Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH2:10]([NH2:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH2:10]([NH:16][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCN
Reactant: COc1cccc(Cl)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCCCCCNc1cccc(OC)c1
Yield: 95.5 %

Procedure:
3-Chloroanisole (74 mg, 0.52 mmol) reacted with n-hexylamine (65 mg, 0.64 mmol) according to procedure B using 1 mol % of Pd(dba)2, 2 mol % of Ph5FcP(t-Bu)2, and sodium tert-butoxide (58 mg, 0.60 mmol) in toluene at 100° C. to give the title compound (103 mg, 95%) as a colorless oil. Also 3-bromoanisole was converted to the title amine in 85% yield by procedure A: 1H-NMR (400 MHz, CDCl3): δ 6.99 (t, 1H, J=8.0 Hz), 6.19-6.13 (m, 2H), 6.08 (app.t, 1H, J=2.4 Hz), 3.70 (s, 3H), 3.55 (bs, 1H), 3.01 (t, 2H, J=7.2 Hz), 1.53 (m, 2H), 1.33 (m, 2H), 1.24 (m, 4H), 0.83 (t, 3H, J=6.8 Hz). 13C{1H}-NMR (100 MHz, CDCl3): δ 160.81, 149.91, 129.87, 105.86, 102.09, 98.53, 55.01, 43.95, 31.61, 29.47, 26.81, 22.60, 14.01. GC/MS(EI): m/z 207 (M+), 136. Anal. Calcd for C13H21NO: C, 75.23; H, 10.21; N, 6.76. Found: C,75.25; H, 10.33; N, 6.86.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].C(Cl)(Cl)Cl.O.Cl>C(O)C.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(OC)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc(C(=O)O)c(OC)c1
Temperature: 32.5 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
53 g of methyl 2,4-dimethoxybenzoate was dissolved in 160 mL of ethanol, to which 104 mL of a 5M aqueous solution of sodium hydroxide was added, and this mixture was stirred for 2 hours at 25 to 40° C. Then, chloroform and water were added to the reaction mixture, which was adjusted to pH 2 with 6M hydrochloric acid, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure to yield 45 g of 2,4-dimethoxybenzoic acid as white solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:12][C:13]1[C:14]([N:29]2[CH2:38][CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]2[CH3:39])=[N:15][C:16]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[N:17][C:18]=1[CH2:19][OH:20]>ClCCl>[CH3:12][C:13]1[C:14]([N:29]2[CH2:38][CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]2[CH3:39])=[N:15][C:16]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[N:17][C:18]=1[CH2:19][O:20][C:1](=[O:3])[CH3:2]
Reactant: Cc1c(CO)nc(Nc2ccc(F)cc2)nc1N1CCc2ccccc2C1C
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCc1nc(Nc2ccc(F)cc2)nc(N2CCc3ccccc3C2C)c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 108.1 %

Procedure:
Acetyl chloride (2.71 μl, 39.6 μmol) and triethylamine(20 μl, 142.6 μmol) were added to a suspension of 5-methyl-6-hydroxymethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine (10 mg, 26.4 μmol) in dichloromethane(1 ml) and stirred for 1 day at a room temperature. The reaction mixture was purified with a silica gel column chromatography (ethylacetate/n-hexane=1/1) to give 12 mg of the titled compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH:16](OS(C)(=O)=O)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[SH:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:32]([NH:36][C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[N:31][CH:30]=[CH:29]2>CN(C=O)C>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH:16]([S:25][C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[C:32]([NH:36][C:37](=[O:44])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[N:31][CH:30]=[CH:29]3)[CH2:15]1)=[O:13])([CH3:8])([CH3:9])[CH3:10]
Reactant: O=C(Nc1nccc2cc(S)ccc12)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(Sc2ccc3c(NC(=O)c4ccccc4)nccc3c2)C1

Procedure:
Potassium carbonate (44 mg, 0.32 mmol) and 3-methanesulfonyloxypiperidine-1-carboxylic acid tert-butyl ester (70 mg, 0.264 mmol) were added to a solution of the above N-(6-mercaptoisoquinolin-1-yl)-benzamide residue in DMF (2 ml). The mixture was irradiated in a microwave at 160° C. for 600 s then concentrated in vacuo to give a residue. The residue was purified by preparative HPLC to give 3-(1-benzoylaminoisoquinolin-6yl-sulfanyl)piperidine-1--carboxylic acid tert-butyl ester (18 mg), EIMS: m/z=464.3 [M+H]+ and m/z=486.5 [M+Na]+.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[CH3:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH:28]=O)[N:24]=1>>[CH3:18][O:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:9]=1[CH:2]1[N:1]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([C:23]3[N:24]=[C:20]([CH3:19])[S:21][CH:22]=3)[CH:26]=2)[C:5](=[O:7])[CH2:4][CH2:3]1
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Reactant: Cc1nc(-c2cccc(C=O)c2)cs1
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1cccc(-c2csc(C)n2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate with commercially available 3-(2-methylthiazol-4-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.81 min.; [M+H]+: 409.15 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28](I)[CH:27]=[CH:26][C:25]=3[CH3:31])[C:5]2=[CH:4][CH:3]=1.C[Si]([C:37]#[CH:38])(C)C.C(N(CC)CC)C.[OH-].[Na+]>O1CCCC1.CO.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:37]#[CH:38])[CH:27]=[CH:26][C:25]=3[CH3:31])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(I)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#Cc1ccc(C)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Yield: 53.7 %

Procedure:
In a manner similar to the method described in example 193, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-iodo-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione prepared in example 198c (0.27 g, 0.47 mmol) was reacted with trimethylsilyl acetylene (92 mg, 0.94 mmol), CuI (0.18 g, 0.94 mmol), triethylamine (95 mg, 0.94 mmol), and dichlorobis(triphenylphosphine)palladium (66 mg, 0.094 mmol) in anhydrous tetrahydrofuran, and then treated with aqueous NaOH in methanol to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-ethynyl-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.12 g, 54%)
Reaction SMILES: [C:1]([O:9][C@H:10]1[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:13]([O:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:11]1O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(F)([F:48])C1C=CC=C(C)C=1)CC)C>C(#N)C>[C:1]([O:9][C@H:10]1[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:13]([O:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:11]1[F:48])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)C(F)(F)c1cccc(C)c1
Reactant: O=C(OC[C@H]1O[C@H](OC(=O)c2ccccc2)[C@H](O)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Product: O=C(OC[C@H]1O[C@H](OC(=O)c2ccccc2)[C@H](F)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 200 °C
Reaction time: 0.33 h
Yield: 55 %

Procedure:
Into a pressure resistant vessel (200 ml) of the closed type which was made of Teflon and attached with a fiber optic temperature sensor, a stirrer rod, α-D-ribofuranose 1,3,5-tribenzoate (11 mmole; 5.1 g) and 50 ml of acetonitrile were placed. To the resultant mixture, N,N-diethyl-α,α-difluoro(3-methyl)benzylamine (23.2 mmole; 49.5 g) was slowly added under a nitrogen atmosphere. The temperature was then raised to 200° C. at a rate of 20° C./min under stirring, and the reaction was allowed to proceed for 20 minutes. After the reaction was completed, the reaction product was poured into 200 ml of ice water, and the organic layer was separated. The aqueous layer was treated by extraction with 50 ml of acetonitrile. The obtained two organic layers were combined, washed with pure water, dried with magnesium sulfate and then filtered. The obtained organic solution was concentrated using an evaporator, and the concentrated solution was analyzed in accordance with the liquid chromatography. As the result, 2.8 g (the yield: 55%) of 2-deoxy-2-fluoro-α-D-ribofuranose 1,3,5-tribenzoate of the object compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.[CH:26]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:24])(=[O:25])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([NH:32][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:11])[CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Reactant: NC1CCCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)NC2CCCCC2)c1
Reaction time: 3 h

Procedure:
To the mixture of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (1.09 g, 3 mmol) and cyclohexyl amine (1.4 ml, 12 mmol) in DMF (10 ml), added PyBOP (1.56 g, 3 mmol) then triethyl amine (0.4 ml, 3 mmol). Stirring was kept for 3 hours. Diluted with EtOAc, washed with 1N HCl, water and brine. Dried over anhydrous sodium sulfate. Concentrated, the residue was dissolved in DMSO and purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column). The title compound was obtained as light yellow powder. MS calcd for (C21H26BN3O5S): 443.17. MS found (ESI negative): (M−H)−=442.2. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.87 (s, 1H), 7.90 (d, J=6 Hz, 1H), 7.41 (s, 1H), 7.39 (d, J=8.8 Hz, 1H), 7.20 (d, J=8 Hz, 1H), 7.08 (dd, J=8 Hz, 1H), 6.45 (d, J=2 Hz, 1H), 6.33 (dd, J=8.8 Hz, 1H), 4.85 (s, 2H), 3.75 (s, 2H), 3.55 (m, 1H), 1.80-1.50 (m, 5H), 1.30-1.10 (m, 5H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[CH2:10][C@H:9]1[CH2:22][OH:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>C(Cl)Cl.CS(C)=O.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[CH2:10][C@H:9]1[CH:22]=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.9 %

Procedure:
89.1 To a stirred, cooled (0° C.) solution of 1.48 g (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (example 17.1) in 30 ml CH2Cl2/DMSO 1:1 under an argon atmosphere were added 5.7 ml triethylamine and 3.92 g SO3-pyridine complex in one portion. The clear solution (slowly warming up to room temperature) was then stirred for 3 h. The mixture was diluted with EtOAc and washed with 1 N HCl. The aqueous phase was back extracted with EtOAc. The combined organics were washed with 1 N HCl, H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by chromatography (silica gel; cyclohexane/EtOAc 1:1) to give 985 mg (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester as white amorphous solid. MS 359.0 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:23]1[CH:24]=[CH:25][C:20]([C:19]([F:30])([F:29])[F:18])=[CH:21][CH:22]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: COC(=O)c1c(O)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2sc1=O

Procedure:
4-Hydroxy-2-oxo-7-(4-trifluoromethyl-phenyl)-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5 e) and 4-trifluoromethylphenylboronic acid under conditions analogous to Example 7(a). MS ESI(−) m/e: 379.05 (M−1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([S:17][C:18]3[CH:23]=[CH:22][C:21]([C:24](=[O:33])[NH:25][C:26]4[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=4)=[CH:20][C:19]=3[N+:34]([O-])=O)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>O.C(O)C.C(OCC)(=O)C.[Fe]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([S:17][C:18]3[CH:23]=[CH:22][C:21]([C:24](=[O:33])[NH:25][C:26]4[CH:27]=[CH:28][C:29]([Br:32])=[CH:30][CH:31]=4)=[CH:20][C:19]=3[NH2:34])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(Sc3ccc(C(=O)Nc4ccc(Br)cc4)cc3[N+](=O)[O-])ccc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1ccc2cc(Sc3ccc(C(=O)Nc4ccc(Br)cc4)cc3N)ccc21
Temperature: 25 °C
Yield: 91.5 %

Procedure:
A suspension of the product of Example 59D (75 mg, 0.132 mmol), iron powder (45.3 mg, 0.811 mmol), and ammonium chloride (46 mg, 0.864 mmol) in water (1 mL) and ethanol (2 mL) was heated at 95° for 30 minutes. The reaction was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with water (2×25 mL) and brine (25 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation under vacuum to afford the title compound as a yellow solid (65 mg, 92%).
Reaction SMILES: NC1C(Cl)=CC(C(NCCN(CC)CC)=[O:7])=C(OCCSC)C=1.[NH2:24][C:25]1[C:40]([Cl:41])=[CH:39][C:28]([C:29]([NH:31][CH2:32][CH2:33][N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])=[O:30])=[C:27]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][S:47][CH3:48])[CH:26]=1>>[NH2:24][C:25]1[C:40]([Cl:41])=[CH:39][C:28]([C:29]([NH:31][CH2:32][CH2:33][N:34]([CH2:35][CH3:36])[CH2:37][CH3:38])=[O:30])=[C:27]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][S:47]([CH3:48])=[O:7])[CH:26]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCSC
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCCCSC
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCCCS(C)=O
Yield: 78 %

Procedure:
The general procedure from Example 21 is repeated except that the 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[2-(methylthio)ethoxy]benzamide utilized therein was replaced with the product from Step A to give the title compound in 78% yield after chromatography on silica and crystallization from methylene chloride-ether, as a solid, mp. 80°-83° C.
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:12](N(CC)CC)C.CI>C(Cl)Cl>[CH3:12][S:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CCN(CC)CC
Reactant: Oc1ccc2nc(S)oc2c1
Solvent: ClCCl
Solvent: CI
Product: CSc1nc2ccc(O)cc2o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the 2-mercaptobenzo[d]oxazol-6-ol (1.55 g, 9.28 mmol, 1.0 eq) in 20 mL of methylene chloride was added triethylamine (1.87 g, 18.56 mmol, 2.0 eq) and methyl iodide (1.77 g, 13.92 mmol, 1.5 eq) at room temperature. The reaction mixture was stirred at rt for 3 hours. The mixture was diluted with 100 mL of methylene chloride. The resulting mixture was washed with water (10 mL), brine (10 mL), then dried over MgSO4, filtered, and evaporated under reduced pressure to give crude product, which was purified by silica gel column eluted with ethyl acetate and hexane to give the titled compound. MH+=182.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:25]2[C:26]([CH3:40])=[CH:27][C:28]([O:31][CH2:32][C:33]3([C:37]([OH:39])=[O:38])[CH2:36][CH2:35][CH2:34]3)=[N:29][CH:30]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[N:9](COCC[Si](C)(C)C)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=1>FC(F)(F)C(O)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:25]2[C:26]([CH3:40])=[CH:27][C:28]([O:31][CH2:32][C:33]3([C:37]([OH:39])=[O:38])[CH2:36][CH2:35][CH2:34]3)=[N:29][CH:30]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[NH:12][C:11]([C:13]([F:14])([F:16])[F:15])=[CH:10][N:9]=1
Reactant: Cc1cc(OCC2(C(=O)O)CCC2)ncc1-c1ccc(-c2nc(C(F)(F)F)cn2COCC[Si](C)(C)C)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc(OCC2(C(=O)O)CCC2)ncc1-c1ccc(-c2ncc(C(F)(F)F)[nH]2)c(Cl)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 86.8 %

Procedure:
In trifluoroacetic acid (2.0 mL) and water (0.2 mL) was dissolved 1-{[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarboxylic acid (202 mg), and the solution was stirred at 50° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, the pH of the residue was made 4 with a saturated aqueous sodium hydrogen carbonate solution and 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated brine, the organic layer was separated and concentrated under reduced pressure. Isopropyl ether was added to the obtained residue, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 1-{[(5-{3-chloro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarboxylic acid (137 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][N:5]1[C:11](=[O:12])[C@@H:10]([NH:13][C:14](=[O:23])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][NH:8][C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]1=2.C(=O)([O-])[O-].[Ca+2].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:28])[CH2:4][N:5]1[C:11](=[O:12])[C@@H:10]([NH:13][C:14](=[O:23])[CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:9][N:8]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]1=2
Reactant: BrCc1ccccc1
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)CCc2ccccc2)CNc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)CCc2ccccc2)CN(Cc2ccccc2)c2ccccc21
Temperature: 80 °C
Yield: 74.5 %

Procedure:
[2-Oxo-3-(3-phenylpropionylamino)-2,3,4,5-tetrahydrobenzo-[b][1,4]diazepin-1-yl]acetic acid methyl ester (104a; 500 mg, 1.31 mmol), calcium carbonate (155 mg, 1.58 mmol), and benzyl bromide (170 μl, 1.44 mmol) were taken into 10 ml of dimethylformamide and heated to 80° C. for 8 hours. The mixture was diluted with 150 ml of ethyl acetate and washed 4 times with 50 ml of water. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to give a viscous, yellow oil that was purified by flash chromatography eluting with dichloromethane/ethyl acetate (8:2) to give 460 mg (75%) of the title compound as a white solid. 1H NMR (CDCl3) δ 7.34-7.05 (14 H, m), 6.32-6.28 (1H, d), 4.84-4.76 (1H, d), 4.76-4.70 (1H, m), 4.43-4.37 (1H, d), 4.26-4.18 (1H, d), 4.06-4.00 (1H, d), 3.79 (3H, s), 3.45-3.37 (1H, m), 3.02-2.95 (1H, m), 2.90-2.82 (2H, m), 2.5-2.34 (2H, m).
Reaction SMILES: C(OC([N:8]1[C@H:13]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=O)(C)(C)C.[ClH:24]>O1CCOCC1>[ClH:24].[CH2:17]([O:16][C:14]([C@@H:13]1[CH2:12][C@@H:11]2[C@@H:9]([CH2:10]2)[NH:8]1)=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)[C@@H]1C[C@H]2C[C@H]2N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 3-benzyl ester 2-tert-butyl ester (2.69 g, 8.48 mmol) in dioxane was added HCl (4N in dioxane, 10.6 mL, 42.4 mmol). The reaction mixture was stirred at RT overnight and subsequently lyophilized. MS (LC/MS): 218 [M+H]+.
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:5]2[C@@H:4]2[CH2:21][CH2:22][CH2:23][N:3]12.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:33]2)=CC=1>C1(C)C=CC=CC=1>[S:33]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:5]2[C@@H:4]2[CH2:21][CH2:22][CH2:23][N:3]12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1ccccc1-2
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=S)c1ccccc1-2

Procedure:
A mixture of 5.0 g (0.0161 mol) of ethyl (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate and 3.46 g (0.0086 mol) of 2,4-bis(p-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulphide is heated to boiling under reflux for 1.5 hours with 30 ml of toluene. This solution is chromatographed on silica gel using ethyl acetate for the elution. There is obtained ethyl (S)-11,12,13,13a-tetrahydro-9-thioxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate which is recrystallised from 180 ml of ethyl acetate and then melts at 227°-229° C.
Reaction SMILES: [C:1]1([C:7]2([OH:21])[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:14][C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:23][C:24](=[O:46])[C@@H:25]([CH2:44]O)[NH:26]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[C:1]1([C:7]2([O:21][CH2:44][C@H:25]([C:24]([OH:46])=[O:23])[NH2:26])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[O:14][C:15]3[C:20]2=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: OC1(c2ccccc2)c2ccccc2Oc2ccccc21
Product: N[C@H](COC1(c2ccccc2)c2ccccc2Oc2ccccc21)C(=O)O

Procedure:
from 9-phenyl-9H-xanthen-9-ol (Example 1f) and Nα -(9-fluorenylmethoxycarbonyl)-D-serine methyl ester;