CBr)cc1
Solvent: O
Solvent: CCO
Product: Br
Product: Cc1ccc(C(=O)CSc2nc3ccccc3s2)cc1
Yield: 18 %

Procedure:
A mixture of 2-mercaptobenzothiazole (570 mg, 3.34 mmol) and 2-bromo-4′-methylacetophenone (870 mg, 3.67 mmol) was refluxed in ethanol (15 mL) for 90 minutes. The solution was cooled in the fridge to give a yellow solid in 18% yield: mp 76-78° C.; 1H-NMR (DMSO-d6) 2.42 (s, 3H), 5.15 (s, 2H), 7.36 (t, 1H), 7.41 (d, 2H), 7.44 (t, 1H), 7.78 (d, 1H), 8.00 (m, 3H); Anal. (C16H14BrNOS2½ H2O) C, H, N.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-])=O)[CH:11]=1)[CH2:7][OH:8])([O-:3])=[O:2].C(N(CC)CC)C.C(O)=O>C(OCC)(=O)C.[Pd]>[NH2:12][C:10]1[CH:9]=[C:6]([CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=1)[CH2:7][OH:8]
Reactant: O=[N+]([O-])c1cc(CO)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O=CO
Product: Nc1cc(CO)cc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A three neck flask fitted with a reflux condenser and an addition funnel was charged with 3,5-dinitrobenzyl alcohol (10 g, 50 mmol), 10% Pd/C (630 mg) and triethylamine (35 mL, 251 mmol). This was placed in a 70° C. oil bath and through the addition funnel was added 90% formic acid (10 mL, 234 mmol) dropwise. The reaction was heated for 30 minutes and cooled to room temperature. The clear yellow supernatant was filtered through celite and the lower layer containing the catalyst was treated with acetone, filtered through celite and rinsed with acetone. The filtered organic layers were combined and concentrated to give an orange oil. The oil was diluted in ethyl acetate which was washed with H2O, dried (MgSO4), filtered and concentrated to give crude 3-amino-5-nitrobenzyl alcohol as an orange solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.S(=O)(=O)(O)O.[CH3:17]O>>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[C:4]([OH:11])[CH:3]=1
Reactant: CO
Reactant: Cc1ccc(C(=O)O)c(O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C)cc1O
Temperature: 25 °C
Yield: 90 %

Procedure:
4-Methyl-2-hydroxybenzoic acid (100 g, 658 mmoles) was dissolved in anhydrous methanol (500 mL) and concentrated sulfuric acid (25 mL) was added carefully. The solution was refluxed for 18 hours, then cooled to room temperature. The reaction mixture was concentrated to about 150 mL, and ethyl acetate (250 mL) was added. The ethyl acetate solution was washed twice with saturated aqueous sodium bicarbonate (250 mL portions) and then with saturated aqueous sodium chloride (100 mL). The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered, and evaporated to a clear, reddish-brown liquid. This crude product was vacuum distilled (oil pump) to afford a clear, viscous liquid that solidified on standing to afford 98.1 g (90% yield) of methyl 4-methyl-2-hydroxybenzoate.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([CH2:12]Br)[CH:3]=1.[CH3:14][N:15]1[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:8])[N:21]([CH:18]1[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]1)[CH2:12]2
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: CN1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN1CCC(N2Cc3cc(Br)ccc3C2=O)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (0.3 g, 1 mmol; AstaTech Cat. No. 27012), 1-methylpiperidin-4-amine (0.14 g, 1.3 mmol)(Combi-blocks Cat. No. 4003460), and potassium carbonate (0.19 g, 1.4 mmol) in ethanol (5 mL) in a sealed reaction vial was stirred at 80° C. for 1 h. After cooling the solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.1 g). LCMS (M+H)+=309.0/311.0.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)[OH:7].O[CH:13]([C:15]1[S:19][C:18]([CH2:20][C:21]([OH:23])=[O:22])=[CH:17][CH:16]=1)[CH3:14].[CH3:24][C:25]1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][C:18]1[S:19][C:15]([CH:13]([C:8]2[C:6](=[O:7])[C:5]([CH3:9])=[C:4]([CH3:10])[C:3](=[O:11])[C:2]=2[CH3:1])[CH3:14])=[CH:16][CH:17]=1)[CH3:25]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: CC(O)c1ccc(CC(=O)O)s1
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1ccc(C(C)C2=C(C)C(=O)C(C)=C(C)C2=O)s1
Temperature: 50 °C
Yield: 804.6 %

Procedure:
Trimethylhydroquinone (1.5 g, 10 mmole) and 5-(1-hydroxyethyl)-2-thienylacetic acid (2.5 g, 8.5 mmole) were added to 50 ml of toluene, and D-camphorsulfonic acid (0.2 g) was added to the mixture, followed by heating at 50° C. for 6 hours with stirring. After cooling, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in THF. An aqueous solution of ferric chloride was added to the solution, followed by stirring at room temperature for 10 minutes. The reaction solution was extracted with isopropyl ether, and the organic layer was washed with water, dried and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography using IPE:hexane (1:1) to give ethyl-5-[1-(3,5,6-trimethyl-1,4-benzoquinon-2yl)ethyl]-2-thienylacetate (2.4 g, 72%). Hydrolysis of this compound with 6N hydrochloric acid in THF yielded 5-[1-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)ethyl]-2-thienylacetic acid (2.1 g, 90%). δ 6.69(2H,m), 4.61(1H,m), 3.73(2H,s), 1.98(9H,s), 1.61(3H,d, 7 Hz).
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12]O)=[C:8]([CH3:14])[CH:7]=1.CN(C)C=O>ClCCl>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][Cl:3])=[C:8]([CH3:14])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(Br)ccc1CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(Br)ccc1CCl
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Add thionyl chloride (14.31 mL, 0.2 mol) to a solution of (4-bromo-2-methyl-phenyl)methanol (32.9 g, 0.16 mol) in dichloromethane (200 mL) and dimethylformamide (0.025 mol, 2.0 mL) at 0° C. After 1 hour at room temperature, pour the mixture into ice-water (100 g), extract with dichloromethane (300 mL), wash extract with 5% aq. sodium bicarbonate (30 mL) and brine (200 mL), dry over sodium sulfate, filter, and concentrate under reduced pressure to provide the crude title compound as a white solid (35.0 g, 0.16 mol). The material is used in the next step without further purification. 1H NMR (CDCl3): δ 2.38 (s, 3H), 4.52 (s, 2H), 7.13-7.35 (m, 3H).
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[CH2:7][S:8][CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:3].N1C=CC=CC=1.[NH2:27][C:28]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][C:29]=1[C:30]([NH:32][C:33]1[CH:37]=[CH:36][N:35]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[C:40]([CH3:45])[CH:39]=2)[N:34]=1)=[O:31]>ClCCl>[Cl:50][C:47]1[CH:48]=[CH:49][C:28]([NH:27][C:2]([C:4]2[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=2)[CH2:7][S:8][CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:3])=[C:29]([C:30](=[O:31])[NH:32][C:33]2[CH:37]=[CH:36][N:35]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[C:40]([CH3:45])[CH:39]=3)[N:34]=2)[CH:46]=1
Reactant: Cc1ccc(-n2ccc(NC(=O)c3cc(Cl)ccc3N)n2)cc1C
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(-n2ccc(NC(=O)c3cc(Cl)ccc3NC(=O)c3cccc(CSCCC(=O)OC(C)(C)C)c3)n2)cc1C
Yield: 41.1 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-(chlorocarbonyl)benzylthio)propanoate (185 mg, 0.59 mmol, 1.00 equiv) in dichloromethane (10 mL), and pyridine (140 mg, 1.77 mmol, 3.00 equiv). This was followed by dropwise addition of a solution of 2-amino-5-chloro-N-(1-(3,4-dimethylphenyl)-1H-pyrazol-3-yl)benzamide (200 mg, 0.59 mmol, 1.00 equiv) in dichloromethane (2 mL) with stirring. The resulting solution was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (10:1) to yield 150 mg (33%) of product as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[C:14]2[C@H:13]3[CH2:15][C@H:12]3[CH2:11][C:10]=2[C:9]([C:16]([OH:18])=O)=[N:8]1.Cl.[F:20][C:21]([F:27])([F:26])[C:22]1([NH2:25])[CH2:24][CH2:23]1>>[F:20][C:21]([F:27])([F:26])[C:22]1([NH:25][C:16]([C:9]2[C:10]3[CH2:11][C@@H:12]4[CH2:15][C@@H:13]4[C:14]=3[N:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)[N:8]=2)=[O:18])[CH2:24][CH2:23]1
Reactant: O=C(O)c1nn(-c2cnccn2)c2c1C[C@@H]1C[C@H]21
Reactant: NC1(C(F)(F)F)CC1
Agent: Cl
Product: O=C(NC1(C(F)(F)F)CC1)c1nn(-c2cnccn2)c2c1C[C@@H]1C[C@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method UU using Intermediate 4 and 1-(trifluoromethyl)cyclopropanamine hydrochloride. LCMS m/z=350.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.47 (td, J=4.6, 3.2 Hz, 1H), 1.23-1.29 (m, 3H), 1.39-1.43 (m, 2H), 2.27-2.33 (m, 1H), 2.74-2.80 (m, 1H), 2.94 (d, J=16.8 Hz, 1H), 3.02 (dd, J=16.7 and 6.2 Hz, 1H), 7.31 (s, 1H), 8.42 (dd, J=2.5 and 1.5 Hz, 1H), 8.52 (d, J=2.5 Hz, 1H), 9.26 (d, J=1.4 Hz, 1H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]1([CH2:13][CH2:14][CH2:15][SH:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.F[C:18]1[N:32]=[C:31]([F:33])[CH:30]=[CH:29][C:19]=1[C:20]([NH:22][CH2:23][C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)=[O:21].CCCCCC.CC(=O)OCC>CN(C=O)C>[F:33][C:31]1[N:32]=[C:18]([S:16][CH2:15][CH2:14][CH2:13][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:19]([C:20]([NH:22][CH2:23][C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[O:21])=[CH:29][CH:30]=1
Reactant: O=C(NCc1cccs1)c1ccc(F)nc1F
Reactant: SCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCc1cccs1)c1ccc(F)nc1SCCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
919 mg (6.0 mmol) of K2CO3 and 305 mg (2.0 mmol) of 3-phenylpropane-1-thiol were added to a solution of 509 mg (2.0 mmol) of 2,6-difluoro-N-(thiophen-2-ylmethyl)-nicotinamide in DMF (10 ml), and the mixture was stirred for 1 h at RT. Dilution with water and extraction with EA were then carried out. The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. CC (hexane/EA 4:1) of the residue yielded 336 mg (0.9 mmol, 43%) of 6-fluoro-2-(3-phenylpropylthio)-N-(thiophen-2-ylmethyl)pyridine-3-carboxylic acid amide. MS: m/z 387.1 [M+H]+.
Reaction SMILES: [OH:1][C@@H:2]([CH2:13][O:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]2)[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]([O-:12])=O)[CH2:6][CH2:5]1.[Li+].[CH2:26]([NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:34]([N:33]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:10]([CH:7]1[CH2:8][CH2:9][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:13][O:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][CH:19]=[N:20]3)[CH2:5][CH2:6]1)=[O:12])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: O=C([O-])C1CCN(C[C@@H](O)COc2cccc3ncccc23)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(C1CCN(C[C@@H](O)COc2cccc3ncccc23)CC1)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 18 h

Procedure:
Lithium (R)-1-[2-hydroxy-3-(quinolin-5-yloxy)-propyl]-piperidine-4-carboxylate (32) (100 mg; 0.297 mmol) is dissolved in methylene chloride (3 mL) at ambient temperature. Dibenzylamine (41) (62 mg; 0.312 mmol), N,N-diisopropylethylamine (85 mg; 0.654 mmol) and PyBOP (186 mg; 0.357 mmol) are added sequentially. The reaction is stirred for 18 hr. at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography with gradient elution (90% ethyl acetate in hexanes, then 50%→100% acetone in hexanes) affording the desired product (42) as a solid. CIMS (NH3Cl): 510 (MH+)
Reaction SMILES: [Ca:1].[O:2]1[CH2:6][CH2:5][C@H:4]([O:7][C:8](=[O:42])[NH:9][C@H:10]([C@H:18]([O:37][P:38]([OH:41])([OH:40])=[O:39])[CH2:19][N:20]([CH2:33][CH:34]([CH3:36])[CH3:35])[S:21]([C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3]1.CO.C(OCC)(=O)C>O>[CH3:36][CH:34]([CH2:33][N:20]([S:21]([C:24]1[CH:25]=[CH:26][C:27]([NH2:30])=[CH:28][CH:29]=1)(=[O:22])=[O:23])[CH2:19][C@@H:18]([O:37][P:38]([O-:40])([O-:41])=[O:39])[C@@H:10]([NH:9][C:8]([O:7][C@@H:4]1[CH2:3][O:2][CH2:6][CH2:5]1)=[O:42])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:35].[Ca+2:1]
Reactant: CC(C)CN(C[C@@H](OP(=O)(O)O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CCOC1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: [Ca]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)CN(C[C@@H](OP(=O)([O-])[O-])[C@H](Cc1ccccc1)NC(=O)O[C@H]1CCOC1)S(=O)(=O)c1ccc(N)cc1
Product: [Ca+2]
Reaction time: 0.33 h

Procedure:
Calcium salt of (3S)-tetrahydrofuran-3-yl[(2S,3R)-4-{(2-methylpropyl)[(4-nitrophenyl)sulfonyl]amino}-1-phenyl-3-(phosphonooxy)butan-2-yl]carbamate (5 g) was added into a mixture of methanol (50 mL) and ethyl acetate (50 mL) at 20° C. to 25° C. and stirred for 20 minutes. The reaction mixture was filtered through Celite bed and the bed was washed with methanol:ethyl acetate (1:1, 12.5 mL). Palladium-carbon (10%; 1 g) was added to the filtrate and stirred at 20° C. to 25° C. under hydrogen pressure 30 to 40 psi for 4 to 5 hours. The resultant mixture was filtered over Celite bed and the bed was washed with methanol:ethylacetate (1:1; 12.5 mL). The solvent was removed from the filtrate under vacuum at 40° C. to 45° C. to obtain a residue. De-ionized water (50 mL) was added to the residue and stirred at 90° C. to 95° C. for 2 to 3 hours. The reaction mixture was cooled to 20° C. to 25° C. and stirred for 2 hours further. The solid obtained was filtered, washed with de-ionized water (10 mL) and dried at 40° C. Industrial methylated spirit (52.5 mL) was added to the dried solid at 20° C. to 25° C., heated at 70° C. to 72° C., stirred for 15 minutes, filtered at hot condition through Celite bed and washed with hot industrial methylated spirit (17.5 mL). The filtrate was heated at 70° C. to 72° C. followed by the addition of de-ionized water (10.5 mL). The mixture was cooled to 20° C. to 25° C., stirred for 2 hours further, filtered, washed industrial methylated spirit: de-ionized water (1:1, 10 mL) and dried at 40° C. under vacuum to obtain the title compound.
Reaction SMILES: C([N:14]1[CH2:17][C:16]2([C:21](=[O:22])[NH:20][C:19](=[O:23])[NH:18]2)[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:24]([OH:27])(=[O:26])[CH3:25].[H][H]>[Pd].CO.C(OCC)C>[C:24]([OH:27])(=[O:26])[CH3:25].[CH2:15]1[C:16]2([C:21](=[O:22])[NH:20][C:19](=[O:23])[NH:18]2)[CH2:17][NH:14]1
Reactant: [H][H]
Reactant: O=C1NC(=O)C2(CN(C(c3ccccc3)c3ccccc3)C2)N1
Agent: [Pd]
Solvent: CCOCC
Solvent: CO
Solvent: CC(=O)O
Product: O=C1NC(=O)C2(CNC2)N1
Yield: 69.3 %

Procedure:
A mixture of 2-benzhydryl-2,5,7-triazaspiro[3.4]octane-6,8-dione (0.258 g, 0.839 mmol) and 10% palladium on carbon (0.179 g, 0.168 mmol) in 4 mL MeOH was treated with acetic acid (0.0961 mL, 1.68 mmol) and the slurry was stirred under a balloon containing hydrogen overnight. The reaction was filtered, rinsed with MeOH, and concentrated in vacuo to give an oil. Concentration from benzene gave a solid which was suspended in diethylether, sonicated, filtered, and dried in vacuo to give 2,5,7-triazaspiro[3.4]octane-6,8-dione acetate (0.117 g, 69.3% yield) as a white solid.