Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10](=[CH2:29])[CH2:11][N:12]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[O:27][CH3:28])[C:13](=[O:17])[CH:14]=[N+]=[N-])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C1(C(F)(F)F)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Rh+2]>[Si:1]([O:8][CH2:9][C:10]12[CH2:29][CH:14]1[C:13](=[O:17])[N:12]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[O:27][CH3:28])[CH2:11]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=C(CO[Si](C)(C)C(C)(C)C)CN(Cc1ccc(OC)cc1OC)C(=O)C=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: FC(F)(F)c1ccccc1
Product: COc1ccc(CN2CC3(CO[Si](C)(C)C(C)(C)C)CC3C2=O)c(OC)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 35.4 %

Procedure:
Under argon atmosphere, to a solution of N-[2-(tert-butyldimethylsilanyloxymethyl)allyl]-2-diazo-N-(2,4-dimethoxybenzyl)acetamide (43 mg) in benzotrifluoride (0.4 ml) was added rhodium (II) acetate dimer dihydrate (2.4 mg) at room temperature, and the mixture was stirred at 50° C. for 24 hours. This reaction mixture was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1) to give the titled compound (14.2 mg).
Reaction SMILES: CSC.B.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.[CH3:26][C:27]1[C:45]([C:46]([F:49])([F:48])[F:47])=[CH:44][C:30]2[N:31]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32][CH2:33][CH2:34][C:35](=[O:36])[C:29]=2[CH:28]=1.CO>ClCCl>[OH:36][C@@H:35]1[CH2:34][CH2:33][CH2:32][N:31]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:30]2[CH:44]=[C:45]([C:46]([F:49])([F:47])[F:48])[C:27]([CH3:26])=[CH:28][C:29]1=2
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCCC2=O
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: ClCCl
Solvent: CSC
Solvent: CO
Product: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@H]2O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
Add a solution of borane dimethylsulfide complex (3.8 mL, 7.58 mmol, 2 M in tetrahydrofuran) dropwise to a solution of (S)-2-methyl-CBS-oxazaborolidine (9.5 mL, 9.48 mmol, 1M in toluene) in dichloromethane (20 mL) at −30° C. under nitrogen. Stir the mixture for 30 min and add a solution of tert-butyl 7-methyl-5-oxo-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (2.17 g, 6.32 mmol) in dichloromethane (20 mL) dropwise and warm the mixture slowly to 0° C. Pour the mixture into methanol (200 mL) at −20° C. and slowly warm the stirring mixture to room temperature over 1 h. Remove the solvents under reduced pressure and purify the residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:2), to provide the title compound as a colorless oil (1.65 g, 76%). APCI MS m/z 345 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([O:13][CH2:14][C:15]2[C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:17][O:18][C:19]=2[CH3:20])=[CH:10][C:11]=1[CH3:12])=[O:5])C.C(OC(C1N=NC(OCC2C(C3C=CC=CC=3)=NOC=2C)=CC=1)=O)C>>[CH3:12][C:11]1[CH:10]=[C:9]([O:13][CH2:14][C:15]2[C:16]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[N:17][O:18][C:19]=2[CH3:20])[N:8]=[N:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1nnc(OCc2c(-c3ccccc3)noc2C)cc1C
Agent: CCOC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nn1
Product: Cc1cc(OCc2c(-c3ccccc3)noc2C)nnc1C(=O)O
Yield: 81.6 %

Procedure:
As described for example 11a, 4-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid ethyl ester (2.30 g, 6.52 mmol), instead of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid ethyl ester, was converted to the title compound (1.73 g, 82%) which was obtained as an off-white solid. MS: m/e=324.4 [M−H]−.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH:16]([OH:18])[CH3:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].C(OCC)(=O)C>CS(C)=O>[CH2:1]([O:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH:16]([O:18][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH3:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)[C@H]1CC[C@H](COCc2ccccc2)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(O[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H](COCc2ccccc2)CC1
Temperature: 25 °C

Procedure:
In 50 ml of dry dimethyl sulfoxide were dissolved 2.0 g of trans-4-benzyloxymethyl-1-(1-hydroxyethyl)cyclohexane, and 2.24 ml of triethylamine and 1.88 g of t-butyldimethylsilyl chloride were added thereto with stirring at room temperature, and the mixture was stirred at room temperature for 2 hours and 50 minutes. To the reaction mixture were added 200 ml of ethyl acetate, and the mixture was washed successively with an aqueous citric acid solution, an aqueous sodium chloride solution, an aqueous sodium bicarbonate solution and an aqueous sodium chloride solution. The mixture was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: cyclohexane/ethyl acetate=50/1) to obtain 2.76 g of the desired compound as a colorless oil.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].[Cl:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCO.O1CCOCC1>[Cl:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=2[O:11][CH3:12])[CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COc1ccc([N+](=O)[O-])cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: C1COCCO1
Product: COc1ccc([N+](=O)[O-])cc1-c1cccc(Cl)c1
Temperature: 90 °C
Yield: 64 %

Procedure:
In a 3-neck 500 mL round bottomed flask equipped with a stir bar, condenser and nitrogen lines was placed was placed 2-iodo-1-methoxy-4-nitrobenzene (7.0 g, 25.1 mmol), 3-chlorophenylboronic acid (4.32 g, 27.6 mmol), potassium carbonate (10.4 g, 75.3 mmol), triphenylphosphine (1.98 g, 7.53 mmol), 1,4-dioxane (50 mL), 50% aqueous EtOH followed by palladium acetate (564 mg, 2.51 mmol). The mixture was heated to 90° C. in an oil bath for 16 hours and then quenched with 1M aqueous HCl (80 mL). After the reaction mixture was filtered through Celite, water (100 mL) and 1M aqueous HCl (100 mL) were added followed by extractions with ethyl acetate (3×150 mL). The organic portions were combined, washed with brine (250 mL), dried (MgSO4) and concentrated. The residue was purified by column utilizing 20% EtOAc/Hexanes as the eluent to produce 4.26 g of I-256 as an orange solid in 64% yield. MS (ESI+): 263.3 (M+).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[N:8]=1.[I:17]I.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1.CCCCCC>[Cl:6][C:7]1[C:12]([I:17])=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[N:8]=1
Reactant: II
Reactant: FC(F)(F)c1cccc(Cl)n1
Agent: O=S([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(I)c(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.3 %

Procedure:
A hexane solution of n-butyl lithium (3.8 mL) was added to a tetrahydrofuran (10 mL) solution of 2,2,6,6-tetramethylpyrrolidine (0.93 mL) at −78° C. The reaction mixture was stirred at the same temperature for 30 minutes. A tetrahydrofuran (5 mL) solution of 2-chloro-6-trifluoromethylpyridine (1.0 g) was added dropwise to the reaction mixture, and the solution was further stirred at −78° C. for 30 minutes. A tetrahydrofuran (5 mL) solution of iodine (1.54 g) was added to the solution, and the temperature of the solution was increased to the room temperature. An aqueous sodium sulfite solution was added to the solution, and the solution was extracted with diethyl ether. The organic layer was sequentially washed with an aqueous sodium sulfite solution, an aqueous sodium hydrogencarbonate solution, and a saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=100:0 to 95:5). The title compound (750 mg) was obtained as pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1[CH:8]=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]12[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][C:18]([NH2:26])=[N:17]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:35][C:36]1[C:41](B(O)O)=[CH:40][CH:39]=[CH:38][N:37]=1>O.O1CCOCC1.O>[Cl:12][C:10]1[N:9]=[CH:8][C:7]2[O:13][C:14]3[C:4]([C:5]4([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[O:19][C:18]([NH2:26])=[N:17]4)[C:6]=2[CH:11]=1)=[CH:3][C:2]([C:41]1[C:36]([F:35])=[N:37][CH:38]=[CH:39][CH:40]=1)=[CH:16][CH:15]=3
Reactant: NC1=NC2(c3ccccc3O1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Reactant: OB(O)c1cccnc1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: NC1=NC2(c3ccccc3O1)c1cc(-c3cccnc3F)ccc1Oc1cnc(Cl)cc12
Temperature: 100 °C

Procedure:
A microwave tube was charged with 7′-bromo-3′-chlorospiro[benzo[e][1,3]oxazine-4,5′-chromeno[2,3-c]pyridin]-2-amine (0.135 g, 0.315 mmol), potassium phosphate tribasic (0.078 mL, 0.945 mmol), 2-fluoro-3-pyridineboronic acid (0.049 g, 0.346 mmol) in dioxane water (3 mL, 1:1). The reaction mixture was heated in microwave at 100° C. for 40 min. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with saturated sodium bicarbonate solution twice, then dried on sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography with gradient of 20-100% EtOAc/Hexane to give 3′-chloro-7′-(2-fluoropyridin-3-yl)spiro[benzo[e][1,3]oxazine-4,5′-chromeno[2,3-c]pyridin]-2-amine. This material (0.049 g, 0.110 mmol) was combined with potassium phosphate tribasic (0.027 mL, 0.330 mmol), 5,6-dihydro-2H-pyran-3-ylboronic acid (0.028 g, 0.220 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (3.90 mg, 5.51 μmol) in dioxane/water (1 mL, 3:1). The mixture was heated to 100° C. for 1 h. The reaction was completed and it was poured into water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried on sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography with gradient of 70-100% EtOAc/Hexane to give the desired product. MS m/z=493.1 [M+H]+.
Reaction SMILES: C([Li])CCC.[CH2:6]1[CH2:25][O:24][C:8]2([CH2:13][CH2:12][CH:11]([CH3:14])[CH:10]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:9]2)[O:7]1.C1(C(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][OH:56].[Cl-].[NH4+]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH2:25]1[CH2:6][O:7][C:8]2([CH2:13][CH2:12][CH:11]([CH3:14])[C:10]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][OH:56])([S:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)(=[O:17])=[O:16])[CH2:9]2)[O:24]1
Reactant: OCCCCCCCCCCBr
Reactant: CC1CCC2(CC1S(=O)(=O)c1ccccc1)OCCO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1CCC2(CC1(CCCCCCCCCCO)S(=O)(=O)c1ccccc1)OCCO2
Reaction time: 0.17 h
Yield: 97 %

Procedure:
A solution of n-butyl lithium (1.8 ml) was added dropwise to a solution of 560 mg of 1,1-(ethylenedioxy)-4-methyl-3-(phenylsulfonyl)-cyclohexane and 4 mg of triphenylmethane in 5 ml of THF under argon stream at −78° C. The resulting mixture was stirred for 10 minutes and then reacted at room temperature for 1 hour. HMPA (1 ml) was added and the resulting mixture was recooled to −78° C., followed by the dropwise addition of a solution of 166 mg of 10-bromo-1-decanol in 2 ml of THF. After stirring the reaction at −20° C. for 2 hours, the reaction mixture was poured into a saturated solution of ammonium chloride. The resulting mixture was extracted with ethyl ether. The organic layer was washed with water and saturated saline and then, dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column while using hexane-ethyl acetate, whereby 1,1-(ethylenedioxy)-3-(10-hydroxydecyl)-4-methyl-3-(phenylsulfonyl)-cyclohexane was obtained in the form of a colorless oil. Yield: 97%, TLC: (hexane-AcOEt: 6-4) Rf=0.14
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CCN(C(C)C)C(C)C.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](Cl)=[O:27].O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:26]([C:22]2[S:21][CH:25]=[CH:24][CH:23]=2)=[O:27])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1cccs1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1cccs1

Procedure:
The title compound was synthesized from 4-fluoro-3-nitro-phenylamine (2.00 g, 12.81 mmol) dissolved in THF (25 mL) and Hunig's base (3.312 g, 25.62 mmol) to which was added thiophene-2-carbonyl chloride (1.878 g, 12.81 mmol) drop wise over 10 minutes. Reaction mixture was stirred at room temperature for 1 hr at which time water was added and the title compound was collected by filtration (3.25 g, 95%).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[CH3:9][S:10]C1C=CC(O)=CC=1>>[CH3:9][S:10][C:1]1[CH:2]=[C:3]([CH3:8])[CH:4]=[CH:5][C:6]=1[OH:7]
Reactant: CSc1ccc(O)cc1
Reactant: Cc1ccc(O)cc1
Product: CSc1cc(C)ccc1O
Temperature: 176 °C
Yield: 58.4 %

Procedure:
p-Cresol (1.2 g, 0.01 mole), para-(methylthio)phenol (3.0 g, 0.02 mole), and H ELZ-20 from Example 27 (1.0 g) were combined and heated at 176° C. for 14 hours. The mixture was cooled to room temperature and filtered. The catalyst was washed several times with ether. The filtrate and ether washings were combined, and volatiles were removed on a rotary flash evaporator. GC analysis indicated the presence of 2-methylthio-4-methylphenol (0.9 g, 56% yield).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:13](=[O:15])[CH3:14])[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(O)(=O)C.[Br:22]Br.O>CO>[Br:22][CH2:14][C:13]([C:9]1([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:16])([F:17])[F:1])=[CH:8][CH:7]=2)[CH2:10][CH2:11][CH2:12]1)=[O:15]
Reactant: BrBr
Reactant: CC(=O)C1(c2ccc(C(F)(F)F)cc2)CCC1
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: O=C(CBr)C1(c2ccc(C(F)(F)F)cc2)CCC1
Temperature: 0 °C
Yield: 80 %

Procedure:
1-[1-(4-Trifluoromethyl-phenyl)-cyclobutyl]-ethanone (1.06 g) in methanol (8 mL) was cooled to 0° C. Acetic acid containing 30% HBr (0.35 mL) was added, and then precisely 1 molar equivalent of bromine was added dropwise. The reaction mixture was maintained at 0° C. overnight, poured into 20 mL of water, and extracted with ether. The extracts were dried, filtered, concentrated, and purified on silica gel to give pure 2-bromo-1-[1-(4-trifluoromethyl-phenyl)-cyclobutyl]-ethanone (1.12 g, 80%). Data for this bromoketone: MS 321 (M); 1H NMR (300 MHz, CDCl3) δ 7.82 (d, 8 Hz, 2H), 7.39 (d, 8 Hz, 2H), 3.82 (s, 2H), 2.80-2.95 (m, 2H), 2.45-2.60 (m, 2H), 1.90-2.10 (m, 2H).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][O:7][C:8]1[CH:12]=[CH:11][S:10][CH:9]=1.O=P(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[CH3:6][O:7][C:8]1[CH:12]=[CH:11][S:10][C:9]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: COc1ccsc1
Reactant: O=S(=O)(O)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccsc1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
Chlorosulfonic acid (ClSO3H, 2.31 g, 19.62 mmol) was slowly added at 0° C. to a solution of 3-methoxythiophene (2.29 g, 19.62 mmol) in CHCl3 (80 ml) The resulting mixture was stirred at 0° C. for 30 min. The solvent was evaporated under reduced pressure, at room temperature, the residue was suspended in POCl3 (15 ml, 156.96 mmol), and PCl5 (8.2 g, 39.24 mmol) was added slowly. The reaction was stirred at 60° C. for 18 h, then cooled to room temperature and poured onto crushed ice (200 g). The aqueous mixture was extracted with CHCl3 (2×150 ml) and the combined organic layers was dried (MgSO4). The solid was removed by filtration and the filtrate was concentrated to give 3-methoxy-2-thiophenesulfonyl chloride as a brown oil (1.81 g, 43% yield).
Reaction SMILES: [NH:1]([C:23]([O:25]C(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:20]([OH:22])=[O:21])[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH:30]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[C@H:31](C(ON1C(=O)CCC1=O)=O)[CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39][CH2:40][C:41]1[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=1[Cl:43])=[O:38]>>[NH:30]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[C@H:31]([C:23]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:20]([OH:22])=[O:21])[CH2:11][O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6])=[O:25])[CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39][CH2:40][C:41]1[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=1[Cl:43])=[O:38]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1Cl)C(=O)ON1C(=O)CCC1=O
Product: CC(C)C[C@H](NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1Cl)NC(=O)OC(C)(C)C)C(=O)N[C@@H](COCc1ccccc1)C(=O)O
Yield: 63.7 %

Procedure:
By using 4,61 g of Boc-Leu-Ser(Bzl)-OH Japanese Patent Kokai (Laid-open) No. 61-112099 (1986) and 5.61 g of Boc-Lys(Cl-Z)-OSu, and the same procedure as in Reference Example 31 was repeated to obtain 4.92 g (yield: 64.0%) of the above-mentioned objective product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Al](Cl)(C)C.[CH3:13][N:14]([CH3:37])[C:15]([N:17]1[CH2:20][CH:19]([O:21][C:22]2[C:27]3[CH:28]=[C:29]([CH3:31])[O:30][C:26]=3[CH:25]=[C:24]([C:32](OCC)=[O:33])[CH:23]=2)[CH2:18]1)=[O:16]>ClCCl>[CH3:37][N:14]([CH3:13])[C:15]([N:17]1[CH2:20][CH:19]([O:21][C:22]2[C:27]3[CH:28]=[C:29]([CH3:31])[O:30][C:26]=3[CH:25]=[C:24]([C:32]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=3)=[O:33])[CH:23]=2)[CH2:18]1)=[O:16]
Reactant: CCOC(=O)c1cc(OC2CN(C(=O)N(C)C)C2)c2cc(C)oc2c1
Reactant: Cc1ccc(N)nc1
Agent: C[Al](C)Cl
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cc(OC3CN(C(=O)N(C)C)C3)c3cc(C)oc3c2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
To a solution of 2-amino-5-methyl pyridine (203 mg, 1.88 mmol) in dichloromethane (5 mL) at 0° C. was added Al(CH3)2Cl (1.88 mL, 1M in hexanes) drop wise. After the addition, the ice-bath was removed, and the mixture was stirred for 30 minutes at room temperature. Ethyl 4-({1-[(dimethylamino)carbonyl]azetidin-3-yl}oxy)-2-methyl-1-benzofuran-6-carboxylate (65 mg, 0.19 mmol) was added and the stirring was continued for 14 h. The reaction was quenched with potassium sodium tartrate tetrahydrate (20% w/w) cautiously. The product was extracted with CHCl3, washed with brine and dried over Na2SO4. The product was purified by gradient silica gel chromatography using CHCl3/MeOH (95/5 to 85/15) to give the title compound (70 mg, 90%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.15 (s, 3 H) 2.37 (s, 3 H) 2.78 (s, 6 H) 3.30-3.44 (m, 2 H) 3.44-3.60 (m, 1 H) 3.88 (dd, J=12.13, 6.06 Hz, 1 H) 4.05 (dd, J=11.75, 2.40 Hz, 1 H) 6.70 (s, 1 H) 6.98 (d, J=9.60 Hz, 1 H) 7.71-7.85 (m, 1 H) 7.92 (s, 1 H) 8.17 (d, J=8.34 Hz, 1 H) 8.28-8.44 (m, 2 H); MS (ESI, pos): 409.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH2:17][O:18][C:19]3[CH:51]=[CH:50][C:22]([CH2:23][CH:24]4[S:28][C:27](=[O:29])[N:26](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[C:25]4=[O:49])=[CH:21][CH:20]=3)=[CH:16][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C(=O)([O-])O.[Na+]>O>[OH2:18].[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH2:17][O:18][C:19]3[CH:51]=[CH:50][C:22]([CH2:23][CH:24]4[S:28][C:27](=[O:29])[NH:26][C:25]4=[O:49])=[CH:21][CH:20]=3)=[CH:16][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH2:17][O:18][C:19]3[CH:51]=[CH:50][C:22]([CH2:23][CH:24]4[S:28][C:27](=[O:29])[NH:26][C:25]4=[O:49])=[CH:21][CH:20]=3)=[CH:16][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1SC(Cc2ccc(OCc3ccc4c(c3)ncn4Cc3ccccc3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=O)C(Cc2ccc(OCc3ccc4c(c3)ncn4Cc3ccccc3)cc2)S1
Temperature: 50 °C
Reaction time: 3 h
Yield: 101.4 %

Procedure:
A mixture of 0.26 g of 5-[4-(1-benzylbenzimidazol-5-ylmethoxy)benzyl]-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 29), 3 ml of acetic acid and 1 ml of water was stirred for 3 hours at 50° C. in oil bath. At the end of this time, the reaction mixture was neutralized with sodium hydrogencarbonate and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure, and the resulting residue was recrystallized from a mixture of ethanol and methanol, to give 116 mg of the title compound, melting at 185°-187° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH2:11])[S:9][CH:10]=1)=[O:5])C.[C:12](Cl)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:12]([NH:11][C:8]1[S:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1csc(N)n1
Solvent: c1ccncc1
Product: O=C(O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Yield: 71.7 %

Procedure:
A solution of the commercially available 2-amino-thiazole-4-carboxylic acid ethyl ester 2a (3.8 g, 22 mmol) and trityl chloride (6.8 g, 24.3 mmol) in 30 ml pyridine was stirred at room temperature for 16 hours. The precipitate was filtered off and the filtrate was concentrated to reduce the volume to 20 ml. To the crude 2-(trityl-amino)-thiazole-4-carboxylic acid ethyl ester in 20 ml pyridine was added a solution of sodium hydroxide (5.4 g) in 50 ml of 60% ethanol in water. The reaction mixture was stirred at room temperature over the weekend, and was then acidified with acetic acid to pH 5. The precipitate was collected and dried to give 2-(tritylamino)-thiazole-4-carboxylic acid as a white solid (6.1 g, 72% yield). LC/MS (m/z 385.08 (M−H)+); HPLC Rt: 3.732 min.