Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC2=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1CCc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-methoxyindan-1-one (200 g, 1.235 mol) in 2 L of anhydrous dichloromethane was added BBr3 (234 mL, 2.469 mol) slowly at −78° C. The mixture was warmed slowly to rt and stirred overnight. Then the mixture was poured slowly into ice-water (2 L) with vigorously stirring for 30 min. The result mixture was filtered to give a solid. The filtrate was separated, and the aqueous phase was extracted with EtOAc (2×500 mL). The combined organic phases were washed with brine (1 L) and dried over Na2SO4 and concentrated to dryness to obtain another batch of solid. The combined solids were dried in vacuo to give the title compound. 1H-NMR (400 MHz, MeOD): δ 7.55 (d, J=8.1 Hz, 1H), 6.78-6.84 (m, 2H), 3.03-3.06 (m, 2H), 2.60-2.63 (m, 2H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1I.[Li]CCCC.[B:16](OC)([O:19]C)[O:17]C>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1[B:16]([OH:19])[OH:17]
Reactant: Cc1cc(I)c(F)cc1F
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(B(O)O)c(F)cc1F
Reaction time: 0.17 h
Yield: 88 %

Procedure:
To 94A (2.8 g, 11 mmol) in THF (50 mL) was added n-BuLi (1.6M in hexane, 8.9 mL) at −78° C. After 10 min stirring, trimethyl borate (2.5 mL) was introduced. The mixture was stirred from −78° C. to rt overnight. The reaction was quenched by 1N HCl and extracted with EtOAc. The organic layer was separated and washed with saturated Na2S2O3, brine and dried over MgSO4. Evaporation of solvent gave product 94B (1.66 g, 88% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 2.22 (s, 3H) 6.82 (t, J=9.23 Hz, 1H) 7.26 (t, J=7.69 Hz, 1H).
Reaction SMILES: N[C:2]1[S:3][C:4]([CH:11]([CH3:13])[CH3:12])=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.N([O-])=O.[Na+]>OP=O>[CH3:13][CH:11]([C:4]1[S:3][CH:2]=[N:6][C:5]=1[C:7]([O:9][CH3:10])=[O:8])[CH3:12]
Reactant: COC(=O)c1nc(N)sc1C(C)C
Agent: O=N[O-]
Agent: O=PO
Agent: [Na+]
Product: COC(=O)c1ncsc1C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a solution of methyl 2-amino-5-(1-methylethyl)-1,3-thiazole-4-carboxylate (2.15 g) (available from ABCR) in 30% hypophosphorus acid (53 ml) at −5° C. was added, slowly beneath the surface, maintaining the temperature between −5 and 0° C., sodium nitrite (1.6 g) and the mixture was stirred for a further 1 h at 0° C. The cooling bath was removed for 2 h, then replaced while a cool solution of sodium hydroxide (8.5 g) in water (100 ml) added slowly. The solution was neutralised by the addition of solid sodium hydrogencarbonate and extracted with diethyl ether (50 ml), then dried over sodium sulphate. The mixture was evaporated and purified by chromatography on silica gel eluting with a gradient of ethyl acetate in cyclohexane to give the title compound (1.9 g) as a yellow oil.
Reaction SMILES: [CH3:1][C:2](=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7].[H][H].O(C(C)C)[K].CCCCCC>C1C=CC=CC=1>[CH3:1][CH:2]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:3][CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7]
Reactant: [H][H]
Reactant: CC(C)=CCCC(C)=Nc1ccccc1
Agent: CC(C)O[K]
Solvent: c1ccccc1
Solvent: CCCCCC
Product: CC(C)=CCCC(C)Nc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of N-(1,5-dimethyl-4-hexenylidene)aniline (2.0 g) in benzene (2 ml) was added under a flow of hydrogen gas to a mixture of RuHCl(R,R—BINAP)(R,R—CYDN) (5 mg) and KOiPr (5 mg) in a Schlenk flask. The flask was then cooled to liquid nitrogen temperature, filled with H2 gas, closed and allowed to gradually warm to room temperature. The mixture was vigorously stirred for 24 hours. A 1H NMR spectrum of the reaction mixture indicated complete conversion of the imine to the amine. Hexane (10 ml) was added to the mixture, which was then eluted (hexane) through a short column of silica gel in order to remove the spent catalyst and KOiPr. Evaporation of the hexane under reduced pressure resulted in spectroscopically pure N-(1,5-dimethyl-4-hexenyl)aniline, as verified by 1H and 13C NMR.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[BH4-].[Na+].[N:6]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:18]2[C@@H:9]([C@H:10]([C:19](OCC)=[O:20])[NH:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=32)[CH2:8][CH2:7]1.C(=O)([O-])O.[Na+]>O1CCCC1CCO.O1CCCC1.C(OCC)(=O)C>[OH:20][CH2:19][C@H:10]1[C@H:9]2[CH2:8][CH2:7][N:6]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:18]2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:11]1
Reactant: CCOC(=O)[C@@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: OCCC1CCCO1
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](CO)Nc3ccccc3[C@@H]21
Reaction time: 0.5 h
Yield: 2.3 %

Procedure:
To a solution of calcium chloride (12.5 g, 113.1 mmol) in a mixture of tetrahydrofuran-ethanol (200 ml-200 ml) was added sodium borohydride (8.5 g, 226.2 mmol) at 0° C. and the mixture was stirred for 30 min. A solution of 1-tert-butyl 4-ethyl (3aR*,4R*,9bR*)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1,4-dicarboxylate (14.6 g, 46.6 mmol) in tetrahydrofuran (50 ml) was added at 0° C., and the mixture was stirred at room temperature for 16 hrs. Saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added, and the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried (over anhydrous MgSO4) and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (1:9, v/v) to give the title compound (326 mg, 96%) as an oil.
Reaction SMILES: [OH:1][CH:2]([CH3:12])[CH2:3][CH2:4][C@@H:5]([CH3:11])[CH2:6][C:7]([O:9][CH3:10])=[O:8].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:11][C@H:5]([CH2:4][CH2:3][C:2](=[O:1])[CH3:12])[CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C[C@H](C)CCC(C)O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)C[C@H](C)CCC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
To a solution of alcohol from Step 2 (293 mg) in CH2Cl2 (12 mL) was added a mixture of pyridinium chlorochromate (542 mg, 1.5 eq) and celite (542 mg). The suspension was stirred at r.t. overnight, and allowed to settle. The supernatant was collected and evaporated down to a residue which was chromatographed on silica gel, eluting with a 1:2 mixtue of EtOAc and hexane, to afford the desired ketone as a colorless liquid (189 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH2:12][CH2:11][CH2:10][C:9](=[O:13])[CH:8]=2)[CH:2]=1.[BH4-].[Na+]>CCO.CO.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]2[CH2:12][CH2:11][CH2:10][C@H:9]([OH:13])[CH2:8]2)[CH:2]=1
Reactant: O=C1C=C(c2cccnc2)CCC1
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: O[C@H]1CCC[C@@H](c2cccnc2)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 74.9 %

Procedure:
A mixture of 3-(3-pyridyl)-2-cyclohexen-1-one (19.1 g, 110 mmol) and 10% Pd/C (1.91 g) in EtOH (300 mL) was stirred under hydrogen atmosphere for 16 h. The catalyst was removed by filtration over Celite and the filtrate was concentrated in vacuo. To a solution of crude product in MeOH (360 ml) was added portionwise NaBH4 (2.08 g. 55.0 mmol) at 3° C., and stirred for 30 min at same temperature. The reaction mixture was poured into ice-water and then extracted with AcOEt. The organic layer was dried over anhyd Na2SO4 followed by the removal of solvent. The crude product was purified by column chromatography (NH, Hexane/EtOAc=2/1) to yield cis-3-(3-pyridyl)cyclohexanol (14.6 g, 75%) as colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]2[C:9](=[O:15])[NH:10][C:11](=[S:14])[NH:12][CH:13]=2)[CH:4]=[N:3]1.I[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([C:33]([F:36])([F:35])[F:34])[CH:27]=2)=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][S:14][C:11]3[NH:12][CH:13]=[C:8]([CH2:7][C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[C:9](=[O:15])[N:10]=3)=[CH:20][CH:21]=2)=[CH:27][C:28]=1[C:33]([F:34])([F:35])[F:36]
Reactant: Cn1cc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Reactant: FC(F)(F)c1cc(Oc2ccc(CCI)cc2)ccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cn1cc(Cc2c[nH]c(SCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Temperature: 120 °C
Yield: 21.9 %

Procedure:
A mixture of 5-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (98 mg, 0.442 mmol), 4-chloro-3-(trifluoromethyl)phenyl 4-(2-iodoethyl) phenyl ether (157 mg, 0.368 mmol) and DIPEA (0.193 mL, 1.104 mmol) in chloroform (2 mL) was heated with a microwave reactor at 120° C. for 0.5 h. Purification via reverse phase flash chromatography then afforded the title compound (42 mg, 21.91% yield). LCMS: rt=3.63 min, [M+H+]=521
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[CH2:21][S:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:7]=1)[CH3:2].[CH3:28][C:29]([CH3:34])([CH3:33])[C:30](Cl)=[O:31]>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:30](=[O:31])[C:29]([CH3:34])([CH3:33])[CH3:28])=[CH:16][C:15]=2[CH2:21][S:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(Cl)c(Oc2ccc(N)cc2CSC(C)(C)C)c1
Reactant: CC(C)(C)C(=O)Cl
Product: CCOC(=O)Cc1ccc(Cl)c(Oc2ccc(NC(=O)C(C)(C)C)cc2CSC(C)(C)C)c1

Procedure:
As described for Example 21, [3-(2-bromomethyl-4-nitro-phenoxy)-4-chloro-phenyl]-acetic acid ethyl ester and 2-methyl-2-propanethiol were reacted to provide [3-(2-tert-butylsulfanylmethyl-4-nitro-phenoxy)-4-chloro-phenyl]-acetic acid ethyl ester, which was reduced to [3-(4-amino-2-tert-butylsulfanylmethyl-phenoxy)-4-chloro-phenyl]-acetic acid ethyl ester. The amine was treated with trimethylacetyl chloride to provide {3-[2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-chloro-phenyl}-acetic acid ethyl ester. Hydrolysis of the ester provided the acid.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:4][CH:5]=[CH2:6].N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl>[Si:20]([O:1][CH2:2][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:4][CH:5]=[CH2:6])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CC[C@@H](CO)NC(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C=CC[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
To a solution of (S)-tert-butyl 1-hydroxypent-4-en-2-ylcarbamate (165 g, 0.82 mol) and imidazole (72.5 g, 1.07 mol) in DCM (3 L) was added TBS-Cl (135.4 g, 0.9 mol). The reaction was stirred at RT overnight and filtered. The filtrate was concentrates. The resulting residue was dissolved in EtOAc (L) and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated to give (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)pent-4-en-2-ylcarbamate (222.0 g), which was used in the next step without further purification. LRMS (M+H+) m/z 316.2.
Reaction SMILES: [SH2:1].[Na].CS(O[CH:8]([CH2:10][CH:11]([S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH:12]=[O:13])[CH3:9])(=O)=O.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:9][CH:8]1[S:1][CH:12]([OH:13])[CH:11]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10]1
Reactant: CC(CC(C=O)Sc1ccccn1)OS(C)(=O)=O
Reactant: S
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1CC(Sc2ccccn2)C(O)S1
Yield: 25456.4 %

Procedure:
0.74 g of sodium hydrogen sulfide (Wako Pure Chemical Industries, Ltd.) was added to a solution of 0.60 mg of 5-oxo-4-(pyridin-2-ylsulfanyl)pentan-2-yl methanesulfonate in 10 mL of N,N-dimethylformamide at a temperature of 0° C. to 10° C., and the obtained mixture was then stirred at the same temperature as described above for 1.5 hours. Thereafter, 30 mL of ethyl acetate and 30 mL of a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture, and the water layer was then removed. The organic layer was successively washed with 30 mL of water and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by column chromatography (hexane/ethyl acetate=5/1), so as to obtain 120 mg of 5-methyl-3-(pyridin-2-ylsulfanyl)thiolan-2-ol in the form of a light yellow oily product.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:21][F:22])[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:6]2[CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=[CH:17][C:5]=2[O:4]1.[OH-].[Na+]>C(O)C>[NH2:18][C:15]1[CH:16]=[CH:17][C:5]2[O:4][C:3]([CH2:2][F:1])([CH2:21][F:22])[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:6]=2[CH:14]=1
Reactant: CCOC(=O)C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(N)cc21
Yield: 13.7 %

Procedure:
A mixture of 42.0 g of ethyl 2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4-carboxylate, 88 g of stannous chloride and 500 ml of ethyl alcohol was heated while refluxing for 2 hours. A 2N aqueous solution of sodium hydroxide was added to the reaction mixture, followed by extracting with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and then concentrated under (reduced pressure to obtain 5,2 g of ethyl 6-amino-2,2-bisfluoromethyl-2H-1-benzopyran-4-carboxylate as an oily substance.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]=[C:9]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:10]=[CH:11][C:5]2=[N:4][CH:3]=1.[CH3:22][O-:23].[Na+]>CO>[CH3:22][O:23][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:10]=[CH:11][C:5]2=[N:4][CH:3]=1
Reactant: C[O-]
Reactant: COc1ccc(COc2ccc3ncc(Br)nc3n2)cc1
Agent: [Na+]
Solvent: CO
Product: COc1ccc(COc2ccc3ncc(OC)nc3n2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59 %

Procedure:
3-Bromo-6-({[4-(methyloxy)phenyl]methyl}oxy)pyrido[2,3-b]pyrazine (1.19 g, 3.44 mmol) was suspended in methanol and a solution of sodium methoxide (25% in methanol, 10.1 mL) was added at room temperature under argon. After 20 min all the solid went into solution, the reaction was stirred overnight at rt. The solvent was removed and the residue partitioned between water (250 mL) and 10% MeOH/DCM (200 mL). The aqueous phase was extracted with 10% MeOH/DCM (2×100 mL). The combined organic phases were dried, evaporated and subjected to column chromatography on silica gel eluting with DCM to afford 0.6 g of the title compound (59%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11](Cl)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:19]2[CH2:21][CH2:20]2)[CH:7]=1)=[O:5])C.[OH:22][CH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][NH:27][CH2:28]2.C(N(CC)CC)C>C(Cl)(Cl)Cl>[OH:22][CH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][N:27]([C:11]1[N:10]=[C:9]3[C:14]([C:15](=[O:16])[C:6]([C:4]([OH:3])=[O:5])=[CH:7][N:8]3[CH:19]3[CH2:20][CH2:21]3)=[CH:13][C:12]=1[F:17])[CH2:28]2
Reactant: OCc1cccc2c1CNC2
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cn(C2CC2)c2nc(N3Cc4cccc(CO)c4C3)c(F)cc2c1=O
Yield: 19 %

Procedure:
310 mg of 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4- oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, 298 mg of 4-hydroxymethylisoindoline, 0.42 ml of triethylamine, and 5 ml of anhydrous chloroform were processed in a similar manner as in Example 107 to produce 75 mg of 7-(4- hydroxymethyl-2-isoindolinyl)-1-cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH:5]([CH3:9])[C:6]([OH:8])=O.C(Cl)Cl.[C:13]([O:17][C:18]([N:20]1[C:24]([NH2:25])=[CH:23][C:22]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[N:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C.Cl>>[C:13]([O:17][C:18]([N:20]1[C:24]([NH:25][C:6](=[O:8])[CH:5]([CH3:9])[CH2:4][CH2:3][CH2:2][Br:1])=[CH:23][C:22]([C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[N:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(CCCBr)C(=O)O
Reactant: CC(C)(C)OC(=O)n1nc(-c2ccc(Cl)cc2)cc1N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(CCCBr)C(=O)Nc1cc(-c2ccc(Cl)cc2)nn1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.2 %

Procedure:
To a solution of 5-bromo-2-methyl-pentanoic acid (1.79 g, 9.2 mmol, 1 eq) in anhydrous DCM (8 mL) oxalyl chloride (1.0 mL, 12.0 mmol, 1.3 eq) was added dropwise and the mixture was stirred at room temperature for 16 hours. After evaporation of the solvent and the excess oxalyl chloride, the residue was dissolved in anhydrous DCM (8 mL) and a solution of 5-amino-3-(4-chloro-phenyl)-pyrazole-1-carboxylic acid tert-butyl ester (2.7 g, 9.2 mmol, 1.0 eq) and triethylamine (1.7 mL, 12 mmol, 1.3 eq) was added dropwise at 0° C. The mixture was allowed to reach room temperature and stirred at room temperature for 24 hours, after which another 0.5 eq of activated 5-bromo-2-methyl-pentanoic acid was added. HCl 1M was added; the crude was extracted with DCM and purified through SiO2 column (eluent DCM) to give 3.3 g (yield 97%) of the title product.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([NH:10][CH2:11][C:12]([NH:14][C@H:15]([C:23]([NH:25][C:26]1[CH:35]=[C:34]2[C:29]([C:30]([CH3:37])=[CH:31][C:32](=[O:36])[O:33]2)=[CH:28][CH:27]=1)=[O:24])[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[NH:22])[NH2:21])=[O:13])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[OH:6].C(N(CC)CC)C.[C:45]([O:49][C:50]([NH:52][C@H:53]([C:58](O)=[O:59])[C@H:54]([CH2:56][CH3:57])[CH3:55])=[O:51])([CH3:48])([CH3:47])[CH3:46].CCOCC>CN(C=O)C>[C:45]([O:49][C:50]([NH:52][C@H:53]([C:58]([NH:1][C@H:2]([C:8]([NH:10][CH2:11][C:12]([NH:14][C@H:15]([C:23]([NH:25][C:26]1[CH:35]=[C:34]2[C:29]([C:30]([CH3:37])=[CH:31][C:32](=[O:36])[O:33]2)=[CH:28][CH:27]=1)=[O:24])[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[NH:21])[NH2:22])=[O:13])=[O:9])[CH2:3][CH2:4][C:5](=[O:6])[OH:7])=[O:59])[C@H:54]([CH2:56][CH3:57])[CH3:55])=[O:51])([CH3:46])([CH3:48])[CH3:47]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1cc(=O)oc2cc(NC(=O)[C@H](CCCNC(=N)N)NC(=O)CNC(=O)[C@@H](N)CCC(=O)O)ccc12
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)O)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)Nc1ccc2c(C)cc(=O)oc2c1
Yield: 85 %

Procedure:
7-(L-glutamylglycyl-L-arginyl)amino-4-methyl-coumarin (100 mg, 0.18 mM) was dissolved in DMF (2 ml), and triethylamine (0.03 ml) was added thereto with stirring and cooling. This mixture was adjusted to pH about 7, and the N-hydroxysuccinimide ester of tert-butyloxycarbonyl-L-isoleucine (75.4 mg, 0.23 mM) was added thereto. This mixture was stirred for 3 days at room temperature. To this mixture excess ether was added and the produced precipitate was separated by filtration and dried. This material was dissolved in methyl alcohol (2 ml), and ether (20 ml) was added thereto for reprecipitation to give 7-(Nα -tert-butyloxycarbonyl-L-isoleucyl-L-glutamylglycyl-L-arginyl)amino-4-methylcoumarin [VII] (120 mg, yield: 86.3%).
Reaction SMILES: Br[C:2]1[C:3]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16][C:4]=2[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH2:13][O:14][CH3:15])[CH2:9][CH2:8][CH2:7]2.[CH3:28][N:29](C)C(=O)C>[C-]#N.[Zn+2].[C-]#N.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.[Zn]>[C:28]([C:2]1[C:3]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16][C:4]=2[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH2:13][O:14][CH3:15])[CH2:9][CH2:8][CH2:7]2)#[N:29]
Reactant: CC(=O)N(C)C
Reactant: COCCN1CCCc2cc3c(c(Br)c21)CCN(C(=O)OC(C)(C)C)CC3
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [C-]#N
Agent: [Zn+2]
Product: COCCN1CCCc2cc3c(c(C#N)c21)CCN(C(=O)OC(C)(C)C)CC3
Temperature: 100 °C
Reaction time: 15 h

Procedure:
A solution of 200 mg of t-butyl 11-bromo-1-(2-methoxyethyl)-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate, 34 mg of zinc cyanide, 13 mg of bis(tri-t-butylphosphine)palladium, and 10 mg of zinc powder in 4 ml of N,N-dimethylacetamide was substituted with argon and then stirred at 100° C. for 15 hours. The reaction mixture was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 132 mg of t-butyl 11-cyano-1-(2-methoxyethyl)-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate as a colorless viscous substance.
Reaction SMILES: [Cl:1][C:2]1([C:5]2([CH2:8][O:9][C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[CH2:7][O:6]2)[CH2:4][CH2:3]1.[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1([C:5]([OH:6])([CH2:7][N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)[CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:4][CH2:3]1
Reactant: Clc1ccc(OCC2(C3(Cl)CC3)CO2)cc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OC(COc1ccc(Cl)cc1)(Cn1cncn1)C1(Cl)CC1
Yield: 37.9 %

Procedure:
A solution 27.9 g (0.11 mol) of 2-(1-chlorocyclopropyl)-2-(4-chloro-phenoxymethyl)-oxirane in 50 ml of acetonitrile is added dropwise under a nitrogen atmosphere to a mixture of 29 g (0.42 mol) of 1,2,4-triazole, 19 g (0.14 mol) of potassium carbonate and 100 ml bf acetonitrile, and the reaction mixture is boiled under reflux. After completion of the addition, the mixture is heated for a further 8 hours under reflux. The mixture is then filtered off from the solid residue with suction and the filtrate is concentrated under reduced pressure. The remaining residue is taken up in ethyl acetate. The resultant solution is washed with water, dried over sodium sulphate and concentrated under reduced pressure. The product thus obtained is purified chromatographically through silica gel using chloroform/ethanol=97:3 as eluent. In this manner, 13.7 g (39% of theory) of 2-(1-chlorocyclopropyl)-1-(4-chlorophenoxy)-3-(1,2,4-triazol-1-yl)-propan-2-ol are obtained in the form of an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[N:11][C:10]([C:14](O)=[O:15])=[N:9]2)=[CH:4][CH:3]=1.B>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[N:11][C:10]([CH2:14][OH:15])=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1nc(C(=O)O)nn1-c1ccc(F)cc1
Agent: B
Solvent: C1CCOC1
Product: Cc1nc(CO)nn1-c1ccc(F)cc1
Yield: 45.9 %

Procedure:
To a suspension of 1-(4-fluoro-phenyl)-5-methyl-1H-[1,2,4]triazole-3-carboxylic acid (may be prepared in analogy to DE3525205, 1986, 10.7 g, 48.4 mmol) in THF (50 mL) was added borane (1 M in THF, 121 mL, 121 mmol) and the resulting suspension was heated to reflux for 1 h. After concentration and extraction with aqueous sodium hydrogencarbonate and ethyl acetate the combined organic layers were washed with brine and dried over sodium sulfate. Concentration and purification by chromatography (SiO2, hexane:ethyl acetate=100:0 to 33:67) afforded the title compound (4.60 g, 46%) as a white solid. MS: m/e=208.4 [M+H]+.