Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]([OH:24])=[O:23])[CH2:17][CH2:16]1)=O.[CH2:25]([S:27]([C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34](=[O:39])[CH2:33]2)(=[O:29])=[O:28])[CH3:26]>>[CH2:25]([S:27]([C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34](=[O:39])/[C:33]/2=[CH:1]\[C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH2:12][CH2:13][CH2:14][N:15]1[CH2:16][CH2:17][N:18]([CH2:21][C:22]([OH:24])=[O:23])[CH2:19][CH2:20]1)(=[O:28])=[O:29])[CH3:26]
Reactant: O=Cc1[nH]c2c(c1CCCN1CCN(CC(=O)O)CC1)CCCC2
Reactant: CCS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CCS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCCN1CCN(CC(=O)O)CC1)CCCC3)C(=O)N2
Yield: 30.8 %

Procedure:
{(4-[3-(2-Formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propyl]-piperazin-1-yl}-acetic acid (50 mg, 0.15 mmol), prepared as described in Example 18, was condensed with 5-ethylsulfonyloxindole (66 mg, 60% pure) following the same procedure used in example 1. The formed solid was purified by flash chromatography, eluting with (dichloromethane: methanol 8:1, 5:1:0.01 acetic acid) to give 25 mg of the desired product.
Reaction SMILES: [CH3:1][C:2]1[C:16]([CH3:17])=[CH:15][C:5]2[NH:6][C:7]([C:9]3[C:13]([NH2:14])=[CH:12][NH:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[CH2:28][C:29](Cl)=[O:30].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>ClCCl>[CH3:17][C:16]1[C:2]([CH3:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]3[C:13]([NH:14][C:29](=[O:30])[CH2:28][N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[CH:12][NH:11][N:10]=3)=[N:6][C:5]=2[CH:15]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1cc2nc(-c3n[nH]cc3N)[nH]c2cc1C
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2nc(-c3n[nH]cc3NC(=O)CN3CCOCC3)[nH]c2cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine [100 mg, Example 233(c)] and diisopropylethylamine (307 μl) in dichloromethane (10 ml) was treated with chloroacetyl chloride (105 μl). The reaction mixture was stirred for 30 minutes at room temperature, then treated with morpholine (575 μl), then kept at room temperature overnight and then evaporated. The oily residue was partitioned between ethyl acetate and water and the organic phase was washed with water, then dried over magnesium sulfate and then evaporated. The residue was subjected to flash chromatography on silica eluting with ethyl acetate to give the N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-morpholin-4-yl-acetamide (49.9 mg) as an off-white solid. MS: 355.68 (M+H)+. HPLC (METHOD B1): RT=8.28 minutes.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=2[C:16]([F:19])([F:18])[F:17])[CH:6]=1>C(O)C.[Pd]>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=2[C:16]([F:19])([F:17])[F:18])[CH:6]=1
Reactant: Cc1cn(-c2ccc([N+](=O)[O-])cc2C(F)(F)F)cn1
Agent: [Pd]
Solvent: CCO
Product: Cc1cn(-c2ccc(N)cc2C(F)(F)F)cn1
Yield: 101.1 %

Procedure:
4-Methyl-1-(2-(trifluoromethyl)-4-nitrophenyl)-1H-imidazole (1.1 g, 4.1 mmol) was suspended in 50 mL of anhydrous ethanol. The mixture was hydrogenated with 0.11 g of 10% Pd—C at 40 psi for 3 hrs. Then Pd—C was removed by filtration. The filtrate was evaporated to give the title compound 1.0 g as a yellow solid (102.0%). 1H NMR (300 MHz, CDCl3) δ: 7.42 (1H, s), 7.08-7.11 (1H, d, J=8.4 Hz), 6.99 (1H, d, J=2.4 Hz), 6.80-6.84 (1H, dd, J=2.1 and 8.4 Hz), 6.74 (1H, s), 4.14 (2H, brs), 2.27 (3H, s). LCMS: m/z [M+H]+ 242.0957.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:63][N:64]1[CH2:69][CH2:68][N:67]([CH2:70][CH:71]2[CH2:76][CH2:75][CH2:74][CH2:73][NH:72]2)[CH2:66][CH2:65]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:72]1[CH2:73][CH2:74][CH2:75][CH2:76][CH:71]1[CH2:70][N:67]1[CH2:68][CH2:69][N:64]([CH3:63])[CH2:65][CH2:66]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CN1CCN(CC2CCCCN2)CC1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCCCC3CN3CCN(C)CC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 1-methyl-4-(piperidin-2-ylmethyl)-piperazine in DMSO at ambient temperature.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.O1CCCC1.[CH3:24][C@H:25]1[CH2:30][CH2:29][C@H:28](O)[CH2:27][CH2:26]1.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>>[CH3:18][C@@:12]1([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([O:1][C@H:28]4[CH2:29][CH2:30][C@@H:25]([CH3:24])[CH2:26][CH2:27]4)[CH:3]=3)[CH:8]=2)[CH2:16][O:15][C:14](=[O:17])[NH:13]1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Reactant: C[C@H]1CC[C@H](O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@]1(c2ccc3cc(O[C@H]4CC[C@@H](C)CC4)ccc3c2)COC(=O)N1
Temperature: 25 °C

Procedure:
(R)-4-(6-Hydroxynaphthalen-2-yl)-4-methyl-oxazolidin-2-one (Example 4, 0.3144 g, 0.001292 mol) was dissolved in tetrahydrofuran (5.00 mL, 0.0616 mol) in a capped 40 mL vial. trans-4-Methyl-cyclohexanol (0.177 g, 0.00155 mol) and triphenylphosphine polymer-bound (1.12 g, 0.00207 mol) were added and the mixture was stirred at room temperature. Diisopropyl azodicarboxylate (0.407 mL, 0.00207 mol) was added and the mixture was stirred for 2 days at room temperature. The mixture was filtered through CELITE™, concentrated and purified by flash column chromatography (0-30% EtOAc in methylene chloride) to give 0.3059 g of the title compound (69% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CCOCC.O>[CH2:17]([N:12]1[CH:11]=[C:10]([C:13]([F:14])([F:16])[F:15])[N:9]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: FC(F)(F)c1cnc(-c2ccc(Br)cc2)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: FC(F)(F)c1cn(Cc2ccccc2)c(-c2ccc(Br)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
A mixture of 2-(4-bromophenyl)-5-(trifluoromethyl)-1H-imidazole (3 g), benzyl bromide (3.52 g), potassium carbonate (2.85 g) and N,N-dimethylformamide (30 mL) was stirred at room temperature overnight. To the reaction mixture were added water and ether, and the liquids were separated. The organic layer was separated, washed with water and then with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in toluene, and purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0 to 70:30) to obtain 1-benzyl-2-(4-bromophenyl)-4-(trifluoromethyl)-1H-imidazole (3.40 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[S:8][N:7]=[N:6][C:5]=1[CH3:9].[CH2:10](Br)[CH:11]=[CH2:12].C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]([CH3:23])=O>>[CH2:10]([N:2]([CH2:3][C:4]1[S:8][N:7]=[N:6][C:5]=1[CH3:9])[CH2:23][CH:21]=[CH2:20])[CH:11]=[CH2:12]
Reactant: CC(C)=O
Reactant: Cc1nnsc1CN
Reactant: C=CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCN(CC=C)Cc1snnc1C
Reaction time: 20 h
Yield: 67 %

Procedure:
To 15 ml of acetone were added 0.50 g (3.0 mmol) of 5-aminomethyl-4-methyl-1,2,3-thiadiazole hydrochloride, 1.10 g (9.0 mmol) of allyl bromide and 2.1 g (15 mmol) of potassium carbonate. The resulting mixture was stirred for 20 hours with heating under reflux. After the reaction was completed, the reaction mixture was filtered to remove the precipitated matter, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using 3:1 mixture of n-hexane and ethyl acetate. Thus, 0.42 g of the objective compound was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]([OH:23])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]([O:23][CH3:24])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)cc2C(=O)O)CC1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1cc(Cl)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2-Carboxy-4-chloro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.64 g, 1.88 mmol) in toluene: methanol (9:1) was added a trimethylsilyldiazomethane (2.0 M in hexanes) (1.05 mL, 2.07 mmol) and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and purified using gradient elution from hexane/ethyl acetate (10%) to hexane/ethyl acetate (50%). 1H-NMR (CDCL3) δ: 1.45 (9H, s), 2.90-3.00 (4H, m), 3.50-3.60 (4H, m), 3.90 (3H, s), 6.90-7.00 (1H, d), 7.35-7.45 (1H, dd), 7.80 (1H, d). ESI-MS m/z: 355 (M+1), UV retention time: 3.11 min.
Reaction SMILES: [CH2:1]([N:8]1[CH:17]2[CH:12]([CH:13]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:15][CH2:16]2)[NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32](Cl)=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30].[OH-].[Na+]>C(Cl)Cl>[CH2:1]([N:8]1[CH:17]2[CH:12]([CH:13]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:15][CH2:16]2)[N:11]([C:32](=[O:33])[CH2:31][C:26]2[CH:27]=[CH:28][C:29]([Cl:30])=[C:24]([Cl:23])[CH:25]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNC3C(N4CCCC4)CCCC32)cc1
Reactant: O=C(Cl)Cc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCN(Cc2ccccc2)C2CCCC(N3CCCC3)C21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(4aRS,5SR,8aRS)-1-Benzyl-5-(pyrrolidin-1-yl)perhydroquinoxaline (325 mg, 1.09 mmol) was dissolved in abs. CH2Cl2 (35 ml). 2-(3,4-Dichlorophenyl)acetyl chloride (291 mg, 1.3 mmol) was added dropwise and the mixture was stirred at room temperature. After 30 minutes, 2 N NaOH (35 ml) was added and the mixture was stirred vigorously for 2 hours. The aqueous phase was separated off. The organic phase was extracted by shaking three times with HCl (1 N). The aqueous phase was then brought to pH 8 with NaOH (2 N) and extracted by shaking three times with CH2Cl2. The organic phases were dried over Na2SO4 and evaporated in vacuo. A pale yellow solid was obtained.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[NH:15][C:14](=[O:18])[CH:13]=[N:12]2)=[C:7]([F:19])[CH:6]=1)([CH3:3])[CH3:2].[H-].[Na+].I[CH3:23].Cl>CN(C)C=O>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[N:15]([CH3:23])[C:14](=[O:18])[CH:13]=[N:12]2)=[C:7]([F:19])[CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(-n2ncc(=O)[nH]c2=O)c(F)c1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-n2ncc(=O)n(C)c2=O)c(F)c1
Reaction time: 1 h
Yield: 81.5 %

Procedure:
A solution of 3.25 g (0.0123 mole) of 2-(4-isopropoxy-2-fluorophenyl)-1,2,4-triazine-3,5-dione in 30 mL of N,N-dimethylformamide was added to a suspension of 0.50 g (0.0125 mole) of sodium hydride in 30 mL of N,N-dimethylformamide at ambient temperature. When gas evolution had ceased, 3.55 g (0.025 mole) of iodomethane was added in one portion. This mixture was stirred for one hour without heating and was then poured into 300 mL of dilute hydrochloric acid. The resulting mixture was extracted several times with diethyl ether, and the extracts were combined. The ether extract was washed in succession with water and a saturated aqueous solution of sodium chloride. It was then dried over anhydrous magnesium sulfate and filtered through a short column of silica gel. The solvent was evaporated under reduced pressure, leaving 2.80 g of 2-(4-isopropoxy-2-fluorophenyl)-4-methyl-1,2,4-triazine-3,5-dione as a syrup. The NMR was consistent with the proposed structure.
Reaction SMILES: Br[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:15][C:16]1[CH:17]=[C:18]([OH:25])[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[F:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[O:25][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OC(c2ccccc2)c2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Bromodiphenylmethane (3.5 g) and 3-fluoro-4-nitrophenol were dissolved in N,N-dimethylformamide (30 mL), and then K2CO3 (4.2 g) was added and the reaction stirred at room temperature for 60 hours. The reaction was partitioned between water and ethyl acetate. The organic layer was washed with 2M aqueous Na2CO3 and brine, then dried over Na2SO4. After filtration and concentration, the crude material was purified by column chromatography using 1.5-2.0% ethyl acetate in hexanes.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[CH3:24][CH:25]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C=O)C>[CH3:8][C:6]1[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=[C:2]([N:27]2[CH2:28][CH2:29][CH2:30][CH:25]([CH3:24])[CH2:26]2)[N:7]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Reactant: CC1CCCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCC(C)C2)nc1-c1ccc(C)cc1
Temperature: 110 °C
Yield: 56.5 %

Procedure:
A mixture of methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.100 g; 0.300 mmol), 3-methylpiperidine (0.106 mL; 0.901 mmol) and triethylamine (0.211 mL; 1.50 mmol) in a mixture of tetrahydrofuran (2 mL) and DMF (0.4 mL) was heated at 110° C. in a sealed tube for 18 h. After cooling, the reaction mixture was diluted in a saturated solution of sodium hydrogen carbonate and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-20%) in heptane furnished 0.067 g (57%) of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([CH:3]1[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH2:6][CH2:5][NH:4]1)[CH3:2].[CH3:12][N:13]=[C:14]=[O:15]>O1CCOCC1.C(OCC)(=O)C>[CH2:1]([CH:3]1[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH2:6][CH2:5][N:4]1[C:14](=[O:15])[NH:13][CH3:12])[CH3:2]
Reactant: CCC1NCCc2[nH]cnc21
Reactant: CN=C=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCC1c2nc[nH]c2CCN1C(=O)NC

Procedure:
A solution of 1.51 g of 4-ethyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine and 2.28 g of methyl isocyanate in 20 ml of dry dioxane is refluxed for 1.5 h. The solution is cooled and filtered. The solid collected is dissolved in 30 ml of methanol and treated with 7 ml of 2N sodium hydroxide for 2 h at room temperature. After neutralization the solution is extracted with chloroform. Evaporation of the solvent leaves a residue that is taken up in ethyl acetate. 1.05 g of the title compound, m.p. 240°, are collected.
Reaction SMILES: Cl[CH2:2][C:3]#N.[OH2:5].O.[C:7]1([CH:15]=[C:13]([OH:14])[CH:12]=[C:10]([OH:11])[CH:9]=1)[OH:8].Cl>CCOCC.[Cl-].[Zn+2].[Cl-]>[OH:8][C:7]1[C:15]2[C:2](=[O:5])[CH2:3][O:14][C:13]=2[CH:12]=[C:10]([OH:11])[CH:9]=1
Reactant: O
Reactant: N#CCCl
Reactant: Oc1cc(O)cc(O)c1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Product: O=C1COc2cc(O)cc(O)c21
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.7 %

Procedure:
Chloroacetonitrile (4 ml, 63.2 mmol) was added dropwise to a stirred solution containing phloroglucinol dihydrate (10 g, 61.7 mmol) and zinc chloride (8.5 g, 62.4 mmol) in anhydrous ether (100 ml) at room temperature. The resulting solution was then saturated with hydrogen chloride gas. After stirring at room temperature for 24 hours, the orange precipitates were filtered and washed with anhydrous ether (50 ml). The precipitates were then dissolved in water (100 ml) and heated at 100° C. for 1 hr. The solution was allowed to cool to ambient temperature, and aqueous sodium hydroxide (20% w/v) (10 ml) was then added. After stirring at room temperature for an additional 30 minutes, the reaction mixture was acidified by adding dilute hydrochloric acid (1M, 50 ml) and was extracted with ethyl acetate (2×250 ml). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to afford a light orange solid which was then recrystallized from ethyl acetate to give 4,6-dihydroxy-3-benzofuranone as a light orange powder (9.5 g, 93%).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([C@@:10]1([CH2:24][CH:25]=[O:26])[CH2:14][C:13](=[O:15])[N:12]([C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C>CO>[C:3]([O:7][C:8]([C@@:10]1([CH2:24][CH2:25][OH:26])[CH2:14][C:13](=[O:15])[N:12]([C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: C[C@H](c1ccccc1)N1C[C@@](CC=O)(C(=O)OC(C)(C)C)CC1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@H](c1ccccc1)N1C[C@@](CCO)(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Yield: 80.6 %

Procedure:
Sodium borohydride (465 mg) was added to a solution of (3S)-5-oxo-3-(2-oxoethyl)-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (2.71 g, 8.19 mmol) in methanol at −40° C. After heating to room temperature, a 10% citric acid solution was added to the reaction solution, and the mixture was stirred. The reaction solution was poured into a mixture of ethyl acetate (50 mL) and a 10% citric acid solution (10 mL), followed by extraction with ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (100 mL), and then the organic layers were combined and washed with brine (50 mL×2). The resulting organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:1→0:1→ethyl acetate-methanol=10:1) to give 2.20 g (81%) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:10][C:4]1[CH:3]=[C:2]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[F:11])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: OB(O)c1ccccc1F
Reactant: N#Cc1ccc(Br)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2ccccc2F)cc1Cl
Yield: 99.3 %

Procedure:
A mixture of 4-bromo-2-chlorobenzonitrile (2.2 g, 10 mmol) and 2-fluorobenzeneboronic acid (1.82 g, 13 mmol) in tetrahydrofuran (30 ml) was treated with 2M sodium carbonate (13 ml) then degassed with nitrogen for 10 min. Tetrakis(triphenylphosphine)palladium(0) (0.58 g, 0.5 mmol) was added and this mixture was heated under reflux for 12 h. The resulting mixture was partitioned between dichloromethane and water. The organics were washed with water, brine, dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo. Purification of the residue by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (5-15%) gave 3-chloro-2′-fluorobiphenyl-4-carbonitrile as a white solid (2.3 g, 99%): δH (400 MHz, CDCl3) 7.17-7.57 (5H, m), 7.64-7.75 (2H, m).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH:8][C:9](=[O:38])[O:10][C@@H:11]2[CH2:27][C@@H:26]3[C@@:14]([CH3:37])([C@@H:15]4[C@@H:23]([CH2:24][CH2:25]3)[C@:22]3(O)[C@@:18]([CH3:36])([C@@H:19]([C:29]5[CH:30]=[CH:31][C:32](=[O:35])[O:33][CH:34]=5)[CH2:20][CH2:21]3)[CH2:17][CH2:16]4)[CH2:13][CH2:12]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O=S(Cl)Cl>N1C=CC=CC=1>[N:1]1([CH2:6][CH2:7][NH:8][C:9](=[O:38])[O:10][C@@H:11]2[CH2:27][C@@H:26]3[C@@:14]([CH3:37])([C@@H:15]4[C@@H:23]([CH2:24][CH2:25]3)[C:22]3[C@@:18]([CH3:36])([C@@H:19]([C:29]5[CH:30]=[CH:31][C:32](=[O:35])[O:33][CH:34]=5)[CH2:20][CH:21]=3)[CH2:17][CH2:16]4)[CH2:13][CH2:12]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@]12CC[C@H](OC(=O)NCCN3CCCC3)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccc(=O)oc3)CC[C@]12O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: C[C@]12CC[C@H](OC(=O)NCCN3CCCC3)C[C@H]1CC[C@H]1C3=CC[C@H](c4ccc(=O)oc4)[C@@]3(C)CC[C@@H]12
Reaction time: 2 h
Yield: 78.6 %

Procedure:
To a solution of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-(pyrrolidin-1-yl)ethylcarbamate (54 mg, 0.1 mmol, 1 eq) in pyridine (3 mL) was added SOCl2(71.4 mg, 0.6 mmol) at 0° C. The mixture was stirred at this temperature for about 2 h, quenched with saturated NaHCO3, and extracted with EtOAc. The organic layers were combined, dried with Na2SO4, concentrated and purified via Preparative TLC to afford (3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-(pyrrolidin-1-yl)ethylcarbamate (40 mg, 78.7%). LCMS (M+H+) m/z calculated 508.33. found 509.4. 1H NMR (CD3OD, 400 MHz) δ 7.63 (m, 2 H), 6.38 (m, 1 H), 5.36 (m, 1 H), 5.00 (m, 1 H), 3.38 (m, 2 H), 3.10 (m, 6 H), 2.90 (m, 1H), 2.60 (m, 1 H), 2.50 (m, 1 H), 2.30-1.30 (m, 21 H), 1.10(s, 3 H), 0.86 (s, 3 H).