Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[C:13]2[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.[C:29](=O)(O)[O-:30].[Na+].CCOCC>O1CCCC1.C(O)(=O)C>[N:23]1([CH2:22][CH2:21][NH:20][C:29](=[O:30])[O:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([CH:9]3[CH2:10][CH2:11][CH2:12][N:8]3[CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:14]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: NCCN1CCOCC1
Reactant: Oc1cccc(C2CCCN2Cc2ccccc2)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C(NCCN1CCOCC1)Oc1cccc(C2CCCN2Cc2ccccc2)c1
Reaction time: 48 h
Yield: 54 %

Procedure:
To a solution of 3-[1-phenylmethyl-2-pyrrolidinyl]phenol (0.64 g) in dry tetrahydrofuran (20 ml) was added 1,1-carbonyldiimidazole (0.61 g) at ambient temperature, under nitrogen. The reaction mixture was stirred for 48 hrs, glacial acetic acid (0.50 ml) was added followed by a solution of 4-(2-aminoethyl)morpholine (0.43 ml) in tetrahydrofuran (1.0 ml) and glacial acetic acid (0.20 ml). After 3 hrs, the reaction mixture was poured into saturated sodium bicarbonate solution and ether. The layers were separated, and the aqueous phase was extracted with ether (2 times). The combined organic extracts were washed with saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by radial chromatography, using ether as the eluent. The appropriate fractions were collected and concentrated to give 0.56 g (54%) of product. Recrystallization from ether/petroleum ether gave the analytical sample, mp 74°-77° C.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.[C:11]1(=[O:19])[O:18][C:16](=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1>C(OCC)(=O)C>[N+:7]([C:6]1[CH:5]=[CH:4][C:3]([O:10][C:11](=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:2][CH:1]=1)([O-:9])=[O:8]
Reactant: O=C1CCCCC(=O)O1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: CCOC(C)=O
Product: O=C(O)CCCCC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
28 g of finely powdered p-nitrophenol were added to 25.6 g of adipic anhydride and the mixture was stirred at room temperature overnight, whereupon the contents of the flask solidified. The mass was melted, whilst stirring, and the melt was dissolved in 350 ml of ethyl acetate. The solution was extracted several times with water and the ethyl acetate was distilled off in vacuo. The residue was recrystallised three times from acetonitrile. Yield: 45.2 g (85% of theory) of melting point 104°-105° C.
Reaction SMILES: [C:1]1([C@@H:7]([N:9]2[C@@H:14]([C:15]([O:17]CC)=[O:16])[C@H:13]3[CH2:20][C@@H:10]2[CH2:11][CH2:12]3)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[OH-].[Na+]>O1CCCC1>[C:1]1([C@@H:7]([N:9]2[C@@H:14]([C:15]([OH:17])=[O:16])[C@H:13]3[CH2:20][C@@H:10]2[CH2:11][CH2:12]3)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)[C@H]1[C@@H]2CC[C@@H](C2)N1[C@@H](C)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](c1ccccc1)N1[C@H]2CC[C@H](C2)[C@@H]1C(=O)O
Temperature: 65 °C
Reaction time: 21 h
Yield: 82.5 %

Procedure:
To a solution of ethyl (1S, 3R, 4R)-2-[(S)-1-phenylethyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate (601 mg, 2.20 mmol) in tetrahydrofuran (12 ml)-methanol (6 ml) was added 1N sodium hydroxide (12 ml) and the mixture was stirred at 65° C. for 21 hours. The reaction mixture was neutralized and the water phase was concentrated. The residue was dissolved in chloroform and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (0–15% methanol/chloroform), to give (1S, 3R, 4R)-2-[(S)-1-phenylethyl]-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (445 mg, 83%).
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([N:21](C(OC4C=CC=CC=4)=O)[C:22](=[O:30])OC4C=CC=CC=4)[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4].C(N(CC)CC)C.Cl.[NH2:48][C@H:49]([CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:50]([NH2:52])=[O:51]>CN(C)C=O>[CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]([NH:48][C@@H:49]([C:50](=[O:51])[NH2:52])[CH2:53][C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)=[O:30])[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4]
Reactant: NC(=O)[C@H](N)Cc1ccccc1
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(N(C(=O)Oc4ccccc4)C(=O)Oc4ccccc4)c3)ccc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N[C@H](Cc4ccccc4)C(N)=O)c3)ccc21
Reaction time: 18 h
Yield: 76 %

Procedure:
Phenyl N-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (104 mg, 0.200 mmol) and triethylamine (1 ml) were dissolved in N,N-dimethylformamide (3 ml), and (2R)-2-amino-3-phenylpropionamide hydrochloride (201 mg, 1.00 mmol) was added, and the reaction mixture was stirred for 18 hours. The reaction mixture was partitioned between ethyl acetate and the saturated aqueous solution of ammonium chloride. The organic layer was washed with water and brine, and was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate:methanol=50:1). The crystals were precipitated from a solvent mixture of ethyl acetate-hexane, filtered off, and dried under aeration to yield the title compound (77.2 mg, 0.152 mmol, 76%) as white crystals.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[CH:11]=[O:12].[Cl:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-:22].[K+].[K+]>>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[O:20][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[C:11]([OH:12])=[O:22]
Reactant: Cn1nc(C(F)F)c(C=O)c1Cl
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(Cl)c1
Agent: [K+]
Product: Cn1nc(C(F)F)c(C(=O)O)c1Oc1cccc(Cl)c1

Procedure:
The title compound was prepared using 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde and 3-chlorophenol in the manner similar to the method in Production Example 1 above except potassium carbonate was used instead of potassium hydroxide.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([CH2:28][NH:29][CH3:30])=[CH:24][CH:23]=4)[CH:14]=[N:13][C:12]=3[CH:11]=2)=[CH:6][CH:5]=1.[CH3:31][C:32]([CH3:38])([CH3:37])[CH2:33][C:34](Cl)=[O:35].C(N(CC)CC)C.O1CCCC1>C(OCC)(=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][C:22]4[CH:23]=[CH:24][C:25]([CH2:28][N:29]([CH3:30])[C:34](=[O:35])[CH2:33][C:32]([CH3:38])([CH3:37])[CH3:31])=[CH:26][CH:27]=4)[CH:14]=[N:13][C:12]=3[CH:11]=2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CNCc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(Cc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1)C(=O)CC(C)(C)C
Temperature: 60 °C
Reaction time: 3 h
Yield: 78.3 %

Procedure:
A mixture of the compound (85 mg) obtained in Example 4, 3,3-dimethylbutanoyl chloride (31 mg), triethylamine (53 mg) and tetrahydrofuran (2 ml) was stirred at 60° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, and washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane (2:1, volume ratio) to give the title compound (70 mg) as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16]Cl)[N:9]=[CH:8][NH:7][C:6]2=[O:18].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[OH-].[Na+].Cl>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[N:9]=[CH:8][NH:7][C:6]2=[O:18]
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCCl
Reactant: C1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCCCC1
Temperature: 55 °C
Reaction time: 5 h
Yield: 76.2 %

Procedure:
In a 100 mL volume glass vessel equipped with a stirrer and a thermometer were placed 15.0 g (55.8 mmol) of 6-methoxy-7-(3-chloropropoxy)quinazolin-4-one prepared by procedures similar to those of Reference Example V-1, 13.85 g (163 mmol) of piperidine, and 27.4 mL (113.6 mmol) of aqueous sodium hydroxide solution (4.0 mol/L). The resulting mixture was stirred at 55° C. for 5 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and placed under reduced pressure to distill unreacted piperidine off. To the residue was added 18.9 mL (113.4 mmol) of hydrochloric acid (6.0 mol/L), and the mixture was cooled to 0° C. The precipitated crystalline product was collected by filtration and dried at 60° C. under reduced pressure, to give 13.5 g (isolated yield: 76.3%) of 6-methoxy-7-(3-piperidino-propoxy)quinazolin-4-one.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:17].C(Cl)Cl.O.NN>C(O)C>[NH2:3][O:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:17]
Reactant: CC(C)(C)OC(=O)NC(=O)NCCON1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(=O)NCCON
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
To a mixture of tert-butyl ({2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]ethyl}carbamoyl)carbamate 83 (0.56 g, 1.59 mmol) in a solution of DCM (10 mL) and ethanol (2 mL) was added hydrazine hydrate (0.091 mL, 1.59 mmol) at room temperature. The mixture was stirred at room temperature overnight, filtered and concentrated to provide a residue which was subjected to chromatography to give 84 (0.25 g, 72%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Cl.C([O-])([O-])=O.[K+].[K+].[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH3:26])=[C:20]2[C:27]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[S:30](=[O:38])(=[O:37])[NH:29][N:28]=1.Br[CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>CC#N.O.C(Cl)Cl>[C:44]([O:43][C:41](=[O:42])[CH2:40][N:22]1[C:23]2[C:19](=[CH:18][C:17]([F:16])=[CH:25][CH:24]=2)[C:20]([C:27]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[S:30](=[O:37])(=[O:38])[N:29]([CH2:5][C:4]3[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=3)[N:28]=2)=[C:21]1[CH3:26])([CH3:47])([CH3:46])[CH3:45]
Reactant: ClCc1cccc(Cl)c1
Reactant: Cc1[nH]c2ccc(F)cc2c1C1=NNS(=O)(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: Cc1c(C2=NN(Cc3cccc(Cl)c3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
3-Chlorobenzyl chloride (9 μL, 67 μmol) and K2CO3 (10 mg, 72 μmol) were added to a solution of 4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine 1,1-dioxide (20 mg, 61 μmol) in CH3CN (1 mL), and stirred overnight at 80° C. An additional amount of K2CO3 (10 mg, 72 μmol) and tert-butyl bromoacetate (14 μL, 92 μmol) was added, and the reaction mixture stirred an additional 2 h at 80° C. The reaction mixture was diluted with H2O and CH2Cl2, and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the sub-title compound, which was carried onto the next step without further purification or characterization.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-:19].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>CO>[C:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16](=[O:18])[CH2:17][Br:19])=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Br-]
Reactant: CC(=O)c1ccc(OC(=O)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Product: O=C(CBr)c1ccc(OC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
13.50 g (corresponding to 59.66 mmol) of 4′-benzoyloxyacetophenone was dissolved in 1100 ml of methanol, and 34.52 g (corresponding to 71.59 mmol) of tetra-n-butyl ammonium tribromide was added thereto. The mixture was stirred overnight at room temperature, and was distilled off under reduced pressure to remove the solvent. The residue was dissolved in ethyl acetate and washed twice with water and then washed with an aqueous saturated sodium chloride solution. After the ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, the resulting crude product was purified by silica gel column chromatography (elution solvent: hexane/methylene chloride=1/1), to obtain 13.38 g (corresponding to 43.84 mmol) of 4′-benzoyloxy-2-bromoacetophenone (FIG. 3, Step 4).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([Cl:11])(Cl)Cl)[CH:5]=[CH:6][CH:7]=1.C(O)=[O:13]>[Fe](Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8]([Cl:11])=[O:13]
Reactant: Fc1cccc(C(Cl)(Cl)Cl)c1
Reactant: O=CO
Agent: Cl[Fe]Cl
Product: O=C(Cl)c1cccc(F)c1
Temperature: 80 °C

Procedure:
300 g of 3-fluorobenzotrichloride and 1.5 g of iron chloride are placed in an apparatus comprising a 1 l four necked flask equipped with stirrer, thermometer, reflux condenser and dropping funnel. The mixture was heated to 80° C. A total of 53 ml of formic acid were then added over 5 hours in such a manner that the temperature could readily be maintained.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:30])[CH:10]2[NH:14][C:15](=[O:29])[CH2:16][C:17]2[N:18]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[OH:28])[S:20][CH:21]=2)[C:7]=1[C:31]([OH:33])=[O:32])(=[O:3])[CH3:2].[SiH](CC)(CC)[CH2:35]C.FC(F)(F)C(O)=O>C(Cl)CCl>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:30])[CH:10]2[NH:14][C:15](=[O:29])[CH2:16][C:17]2[N:18]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:35])[S:20][CH:21]=2)[C:7]=1[C:31]([OH:33])=[O:32])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(-c4ccccc4O)n3)C2SC1
Reactant: CC[SiH](CC)CC
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1-c1nc(CC(=O)NC2C(=O)N3C(C(=O)O)=C(COC(C)=O)CSC23)cs1
Yield: 73 %

Procedure:
The procedure used for the preparation of 9a was repeated with 8o (193 mg, 0.288 mmol), Et3SiH (0.461 mL, 2.88 mmol), and trifluoroacetic acid (0.887 mL, 11.5 mmol) in dry ClCH2CH2Cl (7 mL) at 0° C. under nitrogen to give 9o (106 mg, 73%) as a white solid after crystallization from THF/CH2Cl2 /hexane. mp 178° C. (dec); IR (KBr) 3550-2800 (br), 3278, 1785, 1735, 1667, 1256 cm-1 ; 1H NMR (DMSO-d6) δ1.98 (3H, s, CH3), 3.45 (1H, d, J=18.1 Hz), 3.59 (1H, d, J=18.1 Hz), 3.74 (2H, s, CH2), 3.96 (3H, s, CH3), 4.65 (1H, d, J=12.8 Hz), 4.96 (1H, d, J=12.8 Hz), 5.07 (1H, d, J=4.8 Hz), 5.71 (1H, dd, J=8.1 and 4.8 Hz), 7.04 (1H, t, J=7.5 Hz), 7.19 (1H, d, J=8.3 Hz), 7.37-7.42 (1H, m), 7.41 (1H, s), 8.22 (1H, d, J=7.5 Hz), 9.06 (1H, d, J=8.1 Hz, NH), 13.62 (1H, br s, CO2H); FDMS m/z 504 (M+ +1); Anal. Calcd for C22H21N3O7S2 : C, 52.48; H, 4.20; N, 8.34. Found: C, 52.72; H, 4.27; N, 8.10
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[C@H:3]([OH:6])[CH2:4][OH:5].[S:9](Cl)(Cl)=[O:10].C(#N)C.I([O-])(=O)(=O)=[O:17].[Na+]>C(Cl)(Cl)(Cl)Cl.O.O.[Ru](Cl)(Cl)Cl>[C:2]([C@H:3]1[CH2:4][O:5][S:9](=[O:10])(=[O:17])[O:6]1)([CH3:8])([CH3:7])[CH3:1]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)[C@H](O)CO
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(C)(C)[C@H]1COS(=O)(=O)O1
Reaction time: 2 h
Yield: 97 %

Procedure:
To 5.63 g (47.63 mmol) of (2S)-3,3-dimethyl-1,2-butanediol in 48 mL of carbon tetrachloride was added 3.47 mL (47.63 mmol) of thionyl chloride. The resulting mixture was heated at reflux for 1 h, and cooled to 0° C., before 48 mL of acetonitrile was added. Then, 1.0 mg (4.8 μmol) of ruthenium(III) chloride hydrate was added, followed by 15.28 g (71.45 mmol) of sodium periodate. The reaction mixture was diluted with 71 mL of water and stirred for 2 h. It was then extracted with diethyl ether. The extract was washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with an ethyl acetate:hexanes solution (3:7) to give 8.33 g (97%) of (4S)-4-tert-butyl-1,3,2-dioxathiolane 2,2-dioxide. Rf=0.30 (3:7 ethyl acetate:hexanes); 1H-NMR (300 MHz, DMSO-d6): δ 4.99–4.88 (m, 2H), 4.78 (t, J=8 Hz, 1H), 0.94 (s, 9H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:18]=[C:17]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH:16]=[CH:15][C:14]=1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:12][C:13]2[CH:18]=[C:17]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[CH:16]=[CH:15][C:14]=2[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CCl)cc1
Reaction time: 1 h

Procedure:
4-(chloromethyl)benzoyl chloride (2 g, 10.58 mmol) was dissolved in THF (20 mL) and a solution of tert-butyl [2-amino-4-(2-thienyl)phenyl]carbamate (3.38 g, 11.64 mmol) and DIPEA (2.033 mL, 11.64 mmol) in THF (50 mL) was added dropwise at room temperature. After stirring for 1 hour, saturated NaHCO3 was added and the products extracted into EtOAc (×2). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was triturated in EtOAc to give tert-butyl [2-{[4-(chloromethyl)benzoyl]amino}-4-(2-thienyl)phenyl]carbamate as a beige powder.
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]2[CH2:6][CH:7]([CH3:26])[N:8]([C:20](=[O:25])[C:21](F)(F)F)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[C:29](OC(=O)CC)(=O)CC>>[Br:1][C:2]1[CH:28]=[CH:27][C:5]2[CH2:6][CH:7]([CH3:26])[N:8]([C:20](=[O:25])[CH2:21][CH3:29])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: CC1Cc2ccc(Br)cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(=O)C(F)(F)F
Reactant: CCC(=O)OC(=O)CC
Product: CCC(=O)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc(Br)ccc2CC1C
Yield: 70 %

Procedure:
1.33 g (3.7 mmoles) of 8-bromo-4-methyl-1-(4-nitrophenyl)-3-trifluoroacetyl-4,5-dihydro-3H-2,3-benzodiazepine (prepared in Example 22, Step D) are acylated with propionic anhydride using the method of Example 1. The crude product is purified by chromatography over a silicagel column that is eluted with a mixture of hexane and ethyl acetate in a ratio of 9:1. Thus, 1.07 g (70%) of the title compound are obtained. M.p.: 178°-180° C.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:65])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[N:56]([CH3:60])[CH:55]=[CH:54]4)[CH:46]([O:61][CH2:62][CH:63]=[CH2:64])[CH2:45]2)[CH:7]([CH3:66])[CH2:6][CH2:5][C:4]1=[O:67])[CH3:2].[H][H]>C(OCC)(=O)C.[Rh]>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:65])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[N:56]([CH3:60])[CH:55]=[CH:54]4)[CH:46]([O:61][CH2:62][CH2:63][CH3:64])[CH2:45]2)[CH:7]([CH3:66])[CH2:6][CH2:5][C:4]1=[O:67])[CH3:2]
Reactant: [H][H]
Reactant: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1Oc1ccc2c(ccn2C)c1
Agent: [Rh]
Solvent: CCOC(C)=O
Product: CCCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1Oc1ccc2c(ccn2C)c1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (20 mg) (EXAMPLE 31) in ethyl acetate (500 μl) was added rhodium on carbon (5 mg). The flask was filled with hydrogen, and the mixture was stirred at room temperature. After 1.5 hours the mixture was filtered through Celite then the solvent was removed in vacuo to give the title compound (20 mg). MASS (FAB) 940 (M+Li); Partial 1H NMR δ: 7.18 (s,1H); 7.16 (d, J=9 Hz, 1H); 6.96 (d, J=3 Hz, 1H); 6.92 (dd, J=9,3 Hz, 1H); 6.34 (d, J=3 Hz, 1H); 4.55 (brd, J=4 Hz, 1H); 3.72 (s, 3 H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:17]2[C:12](=[CH:13][C:14](/[CH:18]=[CH:19]/[C:20](O)=[O:21])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:23][C:24]([F:38])([F:37])[CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1)[NH2:26].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CN(C=O)C.C(OCC)(=O)C>[O:21]=[C:20]([NH:26][CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=1)[C:24]([F:38])([F:37])[F:23])/[CH:19]=[CH:18]/[C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11]2
Reactant: NC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1CCc2cc(/C=C/C(=O)O)ccc21
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCc2cc(/C=C/C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)ccc21
Temperature: 50 °C
Yield: 89.9 %

Procedure:
1.5 g (4.95 mmol) of (2E)-3-{1-[(tert-butoxycarbonyl)amino]-2,3-dihydro-1H-inden-5-yl}acrylic acid and 1.2 g (4.95 mmol) of 2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethanamine were dissolved in 100 ml of DMF, 1.5 g (5.44 mmol) of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride were added, and the reaction mixture was heated to 50° C. overnight. The reaction solution was diluted with ethyl acetate, washed with sal. NaHCO3 solution, 1N hydrochloric acid and sat, sodium chloride solution, dried over sodium sulphate, filtered and concentrated. Chromatographic purification gave 2.3 g (4.45 mmol) of tert-butyl {5-[(1E)-3-oxo-3-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}amino)prop-1-en-1-yl]-2,3-dihydro-1H-inden-1-yl}carbamate (87%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>O1CCOCC1>[NH2:1][C:2]1[N:3]=[C:4]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:8][C:6]=2[N:7]=1
Reactant: Nc1nc(Cl)c2nc(-c3ccc(F)cc3)oc2n1
Reactant: C1CNCCN1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(N2CCNCC2)c2nc(-c3ccc(F)cc3)oc2n1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
To a solution of 5-amino-7-chloro-2-(4-fluorophenyl)-oxazolo[5,4-d]pyrimidine X (50 mg, 0.19 mmol) in dioxane (5 ml) was added diisopropylethylamine (0.28 mmol, 47 μL) and a piperazine derivative (0.28 mmol). The reaction was stirred at 70° C. for 6 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 2% CH3OH in CH2Cl2), yielding the pure title compounds which were characterized by their mass spectra as indicated below: