Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Cl:8][C:9]1[CH:16]=[C:15]([N:17]2[C:21](=[O:22])[CH2:20][C@H:19]([OH:23])[C@@H:18]2[CH3:24])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12].[CH3:25][C:26]([CH3:28])=[O:27].C(O)(=O)C>C1COCC1.O>[Cl:8][C:9]1[CH:16]=[C:15]([N:17]2[C:21](=[O:22])[C@@H:20]([C:26]([OH:27])([CH3:28])[CH3:25])[C@H:19]([OH:23])[C@@H:18]2[CH3:24])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12]
Reactant: C[C@H]1[C@@H](O)CC(=O)N1c1ccc(C#N)c(Cl)c1
Reactant: CC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: C[C@H]1[C@@H](O)[C@H](C(C)(C)O)C(=O)N1c1ccc(C#N)c(Cl)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 24.5 %

Procedure:
A solution of diisopropylamine (0.150 mL) in THF (7 mL) was cooled to −78° C., and n-butyllithium-hexane solution (0.648 mL, 1.6 mol/L) was added dropwise. After the completion of the dropwise addition, the mixture was stirred at −78° C. for 1 hr. Subsequently, a solution of 2-chloro-4-[(2S,3S)-3-hydroxy-2-methyl-5-oxopyrrolidin-1-yl]benzonitrile (100 mg) in THF (1.5 mL) was added dropwise, and the mixture was further stirred at −78° C. for 30 min. Acetone (0.124 mL) was added dropwise at −78° C., and the mixture was further stirred at −20° C. to −78° C. for 40 min. Acetic acid (1.0 mL) was added to the reaction mixture, and the mixture was warmed to room temperature. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=10/1→1/3) to give the title compound as a colorless solid (yield: 30.1 mg, 24.5%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH3:12][NH:13][CH2:14][CH:15]=[CH2:16].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:14]([N:13]([CH3:12])[CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH:15]=[CH2:16]
Reactant: C=CCNC
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCN(C)Cc1cccc([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
To solution of 3-nitrobenzaldehyde (1.5 g, 9.92 mmol) in CH2Cl2 (60 mL) was added N-methyl allyl amine (1.19 g, 12.40 mmol), the reaction mixture was stirred for 2 h. Na(OAc)3BH (4.2 g, 19.85 mmol) was then added portionwise over 5 mins. The resulting mixture was stirred at ambient temperature overnight and then quenched with saturated NH4Cl. The product was extracted with CH2Cl2 thrice and the combined organic extracts were washed brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was column purified (EtOAc/Hexane) to furnish 1.1 g of (xA). 1H NMR (400 MHz, CDCl3): δ 8.20 (m, 1H), 8.08-8.12 (m, 1H), 7.65-7.69 (m, 1H), 7.48 (t, 1H), 5.84-5.96 (m, 1H), 5.12-5.26 (m, 2H), 3.58 (s, 2H), 3.02-3.06 (m, 2H), 2.20 (s, 3H). MS (m/z): 207 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:15]2[CH:19]=[CH:18][N:17]=[C:16]2[CH:20]2[CH2:24][CH2:23][O:22][CH2:21]2)=[CH:4][C:5]([CH2:12][O:13][CH3:14])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:25](N1C=CN=C1)(N1C=CN=C1)=[O:26]>ClC1C=CC=CC=1Cl>[CH3:14][O:13][CH2:12][C:5]1[CH:4]=[C:3]2[C:2]([NH:1][C:25](=[O:26])[C:19]3[N:15]2[C:16]([CH:20]2[CH2:24][CH2:23][O:22][CH2:21]2)=[N:17][CH:18]=3)=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COCc1cc(-n2ccnc2C2CCOC2)c(N)cc1C(=O)OC
Solvent: Clc1ccccc1Cl
Product: COCc1cc2c(cc1C(=O)OC)[nH]c(=O)c1cnc(C3CCOC3)n12
Temperature: 120 °C
Reaction time: 3 h
Yield: 70.2 %

Procedure:
A mixture of 6.00 g of methyl 5-amino-2-(methoxymethyl)-4-[2-(tetrahydrofuran-3-yl)-1H-imidazol-1-yl]benzoate, 5.87 g of 1,1′-carbonyldiimidazole, and 30 mL of 1,2-dichlorobenzene was stirred at 120° C. for 3 hours. After air-cooling, the precipitate was collected by filtration. The obtained solid was washed with methanol and air-dried to obtain 4.54 g of methyl 8-(methoxymethyl)-4-oxo-1-(tetrahydrofuran-3-yl)-4,5-dihydroimidazo[1,5-a]quinoxaline-7-carboxylate.
Reaction SMILES: [F:1][C:2]([F:46])([F:45])[C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:6][N:7]([CH3:37])[C:8](=[O:36])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([C:22]#[C:23][CH2:24][N:25]2C(=O)C3C(=CC=CC=3)C2=O)=[N:11][CH:10]=1.O.NN>C(O)C.COC(C)(C)C>[NH2:25][CH2:24][C:23]#[C:22][C:12]1[CH:13]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[C:9]([C:8]([N:7]([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:45])[F:46])[CH:40]=[C:39]([C:41]([F:44])([F:42])[F:43])[CH:38]=2)[CH3:37])=[O:36])=[CH:10][N:11]=1
Reactant: Cc1ccccc1-c1cc(C#CCN2C(=O)c3ccccc3C2=O)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: NN
Solvent: CCO
Solvent: O
Solvent: COC(C)(C)C
Product: Cc1ccccc1-c1cc(C#CCN)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
A mixture of 206 mg (0.324 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-prop-1-ynyl]-N-methyl-4-o-tolyl-nicotinamide and 0.061 ml (0.97 mmol) hydrazine hydrate (51% hydrazine) in 3.5 ml ethanol was stirred at room temperature for 1 h. The reaction mixture was diluted with tert-butyl methyl ether and washed with 1N aqueous sodium hydroxide solution. The aqueous layer was extracted with three portions of tert-butyl methyl ether. The combined organic extracts were dried with sodium sulfate and concentrated. Column chromatography afforded 93 mg (57%) of the title compound as a light brown solid.
Reaction SMILES: [OH-].[K+].CN(N=O)C(N[N+]([O-])=O)=N.[N+](=[CH2:15])=[N-].[F:16][C:17]1[CH:18]=[C:19]([C:30]23[CH2:37][CH2:36][C:33]([CH2:38][CH2:39]/[CH:40]=[CH:41]/[C:42]([O:44][CH3:45])=[O:43])([CH2:34][CH2:35]2)[CH2:32][O:31]3)[CH:20]=[C:21]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH:22]=1>C1COCC1.O.CCOCC>[F:16][C:17]1[CH:18]=[C:19]([C:30]23[CH2:35][CH2:34][C:33]([CH2:38][CH2:39][CH:40]4[CH2:15][CH:41]4[C:42]([O:44][CH3:45])=[O:43])([CH2:36][CH2:37]2)[CH2:32][O:31]3)[CH:20]=[C:21]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH:22]=1
Reactant: C=[N+]=[N-]
Reactant: COC(=O)/C=C/CCC12CCC(c3cc(F)cc(OC4CCCCO4)c3)(CC1)OC2
Agent: CN(N=O)C(=N)N[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1CC1CCC12CCC(c3cc(F)cc(OC4CCCCO4)c3)(CC1)OC2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
To a vigorously stirred 0° C. biphasic solution of Et2O (10 mL), 40% aq. KOH (2 mL, 14.0 mmol) and water (2 mL) was added portionwise N-methyl-N′-nitro-N-nitrosoguanidine (0.844 g, 2.87 mmol) over 15 min. When addition had been completed, the ether layer was separated and dried with KOH pellets. The contents were allowed to stand for 5 min, then redried over fresh KOH pellets. To 5 mL of the diazomethane solution (˜50% of total volume) was added a 0° C. solution of (E)-methyl 5-(1-(3-fluoro-5-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)pent-2-enoate (0.3 g, 0.717 mmol) in THF (2 mL). A mixture of PdOAc2 (0.016 g, 0.072 mmol) in THF (2 mL) was added slowly and the reaction was stirred at 0° C. for 15 min and then the remainder of the diazomethane solution (˜5 mL) was added slowly. The reaction was allowed to warm to rt and stirred for 1 h, then was filtered and then concentrated in vacuo. The residual crude oil was chromatographed (SiO2; gradient from 0% to 30% EtOAc/hexane over 10 min) to give the title compound (0.26 g, 0.601 mmol, 84% yield) as a clear oil. 1H NMR (CDCl3) δ: 6.86 (t, J=1.8 Hz, 1H), 6.74 (ddd, J=10.1, 2.4, 1.5 Hz, 1H), 6.68 (dt, J=10.5, 2.3 Hz, 1H), 5.40 (t, J=3.2 Hz, 1H), 3.93-3.84 (m, 1H), 3.83-3.76 (m, 2H), 3.68 (s, 3H), 3.62 (dtt, J=11.4, 4.1, 1.9 Hz, 1H), 2.03-1.94 (m, 5H), 1.88-1.81 (m, 2H), 1.75-1.56 (m, 7H), 1.43-1.16 (m, 7H), 0.75-0.68 (m, 1H); 19F NMR (CDCl3) δ: −112.1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[Na+].[Na+].C(B(CC)[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)C>COCCOC>[CH3:11][O:10][C:5]1[CH:4]=[C:3]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:2]=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: COc1ccc(Br)cc1C=O
Reactant: CCB(CC)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(-c2cccnc2)ccc1C=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 855 %

Procedure:
A mixture of 5-bromo-2-methoxybenzaldehyde (10.00 g, 1.82 mmol) and tetrakis (triphenylphosphine)palladium (O) (2.10 g, 1.82 mmol, 3.9 mol %) in DME (filtered through Al2O3) (50 ml) was stirred at RT for 0.25 h. Sodium carbonate (2M, 50 ml, 0.10 mol %) and diethyl (3-pyridyl)borane (6.817 g, 46.36 mmol) were added, the mixture heated to reflux for 5.5 h then allowed to stand at RT overnight. The dark brown reaction mixture was partitioned between water (50 ml) and Et2O (100 ml) and the organic layer separated and combined with two further Et2O extracts (1×50 ml, 1×25 ml). The organic phase was extracted with 2N hydrochloric acid (2×50 ml) then the aqueous extract was basified with 3M NaOH and extracted with Et2O (1×150 ml, 2×50 ml). The combined organic extract was washed with brine (50 ml), dried (Na2SO4), concentrated in vacuo then submitted to column chromatography [SiO2; Et2O] to furnish the title compound (3.318 g) as a pale yellow solid (Found: C, 73.40; H, 5.20; N, 6.44. C13H11NO2 requires C, 73.23; H, 5.20; N, 6.57%.).
Reaction SMILES: [OH:1][CH:2]([CH:4]1[CH:7]([C:8]#[C:9][Si](C)(C)C)[NH:6][C:5]1=[O:14])[CH3:3].[F-].[Cs+]>O1CCCC1.CO.O>[OH:1][C@@H:2]([C@H:4]1[C@@H:7]([C:8]#[CH:9])[NH:6][C:5]1=[O:14])[CH3:3]
Reactant: CC(O)C1C(=O)NC1C#C[Si](C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C#C[C@H]1NC(=O)[C@H]1[C@@H](C)O
Temperature: 60 °C
Yield: 27.3 %

Procedure:
A cis/trans mixture (1.0 g) of 3-(1-hydroxyethyl)-4-trimethylsilylethynyl-2-azetidinone is dissolved in a mixture of tetrahydrofuran (10 ml) and methanol (5 ml), and a solution of cesium fluoride (0.2 g) in water (2 ml) is added to the solution. The mixture is stirred at 60° C. for an hour and concentrated under reduced pressure and the residue is extracted with ethyl acetate (20 ml) and tetrahydrofuran (20 ml). The extract is dried over magnesium sulfate, concentrated under reduced pressure and crystallized from ethyl acetate to give 0.18 g of cis-3-[(R)-1-hydroxyethyl]-4-ethynyl-2-azetidinone.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][C@@H:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH2:11])=[CH:7][CH:6]=[CH:5][N:4]=1.[CH3:17][C:18]([O:21][C:22]([NH:24][CH2:25][C:26](O)=[O:27])=[O:23])([CH3:20])[CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[C:18]([O:21][C:22]([NH:24][CH2:25][C:26]([NH:11][C@H:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:9][C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCOC(=O)[C@@H](N)Cc1cccnc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](Cc1cccnc1OC)NC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.5 %

Procedure:
To a 100-mL round-bottomed flask was added ethyl 3-(2-methoxy-3-pyridinyl)alaninate (0.877 g, 3.91 mmol), N-α-t-Boc-glycine (0.753 g, 4.30 mmol, Aldrich, St. Louis, Mo.), HATU (1.784 g, 4.69 mmol, Aldrich, St. Louis, Mo.) and N,N-diisopropylethylamine (2.05 mL, 11.73 mmol, Aldrich, St. Louis, Mo.) in DMF (8 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2×50 mL). The organic extract was washed with saturated NaCl (20 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a light-yellow oil. The crude product was purified by silica gel chromatography, eluting with 60% EtOAc/hexanes to give ethyl N-(tert-butoxy carbonyl)glycyl-3-(2-methoxy-3-pyridinyl)alaninate (1.38 g) as a colorless oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][O:30]1>>[CH3:8][C@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][CH:29]2[CH2:33][CH2:32][CH2:31][O:30]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: BrCCC1CCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 243 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 2-(2-bromoethyl)tetrahydrofuran.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[CH:14][CH:15]=[C:10]3[C:9]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:8]2)=[CH:2]1.[CH3:22][O:23][C:24](=[O:37])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[O:33][CH2:34][CH2:35]Cl>>[CH3:22][O:23][C:24](=[O:37])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[O:33][CH2:34][CH2:35][N:19]1[CH2:18][CH2:17][CH:16]([C:9]2[C:10]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[N:7]([CH2:6][C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)[CH:8]=2)[CH2:21][CH2:20]1
Reactant: COC(=O)c1ccc(OC)cc1OCCCl
Reactant: c1cc2c(C3CCNCC3)cn(Cc3ccoc3)c2cn1
Product: COC(=O)c1ccc(OC)cc1OCCN1CCC(c2cn(Cc3ccoc3)c3cnccc23)CC1
Yield: 37 %

Procedure:
This compound was prepared following the procedure described in example 4, part E, starting with 1.50 g (5.25 mmol) of 1-furan-3-ylmethyl-3-piperidin-4-yl-1H-pyrrolo[2,3-c]pyridine and 1.55 g (6.3 mmol) of 2-(2-chloroethoxy)-4-methoxybenzoic acid methyl ester. After standard work-up and purification, 0.95 g (36% yield) of 2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-4-methoxy-benzoic acid methyl ester were obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH:7]=[O:8])[N:6]=1.[H-].[Na+].[CH2:11](I)[CH2:12][CH3:13]>C1COCC1.CN(C=O)C>[CH3:1][C:2]1[N:3]([CH2:11][CH2:12][CH3:13])[CH:4]=[C:5]([CH:7]=[O:8])[N:6]=1
Reactant: CCCI
Reactant: Cc1nc(C=O)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCn1cc(C=O)nc1C
Reaction time: 0.08 h

Procedure:
2-Methyl-1H-imidazole-4-carbaldehyde (940 mg, 8.5 mmol) was dissolved in THF (40 ml) with DMF (5 ml). NaH (380 mg of a 60% dispersion in mineral oil) was added carefully and the reaction mixture was allowed to stir 5 minutes under nitrogen. Propyl iodide (1.65 g, 9.7 mmol) was added and it was allowed to stir for 1 h, at which time the reaction was judged complete. The solvent was removed under vacuum, and the crude was purified on silica eluted with 100% ethyl acetate −1% MeOH/ethyl acetate to yield the title product as the main isomer (390 mg (30%), 2.6 mmol). 1H NMR (DMSO-d6): δ=9.68 (s, 1H), 8.02 (s, 1H), 3.97 (t, J=7.3 Hz, 2H), 2.31 (s, 3H), 1.71 (sextet, J=7.3 Hz, 2H), 0.85 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[C:11]([I:13])[CH:10]=[C:6]([C:7]([OH:9])=O)[CH:5]=1.[CH3:15][NH:16][CH2:17][CH2:18][CH3:19].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>ClCCl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[C:11]([I:13])[CH:10]=[C:6]([C:7]([N:16]([CH3:15])[CH2:17][CH2:18][CH3:19])=[O:9])[CH:5]=1
Reactant: CCCNC
Reactant: COC(=O)c1cc(I)cc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCCN(C)C(=O)c1cc(I)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.3 %

Procedure:
Mix 5-iodo-isophthalic acid monomethyl ester (3.6 g), N-methyl propyl amine (1.2 mL, 11.8 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.3 g, 11.8 mmol), and 1-hydroxybenzotriazole hydrate (1.6 g, 11.8 mmol) in dichloromethane (40 mL) and stir at room temperature for 4 h. Dilute with dichloromethane (20 mL), wash with water, 5% aqueous ammonium chloride solution, 5% aqueous sodium bicarbonate solution. Dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with ethyl acetate and hexanes) to give the title compound (3.2 g, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:19]=[CH:18][N:17]([CH2:20][CH3:21])[N:16]=3)=[N:11][C:10]=2[C:22]2[CH:27]=[CH:26][C:25]([C:28](=[N:30][OH:31])[NH2:29])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[CH:32](OCC)(OCC)OCC.B(F)(F)F>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:19]=[CH:18][N:17]([CH2:20][CH3:21])[N:16]=3)=[N:11][C:10]=2[C:22]2[CH:27]=[CH:26][C:25]([C:28]3[N:29]=[CH:32][O:31][N:30]=3)=[CH:24][CH:23]=2)=[CH:6][CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: CCn1ccc(-c2nc(-c3ccc(C(N)=NO)cc3)c(Sc3ccc(Cl)cc3)n2C)n1
Agent: FB(F)F
Solvent: CCOC(C)=O
Product: CCn1ccc(-c2nc(-c3ccc(-c4ncon4)cc3)c(Sc3ccc(Cl)cc3)n2C)n1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a suspension of step 4 product (250 mg, 0.552 mmol) in triethyl orthoformate (9.09 ml, 55.2 mmol) was added BF3 etherate (0.699 μl, 5.52 μmol) and the mixture stirred at 110° C. for overnight. The reaction mixture was diluted with EtOAc and washed with NaHCO3 (aq), organic layer was dried, and concentrated. The residue was purified on silica gel column eluting a gradient of 8-70% EtOAc in hexane to afford 3-(4-{5-[(4-chlorophenyl)sulfanyl]-2-(1-ethyl-1H-pyrazol-3-yl)-1-methyl-1H-imidazol-4-yl}phenyl)-1,2,4-oxadiazole (130 mg; more polar; the major regioisomer. There was also a minor regioisomer that was the subject of the next example). 1H NMR (500 MHz), [CDCl3]: 8.78 (s, 1H), 8.28 (m, 2H), 8.15 (m, 2H), 7.55 (m, 1H), 7.22 (m, 2H), 7.06 (m, 2H), 6.95 (m, 1H), 4.28 (q, 2H), 4.00 (s, 3H), 1.60 (t, 3H). LCMS: [M+1]+=463.1 (rt=1.16 min). Human FAAH lysate assay: IC50=28.7 nM.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:11]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)([CH3:13])[CH3:12].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.C(Cl)CCl>[Cl:1][C:2]1[C:3]([C:4]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([CH:11]([CH3:13])[CH3:12])=[CH:15][CH:16]=2)=[O:6])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: CC(C)c1ccc(N)cc1
Reactant: O=C(O)c1cccnc1Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)c1ccc(NC(=O)c2cccnc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-chloronicotinic acid (6.3 g) and 4-isopropylaniline (5.26 ml) and DIEA (10 ml) in CH2Cl2 (200 ml) was added EDC (10 g) and HOBt (5.4 g). The reaction was stirred at RT overnight and washed with 2 N NaOH (100 ml), H2O (250 ml) and brine (100 ml). The organic layer was dried over Na2SO4 and evaporated to give (2-chloro-3-pyridyl)-N-(4-isopropylphenyl)-carboxamide.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[Cl:11])=[O:3].CO[C:14](OC)([N:16]([CH3:18])[CH3:17])[CH3:15]>>[Cl:11][C:5]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[C:14]([N:16]([CH3:18])[CH3:17])[CH3:15]
Reactant: CC(=O)c1cc(Cl)ccc1Cl
Reactant: COC(C)(OC)N(C)C
Product: CC(=CC(=O)c1cc(Cl)ccc1Cl)N(C)C

Procedure:
A mixture of 50.0 g of 2,5-dichloroacetophenone and 50 ml of N,N-dimethylacetamide dimethyl acetal was stirred and heated at reflux for 121/2 hours. The mixture was then cooled and evaporated in vacuo to give an oil which crystallized on scratching to give a dark red solid. This was collected and washed with hexane/ether to give 58.8 g of 1-(2,5-dichlorophenyl)-3-(dimethylamino)-2-buten-1-one as a red solid.
Reaction SMILES: C(OC(=O)C)(=O)C.N1C=CC=CC=1.C[O:15][C:16]1[CH:33]=[CH:32][C:31]2[C@@H:30]3[C@H:21]([C@H:22]4[C@@:26]([CH2:28][CH2:29]3)([CH3:27])[C@@H:25]([O:34]C(=O)C)[C@:24](O)([CH2:38][CH3:39])[CH2:23]4)[CH2:20][CH2:19][C:18]=2[CH:17]=1.COC1C=CC2[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)C(=O)[C@@H](CC)C4)CCC=2C=1.[BH4-].[Na+].COC1C=CC2[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)[C@@H](O)[C@@H](CC)C4)CCC=2C=1.[Li].N.Cl.CO>C(O)C.[Zn]>[OH:34][C@H:25]1[C@@H:24]([CH2:38][CH3:39])[CH2:23][C@H:22]2[C@H:21]3[C@H:30]([CH2:29][CH2:28][C@:26]12[CH3:27])[C@@H:31]1[C:18](=[CH:17][C:16](=[O:15])[CH2:33][CH2:32]1)[CH2:19][CH2:20]3
Reactant: CC[C@]1(O)C[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@]2(C)[C@H]1OC(C)=O
Agent: CC[C@H]1C[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@]2(C)C1=O
Agent: CC[C@H]1C[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@]2(C)[C@H]1O
Agent: Cl
Solvent: CO
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1O

Procedure:
These compounds can be prepared in a 10-stage process from 3-methoxy-1,3,5(10)-estratrien-17-one as starting material. In this process, 3-methoxy-1,3,5(10)-estratrien-17-one is enolized and acylated with acetic anhydride. The thus-obtained Δ16 -enol acetate is epoxidized with m-chloroperbenzoic acid and split in the presence of acetic acid. The resultant 16α-acetoxy-3-methoxy-1,3,5(10)-estratrien-17-one is saponified with sodium hydroxide solution in methanol and rearranged into 17β-hydroxy-3-methoxy-1,3,5(10)-estratrien-16-one. Subsequent Grignard reaction with ethylmagnesium iodide yields 3-methoxy-16,17β-dihydroxy-16α-ethyl-1,3,5(10)-estratriene, which is partially esterified with acetic anhydride/pyridine. The thus-obtained 3-methoxy-17β-acetoxy-16β-hydroxy-16α-ethyl-1,3,5(10)-estratriene is subjected to a Serini reaction with zinc/toulene and heating. The resultant 3-methoxy-16β-ethyl-1,3,5(10)-estratrien-17-one is reduced with sodium borohydride in ethanol. The ensuing 3-methoxy-16β-ethyl-1,3,5(10)-estratrien-17β-ol is reduced with lithium in liquid ammonia and then treated with hydrochloric acid/methanol, yielding the desired 17β-hydroxy-16β-ethyl-4-estren-3-one in a yield of barely 20% of theory.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:9][CH:8]([NH:10][CH2:11][C:12]2[CH:17]=[N:16][C:15]([C:18]3[N:22]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([CH2:29][CH:30]([CH3:32])[CH3:31])=[CH:25][CH:24]=4)[O:20][N:19]=3)=[CH:14][N:13]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+]>C(O)C>[CH2:29]([C:26]1[CH:27]=[CH:28][C:23]([C:21]2[O:20][N:19]=[C:18]([C:15]3[N:16]=[CH:17][C:12]([CH2:11][NH:10][C@@H:8]4[CH2:7][C@H:6]([C:4]([OH:5])=[O:3])[CH2:9]4)=[N:13][CH:14]=3)[N:22]=2)=[CH:24][CH:25]=1)[CH:30]([CH3:32])[CH3:31]
Reactant: CCOC(=O)C1CC(NCc2cnc(-c3noc(-c4ccc(CC(C)C)cc4)n3)cn2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Cc1ccc(-c2nc(-c3cnc(CN[C@H]4C[C@@H](C(=O)O)C4)cn3)no2)cc1
Temperature: 25 °C

Procedure:
A solution of 3-({5-[5-(4-isobutyl-phenyl)-[1,2,4]oxadiazol-3-yl]-pyrazin-2-ylmethyl}-amino)-cyclobutanecarboxylic acid ethyl ester, 2.0 N NaOH (1.0 mL) and ethanol (3.0 mL) was heated in a sealed vial in a microwave to 150° C. for 10 minutes. The reaction mixture was cooled to room temperature and concentrated in vacuo to afford the title compound (0.047 g, 36% yield over 2 steps) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(N(CC)CC)C.[Cl:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>CC#N>[Cl:18][CH2:19][CH2:20][C:21]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5])=[O:22]
Reactant: NC(=O)c1ccccc1N
Reactant: O=C(Cl)CCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NC(=O)c1ccccc1NC(=O)CCCl
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of 2-aminobenzamide (500 mg, 3.68 mmol) and triethylamine (NEt3) (450 mg, 4.41 mmol) in CH3CN (30 mL) was added 3-chloropropanoyl chloride (0.45 mL, 4.41 mmol) dropwise at room temperature. After stirring overnight, the reaction mixture was concentrated to give the desired product (800 mg) as solid, which was used for the next step without further purification. LC-MS: m/z 227 (M+H+).