Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[CH2:8][NH:7][C:6]1=[O:11].CCN(C(C)C)C(C)C.[O:21](C(OC(C)(C)C)=O)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=O.CN(C=O)C>C(Cl)Cl>[C:25]([O:24][C:22](=[O:21])[NH:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[CH2:8][NH:7][C:6]1=[O:11])([CH3:28])([CH3:27])[CH3:26]
Reactant: NCCN1C(=O)CNC1=O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCN1C(=O)CNC1=O
Reaction time: 0.25 h

Procedure:
3-(2-Aminoethyl)-imidazolidine-2,4-dione hydrochloride (14.7 g., 82 mmol) was suspended in DCM (300 mL) and DIPEA (28 mL, 160 mmol) was added. The mixture was stirred for 15 min, and then BOC2O (19.7 g, 90 mmol) was added. The suspension was stirred for 1 h, and then DMF (45 mL) was added. The stirred suspension gradually became a clear solution over the next several h. Stirring was continued for a further 16 h, after which time a thick precipitate had formed. The mixture was concentrated to dryness in vacuo, ensuring the last traces of DMF were removed, and then dissolved in boiling EtOAc (200 mL). Hexane (800 mL) was added, the mixture cooled and allowed to stand for 1 h. The resulting product was collected by filtration. Yield=14.6 g, 73%.
Reaction SMILES: [CH:1]1(/[CH:6]=[CH:7]/[CH:8]=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O.C1(C)C=CC=CC=1.[NH:29]1[CH:33]=[C:32]([C:34]2[C:35]3[CH:42]=[CH:41][N:40]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:36]=3[N:37]=[CH:38][N:39]=2)[CH:31]=[N:30]1>>[CH:1]1([C@H:6]([N:29]2[CH:33]=[C:32]([C:34]3[C:35]4[CH:42]=[CH:41][N:40]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:36]=4[N:37]=[CH:38][N:39]=3)[CH:31]=[N:30]2)[CH2:7][CH:8]=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: O=C/C=C/C1CCCC1
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H](CC=O)C4CCCC4)c3)ncnc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.8 %

Procedure:
A solution of (2E)-3-cyclopentylacrylaldehyde (28, 327 mg, 2.50 mmol, 5.0 equiv), (2R)-2-bis[3,5-bis(trifluoromethyl)phenyl][(triethylsilyl)oxy]methylpyrrolidine ((R)-35, 32 mg, 0.050 mmol, 0.10 equiv) and 4-nitrobenzoic acid (8.5 mg, 0.050 mmol, 0.10 equiv) in anhydrous toluene (5.0 mL, 47 mmol) was stirred at room temperature for 10 min before 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (17, 158 mg, 0.50 mmol) was added. The resulting reaction mixture was stirred at room temperature for 24 h. When LCMS showed that the reaction was deemed complete, the reaction mixture was concentrated under reduced pressure. The residue was directly purified by Combiflash (SiO2) with 0-70% EtOAc/hexane gradient elution to give (3R)-3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanal ((R)-38, 184.1 mg, 219.8 mg theoretical, 83.8% yield) as a pale yellow viscous oil. For (R)-38: C23H33N5O2Si (MW, 439.63), LCMS (EI) m/e 440 (M++H).
Reaction SMILES: COC1C=CC(NC2N=NC(C(NC(C3OC=CC=3)=O)C)=CN=2)=CC=1.Cl.[CH3:27][S:28][C:29]1[N:30]=[N:31][C:32]([CH:35]([NH2:37])[CH3:36])=[CH:33][N:34]=1.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH3:27][S:28][C:29]1[N:30]=[N:31][C:32]([CH:35]([NH:37][C:38](=[O:45])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:36])=[CH:33][N:34]=1
Reactant: CSc1ncc(C(C)N)nn1
Reactant: O=C(Cl)c1ccccc1
Agent: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccco3)nn2)cc1
Agent: Cl
Product: CSc1ncc(C(C)NC(=O)c2ccccc2)nn1
Yield: 83.4 %

Procedure:
In a similar manner as described for Intermediate 59, using 1-[3-(Methylthio)-1,2,4-triazin-6-yl]ethanamine (Intermediate 4) (1.00 g, 5.90 mmol), benzoyl chloride (0.75 mL, 6.50 mmol), to give N-{1-[3-(methylthio)-1,2,4-triazin-6-yl]ethyl}benzamide (1.35 g) as a yellow solid. MS m/z 275 (M+1).
Reaction SMILES: [CH:1]1([CH2:7][C:8](=O)[CH2:9][C:10]([O:12]CC)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:16]([C:19]1[CH:29]=[CH:28][C:22]([C:23]([NH:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1)=[N+:17]=[N-:18].[O-]CC.[Na+].O>C(O)C>[CH:1]1([CH2:7][C:8]2[N:16]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([NH:25][CH2:26][CH3:27])=[O:24])=[CH:28][CH:29]=3)[N:17]=[N:18][C:9]=2[C:10]([OH:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CC(=O)CC1CCCCC1
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
Ethyl 4-cyclohexyl-3-oxobutyrate (0.84 g, 3.96 mmol, 1.25 eq.) obtained in Example 102a) and 4-azido-N-ethylbenzamide (0.60 g, 3.15 mmol) were dissolved in ethanol (20 ml), sodium ethoxide (298 mg, 3.96 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 30 min, and then at 50° C. for 14 hr. Water (20 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was diluted with 2% aqueous sodium carbonate solution (20 ml) and washed with ethyl acetate-hexane (2:1, 50 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, acidified (pH<3) with 6N hydrochloric acid, and extracted with ethyl acetate-THF (4:1, 40 ml) and ethyl acetate (30 ml). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, and diethyl ether and ethyl acetate were added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a pale-yellow powder (1.04 g, 2.91 mmol, 92.4%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=C2CCOCC2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C1(=C(C2C=CC(O)=CC=2)C2C=CC(/C=C/C(N)=O)=CC=2)CCCCC1.[CH3:47][C:48]1([CH3:57])[CH2:53][C:52](=O)[CH2:51][C:50]([CH3:56])([CH3:55])[O:49]1>[Zn].Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[C:52]2[CH2:53][C:48]([CH3:57])([CH3:47])[O:49][C:50]([CH3:56])([CH3:55])[CH2:51]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(C(=C2CCOCC2)c2ccc(Br)cc2)cc1
Reactant: CC1(C)CC(=O)CC(C)(C)O1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: NC(=O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)cc2)cc1
Agent: [Zn]
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(Br)cc2)CC(C)(C)O1
Yield: 76 %

Procedure:
Following the procedure described for compound 46, zinc powder (0.957 g, 14.6 mmole), TiCl4 (0.800 mL, 7.30 mmole), (4-bromophenyl)(4-hydroxyphenyl)methanone (2) (0.512 g, 1.85 mmole) and 2,2,6,6-tetramethyltetrahydro-4H-pyran-4-one (52) (0.851 mL, 5.45 mmole), afforded 0.564 g (76%) of 53 as a white foamy solid. 1H NMR (CDCl3): δ 7.41 (d, J=8.3 Hz, 2H), 7.02 (d, J=8.4 Hz, 2H), 7.01 (d, J=8.4 Hz, 2H), 6.76 (d, J=8.3 Hz, 2H), 4.99 (s, 1H), 2.24 (s, 2H), 2.20 (s, 2H), 1.22 (s, 6H), 1.21 (s, 6H).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH:5]=[CH:6]2)=[CH2:2].C([Al](CC)CC)C>[Cl-].[Cl-].[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Ti+2]>[CH2:1]([CH:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH:5]=[CH:6]2)[CH3:2]
Reactant: C=CC1CC2C=CC1C2
Agent: [Ti+2]
Agent: CC[Al](CC)CC
Agent: [Cl-]
Product: CCC1CC2C=CC1C2
Reaction time: 5 h

Procedure:
The reaction was carried out in the same way as in Example 1 except that the substrate was changed to 5-vinylbicyclo[2. 2. 1]hept-2-ene, 6 mmol of titanocenedichloride and 60 mmol of triethyl aluminum were charged into the autoclave, and the reaction period was set to five hours, to produce 134.7 g of 5-ethylbicyclo[2. 2. 1]hept-2-ene having the purity of 98.9%. Analyses by proton NMR revealed that only the signal of unsaturated proton of norbornene could be noticed in the vicinity of 5.8 ppm (δ) whereas the signal of unsaturated proton of vinyl in the vicinity of 5.0 ppm (δ) could not be noticed.
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:18])=O>>[CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([Cl:18])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(C2CCCCC2)cc1
Product: O=C(Cl)c1ccc(C2CCCCC2)cc1

Procedure:
To 4-cyclohexylbenzoic acid (2 g) is added thionyl chloride (20 ml), and the mixture is refluxed for two hours. The mixture is evaporated to remove the thionyl chloride to give 4-cyclohexylbenzoyl chloride. To a solution of 5-ethoxycarbonylmethyl-7-chloro-2,3,4,5-tetrahydro-1H-benzazepine (2.2 g) in dichloromethane (50 ml) is added pyridine (3.3 g), and to the mixture is added with stirring the above obtained 4-cyclohexylbenzoyl chloride under ice-cooling, and the mixture is stirred at room temperature overnight. To the reaction solution is added water, and the mixture is extracted with dichloromethane. The extract is washed with diluted hydrochloric acid, and washed with water, and dried over magnesium sulfate. The mixture is evaporated to remove the solvent, and the residue is purified by silica gel column chromatography (solvent; dichloromethane) to give 5-ethoxycarbonylmethyl-7-chloro-1-(4-cyclohexylbenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (4 g) as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][N:14]3[C:26]4[C:25]5[N:24]=[CH:23][CH:22]=[CH:21][C:20]=5[N:19]=[CH:18][C:17]=4[N:16]=[C:15]3[CH3:27])[O:10][N:9]=2)=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:36])C=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][N:14]3[C:26]4[C:25]5[N:24]=[CH:23][CH:22]=[CH:21][C:20]=5[N+:19]([O-:36])=[CH:18][C:17]=4[N:16]=[C:15]3[CH3:27])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1nc2cnc3cccnc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: Cc1nc2c[n+]([O-])c3cccnc3c2n1Cc1cc(-c2ccc(F)cc2)no1

Procedure:
The method described in Part E of Example 12 was used to treat 1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-2-methyl-1H-imidazo[4,5-c][1,5]naphthyridine (1.15 g, 3.20 mmol) with mCPBA (0.94 g of 75% pure material followed by 0.25 g) to provide 1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-2-methyl-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine as a dark yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]1([CH2:31][C:32]([OH:34])=[O:33])[C@@H:12]([CH2:13][O:14]CC2C=CC=CC=2)[C:11](=[O:22])[N:10]([C@@H:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[C].[Pd].CO>[C:1]([O:5][C:6]([C@@:8]1([CH2:31][C:32]([OH:34])=[O:33])[C@@H:12]([CH2:13][OH:14])[C:11](=[O:22])[N:10]([C@@H:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH3:24])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](c1ccccc1)N1C[C@@](CC(=O)O)(C(=O)OC(C)(C)C)[C@@H](COCc2ccccc2)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@H](c1ccccc1)N1C[C@@](CC(=O)O)(C(=O)OC(C)(C)C)[C@@H](CO)C1=O
Yield: 80 %

Procedure:
A 10% palladium-carbon catalyst (3.93 g) was added to a solution of (3S,4S)-4-benzyloxymethyl-3-carboxymethyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (3.93 g, 8.41 mmol) in methanol (84.0 mL) in a nitrogen atmosphere. After the atmosphere was replaced with hydrogen, the mixture was stirred in a hydrogen atmosphere at room temperature for three days. After the atmosphere was replaced with nitrogen, the reaction solution was filtered through Celite and concentrated under reduced pressure to give 2.54 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH2:32][CH2:33][CH2:34][CH3:35].FC1C=CC=C(F)C=1C(NC1C=CN(CC2C=C(O)C=CC=2C)N=1)=O>CN(C)C=O>[CH2:32]([O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][N:9]1[CH:10]=[CH:11][C:7]([NH:6][C:4](=[O:5])[C:3]2[C:12]([F:16])=[CH:13][CH:14]=[CH:15][C:2]=2[F:1])=[N:8]1)[CH2:33][CH2:34][CH3:35]
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Reactant: CCCCOc1ccccc1CBr
Agent: Cc1ccc(O)cc1Cn1ccc(NC(=O)c2c(F)cccc2F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1ccccc1Cn1ccc(NC(=O)c2c(F)cccc2F)n1
Temperature: 25 °C
Reaction time: 28 h

Procedure:
2,6-Difluoro-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 9)(89 mg, 0.40 mmol), potassium carbonate (83 mg, 0.60 mmol) and 1-(bromomethyl)-2-(butyloxy)benzene (for a preparation see Intermediate 2)(114 mg, 0.47 mmol) were weighed into a vial with a stirrer. N,N-dimethylformamide (1 ml) was added, the vial was capped and the mixture was stirred at room temperature for 28 h. The reaction mixture was filtered (hydrophobic frit), washing with MeOH to give a total volume of 2 ml. This solution was purified by MDAP (Sunfire column, formic acid buffer) (Method B). The solvent was removed to give the title compound as a colourless solid (9.4 mg); LCMS: (System 4) MH+=386, tRET=3.17 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][CH2:10][C:11](OCC)=[O:12].CC(C[AlH]CC(C)C)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][CH2:10][CH2:11][OH:12]
Reactant: CCOC(=O)CCc1c(C)cccc1Br
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: Cc1cccc(Br)c1CCCO
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of the ester from Step 1 (1 eq.) in THF (0.07M) at −78° C. was added dropwise DIBAL-H (2.1 eq). The reaction mixture was stirred 1 h at −78° C., warm slowly to 0° C. quenched with aqueous 1N HCl and finally diluted with Et2O. The organic extract was washed with aqueous 6N HCl, water, saturated aqueous NaHCO3, brine, dried over MgSO4 filtered and concentrated. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (0 to 50%, in 30 min) afforded the desired compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([OH:18])=O)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([N:29]3[CH2:30][CH2:31][CH:26]([C:23]4[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=4)[CH2:27][CH2:28]3)=[O:18])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn2c(O)c(C(=O)O)cnc12
Reactant: Fc1ccc(C2CCNCC2)cc1
Product: CCOC(=O)c1cnn2c(O)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 61.5 %

Procedure:
In the same manner as in Example 1, step 2 and using 3-ethoxycarbonyl-7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylic acid (1.17 g, 4.65 mmol) obtained in Example 19, step 2 and 4-(4-fluorophenyl)piperidine (1.0 g, 5.58 mmol), the title compound (1.18 g, 62%) was obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:22]=[CH:21][C:8]([CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[CH:7][CH:6]=1)(=[NH:4])=[O:3].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[CH:21][CH:22]=1)(=[N:4][S:31]([CH3:30])(=[O:33])=[O:32])=[O:3]
Reactant: CS(=N)(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N=S(C)(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Reaction time: 1.5 h

Procedure:
A solution of 2-(4-(S-methylsulfonimidoyl)benzyl)isoindoline-1,3-dione (preparation 17b, 2.50 g, 7.95 mmol) and triethylamine (2.2 mL, 16 mmol) in dichloromethane (20 mL) is cooled at 0° C. and treated with methanesulfonyl chloride (620 μL, 8.0 mmol). The mixture is stirred at this temperature for 1.5 h and then washed with water. The organic layer is concentrated under reduced pressure, and the residue is suspended in a mixture of methanol and water. The precipitate is filtered, washed with water, and dried. Yield: 273 mg (8% of theory); ESI mass spectrum: [M+H]+=393, r.t. HPLC: 0.44 min (X012_S01).
Reaction SMILES: BrC1C=CC([C@@H]([N:10]2[CH2:15][CH2:14][C@:13](CC(O)(C)C)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])C)=CC=1.COC1C=C(B2OC(C)(C)C(C)(C)O2)C=CN=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:16]1([CH:13]2[O:12][C:11](=[O:27])[NH:10][CH2:15][CH2:14]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Product: O=C1NCCC(c2ccccc2)O1
Reaction time: 2 h
Yield: 274.8 %

Procedure:
A mixture of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl) -6-phenyl-1,3-oxazinan-2-one (100 mg, 0.23 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)pyridine (68 mg, 1.25 equiv), Pd(dppf)Cl2.CH2Cl2 (19 mg, 10% mol), 2M aq Na2CO3 (1 mL), 1,4-dioxane (3 mL) was degassed, refilled with N2 gas for 3 times before being put into microwave oven for 2 h at 130° C. LC-MS found the reaction was completed. The mixture was diluted with EtOAc (50 mL), washed with water (10 mL) and brine (8 mL), and dried over Na2SO4. After filtration and concentration, the residue was purified by chromatography on a 12-g silica gel column, eluted with a 0 to 10% MeOH in CH2Cl2 gradient to afford (S)-6-(2-hydroxy-2-methylpropyl)-3-(S)-1-(4-(2-methoxypyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (112 mg, quant yield). LC-MS Method 1 tR=1.66 min, m/z=461(M+1).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([SH:23])[CH2:20][CH2:21][CH3:22]>>[CH2:19]([S:23][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCS
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Product: CCCCSC(=O)NC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p.=99° C. and MS: m/e=327 (M+) was prepared in accordance with the general method of example 1 from diphenylacetyl isocyanate and butanethiol.
Reaction SMILES: [CH2:1]1[N:9]2[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[N:12]=[CH:13][C:7]3=[C:8]2[C:3](=[CH:4][CH:5]=[CH:6]3)[CH2:2]1.[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.[NH4+].[OH-]>O1CCCC1.CCOCC>[C:18]1([CH:13]2[NH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[N:9]3[CH2:1][CH2:2][C:3]4=[CH:4][CH:5]=[CH:6][C:7]2=[C:8]34)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Br[Mg]c1ccccc1
Reactant: C1=Nc2ccccc2N2CCc3cccc1c32
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: c1ccc(C2Nc3ccccc3N3CCc4cccc2c43)cc1
Temperature: 0 °C

Procedure:
A stirred mixture of 2.1 g of 1,2-dihydroindolo[1,7-ab][1,5]benzodiazepine in 16 ml of dry tetrahydrofuran is cooled under N2 to 0°-5° C., then treated dropwise with 9.4 ml of a 2.8 molar solution of phenyl magnesium bromide in ether at such a rate as to keep the reaction temperature below 10° C. When the addition is complete, the reaction mixture is refluxed for 3 hours, cooled and then poured into 100 ml ice-water containing 10 ml of concentrated HCl. The resultant mixture is made alkaline with NH4OH and extracted with methylenechloride. The organic phase is separated, washed with brine, dried over Na2SO4 and concentrated to give 6-phenyl-1,2,6,7-tetrahydroindolo[1,7-ab][1,5]benzodiazepine, m.p. 161°-164° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5]([O-:8])(=[O:7])=[O:6].[C:9]1([S+:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.[C:35]12([C:45](Cl)=[O:46])[CH2:44][CH:39]3[CH2:40][CH:41]([CH2:43][CH:37]([CH2:38]3)[CH2:36]1)[CH2:42]2.Cl>C(Cl)Cl>[C:35]12([C:45]([O:1][CH2:2][CH2:3][CH2:4][S:5]([O-:8])(=[O:7])=[O:6])=[O:46])[CH2:42][CH:41]3[CH2:40][CH:39]([CH2:38][CH:37]([CH2:43]3)[CH2:36]1)[CH2:44]2.[C:22]1([S+:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=S(=O)([O-])CCCO
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCCCS(=O)(=O)[O-])C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To a mixture of 2.1 g (5 mmol) of the triphenylsulfonium 3-hydroxypropanesulfonate prepared in Synthesis Example 1-14, 0.6 g (6 mmol) of triethylamine and 10 g of methylene chloride, 2.9 g (6 mmol) of 1-adamantanecarbonyl chloride was added dropwise, followed by stirring for 3 hours at room temperature. Then 5.5 g of 5% aqueous hydrochloric acid was added to quench the reaction. The organic layer was separated from the reaction solution, washed with water, and concentrated in vacuum. Methyl isobutyl ketone was added to the concentrate, which was concentrated in vacuum again while azeotroping off the residual water. Diisopropyl ether was added to the residue, followed by decantation and drying. There was obtained the target compound, triphenylsulfonium 3-(adamantane-1-carbonyloxy)propanesulfonate. Colorless oily matter, 2.3 g, yield 79%. The compound, designated PAG-5, has the following structure.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][NH:16][S:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:11][CH2:10]1)(C)(C)C.Cl>C(Cl)(Cl)Cl.O1CCOCC1>[NH2:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][NH:16][S:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CNS(=O)(=O)c2cccc3ccccc23)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: NC[C@H]1CC[C@H](CNS(=O)(=O)c2cccc3ccccc23)CC1

Procedure:
A suspension of trans-{4-[(naphthalene-1-sulfonylamino)-methyl]-cyclohexylmethyl}-carbamic acid tert-butyl ester (25 g) in chloroform (300 ml) is treated with a 4 N HCl solution in dioxane (300 ml) at 0° C. After completion, the reaction mixture is concentrated in vacuo, the residue is taken up in a 1 N sodium hydroxide solution and dichloromethane. After extraction with dichloromethane, the organics are dried over sodium sulfate and concentrated to 18.5 g of trans-naphthalene-1-sulfonic acid (4-aminomethyl-cyclohexylmethyl) -amide as a white powder melting at 157-162° C. Rf(C3) 0.36.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:11])[C:4]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)=[O:5].[Cl:12]N1C(=O)CCC1=O>CC(O)=O>[Cl:12][C:9]1[S:8][CH:7]=[C:6]([C:4]([N:3]([O:2][CH3:1])[CH3:11])=[O:5])[CH:10]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CON(C)C(=O)c1ccsc1
Solvent: CC(=O)O
Product: CON(C)C(=O)c1csc(Cl)c1
Temperature: 120 °C
Yield: 50.2 %

Procedure:
To a stirred solution of N-methoxy-N-methylthiophene-3-carboxamide (5.0 g, 1.0 eq, prepared from Example 12 step A) in 50 mL CH3COOH was added N-chlorosuccinimide (3.88 g, 1.0 eq). The mixture was then reflux at 120° C. for 4 h. After quenching with water, the mixture was extracted with ethyl acetate. The extract was washed with brine, dried, concentrated, and purified by column chromatography to get 3.0 g desired product (40% yield).