Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH:7]2[CH2:12][CH:11]3[CH2:13][CH2:14][CH:8]2[CH2:9][CH:10]3O)=[CH:4][CH:3]=1.Cl.Cl.[NH2:20][CH2:21][C:22]1[NH:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.ClCCCl>[NH:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=[C:22]1[CH2:21][NH:20][CH:10]1[CH2:9][CH:8]2[CH2:14][CH2:13][CH:11]1[CH2:12][CH:7]2[CH2:6][C:5]1[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: NCc1nc2ccccc2[nH]1
Reactant: OC1CC2CCC1CC2Cc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: Clc1ccc(CC2CC3CCC2CC3NCc2nc3ccccc3[nH]2)cc1
Reaction time: 8 h

Procedure:
Example 6 was prepared in a similar manner to Examples 4 and 5 above. A mixture of 250 mg of 3:1 mixture of exo and endo 5-(4-chloro-benzyl)-bicyclo[2.2.2]octan-2-one was prepared from 5-acetoxy-5-cyanobicyclo[2.2.2]octan-2-one in three sequential steps without isolating intermediate products. The first two steps were similar to those described in Steps 1 and 2 of Example 4 above, sequential treatment with sodium borohydride in ethanol, sodium hydroxide, formed 5-hydroxy-bicyclo[2.2.2]octan-2-one. Olefination, hydrogenation, and Swern oxidation of the product, 5-(4-chloro-benzyl)-bicyclo[2.2.2]octan-2-ol followed. To the resulting product was added 400 mg of 2-aminomethylbenzimidazole dihydrochloride, 150 mg of anhydrous sodium acetate, 10 mL of 1,2-dichloroethane and 400 mg of sodium triacetoxyborohydride, and stirred overnight in a stoppered flask. The mixture was diluted with 50 mL of chloroform and washed with 20 mL of saturated sodium carbonate. The organic extract was dried over magnesium sulfate and concentrated under reduced pressure. Preparative TLC eluting with 95:5:5 ethyl acetate:methanol:triethyl amine gave (1H-benzimidazol-2-ylmethyl)-[5-(4-chloro-benzyl)-bicyclo[2.2.2]oct-2-yl]-amine as a racemic mixture of four diastereomers: MS (m+1)=380.9; 1H NMR (400 MHz, CDCl3) 7.6 (br s, 1H), 7.2 (m, 4H), 7.05 (m, 2H), 4.04 and 4.06 (2×s, 2H), 2.85 (m, 1H), 2.6-5 (m, 3H), 2.0-1.0 (complex, 12H).
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[C:26]([C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27].C(N(CC)CC)C.Cl>CN(C=O)C>[C:26]([C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH:6][CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH2:11]3)=[O:38])=[CH:32][CH:31]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1
Reaction time: 2 h
Yield: 76 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.37 g, 1.0 mmol) and 4-(tert-butyl)phenyl isocyanate (0.18 g, 1.0 mmol) in DMF (20 mL) was added triethylamine (0.22 g, 2.2 mmol) at rt under nitrogen. After 2 h, 4% aqueous HCl (30 ml) was added and the solids were filtered and dried in vacuo providing 1-(4-tert-butyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid, (0.34 g, 76% yield); mp 254-256° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 7.71 (96.94%); 1H NMR (DMSO-d6) δ 1.24 (s, 9H), 1.97-2.01 (m, 1H), 2.35-2.45 (m, 1H), 2.54-2.62 (m, 1H), 2.85-2.97 (m, 1H), 4.30 (d, 2H, J=17.3 Hz), 4.45 (d, 2H, J=17.3 Hz), 5.10 (dd, 1H, J=12.9 Hz, J=4.5 Hz), 6.68 (t, 1H, J=4.8 Hz), 7.23 (dd, 2H, J=8.4 Hz, J=1.5), 7.31 (dd, 2H, J=8.4 Hz, J=1.5 Hz), 7.44 (d, 1H, J=7.8 Hz), 7.51 (s, 1H), 7.69 (d, 1H, J=7.8 Hz), 8.54 (s, 1H), 10.98 (s, 1H); 13C NMR (DMSO-d6) δ 22.5, 31.2, 31.3, 33.8, 42.7, 47.1, 51.6, 117.6, 121.8, 122.9, 125.2, 126.9, 130.3, 137.7, 142.4, 143.4, 144.9, 155.3, 167.9, 170.9, 172.8; LCMS: MH=449; Anal. Calcd for C25H28N4O4+0.5H2O: C, 65.63; H, 6.39; N, 12.25. Found: C, 65.24; H, 6.17; N, 12.29.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([O:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:8]=1)[NH2:5].[O:16]([CH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=O)C1C=CC=CC=1.C(N=C=NCCCN(C)C)C.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.CN1CCCC1=O.[Cl-].[NH4+].O>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[CH2:26][C:25]3[C:24](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:23]2=[O:16])[CH:6]=[C:7]([O:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:8]=1
Reactant: O=C(O)c1ccccc1COc1ccccc1
Reactant: Nc1cc(F)cc(Oc2cccnc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C1c2ccccc2CN1c1cc(F)cc(Oc2cccnc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-fluoro-5-(pyridine-3-yloxy)aniline (200 mg) in pyridine (5.0 ml), 230 mg of 2-(phenoxymethyl)benzoic acid and 250 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide were added, and the reaction solution was stirred at room temperature for 1 hour. Water and a saturated aqueous ammonium chloride solution were added to the reaction solution, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with a 1N aqueous hydrochloric acid solution and a saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product as colorless oil. To a solution of the obtained crude product in N-methylpyrrolidone (5.0 ml) was added 410 mg of potassium carbonate, and the mixture was stirred at 120° C. for 8 hours. The reaction solution was cooled, thereafter diluted with a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The combined organic layers were washed with water and a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resultant residue was purified by silica gel chromatography to yield the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl[C:18]1[C:23]([CH3:24])=[CH:22][C:21]([N+:25]([O-:27])=[O:26])=[CH:20][N:19]=1>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:18]2[C:23]([CH3:24])=[CH:22][C:21]([N+:25]([O-:27])=[O:26])=[CH:20][N:19]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc([N+](=O)[O-])cnc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 66.5 %

Procedure:
Add a suspension of pre-washed NaH (1.27 g, 31.87 mmol, 60% dispersion in mineral oil) in THF (20 mL) to an ice cold solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (6.41 g, 31.87 mmol) in dry THF (80 mL). Allow the mixture to stir for 20 minutes, then add 2-chloro-3-methyl-5-nitro pyridine (5 g, 28.97 mmol) in portions. After addition is completed, remove cooling bath and stir the reaction mixture at 22° C. overnight. Cool the reaction mixture with an ice bath and add a saturated aq. sodium bicarbonate solution (50 mL). Distribute the reaction mixture between ethyl acetate (350 mL) and distilled water (150 mL). Isolate the aqueous phase and extract with ethyl acetate (1×100 mL). Combine organic layers and wash with saturated aq. sodium chloride solution (2×150 mL). Dry the combined organic phases over sodium sulfate and concentrate. Subject residue to silica gel chromatography eluting with hexanes and ethyl acetate to give 4-(3-methyl-5-nitro-pyridin-2-yloxy)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (6.5 g, 67% yield). MS(ES): m/z=360.3 [M+Na].
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]([C:5]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)=[O:4].[ClH:25]>C(OCC)(=O)C.O1CCOCC1>[ClH:25].[CH3:1][N:2]([CH3:24])[C:3]([C:5]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1)=[O:4]
Reactant: CN(C)C(=O)C1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CN(C)C(=O)C1(c2ccccc2)CCNCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
900 mg (2.7 mmole) of N,N-dimethyl-1-t-butoxycarbonyl-4-phenylpiperidine-4-carboxamide (prepared as described in Preparation 1) were dissolved in 10 ml of ethyl acetate, and 5 ml of a 4 N solution of hydrogen chloride in dioxane were added, whilst ice-cooling. The mixture was then stirred at 0° C. for 1 hour. At the end of this time, the crystals which had deposited were collected by filtration, to give 690 mg (yield 95%) of the title compound as white crystals.
Reaction SMILES: [I-].C([N+]1(C)[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10]1)C1C=CC=CC=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[NH2:26].C(=O)([O-])[O-].[K+].[K+]>O.C(O)C>[CH2:16]([CH:11]1[C:12](=[O:15])[CH2:13][CH2:14][N:26]([C:25]2[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:23]([O:22][CH3:21])[CH:24]=2)[CH2:10]1)[CH2:17][CH2:18][CH3:19]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: CCCCC1C[N+](C)(Cc2ccccc2)CCC1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCCCC1CN(c2cc(OC)c(OC)c(OC)c2)CCC1=O
Yield: 204.8 %

Procedure:
A slurry of 1-benzyl-3-butyl-1-methyl-4-oxo-piperidinium iodide (306 mg) in water (2 ml) was added in one portion to a refluxing solution of 3,4,5-trimethoxy aniline (929 mg) and anhydrous potassium carbonate (33 mg) in ethanol (4 ml). The dark solution was heated to reflux for three hours. Water was added and the reaction was extracted twice with DCM. The combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated to leave a dark oil, which was purified by flash chromatography (ethyl acetate/hexanes 1:1) to give the product as a colorless oil (520 mg). MS (ESI): 322.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C@@H:14]([CH3:32])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[H-].[Na+].BrC[C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1.C(O)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:31])[C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:37]4[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=4)=[CH:27][CH:28]=3)[C@@H:14]([CH3:32])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: BrCc1ccncc1
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCc3ccncc3)cc2)c2ccccc21
Reaction time: 0.5 h

Procedure:
The phenol was dissolved in DMF (5 mL) at room temperature. Sodium hydride (60% in oil) was added and the mixture allowed to stir 30 min. 4-Bromomethyl-pyridine was added and the reaction was allowed to stir over night. Ethanol was added and the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography (2/98 methanol/dichloromethane-5/95 methanol/dichloromethane gradient) to afford the product.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([P:20](=[O:31])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1.CCN(CC)CC>C(Cl)Cl>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]([P:20](=[O:31])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:11])=[CH:14][CH:15]=1
Reactant: Cc1ccc(C(O)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of oxalyl chloride (1.75 mL) in CH2Cl2 (60 mL) cooled at −78° C. was added DMSO (2.8 mL) dropwise. The mixture was stirred for 10 min at −78° C. and a solution of di(tert-butyl) hydroxy(4-methylphenyl)methylphosphonate (3.14 g in 20 mL of CH2Cl2 was introduced dropwise. After stirring for 30 min at −78° C., 14 mL of Et3N was added. The resulting mixture was stirred for 30 min at −78° C. and 45 min at room temperature, and then quenched with 200 mL of 50% saturated aqueous NaCl solution. The mixture was extracted with 2×200 mL of 1:1 hexane/EtOAc and the extract was dried over MgSO4 and concentrated to give 3 g of the title compound as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=O)[CH3:18])[C:12]=2[OH:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:21]([C:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[C:27]([OH:35])[CH:26]=1)=[O:24])[NH2:22]>C(O)(C)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=[N:22][NH:21][C:23]([C:25]3[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[C:27]([OH:35])[CH:26]=3)=[O:24])[CH3:18])[C:12]=2[OH:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(C(=O)NN)cc1O
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O
Solvent: CC(C)O
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(C(C)(C)C)cc3)c2O)cc1O
Temperature: 0 °C
Yield: 80.7 %

Procedure:
1-[5-(4-tert-Butylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (0.578 mmol, 157.5 mg) synthesized in Synthetic Example 3, methyl 4-hydrazinocarbonyl-2-hydroxybenzoate (0.578 mmol, 121.6 mg) synthesized in Reference Synthetic Example 43 and p-tosylic acid monohydride (30 mol %, 30 mg) were dissolved in isopropyl alcohol (15 mL) and stirred under heating with reflux for 8 hours, and the reactor was cooled to 0° C. The reaction solution was filtered and dried by means of a vacuum pump to give the desired product as a white solid (216.6 mg, yield 81%).
Reaction SMILES: [C:1]([CH:5]1[C:10](=[O:11])[CH2:9][CH:8]([CH2:12][CH2:13][S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:7][C:6]1=[O:25])(=O)[CH2:2][CH3:3].Cl.[CH2:27]([O:30][NH2:31])[CH:28]=[CH2:29].C(N(CC)CC)C.O>C(O)C>[CH2:27]([O:30][NH:31][C:1](=[C:5]1[C:6](=[O:25])[CH2:7][CH:8]([CH2:12][CH2:13][S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:9][C:10]1=[O:11])[CH2:2][CH3:3])[CH:28]=[CH2:29]
Reactant: CCC(=O)C1C(=O)CC(CCSc2ccc(C(F)(F)F)cc2)CC1=O
Reactant: C=CCON
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: C=CCONC(CC)=C1C(=O)CC(CCSc2ccc(C(F)(F)F)cc2)CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.19 Gram of 2-propionyl-5-[2-(4-trifluoromethylphenylthio)ethyl]cyclohexane-1,3-dione was dissolved in 5 ml of ethanol, and 0.07 g of allyloxyamine hydrochloride and 0.06 g of triethylamine were added to the resulting solution which was then stirred overnight at room temperature. The reaction solution was poured into water, acidified and extracted with chloroform. After removing chloroform, the residue was purified by thin layer chromatography (eluent, hexane:ethyl acetate=5:1) to obtain 0.13 g of 2-(1-allyloxyaminopropylidene)-5-[2-(4-trifluoromethylphenylthio)ethyl]cyclohexane-1,3-dione.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:9])[N:3]=1.[CH:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](OC2C=CC=CC=2)=[N:18][C:19]#[N:20])=[CH:12][CH:11]=1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([CH3:9])[C:5]([NH:8][C:17](=[N:18][C:19]#[N:20])[O:16][C:13]2[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: Cc1nc(N)ccc1N
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: COCCOC
Product: Cc1nc(N)ccc1NC(=NC#N)Oc1ccccc1
Yield: 41.2 %

Procedure:
A stirred mixture of the product from Step 1 (4.34 g, 0.0353 mol), diphenylcyanocarbonimidate (8.4 g, 0.0353 mol) and ethylene glycol dimethyl ether (40 ml) was kept under nitrogen at ambient temperature (25° C.) for 18 hours. The mixture was concentrated and the residue was purified by silica gel chromatography and crystallization from MeOH-EtOAc-hexane to give 3.89 g of the titled product, mp 189°-190° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[C@@H:24]2[CH2:28][C@H:27]([N:29]3[CH:33]=[C:32]([CH2:34][OH:35])[CH:31]=[N:30]3)[C@@H:26]([OH:36])[C@H:25]2[OH:37])=[C:17]([NH:38][CH2:39][CH:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:16]=1)=[O:14].[CH2:53]([N:55]=[C:56]=[O:57])[CH3:54].C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:53]([NH:55][C:56](=[O:57])[NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[C@@H:24]2[CH2:28][C@H:27]([N:29]3[CH:33]=[C:32]([CH2:34][OH:35])[CH:31]=[N:30]3)[C@@H:26]([OH:36])[C@H:25]2[OH:37])=[C:17]([NH:38][CH2:39][CH:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:16]=1)=[O:14])[CH3:54]
Reactant: NCCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1
Reactant: CCN=C=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)NCCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1

Procedure:
9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid (3-amino-propyl)-amide trifluoroacetate (Example 63) (10 mg, 0.027 mmol) is dissolved in dry DMF (0.25 ml). Ethyl isocyanate (0.92 mg, 0.013 mmol) is dissolved in dry DMF (0.25 ml). The two solutions were combined and triethylamine (>1 eq) is added. The reaction mixture is allowed to stand at room temperature over night. The solvent is removed in vacuo. Purification is carried out using mass directed preparative LC-MS eluting with acetonitrile: water: trifluoroacetic acid to afford the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[S:12])[N:8]([CH3:13])[C:7]2=[O:14].[C:15](=O)([O-])[O-].[K+].[K+].N[C@H](C(O)=O)CCSC>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([S:12][CH3:15])[N:8]([CH3:13])[C:7]2=[O:14]
Reactant: O=C([O-])[O-]
Reactant: Cn1c(=S)[nH]c2c(Br)cccc2c1=O
Agent: CSCC[C@H](N)C(=O)O
Agent: [K+]
Solvent: C1CCOC1
Product: CSc1nc2c(Br)cccc2c(=O)n1C
Yield: 100 %

Procedure:
A suspension of 8-bromo-3-methyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (1.00 g, 3.69 mmol), potassium carbonate (0.510 g, 3.69 mmol), and Met (0.344 mL, 5.53 mmol) in THF (7.0 mL) was stirred at 25° C. for 3d. The mixture was vacuum filtered, and the filtrate was concentrated in vacuo to provide 8-bromo-3-methyl-2-(methylthio)quinazolin-4(3H)-one (1.052 g, 3.69 mmol, 100% yield) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ ppm 8.18 (1H, dd, J=7.9, 1.1 Hz), 7.96 (1H, dd, J=7.6, 1.2 Hz), 7.22 (1H, t, J=7.8 Hz), 3.62 (3H, s), 2.75 (3H, s). m/z (ESI, +ve) 284.9 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:41])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([CH3:40])[CH:35]=2)[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:16]1([CH2:15][O:14][C:12]2[C:11]([C:19]([F:21])([F:22])[F:20])=[CH:10][C:9]3[NH:23][C:24](=[O:41])[CH2:25][C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]5[CH:39]=[CH:38][N:37]=[C:36]([CH3:40])[CH:35]=5)[CH:29]=4)=[N:7][C:8]=3[CH:13]=2)[CH2:17][CH2:18]1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC4CC4)cc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(OCC5CC5)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (5-cyclopropylmethoxy-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M177) (279 mg, 0.48 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (144 mg, 64%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].C1CCN2C(=NCCC2)CC1.Br[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29]>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:6](=[O:11])[C:5]2=[O:12]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: COC(=O)CCCBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COC(=O)CCCN1C(=O)C(=O)c2cc(I)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
Into a solution of 5-iodo-1H-indole-2,3-dione (1.0 g, 3.66 mmol) in anhydrous THF (18 ml) were added DBU (0.82 mL, 5.49 mmol) and methyl 4-bromobutanoate (0.6 mL, 5.49 mmol). After stirring at rt for 2 hrs, the reaction mixture was quenched with water (60 mL) and HCl (IN, 10 mL). Extraction with EtOAc (3×50 mL), drying over MgSO4 and evaporation under vacuo gave a residue. Purification by flash chromatography (chexanes/Et2O (1/3)) gave the title compound as an orange powder (1.10 g, 71%) in 90.1% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: CS([O:5][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH2:9]3)O1)[CH2:13]2)(=O)=O.[Cl-].[Cl-].[Cl-].[Al+3].[OH-].[Na+]>ClCCCl.O.C1COCC1>[O:5]=[C:6]1[CH2:15][CH:10]2[CH2:11][CH:12]([CH2:14][C:8]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:9]2)[CH2:13]1
Reactant: CCOC(=O)CC12CC3CC(C1)CC(OS(C)(=O)=O)(C3)O2
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CCOC(=O)CC1=CC2CC(=O)CC(C1)C2
Temperature: 25 °C
Yield: 92 %

Procedure:
A mixture of mesylate (3) (1.435 g, 4.5 mmol) and anhydrous aluminium trichloride (720 mg, 5.4 mmol) in distilled 1,2-dichloroethane (12 mL) was stirred was stirred under argon at reflux temperature for 10 min then cooled to r.t. The reaction mixture was diluted with water (24 mL) and THF (24 mL), made basic with 5 M NaOH (30 mL) and stirred at r.t. 30 min before extraction with DCM (2×50 mL), then with AcOEt (2×50 mL). The combined organic layers were dried with MgSO4 and concentrated under reduced pressure to afford a pale yellow oil. Purification by flash chromatography (AcOEt/cyclohexane 0/10 to 3/7, v/v) afforded the desired enone (4) as colorless oil (920 mg, 92%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12](I)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19](=O)([O-])[O-:20].[Cs+].[Cs+]>CO.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:20][CH3:19])=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(I)cc2C1
Agent: [Cu]I
Agent: [Cs+]
Solvent: CO
Product: COc1cc2c(cc1Cl)CN(C(=O)OC(C)(C)C)C2
Temperature: 140 °C
Reaction time: 16 h

Procedure:
Lit. Org. Lett. 2002, 4(6), 973-976. To a stirred suspension of 1.84 mmol 5-chloro-6-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A3(c)) in 7 ml methanol were added 0.18 mmol copper(I) iodide, 3.69 mmol cesium carbonate and 0.37 mmol 1,20-phenanthroline and the reaction mixture was stirred at 140° C. for 16 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a light red solid. MS (m/e): 230.2 ({37Cl}[M+H-Me2C═CH2]+, 42%), 228.2 ({35Cl}[M+H-Me2C═CH2]+, 100%).