Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36].O.[OH-].[Li+]>O1CCOCC1.O>[Cl:36][C:8]1[CH:9]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])[C:11]([Cl:13])=[CH:12][C:7]=1[C:6]([NH:5][CH2:4][C:3]([OH:38])=[O:2])=[O:37]
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
To a suspension of 0.148 g (0.27 mmol) {2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-acetic acid methyl ester (Example 29) in 1.5 mL dioxane and 1.5 mL water was added 0.014 g (0.33 mmol) lithium hydroxide monohydrate. After 2 hours stirring at room temperature the organic solvent was evaporated. The pH of the resulting yellow solution was adjusted to 1 with 1M aqueous hydrochloric acid and the solution was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to give 0.091 g (63%) of the title compound as a yellow foam. MS (ESI): m/z=541.104 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:6][CH2:5]1>CCO>[OH:3][C@@H:4]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[C@H:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:6][CH2:5]1
Reactant: CCOC(=O)[C@@H]1CCC(=O)CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)[C@@H]1CC[C@H](O)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
NaBH4 (36 g, 1.0 mol) was added in portions to a solution of (S)-1-tert-butyl 2-ethyl 5-oxopiperidine-1,2-dicarboxylate (250 g, 0.92 mol) in EtOH (1500 mL) at −40° C. The reaction mixture was then stiffed at −40° C. for 0.5 hr then quenched with 10% HOAc solution. After diluting with water, the mixture was extracted with DCM three times. The combined organic layer was concentrated in vacuum and purified by silica gel column chromatography (1:1 petroleum ether/EtOAc) to afford (2S,5S)-1-tert-butyl 2-ethyl 5-hydroxypiperidine-1,2-dicarboxylate (205 g, 80%) as a yellow oil.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC(C)([O-])C.[K+].Br[C:36]1[CH:41]=[C:40]([CH3:42])[C:39]([NH:43][C:44](=[O:50])[CH2:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[C:38]([CH3:51])[CH:37]=1.[F:52][C:53]([F:65])([F:64])[C:54]1[CH:55]=[N:56][C:57]2[CH2:58][CH2:59][NH:60][CH2:61][C:62]=2[CH:63]=1>C1(C)C=CC=CC=1>[CH3:42][C:40]1[CH:41]=[C:36]([N:60]2[CH2:59][CH2:58][C:57]3[N:56]=[CH:55][C:54]([C:53]([F:52])([F:64])[F:65])=[CH:63][C:62]=3[CH2:61]2)[CH:37]=[C:38]([CH3:51])[C:39]=1[NH:43][C:44](=[O:50])[CH2:45][C:46]([CH3:49])([CH3:48])[CH3:47]
Reactant: FC(F)(F)c1cnc2c(c1)CNCC2
Reactant: Cc1cc(Br)cc(C)c1NC(=O)CC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCc3ncc(C(F)(F)F)cc3C2)cc(C)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Bis(dibenzylidineacetone)palladium (4 mg, 0.069 mmol) and (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethylamine (7 mg, 0.015 mmol) were added to dry toluene (1 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (36 mg, 0.32 mmol), N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide (52 mg, 0.17 mmol) and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine (WO/04069162) (40 mg, 0.15 mmol) were then added and the reaction mixture was stirred at 80° C. over night. The reaction mixture was then cooled to room temperature, concentrated and purified by biotage (75% Ethyl acetate:Hexanes) to afford the desired compound as a solid. 1H NMR (DMSO-d6, 400 MHz) δ 1.05 (s, 9H), 2.11 (s, 6H), 2.17 (s, 2H), 3.08 (t, J=5.6 Hz, 2H), 3.64 (t, J=5.9 Hz, 2H), 4.48 (s, 2H), 6.76 (s, 2H), 8.08 (s, 1H), 8.75 (s, 1H), 8.90 (s, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][C:17]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)=[C:18]([C:20]([NH:22][C:23]3[S:24][CH:25]=[CH:26][N:27]=3)=[O:21])[N:19]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C1(SC)C=CC=CC=1.[OH-].[Na+]>FC(F)(F)C(O)=O>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][C:17]([C:28]3[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=3)=[C:18]([C:20]([NH:22][C:23]3[S:24][CH:25]=[CH:26][N:27]=3)=[O:21])[N:19]=2)=[CH:11][CH:10]=1
Reactant: Cc1ccc(-c2[nH]c(-c3ccc(OCc4ccccc4)cc3)nc2C(=O)Nc2nccs2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2[nH]c(-c3ccc(O)cc3)nc2C(=O)Nc2nccs2)cc1
Reaction time: 6 h
Yield: 56.6 %

Procedure:
2-(4-Benzyloxyphenyl)-5-(4-methylphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide (5.10 g) obtained in Example 22(3) and thioanisole (6.4 ml) were dissolved in trifluoroacetic acid (100 ml) and the mixture was stirred for 6 hr. The reaction mixture was made alkaline with 2 M aqueous sodium hydroxide solution and then acidified withaqueouscitricacid. Themixturewasextractedwithethylacetate. The ethyl acetate layer was washed with saturated brine and, after drying, the solvent was evaporated. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=6:4) and recrystallized from ethyl acetate and hexane to give 2-(4-hydroxyphenyl)-5-(4-methylphenyl)-N-(2-thiazolyl)imidazole-4-carboxamide (2.33 g), melting point 286-289° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:4]=[CH:5][N:6]=1.C([Li])CCC.[O:20]=[C:21]1[CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]1>O1CCCC1>[CH3:14][Si:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][O:8][CH2:7][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH2:1][C:21]1([OH:20])[CH2:24][NH:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: Cc1nccn1COCC[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccnc1CC1(O)CNC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.8 %

Procedure:
A solution of 2-methyl-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole (0.5 g, 2.3 mmol) (prepared using procedures similar to those described in Clader et. al. J. of Med. Chem. 1995, 38(10), 1600-7) in tetrahydrofuran (5 mL) was cooled to −78° C., and n-butyllithium was added (2.5 M in hexanes, 0.990 mL, 2.5 mmol). After 2 hours, 1,1-dimethylethyl 3-oxoazetidine-1-carboxylate (0.60 g, 3.5 mmol), prepared using procedures similar to those described in Example 3, in 2.0 mL tetrahydrofuran was added and the solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was quenched with an excess of saturated aqueous ammonium chloride solution and partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 3:1 hexanes/ethyl acetate) gave 0.37 g (41%) of 3-{[1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazol-2-yl]methyl}azetidin-3-ol: 1H NMR (400 MHz, CDCl3): 6.96-6.92 (m, 1H), 5.23 (s, 2H), 3.98 (d, 2H), 3.79 (d, 2H), 3.52-3.47 (m, 2H), 3.13 (s, 2H), 1.43 (s, 9H), 0.94-0.88 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([NH2:13])=[O:12])=[CH:5][CH:4]=1.Cl[CH:17]([C:23]([CH3:25])=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH2:21]([O:20][C:18]([C:17]1[O:12][C:11]([CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:14])([F:15])[F:1])=[CH:8][CH:7]=2)=[N:13][C:23]=1[CH3:25])=[O:19])[CH3:22]
Reactant: NC(=O)CCc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(Cl)C(C)=O
Product: CCOC(=O)c1oc(CCc2ccc(C(F)(F)F)cc2)nc1C
Temperature: 150 °C
Reaction time: 8 h

Procedure:
18.6 g 3-(4-Trifluoromethyl-phenyl)-propionamide and 42.8 ml ethyl 2-chloroacetoacetate were mixed and stirred at 150° C. for eight hours. Excess ethyl 2-chloroacetoacetate was removed in vacuo (oil pump) and the residue purified by chromatography on silica gel with the eluent petroleum benzene:ethyl acetate=3:1 to obtain 13.75 g 4-methyl-2-[2-(4-trifluoromethyl-phenyl)-ethyl]-oxazole-5-carboxylic acid ethyl ester as an oil.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]([F:23])([F:22])[O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1>C(O)C>[F:23][C:4]([F:3])([F:22])[O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([N:15]2[CH2:16][CH2:17][CH:18]([OH:21])[CH2:19][CH2:20]2)(=[O:13])=[O:14])=[CH:10][CH:11]=1
Reactant: O=C1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=S(=O)(c1ccc(OC(F)(F)F)cc1)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
NaBH4 (719 mg, 19.0 mmol) was added in portions to a suspension of 1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-one (3.07 g, 9.50 mmol) in ethanol (50 ml) at 0° C. and stirred at room temperature for 2 hours. The reaction was quenched with acetone (50 ml) at 0° C. and concentrated in vacuo. The residue was diluted with ethyl acetate (100 ml), washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo to give 1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-ol (3.09 g, 100%) as a white solid: LCMS: 326 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([F:13])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].CN1C(=O)CCC1.CCN(C(C)C)C(C)C.[Cl:30][C:31]1[N:36]=[C:35](Cl)[C:34]([Cl:38])=[CH:33][N:32]=1>>[Cl:30][C:31]1[N:36]=[C:35]([NH:1][C:2]2[C:11]([F:12])=[CH:10][C:9]([F:13])=[CH:8][C:3]=2[C:4]([NH:6][CH3:7])=[O:5])[C:34]([Cl:38])=[CH:33][N:32]=1
Reactant: CNC(=O)c1cc(F)cc(F)c1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(F)cc(F)c1Nc1nc(Cl)ncc1Cl
Temperature: 100 °C

Procedure:
To a solution of 2-Amino-3,5-difluoro-N-methyl-benzamide (1.099 g, 0.006 mol) and NMP (6 mL, 0.06 mol) was added DIEA (1.23 mL, 7.8 mmol) followed by 2,4,5-Trichloro-pyrimidine (0.812 mL, 7.1 mmol) and the reaction mixture was heated at 100° C. for 16 h. Title compound isolated as an off-white solid (1.10 g, 56%), MP=220-221, HPLC purity=95%, LCMS=333.38 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.94 (s, 1H), 8.22 (s, 1H), 7.12-7.06 (m, 2H), 6.17 (s, 1H), 2.99 (s, 3H).
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH2:13][CH3:14].[C:15]12([CH2:25][C:26](Cl)=[O:27])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2>>[C:15]12([CH2:25][C:26]([NH:1][N:2]3[C:11](=[O:12])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]=[C:3]3[CH2:13][CH3:14])=[O:27])[CH2:22][CH:21]3[CH2:20][CH:19]([CH2:18][CH:17]([CH2:23]3)[CH2:16]1)[CH2:24]2
Reactant: CCc1nc2ccccc2c(=O)n1N
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: CCc1nc2ccccc2c(=O)n1NC(=O)CC12CC3CC(CC(C3)C1)C2

Procedure:
3-Amino-2-ethyl-4(3H)-quinazolinone and 1-adamantaneacetyl chloride were reacted as described in Example 5 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.23 (t, J=7.3 Hz, 3H), 1.60-1.74 (m, 12H), 1.92-1.99 (m, 3H), 2.08-2.18 (m, 2H), 2.58-2.79 (m, 2H), 7.50-7.56 (m, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.82-7.88 (m, 1H), 8.12 (dd, J=8.1, 1.4 Hz, 1H), 10.82 (s, 1H) ppm; MS (DCI/NH3) m/z 366 (M+H)+; Elemental Analysis: Calculated for C22H27N3O2.0.75H2O: C, 69.72; H, 7.58; N, 11.09. Found: C, 69.85; H, 7.77; N, 10.98.
Reaction SMILES: [K].[Br:2][C:3]1[C:13]([Br:14])=[C:12]([Br:15])[C:11]([Br:16])=[C:5]2[C:6]([NH:8][C:9](=[O:10])[C:4]=12)=[O:7].[Br:17][C:18]1[C:23]([C:24](Cl)=[O:25])=[C:22]([Br:27])[C:21]([Br:28])=[C:20]([Br:29])[C:19]=1[Br:30]>O1CCOCC1>[Br:17][C:18]1[C:23]([C:24]([N:8]2[C:9](=[O:10])[C:4]3=[C:3]([Br:2])[C:13]([Br:14])=[C:12]([Br:15])[C:11]([Br:16])=[C:5]3[C:6]2=[O:7])=[O:25])=[C:22]([Br:27])[C:21]([Br:28])=[C:20]([Br:29])[C:19]=1[Br:30]
Reactant: O=C(Cl)c1c(Br)c(Br)c(Br)c(Br)c1Br
Reactant: O=C1NC(=O)c2c(Br)c(Br)c(Br)c(Br)c21
Agent: [K]
Solvent: C1COCCO1
Product: O=C(c1c(Br)c(Br)c(Br)c(Br)c1Br)N1C(=O)c2c(Br)c(Br)c(Br)c(Br)c2C1=O
Temperature: 25 °C

Procedure:
The potassium salt of 3,4,5,6-tetrabromophthalimide (0.10 mole) and dioxane (1200 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Pentabromobenzoyl chloride (0.10 mole) is then added dropwise, with stirring, to the reaction mixture at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is stripped of solvent to yield the desired product N-(pentabromobenzoyl)-3,4,5,6-tetrabromophthalimide.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)#[CH:2].Br[C:10]1[CH:11]=[CH:12][C:13]2[O:19][CH2:18][CH2:17][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:15][C:14]=2[CH:24]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(N(CC)CC)C>[C:3]1([C:1]#[C:2][C:10]2[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:15][C:14]=3[CH:24]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2OCC1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)C1=Cc2cc(C#Cc3ccccc3)ccc2OCC1
Temperature: 80 °C
Reaction time: 17 h
Yield: 69.2 %

Procedure:
A mixture of ethynylbenzene (511 mg, 5.00 mmol), methyl 7-bromo-2,3-dihydro-1-benzooxepine-4-carboxylate (708 mg, 2.50 mmol), dichlorobis(triphenylphosphine)palladium (176 mg, 0.25 mmol), copper iodide (48 mg, 0.25 mmol) and triethylamine (15 ml) was stirred at 80° C. for 17 hours. The reaction mixture was concentrated under reduced pressure and was mixed with ethyl acetate (70 ml), and the resulting mixture was washed successively with 1 N hydrochloric acid (5 ml×3) and an aqueous saturated solution of sodium chloride (5 ml). The organic layer was dried with anhydrous magnesium sulfate and was then concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel: 35 g, ethyl acetate/hexane=1/19). The objective fractions were concentrated under reduced pressure and were mixed with diisopropyl ether, and an insoluble material was collected by filtration. The insoluble material was washed with diisopropyl ether and was then dried under reduced pressure to obtain methyl 7-phenylethynyl-2,3-dihydro-1-benzooxepine-4-carboxylate (525 mg, 1.73 mmol, 69%).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:10][C@H:9]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:8][CH2:7][C@@H:6]1[N:16]1[CH2:20][CH2:19][C@H:18]([NH:21]C(=O)OCC2C=CC=CC=2)[C:17]1=[O:32])(=[O:3])[CH3:2]>CO.[Pd]>[NH2:21][C@H:18]1[CH2:19][CH2:20][N:16]([C@H:6]2[CH2:7][CH2:8][C@@H:9]([NH:11][C:12]([CH3:15])([CH3:13])[CH3:14])[CH2:10][C@H:5]2[NH:4][C:1](=[O:3])[CH3:2])[C:17]1=[O:32]
Reactant: CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.6 %

Procedure:
To a solution of benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-(tert-butylamino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (43.3 g, 98 mmol) in methanol (400 ml), 10% wet Pd/C (4.34 g) was added. The mixture was evacuated and back-filled with hydrogen with a hydrogen balloon. The mixture was stirred at room temperature for 5 h. The mixture was filtered and washed with methanol (500 ml) and concentrated under vacuum to dryness. The crude product obtained was distilled with IPA (2×100 ml) under reduced pressure to give product N-((1R,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)cyclohexyl)acetamide as an oil (30 g, 98% yield). This amine was used in the next step without further purification.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:13]=1[CH:14]=[O:15].C(OC=O)=O>C1COCC1>[Br:20][C:17]1[CH:18]=[CH:19][C:12]([NH:11][CH:1]=[O:3])=[C:13]([CH:14]=[O:15])[CH:16]=1
Reactant: Nc1ccc(Br)cc1C=O
Reactant: CC(=O)OC(C)=O
Agent: O=COC=O
Solvent: O=CO
Solvent: C1CCOC1
Product: O=CNc1ccc(Br)cc1C=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To acetic acid anhydride (34.8 ml) was added formic acid (17.0 ml) at 0° C. and the mixture was stirred at 60° C. for 2 hours, cooled and diluted with THF (200 ml). In THF (100 ml) was dissolved 2-amino-5-bromobenzaldehyde (16.40 g), and the mixture was added dropwise to the previously prepared solution of formic acid anhydride in THF at 0° C. The mixture was stirred at 0° C. for 2 hours, and the solvent was evaporated under reduced pressure. The residue was washed with hexane and filtered to give 4-bromo-2-formylphenylformamide (15.24 g, 82%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:24][C:25]([O:27]CC)=O)O[N:9]([CH3:11])[C:8]([CH2:12][C:13]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:7]1)=[O:5])[CH3:2].C[O:31]C(C1N=C(CC2(C3C=CC=CC=3)CCCC2)NC(=O)C=1O)=O>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:12][C:13]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][CH2:15][CH2:16][CH2:17]2)[N:9]([CH3:11])[C:25](=[O:27])[C:24]=1[OH:31])=[O:5])[CH3:2]
Reactant: COC(=O)c1nc(CC2(c3ccccc3)CCCC2)[nH]c(=O)c1O
Reactant: CCOC(=O)CC1(C(=O)OCC)N=C(CC2(c3ccccc3)CCCC2)N(C)O1
Product: CCOC(=O)c1nc(CC2(c3ccccc3)CCCC2)n(C)c(=O)c1O

Procedure:
5-Hydroxy-1-methyl-6-oxo-2-(1-phenyl-cyclopentylmethyl)-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester was synthesized as a brown solid (35 mg, 20%) from 200 mg of 5-ethoxycarbonylmethyl-2-methyl-3-(1-phenyl-cyclopentylmethyl)-2,5-dihydro-[1,2,4]oxadiazole-5-carboxylic acid ethyl ester following the procedure described for 5-hydroxy-6-oxo-2-(1-phenyl-cyclopentylmethyl)-1,6-dihydro-pyrimidine-4-carboxylic acid methyl ester (Example 6). LCMS: m/z=357.0 (MH+).
Reaction SMILES: Cl.[F:2][C:3]([F:21])([F:20])[C:4]1[N:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][NH:11]2)=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.[C:31](Cl)(=[O:34])[O:32][CH3:33]>C(Cl)Cl>[F:21][C:3]([F:2])([F:20])[C:4]1[N:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][N:11]2[C:31]([O:32][CH3:33])=[O:34])=[CH:6][CH:5]=1
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(c2ccc(C(F)(F)F)nc2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(C(F)(F)F)nc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.8 %

Procedure:
Methyl 2-(6-(trifluoromethyl)pyridin-3-yl)piperidine-4-carboxylate hydrochloride (3 g, 9.24 mmol) was dissolved in DCM (50 mL) and DIPEA (4.03 mL, 23.10 mmol). Methyl carbonochloridate (1.019 mL, 12.93 mmol) was added dropwise to the solution. The mixture was stirred at room temperature for 10 minutes. The mixture was washed with 0.1 M HCl (2×100 mL) and satd NaHCO3 (100 mL), then dried through a phase-separator and evaporated yielding crude dimethyl 2-(6-(trifluoromethyl)pyridin-3-yl)piperidine-1,4-dicarboxylate (3 g, 94%) as a dark brown oil. MS m/z 347 (M+H)+
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[CH2:35][CH:36]1[CH2:42][C:39]2([CH2:41][CH2:40]2)[CH2:38][CH:37]1[C:43]([O:45][CH2:46][CH3:47])=[O:44].[F:48][C:49]1[CH:54]=[CH:53][C:52]([SH:55])=[CH:51][CH:50]=1>CN(C)C=O>[F:48][C:49]1[CH:54]=[CH:53][C:52]([S:55][CH2:35][CH:36]2[CH2:42][C:39]3([CH2:41][CH2:40]3)[CH2:38][CH:37]2[C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:51][CH:50]=1
Reactant: Fc1ccc(S)cc1
Reactant: CCOC(=O)C1CC2(CC2)CC1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CC2(CC2)CC1CSc1ccc(F)cc1
Reaction time: 0.08 h

Procedure:
A solution of triphenylphosphine (240 mg, 910 μmol) in dimethylformamide (1.1 mL) was cooled to 0° C. Diisopropyl azodicarboxylate (0.16 mL, 0.81 mmol) was added and the reaction mixture was stirred for 5 min. Ethyl(5R/S,6R/S)-6-(hydroxymethyl)spiro[2.4]heptane-5-carboxylate (100 mg, 0.54 mmol) and 4-fluorothiophenol (86 μL, 0.81 mmol) in dimethylformamide (1.7 mL) were added. After stirring the reaction mixture for 19 h, it was partitioned between ethyl acetate (30 mL) and 1:1 water:saturated aqueous sodium chloride (30 mL). The product was extracted into ethyl acetate and the combined organics were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated using a rotary evaporator. Chromatography of the residue on silica gel eluting with 5:95 ethyl acetate:hexanes provided ethyl(5R/S,6R/S)-6-{[(4-fluorophenyl)sulfanyl]methyl}-spiro[2.4]heptane-5-carboxylate as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([OH:14])[CH3:13])[C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.C(OCC)C>ClCCl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CC(O)c1cc(Cl)cc2c1OCCO2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)cc2c1OCCO2
Reaction time: 16 h

Procedure:
1-(6-Chloro-2,3-dihydrobenzo[b][1,4]dioxin-8-yl)ethanol (258 mg, 1.20 mmol) was dissolved in 4 mL of dichloromethane. PCC (648 mg, 3.00 mmol) was added portionwise and the mixture was stirred for 16 h (reaction is likely to be completed earlier). Diethyl ether (20 mL) was added and stirred for 10 minutes. The heterogeneous mixture was filtered through a plug of celite. The solvent was removed by rotary evaporation to collect the desired product (248 mg, 97%). 1H NMR (400 MHz, CDCl3): δ 7.28 (d, 1H), 7.01 (d, 1H), 4.33 (m, 4H), 2.59 (s, 3H).
Reaction SMILES: C([O:4][C:5]1[C:6]([CH:21]([CH3:23])[CH3:22])=[CH:7][C:8]2[O:12][C:11]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:10][C:9]=2[C:17]=1[CH:18]([CH3:20])[CH3:19])(=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:15]([C:11]1([CH2:13][CH3:14])[CH2:10][C:9]2[C:17]([CH:18]([CH3:20])[CH3:19])=[C:5]([OH:4])[C:6]([CH:21]([CH3:23])[CH3:22])=[CH:7][C:8]=2[O:12]1)[CH3:16]
Reactant: CCC1(CC)Cc2c(cc(C(C)C)c(OC(C)=O)c2C(C)C)O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1(CC)Cc2c(cc(C(C)C)c(O)c2C(C)C)O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 100.3 %

Procedure:
Under argon atmosphere, 432 mg of 5-acetoxy-2,2-diethyl-4,6-diisopropyl-2,3-dihydrobenzofuran was dissolved in 3 ml of anhydrous tetrahydrofuran, a solution of 129 mg of lithium aluminium hydride in 2 ml of anhydrous tetrahydrofuran was added, and the solution was stirred at room temperature for 6 hours. After the reaction was quenched with water, the reaction solution was combined with 10% hydrochloric acid and extracted with ethyl acetate. The organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 1% ethyl acetate) to give 376 mg of 2,2-diethyl-5-hydroxy-4,6-diisopropyl-2,3-dihydrobenzofuran as a light brown solid (yield 100%).