Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16]([F:19])[CH:17]=2)[C:12](=[O:21])[C:11]([C:22]([OH:24])=[O:23])=[CH:10]1.[N+:25]([O-])([O-:27])=[O:26].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:25]([O-:27])=[O:26])=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16]([F:19])[CH:17]=2)[C:12](=[O:21])[C:11]([C:22]([OH:24])=[O:23])=[CH:10]1
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2cc(F)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)c1cn(-c2cc([N+](=O)[O-])c(F)cc2F)c2cc(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 30859.9 %

Procedure:
To 40 ml of conc. sulfuric acid was added 4 g of 1-(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. Potassium nitrate (3.6 mg) was added in portions to the solution, which was stirred for 1 hour at room temperature. The reaction solution was poured into ice water and stirred overnight. The precipitated solid was collected by filtration and washed with water, ethanol and diethyl ether to give 4.2 g of the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([O:21][CH3:22])[CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[C:15]2[CH3:20])=[O:8].[OH:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.O>C1C=CC=CC=1>[OH:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]2[CH:11]=[C:12]([O:21][CH3:22])[CH:13]=[C:14]3[C:19]=2[N:18]=[CH:17][CH:16]=[C:15]3[CH3:20])=[O:8])[CH2:28][CH2:27]1
Reactant: COc1cc(NC(=O)CCCCCBr)c2nccc(C)c2c1
Reactant: OCCN1CCNCC1
Solvent: c1ccccc1
Solvent: O
Product: COc1cc(NC(=O)CCCCCN2CCN(CCO)CC2)c2nccc(C)c2c1
Yield: 72.4 %

Procedure:
A mixture of 7 g (0.019 mol) of 6-bromo-N-(6-methoxy-4-methyl-8-quinolinyl)hexanamide and 4.4 g (0.038 mol) of hydroxyethylpiperazine in 100 ml of benzene was heated under reflux for 48 hours, allowed to cool, mixed well with 50 ml of water and filtered to collect the crude product. Recrystallization from toluene with hexane afforded 5.7 g (72%) of crystalline material, mp 88°-90°.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:13]([CH2:21][C:22](N(OC)C)=[O:23])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:11]=[CH2:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:28]=[C:29]([Mg]Br)[CH3:30]>C1COCC1>[Si:1]([O:8][CH2:9][C@@H:10]([N:13]([CH2:21][C:22](=[O:23])[C:29]([CH3:30])=[CH2:28])[C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])[CH:11]=[CH2:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Reactant: C=C(C)[Mg]Br
Solvent: C1CCOC1
Product: C=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)C(=C)C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To a solution of (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)but-3-en-2-yl(2-(methoxy(methyl)amino)-2-oxoethyl)carbamate (Intermediate 5, 30.79 g, 76.48 mmol) in THF (200 mL) at 0° C. was added prop-1-en-2-ylmagnesium bromide (0.5M in THF) (300 mL, 149.90 mmol). The reaction mixture was stirred at 0° C. for 1 hour. The reaction mixture was quenched with 200 mL 10% citric acid, diluted further with 100 mL water and extracted with ether. The organics were concentrated and the resulting oil was dissolved in ether and washed with water and brine. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-20% ethyl acetate/hexanes) afforded the desired product (26.2 g, 89%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]([CH2:4]Br)=[CH2:3].[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[Mg]Br.[Mg].BrC1SC=CC=1.Cl>CC(C)=O.C(=O)=O.CCOCC>[Br:1][C:2]([CH2:4][C:7]1[S:6][CH:10]=[CH:9][CH:8]=1)=[CH2:3]
Reactant: C=C(Br)CBr
Reactant: Br[Mg]c1cccs1
Agent: Brc1cccs1
Agent: Cl
Agent: O=C=O
Solvent: CC(C)=O
Solvent: CCOCC
Product: C=C(Br)Cc1cccs1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A 1000 ml 3-necked round-bottomed flask was fitted with a mechanical stirrer through a mineral oil sealed bearing, a reflux condenser and a 1000 ml addition funnel. A mixture of 70 g of 2,3-dibromopropene and 100 ml of dry ethyl ether was added. The flask was now cooled to 0° C. in acetone/dry-ice and a solution of thienyl magnesium bromide, prepared from 7.8 of magnesium 50 g of 2-bromothiophene (0.31 mol) and 260 ml of dry ether was added at such a rate so that the temperature did not exceed 38° C. The addition took about 1.5 hrs. Stirring was continued and the acetone/dry-ice bath was replaced with a heating mantle. The mixture was gently refluxed for 1.5 hrs. after which time the flask was again cooled and a solution of 5 ml of 36% hydrochloric acid and 200 g of ice were added. The contents of the flask were then transferred to a separatory funnel, and the ether layer was separated and dried over anhydrous sodium sulfate. The ether was distilled off and the residue was fractionated under reduced pressure (65°-78° C./0.5 mm) yielding 41.8 g (67 percent of theory). The residue, 26 g, consisted mainly of diphenyl, m.p. 69°-71° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[CH:18][CH:19]=2)[C@@H:10]([O:26][CH2:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)[CH2:9]1)=O)(C)(C)C.[ClH:38]>>[ClH:38].[C:16]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=[C:14]([C@H:11]2[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]2[O:26][CH2:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2cccc(-c3ccccc3)c2)[C@@H](OCc2ccc3ccccc3c2)C1
Agent: Cl
Product: c1ccc(-c2cccc([C@H]3CCNC[C@@H]3OCc3ccc4ccccc4c3)c2)cc1
Temperature: 25 °C

Procedure:
A mixture of the title C compound, (3R*,4R*)-4-biphenyl-3-yl-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid t-butyl ester (54 mg, 0.11 mmol) and HCl (5M in 2-propanol, 1 mL, 5 mmol) is stirred for several h at RT (until complete consumption of the starting material). The reaction mixture is evaporated in vacuo to afford (3R*,4R*)-4-biphenyl-3-yl-3-(naphthalen-2-ylmethoxy)-piperidine hydrochloride as a slightly beige foam: MS (LC/MS) 394.1 [M+H]+; Rf 0.23 (DCM/MeOH 9:1).
Reaction SMILES: C[Si](C)(C)[C:3]1[O:7][C:6]([CH3:8])=[C:5]([CH2:9][O:10][C:11](=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:4]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1C(I)=C([OH:39])C(I)=C2OC3C(C4(OC(=O)C5C(Cl)=C(Cl)C(Cl)=C(Cl)C4=5)C=12)=CC(I)=C(O)C=3I.O=O.C(=O)=O.CC(C)=O>C1COCC1>[C:11]([O:10][CH2:9][C:5]1[CH:6]([CH3:8])[O:7][C:3](=[O:39])[C:4]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=C1OC2(c3cc(I)c(O)c(I)c3Oc3c2cc(I)c(O)c3I)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: CCCCCCCCCCCC(=O)OCc1c(C)oc([Si](C)(C)C)c1-c1ccccc1
Agent: O=C=O
Agent: O=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)OCC1=C(c2ccccc2)C(=O)OC1C
Yield: 27 %

Procedure:
The solution of Compound 15 and Rose Bengal in THF was saturated with O2, then cooled to approximately -5° C. (dry ice/acetone bath) and irradiated with a 150 watt flood lamp (maintaining the temperature of the mixture at -5° to 0° C.) for 3 hours. The reaction mixture was then filtered and concentrated to a pink oil which was purified by column chromatography (eluent, EtOAc/hexanes, 1:20 to 1:4) to give 3.4 g (27%) of pure title compound as a colorless oil. An additional 3 g (approximately 25%) of a mixture of the title compound and the 5-desmethyl derivative (ratio 1:1 by proton NMR integration) was also obtained as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:34]1[CH2:37][CH2:36][CH2:35]1>>[N:34]1([C:2]2[N:7]=[CH:6][C:5]([S:8]([N:11]3[CH2:20][CH2:19][C:18]4[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]5[CH:23]=[N:22][N:21]([C:24]6[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=6)[C:16]=5[CH:17]=4)[CH2:12]3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH2:37][CH2:36][CH2:35]1
Reactant: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Reactant: C1CNC1
Product: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCC3)nc1)C2

Procedure:
The title compound was prepared by the method of Preparation 4b using (R)-6-(6-chloropyridine-3-sulfonyl)-1-(4-fluorophenyl)-4a-methoxymethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene and azetidine. LCMS (Method C): 510 (M+H)+, Retention time 10.9 minutes.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.CCO.O>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:32]3[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: Cn1cc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)cn1

Procedure:
A mixture of (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 2.2, 60 mg, 0.134 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (42 mg, 0.202 mmol), Pd(PPh3)2Cl2 (9.44 mg, 0.013 mmol), Na2CO3 (42.8 mg, 0.403 mmol), DME (570 μL), water (163 μL) and EtOH (81 μL) in a MW vial was sealed, evacuated/purge with argon and subjected to MW irradiation at 120° C. for 10 min. The RM was diluted with THF (1 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 46.7 mg, 0.067 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by preparative HPLC (Condition 9, 25% for 0.2 min then 15% to 45% in 14 min) to yield the title compound as a white solid. LC-MS (Condition 2) tR=1.61 min, m/z=448.2/449.2 [M+H]+, m/z=446.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.71-1.80 (m, 1H) 1.81-1.91 (m, 1H) 2.98 (d, J=11.25 Hz, 1H) 3.25-3.39 (m, 0.2H) 3.44-3.53 (m, 1H) 3.89 (s, 3H) 4.22 (s, 1H) 4.84 (s, 1H) 7.34 (d, J=8.56 Hz, 2H) 7.53 (s, 1H) 7.84 (d, J=5.38 Hz, 2H) 7.86-7.88 (m, 1H) 7.94 (d, J=2.45 Hz, 1H) 8.67 (d, J=2.45 Hz, 1H) 10.14 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[S:21][C:22]([C:25]4[N:26]([C:34]5[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:35]=5[Cl:41])[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:29]=4)=[CH:23][CH:24]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(CC(O)=O)(F)F>ClCCl>[Cl:41][C:35]1[CH:36]=[CH:37][C:38]([Cl:40])=[CH:39][C:34]=1[N:26]1[CH:27]=[C:28]([C:30]([F:31])([F:33])[F:32])[N:29]=[C:25]1[C:22]1[S:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[N:15][CH:16]=2)=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ccc(-c4nc(C(F)(F)F)cn4-c4cc(Cl)ccc4Cl)s3)cn2)CC1
Agent: O=C(O)CC(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1cn(-c2cc(Cl)ccc2Cl)c(-c2ccc(-c3ccc(N4CCNCC4)nc3)s2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
4-(5-{5-[1-(2,5-Dichloro-phenyl)-4-trifluoromethyl-1H-imidazol-2-yl]-thiophen-2-yl}-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (104 mg, 0.17 mmol) was mixed with 4 mL 50% trifluoromethylacetic acid in dichloromethane, and stirred at room temperature for 2 hrs. All solvent was removed; the residue was redissolved in dichloromethane and neutralized to pH 7 by saturated NaHCO3. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was precipitated from dichloromethane/Hexane mixture, then filtered and washed several times with dichloromethane to give yellow solid (50 mg, 57% yield). 1H-NMR (400 MHz, CDCl3): δ 3.30-2.97 (m, 4H), 3.57-3.54 (m, 4H), 6.63 (d, J=8.7, 1H), 6.78 (d, J=4.0, 1), 6.96 (d, J=4.0, 1H), 7.31 (s, 1H), 7.60-7.50 (m, 4H), 8.37 (m, 1H). MS (ES): 524.3, 526.5. [M+]+
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)=[CH:15][C:14]=2[CH2:25][N:26]2[CH2:30][CH2:29][O:28][C:27]2=[O:31])[CH:7]=1)C.[OH-].[Li+]>COCCOC.O>[CH3:24][N:22]1[CH:23]=[C:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][C:8]3[CH:7]=[C:6]([CH2:5][C:4]([OH:32])=[O:3])[CH:11]=[CH:10][CH:9]=3)=[C:14]([CH2:25][N:26]3[CH2:30][CH2:29][O:28][C:27]3=[O:31])[CH:15]=2)[CH:20]=[N:21]1
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(-c3cnn(C)c3)cc2CN2CCOC2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: Cn1cc(-c2ccc(Oc3cccc(CC(=O)O)c3)c(CN3CCOC3=O)c2)cn1
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
To the crude solution of {3-[4-(1-methyl-1H-pyrazol-4-yl)-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-phenyl}-acetic acid ethyl ester (0.23 mmol) in DME and H2O was added lithium hydroxide (0.040 g, 0.95 mmol) in H2O (1 mL), and the reaction was stirred at 80° C. for 20 minutes. The mixture was acidified and concentrated, and the residue was dissolved in MeOH (4 mL) and purified by preparative HPLC to give the title compound.
Reaction SMILES: I[C:2]1[N:3]([I:13])[C:4]([OH:12])=[C:5]2[CH:10]=[C:9]([CH3:11])[N:8]=[C:6]2[N:7]=1>C(O)(=O)C.O.[Zn]>[I:13][N:3]1[C:4]([OH:12])=[C:5]2[CH:10]=[C:9]([CH3:11])[N:8]=[C:6]2[N:7]=[CH:2]1
Reactant: Cc1cc2c(O)n(I)c(I)nc-2n1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc2c(O)n(I)cnc-2n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 4.86 g of 2,3-diiodo-4-hydroxy-6-methylpyrrolo[2,3-d]pyrimidine in 100 mL of glacial acetic acid and 25 mL of water are added 1.3 g (20 mmol) of zinc powder. The mixture is stirred at ambient temperature for 18 hours, diluted with 500 mL of water, and cooled. The solid is collected through filtration and dried under vacuum over phosphorus pentoxide to yield 3-iodo-4-hydroxy-6-methylpyrrolo[2,3-d]pyrimidine which can be purified further by chromatography over silica eluting with 2.5% methanol in methylene chloride.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14]([C:16]1[N:17]=[C:18](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:19][CH:20]=1)=O)C.CO>ClCCl>[CH:14]([C:16]1[N:17]=[C:18](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:19][CH:20]=1)=[O:13]
Reactant: CCOC(=O)c1coc(/C=C/c2ccccc2)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: CO
Product: O=Cc1coc(/C=C/c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
Diisobutylaluminum hydride (1.0N hexane solution, 66 ml) was added dropwise to a solution of 4-ethoxycarbonyl-2-(trans-styryl)oxazole (8.57 g) in dichloromethane (80 ml) at −78° C. After 15 minutes, methanol (11 ml) was added dropwise, and the mixture was warmed to room temperature over 1 hour. The reaction mixture was filtered through Celite, and the resultant pasty substance was dissolved in ethyl acetate (200 ml) and a saturated aqueous solution (200 ml) of ammonium chloride was added, and an organic layer was separated. The water layer was then extracted with dichloromethane (2×100 ml). The resultant organic layers were collected and washed with a saturated aqueous solution (100 ml) of sodium hydrogencarbonate and saturated saline (100 ml), combined with the filtrate obtained by the filtration through Celite and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:ethyl acetate=5:1→dichloromethane:methanol=10:1) to obtain the title compound (5.86 g) as colorless needle crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH:17]4[C:19]([OH:22])([CH3:21])[CH3:20])[N:13]([CH3:23])[C:12]=3[CH:24]=2)[C:4](=[O:25])[CH:3]=1.[Cl:26][C:27]1[S:31][CH:30]=[C:29]([CH2:32]O)[CH:28]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:26][C:27]1[S:31][CH:30]=[C:29]([CH2:32][O:1][C:2]2[CH:7]=[CH:6][N:5]([C:8]3[CH:9]=[CH:10][C:11]4[N:15]=[C:14]([CH:16]5[CH2:18][CH:17]5[C:19]([OH:22])([CH3:20])[CH3:21])[N:13]([CH3:23])[C:12]=4[CH:24]=3)[C:4](=[O:25])[CH:3]=2)[CH:28]=1
Reactant: OCc1csc(Cl)c1
Reactant: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(OCc4csc(Cl)c4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 8.7 %

Procedure:
To a mixture of 4-hydroxy-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), (5-chloro-3-thienyl)methanol (77 mg), tributylphosphine (0.219 ml) and THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (223 mg), and the mixture was stirred at 60° C. for 2 h. The solvent was evaporated, and the residue was purified by column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was suspended in toluene, and the insoluble material was collected by filtration to give the title compound (12 mg) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[N:13]([CH3:14])[C:12]2[CH:15]=[CH:16][C:17]([C:19](O)=[O:20])=[CH:18][C:11]=2[N:10]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:43][C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][C:50]=1[CH3:51])[NH2:47]>CN(C=O)C.O>[CH3:43][C:44]1[CH:45]=[C:46]([NH:47][C:19]([C:17]2[CH:16]=[CH:15][C:12]3[N:13]([CH3:14])[C:9]([C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:10][C:11]=3[CH:18]=2)=[O:20])[CH:48]=[CH:49][C:50]=1[CH3:51]
Reactant: Cn1c(-c2c(Cl)cccc2Cl)nc2cc(C(=O)O)ccc21
Reactant: Cc1ccc(N)cc1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccc3c(c2)nc(-c2c(Cl)cccc2Cl)n3C)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 2-(2,6-dichlorophenyl)-1-methyl-1H-benzoimidazole-5-carboxylic acid (100 mg), EDCI (59 mg) and HOBt (42 mg) in DMF (2 mL) was added 3,4-dimethylaniline (38 mg) and the mixture was stirred at room temperature for 18 h. The mixture was poured into water and was extracted with EtOAc. The organic phase was washed with water (3×) and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by flash chromatography using EtOAc/CH2Cl2 (1:5) as eluent to give 2-(2,6-dichlorophenyl)-1-methyl-1H-benzoimidazole-5-carboxylic acid (3,4-dimethylphenyl)-amide as a glasslike solid; MS (m/z) 424 (M+1); 1H NMR (CDCl3, 400 MHz) δ 8.36 (s, 1H), 8.24 (s, 1H), 8.00 d, J=8.59 Hz, 1H), 7.52-7.39 (m, 6H), 7.10 (d, J=8.08 Hz, 1H), 3.65 (s, 3H), 2.28 (s, 3H), 2.25 (s, 3H).
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([NH:13][CH:14]([C:17]2[C:18](=[O:32])[NH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)=[N:21][N:22]=2)[CH2:15][CH3:16])=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)=O>>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[N:22]3[C:17]([C:18](=[O:32])[NH:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=4)=[N:21]3)=[C:14]([CH2:15][CH3:16])[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(NC(=O)[C@H]1CC[C@@H](C(C)(C)C)CC1)c1nnc(-c2cccc([N+](=O)[O-])c2)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc(C2CCC(C(C)(C)C)CC2)n2nc(-c3cccc([N+](=O)[O-])c3)[nH]c(=O)c12

Procedure:
In analogy to the procedure for Example 21A, 5.1 g (11.6 mmol) crude cis-4-tert-butyl-N-{1-[3-(3-nitrophenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}cyclo-hexanecarboxamide (Example 20A), 2.7 g (17.4 mmol) phosphoric trichloride are stirred at reflux for 3 hours and proportionate amounts of the solvents are used.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C@@H:9]2[N:12]([C:13](=[O:15])[CH3:14])[C:11](=[O:16])[C@H:10]2[CH2:17][CH2:18][CH2:19][NH:20][C:21]([NH:33]C(OCC2C=CC=CC=2)=O)=[N:22]C(OCC2C=CC=CC=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:44]>[Pd].CO.C(OCC)(=O)C>[ClH:44].[C:1]1([CH2:7][CH2:8][C@@H:9]2[N:12]([C:13](=[O:15])[CH3:14])[C:11](=[O:16])[C@H:10]2[CH2:17][CH2:18][CH2:19][NH:20][C:21]([NH2:33])=[NH:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)N1C(=O)[C@@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C=Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)N1C(=O)[C@@H](CCCNC(=N)N)[C@@H]1CCc1ccccc1
Yield: 76 %

Procedure:
A methanol/ethyl acetate (3 mL/1 mL) solution of compound 27 (470 mg, 0.82 mmol) and 1N HCl (0.9 mL), containing 10% palladium on carbon, was stirred under a hydrogen atmosphere until TLC indicated the disappearance of the starting material (about 30 min). The suspension was filtered through a pad of Celite, and the filtrate was concentrated to afford 220 mg (76%) of the title product.
Reaction SMILES: [ClH:1].Cl.C([O:10][CH:11]([NH:29][C:30](=[O:41])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]([NH2:40])=[NH:39])[C:12](=[O:28])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])C1C=CC=CC=1>FC(F)(F)C(O)=O>[ClH:1].[NH:37]([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][C:30](=[O:41])[NH:29][CH:11]([OH:10])[C:12](=[O:28])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:38]([NH2:40])=[NH:39]
Reactant: CC(C)(C)OC(=O)CCNCCCCNC(=O)C(NC(=O)CCCCCCNC(=N)N)OCc1ccccc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)NCCCCCCC(=O)NC(O)C(=O)NCCCCNCCC(=O)O
Yield: 22.3 %

Procedure:
0.95 g (1.53 mmol) of t-butyl 11-benzyloxy-19-guanidino-10,13-dioxo-4,9,12-triazanonadecanoate dihydrochloride was dissolved in 10 ml of trifluoroacetic acid under ice-cooling and then allowed to react at room temperature overnight. The trifluoroacetic acid was distilled off under reduced pressure and the residue was dissolved in 10 ml of distilled water. After washing with 1,2-dichloroethane, the pH value of the product was adjusted to 5.0 with 1N NaOH. Then it was diluted to approximately 2 l with distilled water, adsorbed on 125 ml of CM-Sephadex® C-25 (Na) and subjected to gradient elution between 1 l of distilled water and 1 l of 0.07M sodium chloride. The target fractions were combined and concentrated to dryness. The insoluble matters were filter off using 90% ethanol and the filtrate was further desalted with 100 ml of Diaion® HP-20. By eluting with distilled water and lyophilizing, 149.5 mg of the aimed compound was obtained (yield: 22.3%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([N:13]=[N+]=[N-])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.S>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:13]
Reactant: COC(=O)C(CSc1ccccc1)N=[N+]=[N-]
Agent: S
Solvent: c1ccncc1
Product: COC(=O)[C@@H](N)CSc1ccccc1
Yield: 90 %

Procedure:
There was led into 6.3 grams (26.6 mmoles) of the 2-azido-3-phenylmercapto-propionic acid methylester produced according to Example 2 in 80 ml of a 50 volume percent aqueous pyridine solution under stirring at 25° C. a weak stream of hydrogen sulfide. After this time the development of gas was ended. The reaction mixture was freed from the pyridine portion on a rotary evaporator under reduced pressure and the aqueous solution remaining behind extracted 3 times, each time with 40 ml of diethyl ether. The combined organic extracts were dried over magnesium sulfate, the ether removed on a rotary evaporator and the residue freed from residual solvent in a high vacuum. Chromatography on a silica gel column with ethyl acetate yielded 5.06 grams (90% of theory) of S-phenyl cysteine methyl ester.