Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.[CH:8]12[O:17][CH:14]([CH2:15][CH2:16]1)[CH:13]1[CH:9]2[C:10](=[O:19])[CH2:11][C:12]1=[O:18].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:32][C:33]1[CH:38]=[CH:37][C:36]([Pb+3])=[C:35]([CH2:40][CH3:41])[CH:34]=1.Cl>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[Br:32][C:33]1[CH:38]=[CH:37][C:36]([CH:11]2[C:10](=[O:19])[CH:9]3[CH:13]([CH:14]4[O:17][CH:8]3[CH2:16][CH2:15]4)[C:12]2=[O:18])=[C:35]([CH2:40][CH3:41])[CH:34]=1
Reactant: O=C1CC(=O)C2C3CCC(O3)C12
Reactant: CCc1cc(Br)ccc1[Pb+3]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCc1cc(Br)ccc1C1C(=O)C2C3CCC(O3)C2C1=O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
4-Dimethylaminopyridine (3.67 g, 30.0 mmol) and toluene (10 ml) are added to a solution of (1RS,2SR,6RS,7SR)-10-oxatricyclo[5.2.1.02,6]decane-3,5-dione (1.0 g, 6.0 mmol) in chloroform (40 ml) and the reaction mixture is heated to 80° C. 4-Bromo-2-ethylphenyllead triacetate (5.13 g, 9.04 mmol) is added portionwise over 20 minutes, and once the addition is complete the reaction mixture is stirred at 80° C. for a further 4 hours. The mixture is cooled to room temperature, 2M aqueous hydrochloric acid (40 ml) is added, and the mixture is stirred vigorously for 15 minutes, then filtered through a small plug of diatomaceous earth, washing with dichloromethane (40 ml). The organic phase is separated, and the aqueous phase is extracted with dichloromethane. The organic solutions are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give (1RS,2SR,6RS,7SR)-4-(4-bromo-2-ethylphenyl)-10-oxatricyclo[5.2.1.02,6]-decane-3,5-dione.
Reaction SMILES: FC1C(O[C:9]([CH:11]2[CH2:15][C:14](=[O:16])[NH:13][CH2:12]2)=[O:10])=C(F)C(F)=C(F)C=1F.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(Cl)Cl>C1COCC1>[N:21]1([C:9]([CH:11]2[CH2:12][NH:13][C:14](=[O:16])[CH2:15]2)=[O:10])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: O=C1CC(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)CN1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1CC(C(=O)N2CCNCC2)CN1
Temperature: 25 °C
Reaction time: 10 h
Yield: 107 %

Procedure:
To a suspension of 5-oxo-pyrrolidine-3-carboxylic acid pentafluorophenyl ester 17 (40.1 mg, 0.0578 mmol) in 2 mL THF extra dry was added piperazine (19.9 mg, 0.231 mmol) at room temperature. The reaction mixture was stirred for 10 hours at room temperature. Afterwards, 20 mL methylene chloride were added. The resulting organic layer was washed with 20 mL of a saturated aqueous solution of sodium hydrogenocarbonate, dried over magnesium sulfate and the solvent was removed in vacuo. Finally, the crude product was purified by chromatography on silica gel (ethyl acetate:methanol 9:1→1:1) to afford the desired 4-(piperazine-1-carbonyl)-pyrrolidin-2-one 18 as a white solid (12.2 mg, 45.91%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C@:4]([C:18]([N:20]2[CH2:24][CH2:23][CH2:22][C@@H:21]2[CH2:25][OH:26])=[O:19])([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]2[C:10]([CH2:11][CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1.ClCCl>[C:27]([O:26][CH2:25][C@H:21]1[CH2:22][CH2:23][CH2:24][N:20]1[C:18]([C@@:4]1([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:11][CH:12]=[C:3]1[O:2][CH3:1])=[O:19])(=[O:29])[CH3:28]
Reactant: COC1=CCc2ccccc2[C@]1(CCC(C)C)C(=O)N1CCC[C@@H]1CO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC1=CCc2ccccc2[C@]1(CCC(C)C)C(=O)N1CCC[C@@H]1COC(C)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Example 171B (54 mg, 0.15 mmol) in anhydrous pyridine (0.5 mL) was added acetic anhydride (50 μL, 0.53 mmol). The resulting mixture was stirred under a N2 atmosphere at r.t. for 16 h, diluted with dichloromethane (10 mL), and extracted with 0.2 N HCl (2× 10 mL). The organic layer was dried over Na2SO4, and the crude product was purified by column chromatography on silica gel using a solvent gradient of 25-50% ethyl acetate in hexane. The title compound was obtained as a colorless solid (50 mg, 83%). 1H NMR (300 MHz, CDCl3) δ 0.51 (m, 1H), 0.71 (d, J=6.62 Hz, 3H), 0.77 (d, J=6.62 Hz, 3H), 0.94 (m, 2H), 1.39 (m, 2H), 1-64 (m, 3H), 2.04 (m, 1H), 2.04 (s, 3H), 2.26 (m, 1H), 2.49 (m, 1H), 3.16 (m, 1H), 3.47 (m, 1H), 3.59 (s, 3H), 4.11 (m, 1H), 4.25 (m, 1H), 4.41 (m, 1H), 4.97 (m, 1H), 7.14 (m, 4H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[NH:51][C:52]2[CH:58]=[CH:57][CH:56]=[CH:55][C:53]=2[N:54]=1.N1C=CC=CC=1>C(Cl)Cl.O>[NH:51]1[C:52]2[CH:58]=[CH:57][CH:56]=[CH:55][C:53]=2[N:54]=[C:50]1[NH:49][C:40](=[O:42])[CH:39]([C:31]1[CH:32]=[CH:33][C:34]([S:35]([CH3:38])(=[O:36])=[O:37])=[C:29]([Cl:28])[CH:30]=1)[CH2:43][CH:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Reactant: Nc1nc2ccccc2[nH]1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nc3ccccc3[nH]2)cc1Cl
Temperature: 0 °C
Yield: 32.9 %

Procedure:
A solution of triphenylphosphine (118 mg, 0.45 mmol) in methylene chloride (5 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (91 mg, 0.51 mmol). The reaction mixture was stirred at 0° C. until it became homogeneous. The resulting light purple reaction mixture was then treated with 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 16, 100 mg, 0.30 mmol). The reaction mixture was stirred at 0° C. for 20 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminobenzimidazole (60 mg, 0.45 mmol) and pyridine (0.073 mL, 0.91 mmol). The resulting reaction mixture was stirred at 25° C. for 16 h. The reaction was then diluted with water (15 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 60/40 hexanes/ethyl acetate) afforded N-(1H-benzimidazol-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (44 mg, 33%) as a cream colored solid: EI-HRMS m/e calcd for C22H24ClN3O3S (M+) 445.1227, found 445.1213.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][C:11]1[C:16]([N+:17]([O-])=O)=[CH:15][N:14]=[C:13]([NH:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[N:12]=1.NN>[Pd].C(O)C>[NH2:17][C:16]1[C:11]([NH:10][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=2[CH3:9])=[N:12][C:13]([NH:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)=[N:14][CH:15]=1
Reactant: Cc1cc(C)c(Nc2nc(Nc3ccc(C#N)cc3)ncc2[N+](=O)[O-])c(C)c1
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: Cc1cc(C)c(Nc2nc(Nc3ccc(C#N)cc3)ncc2N)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
4-[[4-[(2,4,6-trimethylphenyl)amino]-5-nitro-2-pyrimidinyl]amino]benzonitrile (0.001 mol), Pd/C 10% (0.025 g), ethanol (20 ml), and hydrazine (0.030 mol) were combined to form a slurry and stirred at room temperature for 16 hours. The solvent was removed by rotary evaporation. The residue was taken up in tetrahydrofuran (20 ml) and methanol (1 ml). A second portion of hydrazine (0.5 g) was added, and the reaction was stirred for 16 hours at room temperature. A third portion of hydrazine (0.5 ml) was added and the reaction was stirred for an additional 16 hours at room temperature. The sample was concentrated by rotary evaporation onto silica gel (1 g) and purified by flash chromatography (eluent: 0.5, 1.2% 10% (NH4OH in CH3OH) in CH2Cl2). The desired fractions were purified by preparatory HPLC to yield 0.24 g of 4-[[5-amino-4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile (70%); mp. 224-225° C. (interm. 36).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH:14](O)[CH2:15][CH:16]=[CH2:17].C(O)(C(F)(F)F)=O.[SiH](CC)(CC)CC>C(Cl)Cl>[CH2:14]([C:4]1[C:5]([CH3:13])=[C:6]([O:11][CH3:12])[C:7]([CH3:10])=[C:8]([CH3:9])[C:3]=1[O:2][CH3:1])[CH2:15][CH:16]=[CH2:17]
Reactant: C=CCC(O)c1c(C)c(OC)c(C)c(C)c1OC
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCCc1c(C)c(OC)c(C)c(C)c1OC
Temperature: 25 °C
Yield: 55.4 %

Procedure:
Crude 1-(2,5-dimethoxy-3,4,6-trimethylphenyl)but-3-en-1-ol (9.8 g) in 10 mL CH2Cl2 was added slowly, dropwise to a rapidly stirred, biphasic solution of TFA (10.5 mL, 153 mmol, 5 equiv.) and Et3SiH (6.3 mL, 1.3 equiv). The exothermic reaction was cooled in a room temperature water bath until addition was complete and the reaction stirred for and additional 2 h at room temperature. The brown solution was concentrated via rotovap, azeotroped 3×50 mL MeOH and 3×50 mL heptane and remainder taken up into 100 mL 5% EtOAc/heptane. The organic layer was washed 1×100 mL water, 1×50 mL saturated aqueous NaCl, filtered to remove particulates and dried over Na2SO4. Flash chromatography yielded 5.08 g of 1-(but-3-enyl)-2,5-dimethoxy-3,4,6-trimethylbenzene as a pale yellow oil which solidified upon standing to an off white wax. 1H NMR (400 MHz, CDCl3) δ=5.93 (m, 1 H), 5.08 (m, 1 H), 4.99 (m, 1 H), 3.68 (s, 3 H), 3.65 (s, 3 H), 2.70 (m, 2 H), 2.24 (m, 5 H), 2.18 (s, 6 H) ppm.
Reaction SMILES: [CH3:1][S:2]([NH:5][NH2:6])(=[O:4])=[O:3].C[O:8][C:9](=O)[C:10]1[CH:15]=[C:14]([C:16](=[O:21])[CH2:17][CH2:18][O:19][CH3:20])[C:13]([C:22]([F:25])([F:24])[F:23])=[CH:12][C:11]=1[N:26]=[C:27]=[O:28].[OH-].[Na+]>C1COCC1>[CH3:20][O:19][CH2:18][CH2:17][C:16]([C:14]1[CH:15]=[C:10]2[C:11](=[CH:12][C:13]=1[C:22]([F:23])([F:24])[F:25])[NH:26][C:27](=[O:28])[N:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:9]2=[O:8])=[O:21]
Reactant: COCCC(=O)c1cc(C(=O)OC)c(N=C=O)cc1C(F)(F)F
Reactant: CS(=O)(=O)NN
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCCC(=O)c1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 93.8 %

Procedure:
A solution of CH3SO2NHNH2 (61 mg, 0.555 mmol) in THF (1 mL) was slowly added dropwise to a solution of 2-isocyanato-5-(3-methoxy-propionyl)-4-trifluoromethyl-benzoic acid methyl ester (167 mg, 0.505 mmol) in dry THF (2.6 mL). After stirring the mixture at r.t. for 105 min, aq NaOH (1 M, 0.53 mL) was added and stirring was continued for 60 min. The reaction mixture was concentrated and the residue was taken in EtOAc and washed with water. The aqueous phase was extracted with EtOAc (3×), all organic phases are combined, washed with brine and dried (Na2SO4) and the solvent was evaporated to dryness yielding the title compound (194 mg, 94%) as a white powder, mp 186-191° C.
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:29]1(O)[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[CH3:20][CH:19]([CH3:21])[C:18]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@H:2]([O:1][C:37]3[C:38]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:34]=[CH:35][CH:36]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:12]=1)=[O:22]
Reactant: Oc1cccc2ccccc12
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3cccc4ccccc34)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.9 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 1-naphthol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (4.30 mg, 66.2% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.72 (d, 1H, J=8.5 Hz), 7.59 (d, 1H, J=8.5 Hz), 7.5 (m, 2H), 7.45-7.30 (m, 6H), 7.25 (m, 3H), 7.17 (apparent dd, 1H, J=2.6, 9.0 Hz), 7.01 (apparent d, 1H, J=2.6 Hz), 6.97 (apparent d, 1H, J=7.9 Hz), 5.46 (apparent dd, 1H, J=4.5, 8.1 Hz), 3.12 (m, 2H), 2.61 (m, 2H), 2.53 (apparent sept, partially hidden, 2H, J=7.9 Hz), 2.30-2.10 (m, 6H), 1.90 (m, 2H), 1.25 (d, 6H, J=7.3 Hz, overlapped); ESMS m/e: 507.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:11]([F:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4](F)[CH:3]=1.[CH3:14][O-:15].[Na+]>CN(C=O)C>[Br:1][C:2]1[C:11]([F:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:15][CH3:14])[CH:3]=1
Reactant: C[O-]
Reactant: COC(=O)c1cc(F)c(Br)cc1F
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)c(Br)cc1OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77.4 %

Procedure:
A solution of methyl 4-bromo-2,5-difluorobenzoate (1.0 g, 3.98 mmol) in dry DMF (10 ml) was cooled down to 0° C. Sodium methoxide (25% in MeOH, 0.91 ml, 3.98 mmol) was dried with activated molecular sieves and slowly added to the starting material. The reaction mixture was stirred at 0° C. for 10 min and then at ambient temperature for 30 min. The mixture was then brought back to 0° C. and quenched with EtOAc (50 ml) and aqueous HCl (1 M, 50 ml). The phases were separated and the aqueous phase was extracted with EtOAc (2×100 ml), dried (Na2SO4), filtered and evaporated to give an oil. The crude product was purified by flash column chromatography (isooctane/EtOAc 9:1) gave the title compound (0.81 g, 75%). MS m/z (rel. intensity, 70 eV) 264 (M+, 30), 262 (M+, 31), 233 (65), 231 (bp), 229 (41).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1.Br[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[C:13]1([CH2:12][CH2:11][CH2:10][N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCC1CCCNC1
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: OCC1CCCN(CCCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 10.07 g (87.43 mM) of 3-piperidinemethanol and 19.1 g (96.2 mM) of 1-bromo-3-phenylpropane in 150 ml of acetonitrile was added 18.1 g (131 mM) of potassium carbonate and the mixture was stirred at room temperature for one day. This reaction mixture was poured in water and extracted with 3 portions of ethyl acetate. The pooled organic layer was dried over MgSO4 and the solvent was distilled off under reduced pressure to provide crude 1-(3-phenylpropan-1-yl)piperidine-3-methanol. This crude product was not purified but used as it was in the next reaction. To a solution of this crude 1-(3-phenylpropan-1-yl)piperidine-3-methanol and 14.6 ml (105 mM) of triethylamine in 150 ml of tetrahydrofuran was added a solution of 11.0 g (96.2 mM) of methanesulfonyl chloride in 50 ml of tetrahydrofuran dropwise under ice-cooling and the mixture was further stirred at the prevailing temperature for 0.5 hour. This reaction mixture was poured in water and extracted with 3 portions of ethyl acetate. The pooled organic layer was dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was dissolved in 500 ml of N,N-dimethylformamide, followed by addition of 17.8 g (96.2 mM) of potassium phthalimide, and the mixture was stirred at 100° C. overnight. This reaction mixture was poured in water and extracted with 3 portions of ethyl acetate. The pooled organic layer was dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 to ethyl acetate) to provide the title compound.
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][C:8]=1[C:9]([O:11]C)=O)=[C:2]=[S:3].[CH3:20][C:21]1[N:25]([CH2:26][CH2:27][CH2:28][NH2:29])[CH:24]=[N:23][CH:22]=1>>[CH2:13]([C:6]1[S:5][C:4]2[NH:1][C:2](=[S:3])[N:29]([CH2:28][CH2:27][CH2:26][N:25]3[C:21]([CH3:20])=[CH:22][N:23]=[CH:24]3)[C:9](=[O:11])[C:8]=2[CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cc(Cc2ccccc2)sc1N=C=S
Reactant: Cc1cncn1CCCN
Product: Cc1cncn1CCCn1c(=S)[nH]c2sc(Cc3ccccc3)cc2c1=O

Procedure:
The compound was synthesized starting from methyl 2-isothiocyanato-5-benzylthiophene-3-carboxylate (0.10 g, 0.35 mmol) and 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (5) (0.048 g, 0.35 mmol) as described above.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]([F:16])=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([F:17])[CH:8]=2)[CH2:3]1.[C:18](Cl)(=O)[C:19](Cl)=[O:20].CN(C)C=O.C(Cl)[Cl:30]>>[C:19]([NH:1][CH:2]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]([F:16])=[CH:14][C:10]([C:11]([Cl:30])=[O:13])=[C:9]([F:17])[CH:8]=2)[CH2:3]1)(=[O:20])[CH3:18]
Reactant: NC1CCC(c2cc(F)c(C(=O)O)cc2F)C1
Reactant: O=C(Cl)C(=O)Cl
Reactant: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)NC1CCC(c2cc(F)c(C(=O)Cl)cc2F)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 14.2 g (50 mmole) of 4-[3-(amino)cyclopentyl]-2,5-difluorobenzoic acid in 200 ml of methylene chloride was treated with 6.4 g (50 mmol) of oxalyl chloride and 0.5 ml of dimethylformamide. The reaction mixture was stirred at room temperature for 18 hours and the solvent removed in vacuo. The residue was triturated with toluene which was also removed in vacuo. The residue was used without further purification.
Reaction SMILES: C(Cl)CCl.[C:5]([O:9][C:10](=[O:18])[C:11]([CH3:17])([CH3:16])[CH2:12][C:13]([OH:15])=[O:14])([CH3:8])([CH3:7])[CH3:6].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:29][C:30](=[O:65])/[C:31](/[CH3:64])=[CH:32]/[C@:33]34[CH2:59][C:58](=[O:60])[C:57]([CH:61]([CH3:63])[CH3:62])=[C:34]3[C@@H:35]3[C@@:48]([CH3:51])([CH2:49][CH2:50]4)[C@@:47]4([CH3:52])[C@@H:38]([C@:39]5([CH3:56])[C@@H:44]([CH2:45][CH2:46]4)[C:43]([CH3:54])([CH3:53])[C@@H:42](O)[CH2:41][CH2:40]5)[CH2:37][CH2:36]3)[CH2:28][CH2:27]2)=[CH:22][CH:21]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:16][C:11]([CH3:17])([CH2:12][C:13]([O:15][C@H:42]1[CH2:41][CH2:40][C@@:39]2([CH3:56])[C@@H:44]([CH2:45][CH2:46][C@:47]3([CH3:52])[C@@H:38]2[CH2:37][CH2:36][C@H:35]2[C@@:48]3([CH3:51])[CH2:49][CH2:50][C@@:33]3(/[CH:32]=[C:31](\[CH3:64])/[C:30]([NH:29][C:26]4([C:23]5[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=5)[CH2:27][CH2:28]4)=[O:65])[CH2:59][C:58](=[O:60])[C:57]([CH:61]([CH3:63])[CH3:62])=[C:34]32)[C:43]1([CH3:53])[CH3:54])=[O:14])[C:10]([O:9][C:5]([CH3:8])([CH3:6])[CH3:7])=[O:18]
Reactant: C/C(=C\[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2)C(=O)NC1(c2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)OC(=O)C(C)(C)CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: C/C(=C\[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2)C(=O)NC1(c2ccc(Cl)cc2)CC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
To a solution of DMAP (415 mg, 3.40 mmol), EDC (652 mg, 3.40 mmol) and 4-tert-butoxy-3,3-dimethyl-4-oxobutanoic acid (425 mg, 2.039 mmol) in DCM (10 mL) stirred at 20° C. for 30 min was added (E)-N-(1-(4-chlorophenyl)cyclopropyl)-3-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)-2-methylacrylamide (650 mg, 0.680 mmol). The reaction mixture was stirred at 20° C. for 2 h. The mixture was washed with saturated ammonium chloride, water, and saturated NaHCO3, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by silica gel column eluting with petroleum ether/Ethyl acetate (3:1) to afford 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-((1-(4-chlorophenyl)cyclopropyl)amino)-2-methyl-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (300 mg, 52%) as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.30-7.22 (m, 2H), 7.22-7.14 (m, 2H), 6.59 (s, 1H), 6.32 (s, 1H), 4.51 (dd, J=5.4, 10.9 Hz, 1H), 3.28-3.10 (m, 1H), 2.72 (d, J=10.3 Hz, 1H), 2.55 (s, 3H), 2.41-2.21 (m, 2H), 2.12-0.71 (m, 61H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([Cl:19])=[C:9]([CH:18]=1)[C:10]([NH:12][C:13]1[NH:14][CH:15]=[CH:16][N:17]=1)=[O:11].C(N(CC)CC)C.[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29]>C1COCC1>[Cl:19][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][NH:3][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])=[CH:18][C:9]=1[C:10]([NH:12][C:13]1[NH:14][CH:15]=[CH:16][N:17]=1)=[O:11]
Reactant: NCc1ccc(Cl)c(C(=O)Nc2ncc[nH]2)c1
Reactant: CC(C)C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2ncc[nH]2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
To a suspension of 5-(aminomethyl)-2-chloro-N-(1H-imidazol-2-yl)benzamide dihydrochloride (50 mg, 0.154 mmol, 1.0 equiv) in THF (0.77 mL), add triethylamine (80 μL, 0.57 mmol, 3.7 equiv) and isobutyryl chloride (16.3 μL, 0.154 mmol, 1.0 equiv), and stir the reaction mixture for 1 h at room temperature. Concentrate the reaction mixture under reduced pressure, triturate the crude solids with a mixture of water (10 mL), hexanes (10 mL), and diethyl ether (10 mL), isolate the white solid by filtration and dry in a 40° C. vacuum oven to give the title compound (19 mg, 38% yield): 1H NMR (DMSO-d6, 400 MHz): δ 11.74 (br s, 2H), 8.30 (t, 1H, J=6.0 Hz), 7.42 (d, 1H, J=8.0 Hz), 7.36 (d, 1H, J=2.0 Hz), 7.26 (dd, 1H, J=8.0, 2.0 Hz), 6.73 (br s, 2H), 4.22 (d, 2H, J=5.9 Hz), 2.37 (septet, 1H, J=6.6 Hz), 0.97 (d, 6H, J=6.8 Hz). MS (m/z) (35Cl/37Cl) 321/323 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[C:9]2[N:10]([C:14]([CH2:18][C:19]#[CH:20])=[C:15]([CH3:17])[N:16]=2)[CH:11]=[CH:12][CH:13]=1.Cl[CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][C:24]=1[CH3:29].O>CN(C)C=O>[CH3:17][C:15]1[N:16]=[C:9]2[C:8]([O:7][CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][C:24]=3[CH3:29])=[CH:13][CH:12]=[CH:11][N:10]2[C:14]=1[CH2:18][C:19]#[CH:20]
Reactant: Cc1cnccc1CCl
Reactant: C#CCc1c(C)nc2c(O)cccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCc1c(C)nc2c(OCc3ccncc3C)cccn12
Temperature: 25 °C
Reaction time: 5 h
Yield: 74.1 %

Procedure:
Potassium carbonate (0.52 g) was added to a solution of 8-hydroxy-2-methyl-3-(2-propynyl)imidazo[1,2-a]pyridine (0.5 g) and 4-chloromethyl-3-methylpyridine (0.53 g) in N,N-dimethylformamide (10 ml). The mixture was stirred under a nitrogen atmosphere for 5 hours at room temperature and then poured into water. The resulting precipitates were collected by filtration and recrystallized from ethyl acetate to give 2-methyl-8-(3-methyl-4-pyridylmethoxy)-3-(2-propynyl)imidazo[1,2-a]pyridine (0.58 g).