Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9]1[CH:13]([C:14]([O:16]C(C)(C)C)=[O:15])[CH2:12][N:11]([C:21]2[N:22]=[CH:23][N:24]([CH3:26])[CH:25]=2)[C:10]1=[O:27]>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9]1[CH:13]([C:14]([OH:16])=[O:15])[CH2:12][N:11]([C:21]2[N:22]=[CH:23][N:24]([CH3:26])[CH:25]=2)[C:10]1=[O:27]
Reactant: CN1C(=O)N(c2cn(C)cn2)CC1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)N(c2cn(C)cn2)CC1C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred mixture of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (200 mg, 0.999 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 4-bromo-1-methyl-1H-imidazole (193 mg, 1.199 mmol) in 1,4-dioxane (8 ml) was added potassium phosphate (1060 mg, 4.99 mmol), copper(I) iodide (190 mg, 0.999 mmol) and trans-N,N-dimethylcyclohexane-1,2-diamine (0.158 ml, 0.999 mmol) and the reaction mixture was stirred at reflux under argon for 3 hours. The mixture was cooled to room temperature and diluted with dichloromethane (20 mL) and filtered and washed through with dichloromethane. The filtrate was concentrated under vacuum and taken up in dichloromethane. The solution was washed with 0.880 ammonia (×3), water then brine and separated by hydrophobic frit and the organic layer was reduced under vacuum. The residue was purified by Flashmaster automated silica gel chromatography eluting with 0-20% methanol in dichloromethane to leave an oil which crystallised on standing. The residue was dried under vacuum overnight to give 1,1-dimethylethyl 3-methyl-1-(1-methyl-1H-imidazol-4-yl)-2-oxo-4-imidazolidinecarboxylate (285 mg, 87% yield). LC/MS [M+H]+=281. (ii) Trifluoroacetic acid (1.0 ml, 12.98 mmol) was added to a solution of 1,1-dimethylethyl 3-methyl-1-(1-methyl-1H-imidazol-4-yl)-2-oxo-4-imidazolidinecarboxylate (220 mg, 0.785 mmol) in DCM (2 ml) and the reaction mixture was stirred at room temperature for 5 hours. The solvent was evaporated under vacuum, azeotroping with toluene and the residue was dried under vacuum over the weekend to give crude 3-methyl-1-(1-methyl-1H-imidazol-4-yl)-2-oxo-4-imidazolidinecarboxylic acid trifluoroacetate salt which was taken through to next step without further purification. LC/MS [M+H]+=225.
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[CH3:14].[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.O>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:14][C:5]1[C:6]([C:10]([F:13])([F:12])[F:11])=[N:7][N:8]([CH3:9])[C:4]=1[O:3][CH:2]([F:1])[F:15]
Reactant: Cc1c(C(F)(F)F)nn(C)c1OC(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1nc(C(F)(F)F)c(CBr)c1OC(F)F
Yield: 115.2 %

Procedure:
To a solution of 11.5 g (50.0 mmol) of 5-difluoromethoxy-1,4-dimethyl-3-trifluoromethyl-1H-pyrazole in 50 ml of carbon tetrachloride were added 9.8 g (55.0 mmol) of N-bromosuccinimide and 0.41 (2.5 mmol) of α,α′-azobisisobutyronitrile, followed by heating and refluxing under stirring. The reaction solution was externally irradiated with a light for 1 hour. After the completion of the reaction was confirmed, the reaction solution was poured into water and extracted with chloroform. The resulting organic layer was washed with water and saline, successively, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure to obtain 17.8 g (purity: 72.0%, yield: 82.7%) of 4-bromomethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole.
Reaction SMILES: [CH3:1][N:2]([C@@H:10]([CH3:39])[C:11]([NH:13][C@H:14]([C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C@H:21]1[C:26]([NH:28][C@H:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1)=[O:27])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[F:40][C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[F:40][C:41]1[CH:46]=[CH:45][C:44]([N:23]2[CH2:24][CH2:25][N:20]([C:18]([C@@H:14]([NH:13][C:11](=[O:12])[C@@H:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:7])([CH3:8])[CH3:6])[CH3:39])[CH:15]([CH3:17])[CH3:16])=[O:19])[C@H:21]([C:26]([NH:28][C@H:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:32][CH2:31][CH2:30]3)=[O:27])[CH2:22]2)=[CH:43][CH:42]=1
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCNC[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCN(c2ccc(F)cc2)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21

Procedure:
Intermediate 7 (486 mg, 0.89 mmol), 4-fluorophenylboronic acid (625 mg, 4.47 mmol), Cu(OAc)2 (406 mg, 2.24 mmol) and TEA (451 mg, 4.47 mmol) are all weighed into a flask, then dissolved in dry CH2Cl2 (20 mL). This mixture is stirred for 24 h. at room temperature, at which point some of the desired product had formed by LCMS. A further portion of boronic acid (625 mg, 4.47 mmol) is added and the mixture allowed to stir for a further 24 h, making the desired product the major peak, along with unreacted starting material. This reaction mixture is concentrated under reduced pressure, then loaded directly onto a plug of silica which is eluted with 10% Et2O/CH2Cl2 to isolate the desired product. Unreacted starting material remains at the column baseline under these conditions. The title compound is isolated as a off-white foam (188 mg, 33% yield): 1H NMR δ (CDCl3) 6.92-7.42 (m, 8H), 6.74 (v br s, 1H), 6.09 (br d, J=8.4 Hz, 1H), 3.97-5.27 (br m, 6H), 3.35-3.56 (br m, 2H), 2.62-3.16 (br m, 7H), 1.65-2.14 (m, 5H), 1.47 (s, 9H), 1.31 (br d, J=7.1 Hz, 2H), 1.14 (br d, J=7.1 Hz, 1H), 0.98 (brt, J=7.3 Hz, 2H), 0.79 (br d, J=6.7 Hz, 2H), 0.61 (br d, J=6.7 Hz, 2H); LCMS (APCl+) 639.4 (MH+, 100%).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[C:30]([O:34][C:35](=[O:40])[NH:36][CH2:37][CH2:38][NH2:39])([CH3:33])([CH3:32])[CH3:31]>CC(O)=O>[C:30]([O:34][C:35](=[O:40])[NH:36][CH2:37][CH2:38][NH:39][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4])([CH3:33])([CH3:31])[CH3:32]
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 106.9 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (60 mg, 0.16 mmol) and (2-amino-ethyl)-carbamic acid tert-butyl ester (75 mg, 0.47 mmol) was refluxed for 48 h. After cooling to r.t., AcOH (0.2 mL) was added, and the mixture was concentrated to dryness. The residue was dissolved in EtOAc and washed with 0.1 M HCl, saturated NaHCO3, and brine. The organic layer was dried over MgSO4 and concentrated to give 88 mg of the title compound as a pale yellow solid. MS: (+) m/z 515.30 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:15]=[CH:14][C:13]=2[CH3:26])=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[C:22]([O:21][C:19]([NH:18][C:16]1[CH:15]=[CH:14][C:13]([CH3:26])=[C:12]([C:9]2[CH:8]=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:11][CH:10]=2)[CH:17]=1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CCOC(=O)c1ccc(-c2cc(NC(=O)OC(C)(C)C)ccc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(NC(=O)OC(C)(C)C)cc1-c1ccc(C(=O)O)cc1

Procedure:
5′-tert-Butoxycarbonylamino-2′-methyl-biphenyl-4-carboxylic acid ethyl ester (6.3 g) was stirred in ethanol (75 ml) and 1M sodium hydroxide (30 ml) at 20 C for 18 h. The mixture was then acidified and the ethanol evaporated. The pale beige solid thus formed was collected by filtration and dried (4.26 g)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[N:6][CH:7]=1.[OH:12][C:13]([CH3:46])([CH3:45])[CH2:14][C@@:15]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:20][C:19](=[O:21])[N:18]([C@H:22]([C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)[CH3:23])[CH2:17][CH2:16]1.C([O-])(O)=O.[Na+]>COCCOC.CCO.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>[OH:12][C:13]([CH3:45])([CH3:46])[CH2:14][C@@:15]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:20][C:19](=[O:21])[N:18]([C@H:22]([C:24]2[CH:25]=[CH:26][C:27]([C:2]3[CH:3]=[N:4][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[N:6][CH:7]=3)=[CH:28][CH:29]=2)[CH3:23])[CH2:17][CH2:16]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CC(C)(O)c1ncc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: C[C@@H](c1ccc(-c2cnc(C(C)(C)O)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
To a solution of 2-(5-bromopyrimidin-2-yl)propan-2-ol (30 mg, 0.14 mmol) in DME (6 mL) was added Pd(PPh3)4 (10 mg, 0.01 mmol) under nitrogen. The mixture was stirred at room temperature for 1 h. (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (60 mg, 0.125 mmol) in EtOH (2 mL) was added, followed by addition of satd aq NaHCO3 (2 mL). The mixture was stirred at 100° C. for 2 h, quenched with water, and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4 and concentrated to give (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (17 mg, yield 25.12%). LC-MS Method 2 tR=1.00 min, m/z=490; 1H NMR (CD3OD): δ0.95 (s, 3H), 1.27 (s, 3H), 1.57 (d, 3H), 1.61 (s, 6H), 2.22 (s, 2H), 2.25 (m, 1H), 2.50 (m, 2H), 3.06 (m, 1H), 5.61 (m, 1H), 7.10 (m, 2H), 7.34 (m, 5H), 7.45 (m, 2H), 8.92 (s, 2H).
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:22]([CH3:23])=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][C:16]=2[CH3:24])[C:8]=1[CH3:25])[CH2:4][CH3:5])[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:16]([CH3:24])=[CH:17][C:18]([CH2:19][OH:20])=[CH:21][C:22]=2[CH3:23])[C:8]=1[CH3:25])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Oc1cc(C)nc(Oc2c(C)cc(C=O)cc2C)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)Oc1cc(C)nc(Oc2c(C)cc(CO)cc2C)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
A mixture of 4-[4-(1-ethyl-propoxy)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-benzaldehyde (114 mg, 0.41 mmol) and sodium borohydride (63 mg, 1.6 mmol) in 3 ml of methanol was stirred at room temperature for 2 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give yellow oil. The oil was purified through silica gel using chloroform as eluent to give 70 mg of the title compound as a colorless oil. 1H NMR (CDCl3) δ7.04 (s, 2H), 6.32 (s,1H), 4.55 (s, 2H), 4.21 (m, 1H), 2.30 (brs, 1H), 2.22 (s, 3H), 2.21 (s, 3H), 2.12 (s, 6H), 1.73 (m, 4H), 0.91 (t, 6H) ppm.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:25]=[C:24]([C:26](OC)=[O:27])[CH:23]=[CH:22][C:6]=1[O:7][CH2:8][CH:9]([NH:11][CH2:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)[OH:14])[CH3:10])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:2][CH2:3][C:5]1[CH:25]=[C:24]([CH2:26][OH:27])[CH:23]=[CH:22][C:6]=1[O:7][CH2:8][CH:9]([NH:11][CH2:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)[OH:14])[CH3:10]
Reactant: COC(=O)c1ccc(OCC(C)NCC(O)c2cccc(Cl)c2)c(C(=O)OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(COc1ccc(CO)cc1CO)NCC(O)c1cccc(Cl)c1
Yield: 70.3 %

Procedure:
Following a procedure similar to that described in Example 1, but using 1.28 g of 2-{2-[2,4-bis(methoxycarbonyl)phenoxy]-1-methylethyl}amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 33), 0.463 g of lithium aluminum hydride and 70 ml of dry tetrahydrofuran, and then purifying the reaction product by column chromatography through silica gel, using a 4:1 by volume mixture of ethyl acetate and ethanol as the eluent, 0.78 g of the title compound was obtained having an Rf=0.34 (thin layer chromatography over silica gel, using a 4:1 by volume mixture of ethyl acetate and ethanol as the developing solvent).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[C:12]=1[CH3:20].O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][CH2:20][C:12]1[C:13]([N+:17]([O-:19])=[O:18])=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][CH3:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc([N+](=O)[O-])c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cccc([N+](=O)[O-])c1CBr
Temperature: 25 °C
Yield: 86.7 %

Procedure:
N-bromosuccinimide (590 mg, 3.30 mmol) was added to a solution of 1-methoxy-2-methyl-3-nitro-benzene (500 mg, 3.0 mmol) in carbon tetrachloride (5 mL) followed by a catalytic amount of dibenzoyl peroxide (25 mg). The reaction mixture was heated at reflux for 3 h then cooled to room temperature and poured into water. The organic phase was separated, washed with water (2×20 mL), dried over the anhydrous sodium sulfate and concentrated in vacuo to afford 2-bromomethyl-1-methoxy-3-nitro-benzene (640 mg, 86%) as a solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([Cl:21])[C:6]2[N:7]([C:9]([CH2:19]Cl)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1.[CH3:22][C:23]1[CH:28]=[C:27]([CH3:29])[N:26]=[C:25]([NH2:30])[N:24]=1>>[Cl:2][C:3]1[CH:4]=[C:5]([Cl:21])[C:6]2[N:7]([C:9]([CH2:19][NH:30][C:25]3[N:26]=[C:27]([CH3:29])[CH:28]=[C:23]([CH3:22])[N:24]=3)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1
Reactant: Cc1ccc(-c2nc3c(Cl)cc(Cl)cn3c2CCl)cc1
Reactant: Cc1cc(C)nc(N)n1
Agent: Cl
Product: Cc1ccc(-c2nc3c(Cl)cc(Cl)cn3c2CNc2nc(C)cc(C)n2)cc1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 6,8-dichloro-3-(chloromethyl)-2-p-tolylimidazo[1,2-a]pyridine hydrochloride and 4,6-dimethylpyrimidin-2-amine. m/e+ 412 for C21H20Cl2N5 [M+H]+; 1H-NMR (400 MHz, CDCl3) δ 8.85 (d, J=1.4 Hz, 1H), 7.64 (d, J=8.0 Hz, 2H), 7.48 (d, J=7.7 Hz, 1H), 7.25 (d, J=8.0 Hz, 2H), 7.14 (d, J=7.7 Hz, 1H), 6.41 (s, 1H), 5.02 (s, 2H), 2.40 (s, 3H), 2.36 (s, 3H), 2.33 (s, 3H) ppm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][O:8][C:9]([NH:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[O:10])[CH:2]=1.[Cl-].[NH4+].F[P-](F)(F)(F)(F)F.[N:31]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][O:8][C:9](=[O:10])[NH:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH2:31])=[O:18])=[CH:15][CH:14]=2)[CH:2]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(NCc1ccc(C(=O)O)cc1)OCc1cccnc1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(CNC(=O)OCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-({[(pyridin-3-ylmethoxy)carbonyl]amino}methyl)benzoic acid (1.0 g, 3.49 mmol), ammonium chloride (0.47 g, 8.73 mmol) and BOP (2.32 g, 5.24 mmol) in DMF (10 mL) was treated with DIEA (1.13 g. 8.73 mmol) and the resulting solution was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with water (150 mL) and the resulting solids were filtered, washed with additional water and dried in vacuo to give pyridin-3-ylmethyl{[4-(aminocarbonyl)phenyl]methyl}carbamate as a white solid. MS: cal'd 286 (MH+), exp 286 (MH+).
Reaction SMILES: [CH:1]1([CH2:7][C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:25][C@@H:26]([C:52]([CH3:55])([CH3:54])[CH3:53])[C:27]([N:29]1[C@H:44]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:43][C@:31]2([O:35][C:34](=[O:36])[N:33]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:32]2)[CH2:30]1)=[O:28].CCN(C(C)C)C(C)C.NCCC1N=CNC=1>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([CH2:7][C:8]([NH:25][C@@H:26]([C:52]([CH3:55])([CH3:54])[CH3:53])[C:27]([N:29]2[C@H:44]([C:45]([O:47][C:48]([CH3:50])([CH3:49])[CH3:51])=[O:46])[CH2:43][C@:31]3([O:35][C:34](=[O:36])[N:33]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH2:32]3)[CH2:30]2)=[O:28])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CC1CCCCC1
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@]2(CN(c3ccccc3)C(=O)O2)CN1C(=O)[C@@H](N)C(C)(C)C
Agent: NCCc1c[nH]cn1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)[C@@H]1C[C@@]2(CN(c3ccccc3)C(=O)O2)CN1C(=O)[C@@H](NC(=O)CC1CCCCC1)C(C)(C)C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
Cyclohexylacetic acid (48 mg, 337 μmol, 1.4 eq.), EDC (65 mg, 337 μmol, 1.4 eq.) and HOBt (52 mg, 337 μmol, 1.4 eq.) were combined in DMF (0.3 mL) and stirred for 0.5 hrs. at room temp. (5S,8S)-tert-butyl 7-((S)-2-amino-3-dimethylbutanoyl)-2-oxo-3-phenyl-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylate (F1) (105 mg, 243 μmol, 1 eq.) and DIEA (118 μL 675 μmol, 2.8 eq.) were added to this mixture and the resulting mixture was stirred for 24 hrs at room temp. 1.0 M histamine (aq., 120 μL, 0.5 eq.) was added and the mixture was stirred for 0.5 h. Ethyl acetate was added and the mixture was washed with 1N HCl then 1M K2CO3 and extracted with ethyl acetate (2×). The combined organic layers were concentrated and chromatography using hexanes and ethyl acetate gave 50 mg of (5S,8S)-tert-butyl 7-((S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoyl)-2-oxo-3-phenyl-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylate (G1). 1H NMR (300 MHz, DMSO) 7.90 (d, 1 H), 7.53 (d, 2 H), 7.44-7.37 (m, 2H), 7.14 (m, 1H), 4.47 (d, 1H), 4.30-3.99 (m, 3H), 3.89-3.83 (m, 1H), 3.18 (d, 1H), 2.79-2.67 (m, 1H), 2.27-2.00 (m, 3H), 1.7-1.55 (m, 5H), 1.45-1.39 (m, 11H), 1.2-1.1 (m, 4H), 0.98-0.91 (m, 9H). Later optimization showed that steps E to G could be replaced by doing a single coupling on E1 with (S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoic acid. NMR confirmed that epimerization was not occurring.
Reaction SMILES: [NH2:1][N:2]1[C:6]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]1=[NH:12].[O:13]1C[CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C.C(Cl)(=O)CC>O>[NH2:1][N:2]1[C:6]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]1=[N:12][C:14](=[O:13])[CH2:15][CH3:16]
Reactant: C1CCOC1
Reactant: Cc1cccc2sc(=N)n(N)c12
Agent: CCC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(=O)N=c1sc2cccc(C)c2n1N

Procedure:
A 3.6 g. portion of 3-amino-2-imino-4-methylbenzothiazoline was dissolved in about 100 ml. of tetrahydrofuran, and 2.2 g. of triethylamine was added. The reaction mixture was cooled in an ice bath, and 2 g. of propionyl chloride, dissolved in 2 ml. of tetrahydrofuran, was added dropwise while the mixture was stirred. After the addition was complete, the reaction mixture was stirred at ice bath temperature for about 3 hours, and was then diluted with an equal volume of water. The tetrahydrofuran was removed under vacuum, and the remaining aqueous mixture was filtered to recover the product. After recrystallization from ethanol, the yield of purified product was 3.2 g. of 3-amino-4-methyl-2-propionyliminobenzothiazoline, m.p. 175°-76°C. The product was identified by nuclear magnetic resonance and ultraviolet analysis and by elemental microanalysis.
Reaction SMILES: [Br-].C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:21][CH2:22][CH2:23][CH:24]=[CH:25][CH2:26][CH:27]=[CH:28][CH2:29][CH:30]=[CH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[Br:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCC=CCC=CCC=CCCBr
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCCCC/C=C\C/C=C\C/C=C\CCBr
Temperature: 70 °C

Procedure:
(3Z,6Z,9Z)-3,6,9,-Pentadecatrieyl!triphenyl-phosphonium Bromide. Bromo-3,6,9-pentadecatriene (7.0 g, 24.6 mmol) was treated with 7.5 g (28.6 mmol) of triphenylphosphine in 25 mL of acetonitrile. The mixture was heated to 70° C. under nitrogen atmosphere. Following reaction completion (monitor salt formation by TLC; 72 hours) the mixture was dried for 36 hours under reduced pressure to ensure removal of traces of acetonitrile. The resultant yellow residue, 13.45 g, was used in the next reaction without further purification: IR (neat, cm-1) 3010, 2958, 1652, 1191, 723; 1H NMR (CDCl3) δ 7.93-7.61 (m, 15 H), 5.69-5.12 (m, 6H), 4.02-3.91 (m, 2H), 2.69-2.48 (m, 4H), 2.09-1.92 (m, 2H), 1.89-1.72 (m, 2H), 1.46-1.25 (m, 6H), 0.88 (t, J=6.9 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:22](OC(C)(C)C)(=[O:30])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH2:10][C:22](=[O:30])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C(=O)CC(=O)c1cc(Cl)cc(Cl)c1
Reaction time: 16 h

Procedure:
To a solution of the product from step B (4.1 g, 21.7 mmol) in 100 mL of diethyl ether at −78° C. was added lithium bis(trimethylsilyl)amide (23.9 mL, 23.9 mmol). After 50 min at −78° C. di-tert-butyl oxalate (4.18 g, 20.66 mmol) was added as a solid. The cold bath was removed and after 2 h an additional portion of di-tert-butyl oxalate (530 mg, 2.6 mmol) was added and stirring continued at ambient temperature for 16 h. The reaction was quenched by adding 150 mL of 1N hydrochloric acid and stirring for 1 h. The mixture was extracted with ethyl acetate and the organic layer washed with brine, dried over magnesium sulfate, and concentrated in vacuo to provide the title compound as an oil which was used without further purification. 1H NMR (500 MHz, CDCl3) δ: 7.84 (d, J=1.9 Hz, 2H); 7.59 (d, J=1.9 Hz, 1H); 6.93 (s, 1H); 1.56 (s 9H).