Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([CH:14]=1)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:18]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:20])[CH3:19].O>CS(C)=O>[N+:15]([C:5]1[CH:4]=[CH:3][C:2]([N:24]2[CH2:25][CH2:26][N:21]([C:18](=[O:20])[CH3:19])[CH2:22][CH2:23]2)=[CH:14][C:6]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:17])=[O:16]
Reactant: CC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Nc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])c(Nc3ccccc3)c2)CC1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
The compound (300 mg) prepared in Step 1 and N-acetylpiperazine (300 mg) were dissolved in dimethyl sulfoxide (3 mL), and stirred at 90° C. for 3 hours. The mixture was added with water, and extracted with ethyl acetate. The thus obtained organic layer was washed with saturated brine, the water was removed with sodium sulfate, and the solvent was removed by distillation under reduced pressure. Then, the compound was added with ethyl ether to form a solid, and the solid was filtered to obtain a target compound as a yellow solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]1[N:13]2[CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=3)[CH:16]=[C:12]2[C:11](=[O:28])[NH:10][CH2:9]1)(=O)=O.[N-:29]=[N+:30]=[N-:31].[Na+].O.C([O-])(O)=O.[Na+]>C(#N)C.CN(C=O)C>[N:29]([CH2:6][CH2:7][CH:8]1[N:13]2[CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=3)[CH:16]=[C:12]2[C:11](=[O:28])[NH:10][CH2:9]1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCCC1CNC(=O)c2cc(-c3cccc(OC(F)(F)F)c3)cn21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCC1CNC(=O)c2cc(-c3cccc(OC(F)(F)F)c3)cn21
Yield: 79.1 %

Procedure:
2-{1-oxo-7-[3-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl}ethyl methanesulfonate (150 mg, 0.36 mmol) were reacted with sodium azide (60 mg 0.924 mmol) in acetonitrile/DMF 10 ml/2 ml at 80° C. for 18 hours. The reaction was worked up with water, saturated NaHCO3 and extracted with ethyl acetate. The organic phase, dried on Na2SO4, was filtered and evaporated. The crude was dissolved with diethyl ether and after a while, a solid precipitated, which was filtered to give 104 mg (80%) of 4-(2-azidoethyl)-7-[3-(trifluoromethoxy)phenyl]-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([NH2:15])[CH2:14][CH2:13]1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH:12]1([NH:15][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([I:11])[CH:9]=[CH:10][C:2]=2[OH:1])[CH2:14][CH2:13]1
Reactant: O=C(O)c1cc(I)ccc1O
Reactant: NC1CC1
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(NC1CC1)c1cc(I)ccc1O
Reaction time: 2 h
Yield: 18.1 %

Procedure:
13bh) A mixture of 2.64 g of 2-hydroxy-5-iodo-benzoic acid, 0.69 g of cyclopropylamine and 3.65 g of carbon tetrabromide in 40 ml of methylene chloride is treated portionwise at room temperature with 2.62 g of triphenylphosphine. After 2 hrs. the mixture is filtered and the filtrate is concentrated. Chromatography on silica gel with ethyl acetate/cyclohexane 1:4 gives 550 mg of crude N-cyclopropyl-2-hydroxy-5-iodo-benzamide. Yield: 18%.
Reaction SMILES: O[Li].O.C([O:6][C:7](=[O:25])[CH2:8][C:9]([N:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[CH3:12])=[O:10])C.C1COCC1.Cl>CO.O>[C:16]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:17]=[CH:18][C:13]([N:11]([CH3:12])[C:9](=[O:10])[CH2:8][C:7]([OH:25])=[O:6])=[CH:14][CH:15]=1
Reactant: CCOC(=O)CC(=O)N(C)c1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)CC(=O)O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
LiOH.H2O (25 mg, 0.58 mmol) was added to a solution of N-biphenyl-4-yl-N-methyl-malonamic acid ethyl ester (116 mg, 0.39 mmol) in a mixture of Methanol (0.6 mL), THF (1.5 mL) and H2O (0.4 mL). The resulting mixture was stirred at ambient temperature for 2 hrs. The reaction mixture was concentrated to get a residue. The residue was diluted with water, acidified with conc. HCl. The precipitate was collected and dried to afford 100 mg (95.24%) of N-biphenyl-4-yl-N-methyl-malonamic acid
Reaction SMILES: [CH2:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11]C(=O)OCC3C=CC=CC=3)=[CH:10][C:5]=2[CH2:4][CH2:3][O:2]1.CO.O(C(C)(C)C)[Li].[C:30]([O:33][C@H:34]([CH2:40]Cl)[CH2:35][NH:36][C:37](=[O:39])[CH3:38])(=[O:32])C>CN(C=O)C>[CH2:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:40][C@H:34]([CH2:35][NH:36][C:37](=[O:39])[CH3:38])[O:33][C:30]3=[O:32])=[CH:10][C:5]=2[CH2:4][CH2:3][O:2]1
Reactant: O=C(Nc1ccc2c(c1)CCOC2)OCc1ccccc1
Reactant: CC(=O)NC[C@@H](CCl)OC(C)=O
Agent: [Li]OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CCOC3)C(=O)O1
Temperature: 25 °C
Reaction time: 66 h
Yield: 50.5 %

Procedure:
A solution of phenylmethyl (3,4-dihydro-1H-2-benzopyran-6-yl)carbamate (Step 1, 1.60 g, 5.65 mmol) and MeOH (0.458 mL, 11.3 mmol) in dry DMF (5.6 mL) under N2 is cooled in an ice bath and treated with LiOtBu (1M in THF, 16.95 mL, 16.95 mmol) dropwise over 2 mins. Then, the (1S)-2-(acetylamino)-1-(chloromethyl)ethyl acetate (2.19 g, 11.3 mmol) is added all at once, the cooling bath is removed and the mixture is stirred at ambient temperature for 2.75 days and is then diluted with H2O (20 mL) and extracted with EtOAc (4×50 mL). The combined organic phase is washed with brine (25 mL), dried over MgSO4 and concentrated under reduced pressure, and the residue is chromatographed on a Flash 40M silica gel (90 g, 32-63 μm) cartridge, eluting with a gradient of MeOH/CH2Cl2 (1/99-2/98). Those fractions with an Rf=0.23 by TLC (MeOH/CHCl3, 5/95) are pooled and concentrated and the product triturated with EtOAc to give 828 mg (50%) of the title compound as a white solid, mp 142-145° C. [α]25D=−24° (c 1.01, DMSO).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[C:25](=[O:28])([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:15]([N:14]2[CH2:18][CH2:25][O:28][CH2:3][CH2:4]2)=[O:16])[CH2:10][CH2:9]1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCNCC3)c(F)c2)C(=O)O1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(C(=O)N4CCOCC4)CC3)c(F)c2)C(=O)O1
Yield: 82.5 %

Procedure:
(S)-N-[3-[3-Fluoro-4-[piperazin-1-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (154 mg, 0.4587 mmol) was treated with morphonylcarbonylchloride (82 mg, 0.5504 mmol) and anhydrous potassium carbonate (190 mg, 1.376 mmol) in dimethylformamide (10 ml). The reaction mixture was allowed to react at 30° C. for 8 hrs, after which the reaction mixture was extracted with ethylacetate and water. The organic phase was separated and evaporated under reduced pressure to afford crude product. The crude was purified by column chromatography using silica gel using ethylacetate and methanol (9:1) as the eluent to afford pure title compound as colourless solid (85 mg).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[C:8]([CH2:12][CH2:13][C:14](Cl)=[O:15])([O:10][CH3:11])=[O:9].[BrH:17]>C(#N)C.C(O)(=O)C>[CH3:11][O:10][C:8](=[O:9])[CH2:12][CH2:13][C:14](=[O:15])[CH2:1][Br:17]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Br
Reactant: COC(=O)CCC(=O)Cl
Solvent: CC(=O)O
Solvent: CC#N
Product: COC(=O)CCC(=O)CBr
Temperature: 0 °C
Reaction time: 1 h

Procedure:
30 ml of trimethylsilyldiazomethane (2 M solution in diethyl ether) was added drop wise to a solution of 3-carbomethoxy propionylchloride (3.75 g, 30.5 mmol) in acetonitrile (75 ml) over a period of 10 mins at room temperature. The mixture was then stirred for 1 h. The reaction was cooled to 0° C. and 10g of 33% HBr in acetic acid was added slowly over 20 min, then the reaction was warmed to room temperature and stirred for 16 h. The solvent was removed in vacuo without heating and the residue was dissolved in ethyl acetate (100 ml), washed with 50 ml of saturated sodium bicarbonate solution and then 50 ml of brine. The organics were passed through a phase separator to remove any water and the solvent removed in vacuo. The resultant crude material was purified by kuglerhor distillation under reduced pressure (˜3 mbar, 150° C.) to give 5-bromo-4-oxo-pentanoic acid methyl ester (7g).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:5][N:4]2[C:18]([C:21]#[N:22])=[CH:19][CH:20]=[C:3]12.[OH-:23].[Li+].OO>O1CCCC1.O>[O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:17])[F:16])=[CH:10][CH:9]=2)=[CH:5][N:4]2[C:18]([C:21]([NH2:22])=[O:23])=[CH:19][CH:20]=[C:3]12
Reactant: [OH-]
Reactant: N#Cc1ccc2c(=O)[nH]c(-c3ccc(C(F)(F)F)cc3)cn12
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1ccc2c(=O)[nH]c(-c3ccc(C(F)(F)F)cc3)cn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.5 %

Procedure:
A mixture of 1-oxo-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-pyrrolo[1,2-a]pyrazine-6-carbonitrile, (Example 2), (0.03 g, 98.9 82 mol), suspended in tetrahydrofuran (1 mL) was treated with a solution of lithium hydroxide (7.11 mg, 0.29 mmol) in water (500 μL) and 30 wt % aqueous hydrogen peroxide (40.4 μL, 0.39 mmol). The reaction was stirred at room temperature overnight. At this time, the reaction was concentrated in vacuo. The resulting residue was triturated with water. The resulting solid was collected by filtration and then dried in vacuo to afford 1-oxo-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-pyrrolo[1,2-a]pyrazine-6-carboxylic acid amide (20 mg, 61%) as light yellow solid. 1H NMR (methanol-d4) δ ppm 7.94 (d, J=1.5 Hz, 1H), 7.85-7.90 (m, 2H), 7.80-7.84 (m, 2H), 7.77 (s, 1H), 7.52 (d, J=0.8 Hz, 1H). LC-MS calcd. for C15H11F3N3O2 [(M+H)+] 322, obsd. 322.0.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[CH3:17][N:18]([CH3:20])/[CH:19]=[CH:13]/[C:12]([C:3]1[CH:4]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:6]=[CH:7][C:2]=1[OH:1])=[O:14]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cc(C(F)(F)F)ccc1O
Product: CN(C)/C=C/C(=O)c1cc(C(F)(F)F)ccc1O
Temperature: 110 °C
Yield: 73 %

Procedure:
1-[2-Hydroxy-5-(trifluoromethyl)phenyl]ethanone, (Preparation 32, 7.0 g, 0.034 mol) was taken in dimethylformamide dimethylacetal (18.2 mL, 0.14 mol) at ambient temperature and then heated at 110° C. for 30 minutes. The reaction mixture was concentrated in vacuo and the crude product was crystallised from 2-propanol to afford the title compound as bright yellow solid (6.4 g, 73%). 1HNMR (CDCl3): δ 3.02 (s, 3H) 3.22 (s, 3H), 5.72 (d, 1H), 6.99 (d, 1H), 7.55 (d 1H), 7.89-7.94 (m, 2H), 14.45 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.ClC(OCC(C)C)=O.Cl.[CH3:27][NH:28][O:29][CH3:30]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([C:8]([N:28]([O:29][CH3:30])[CH3:27])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ncccc1Br
Reactant: CNOC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)c1ncccc1Br
Temperature: 25 °C

Procedure:
To a solution of 3-bromopyridine-2-carboxylic acid (3-1; 250 mg, 1.24 mmole) in CH2Cl2 (5 mL) was added Et3N (0.21 mL, 3.72 mmole) then isobutyl chloroformate (0.19 mL, 1.49 mmole) at 0° C. After 30 minutes N,O-dimethylhydroxylamine hydrochloride (181 mg, 1.86 mmole) was added. After 15 minutes the mixture was warmed to RT. After 18 hr the mixture was diluted with H2O and extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column (50% EtOAc/hexanes) gave the title compound (3-2) as a clear oil: 1H-NMR (500 MHz, CDCl3) δ 8.56 (m, 1H), 7.92 (m, 1H), 7.24 (m, 1H), 3.58 (s, 3H), 3.42 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]=1[Br:18])[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:39][C:40](O)([CH3:42])[CH3:41].C1CCN2C(=NCCC2)CC1.Cl>CN(C=O)C>[C:40]([O:13][C:12](=[O:14])[C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:17]([Br:18])=[C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)([CH3:42])([CH3:41])[CH3:39]
Reactant: CC(C)(C)O
Reactant: O=C(O)c1cc(OCc2ccccc2)c(Br)c(OCc2ccccc2)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)c1cc(OCc2ccccc2)c(Br)c(OCc2ccccc2)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a stirred solution of 3,5-bis-benzyloxy-4-bromo-benzoic acid (200b) (153 g, 0.37 mol) in DMF (1 L) was added CDI (90 g, 0.56 mol) in several portions. The solution was stirred at 40° C. for 1 hr. t-BuOH (55 g, 0.74 mol) was added to the mixture and then followed by the drop wise addition of DBU (56.3 g, 0.37 mol). The resulting solution was stirred at 40° C. for 2 days. TLC (EtOAc/petroleum ether=1/10) showed that the reaction was complete. The mixture was cooled to room temperature and poured into ice water (1 L). The mixture was acidified to pH 5 with conc. HCl and stirred for 1 hr. The formed solid was filtered and washed with water, then dried in vacuo to give the title compound (165 g, 86% yield) as a brown solid. 1H NMR (400 MHz, CDCl3): δ 7.57-7.25 (m, 12H), 5.21(s, 4H), 1.58 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[F-:11].[K+].[NH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]([CH3:25])[CH2:17][C:18]2([CH3:24])[CH3:23].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:11][C:2]1[C:3]([C:4]([NH:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]([CH3:25])[CH2:17][C:18]3([CH3:24])[CH3:23])=[O:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: [F-]
Reactant: CC1CC(C)(C)c2cccc(N)c21
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC1CC(C)(C)c2cccc(NC(=O)c3cccnc3F)c21
Temperature: 155 °C
Yield: 47 %

Procedure:
To a solution of 2.6 g (14.8 mmol) of 2-chloronicotinic acid chloride in 15 ml of sulforan was added 2.6 g (46.4 mmol) of potassium fluoride, and the mixture was stirred under heating at 155° C. for 6 hours. After cooling, precipitated crystals were filtered out. The filtrate was added dropwise to a solution of 2 g (11.4 mmol) of 4-amino-1,1,3-trimethylindane and 1.6 g (15.8 mmol) of triethylamine in 10 ml of toluene under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was then added with 30 ml of toluene, washed with water, dried over Glauber's salt and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: n-hexane/ethyl acetate=4/1) to obtain 1.6 g of oil (Compound No. 9 shown in Table 2) in a yield of 47%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:26])[C:11](=[O:25])[C:12]([CH3:24])=[CH:13][C:14]=2[C:15]([NH:17][O:18][CH2:19][CH2:20][O:21]C=C)=[O:16])=[C:4]([F:27])[CH:3]=1.Cl.[OH-].[Na+]>C(O)C.CCOC(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:26])[C:11](=[O:25])[C:12]([CH3:24])=[CH:13][C:14]=2[C:15]([NH:17][O:18][CH2:19][CH2:20][OH:21])=[O:16])=[C:4]([F:27])[CH:3]=1
Reactant: C=COCCONC(=O)c1cc(C)c(=O)n(C)c1Nc1ccc(Br)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C(=O)NOCCO)c(Nc2ccc(Br)cc2F)n(C)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.6 %

Procedure:
To a solution of 2-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridine-3-carboxamide (0.067 g, 0.150 mmol) in ethanol (2 mL) was added aqueous 2 M HCl (0.380 mL, 0.760 mmol). The reaction mixture was stirred for 16 hours at room temperature. The pH of the reaction mixture was adjusted with 1 M NaOH. The reaction mixture was diluted with EtOAc and H2O. The organic layer was separated and washed with saturated NaCl. The combined aqueous layers were back extracted with EtOAc (1×). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to yield 0.060 g (94%) pure desired product as an off-white crystalline solid. MS ESI (+) m/z 414, 416 (M+, Br pattern detected); 1H NMR (400 MHz, CDCl3) δ 9.80 (s, 1H), 8.44 (s, 1H), 7.31 (d, 1H), 7.19 (d, 1H), 6.59 (t, 1H), 4.05 (m, 2H), 3.85 (m, 1H), 3.75 (m, 2H), 3.29 (s, 3H), 2.15 (s, 3H).
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:16]([O:24]CC)(=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1>C(O)C.O>[N:6]1[CH:7]=[CH:8][C:3]([N:20]2[CH2:21][CH2:22][CH:17]([C:16]([OH:24])=[O:23])[CH2:18][CH2:19]2)=[CH:4][CH:5]=1
Reactant: Clc1ccncc1
Reactant: CCOC(=O)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(O)C1CCN(c2ccncc2)CC1
Temperature: 150 °C
Yield: 78.7 %

Procedure:
4-Chloropyridine hydrochloride (9.55 g) and triethylamine (26.0 ml) are dissolved in ethanol (10 ml) and water (30 ml), and thereto is added ethyl isonicotinate (10.00 g). The reaction solution is then heated at 150° C. for 96 hours in a sealed tube. After allowing to cool, ethanol is added to the reaction solution and the insoluble materials are removed by filtration. The filtrate is concentrated under reduced pressure, and the resulting residue is suspended in chloroform. The precipitates are collected by filtration and recrystallized from water/N,N-dimethylformamide to give the title compound (10.34 g).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[F:13][C:14]([F:49])([F:48])[C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]2[O:24][CH:25]=[C:26]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38][CH2:39][N:40]4[CH:44]=[CH:43][N:42]=[C:41]4[CH2:45][CH2:46][NH2:47])=[CH:32][CH:31]=3)[N:27]=2)=[CH:17][CH:16]=1.O>C1COCC1>[F:48][C:14]([F:13])([F:49])[C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]2[O:24][CH:25]=[C:26]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38][CH2:39][N:40]4[CH:44]=[CH:43][N:42]=[C:41]4[CH2:45][CH2:46][NH:47][S:9]([CH3:8])(=[O:11])=[O:10])=[CH:32][CH:31]=3)[N:27]=2)=[CH:17][CH:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triethylamine (109 μl) and methanesulfonyl chloride (36.4 μl) were added to a solution of 2-[1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]ethylamine (200 mg) in THF (4 ml) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was combined with water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Chromatorex; eluent; ethyl acetate) and recrystallized from ethyl acetate-hexane to give the titled compound (126 mg) as colorless needle crystals.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][C:17]=3[F:24])=[CH:13][C:12]=2[CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:26][C:27]1([C:31]([O:33][CH3:34])=[O:32])[CH2:30][NH:29][CH2:28]1>>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]3[CH:23]=[CH:22][C:19]([CH2:20][N:29]4[CH2:30][C:27]([OH:26])([C:31]([O:33][CH3:34])=[O:32])[CH2:28]4)=[CH:18][C:17]=3[F:24])=[CH:13][C:12]=2[CH:25]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(-c2cc3cc(Cc4ccccc4)ccc3o2)c(F)c1
Reactant: COC(=O)C1(O)CNC1
Product: COC(=O)C1(O)CN(Cc2ccc(-c3cc4cc(Cc5ccccc5)ccc4o3)c(F)c2)C1

Procedure:
Synthesized according to Scheme B1 and general procedure I from 4-(5-benzylbenzofuran-2-yl)-3-fluorobenzaldehyde (0.100 g, 0.30 mmol) and methyl 3-hydroxyazetidine-3-carboxylate (0.058 g, 0.30 mmol) to give methyl 1-((4-(5-benzylbenzofuran-2-yl)-3-fluorophenyl)methyl)-3-hydroxyazetidine-3-carboxylate. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.91 (t, J=7.9 Hz, 1H), 7.40-7.61 (m, 2H), 7.15-7.36 (m, 8H), 6.26 (s, 1H), 4.04-4.10 (m, 1H), 4.04 (s, 2H), 3.70 (s, 3H), 3.68-3.69 (m, 1H), 3.63 (d, J=7.9 Hz, 1H), 3.12-3.18 (m, 4H). MS (ESI) m/z: Calculated: 445.2 Observed: 446.1 (M++1).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:34])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:33])[CH2:12][CH2:13][C@@:14]3([C:30](O)=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:36])[CH3:35])(=[O:3])[CH3:2].[Cl-].[CH3:38][CH:39]1[CH2:44][CH2:43][CH2:42][N:41]([CH2:45][C@H:46]2[CH2:50][CH2:49][C@@H:48]([NH2:51])[CH2:47]2)[CH2:40]1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:34])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:33])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:31])[NH:51][C@@H:48]4[CH2:49][CH2:50][C@H:46]([CH2:45][N:41]5[CH2:42][CH2:43][CH2:44][CH:39]([CH3:38])[CH2:40]5)[CH2:47]4)[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:36])[CH3:35])(=[O:3])[CH3:2]
Reactant: CC1CCCN(C[C@H]2CC[C@@H](N)C2)C1
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCCC(C)C4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-acetoxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (0.5 g, 1.04 mmol) (Prepared as described in J. Med. Chem. 2009. 52, 3248-3258) in 50 ml DCM, Oxallyl chloride (2 ml, 15.87 mmol) was added and stirred at room temperature for about 6 hours. Completion of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. The residue was taken in DCM (15 ml) then kept under N2 atmosphere. (1R,3S)-3-((3-methylpiperidin-1-yl)methyl)cyclopentanamine (Intermediate 10, 0.21 g) in DCM, triethyl amine (0.3 ml, 3.12 mmol) was added at 0° C. and stirred for about 15 minutes followed by above prepared acid chloride was added and stirred at room temperature for about 8 hours. Completion of the reaction was monitored by TLC. The reaction mixture was neutralized with sat. NaHCO3 and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 50% ethyl acetate in hexane as eluent to furnish the title compound as a white solid. 1H NMR (300 MHz, CDCl3): 0.57-0.97 (m, 19H); 1.18-1.21 (m, 8H); 1.25-1.41 (m, 12H); 1.49-1.62 (m, 8H); 1.65-1.82 (m, 10H); 1.85-1.98 (m, 4H); 2.56-2.69 (m, 2H); 2.88-3.06 (m, 3H); 3.29-3.38 (m, 1H); 3.89-3.90 (m, 1H); 4.25-4.70 (m, 4H); 5.78 (s, 1H); 6.12-6.15 (m, 1H); MASS: 763 (100%).