Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:17]([O:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:17]([O:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:13](=[O:15])[C@H:9]([CH:10]([CH3:11])[CH3:12])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 100.9 %

Procedure:
N-t-butyloxycarbonyl-L-valine (8.69 g, 40 mmole), L-proline benzylester hydrochloride (9.67 g, 40 mmole) and HOBt (5.40 g, 40 mmole) were dissolved in methylene chloride (150 ml), and N-methylmorcholine (4.05 g, 40 mmole) and WSC hydrochloride (7.67 g, 40 mmole) were added thereto at -30° C. The mixture was stirred for 2 hours at less than ° C., and then overnight at room temperature, washed with aqueous sodium bicarbonate (150 ml, twice), 5% aqueous citric acid (150 ml, twice) and water (150 ml) in the order given and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain N-t-butyloxycarbonyl-L-valyl-L-proline benzylester(yield: 16.32 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:7]([CH2:8][CH:9]([C:11]([OH:13])=[O:12])N)=[CH:6][NH:5]2.C(N(CC)CC)C.N12CCCN=C1CCCCC2.Cl.C[OH:37]>[Cl-].[Cl-].[Zn+2]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14]([C:7]([CH2:8][C:9](=[O:37])[C:11]([OH:13])=[O:12])=[CH:6][NH:5]2)=[CH:15][CH:16]=1
Reactant: NC(Cc1c[nH]c2cc(Cl)ccc12)C(=O)O
Reactant: CO
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)C(=O)Cc1c[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54 %

Procedure:
To 600 mg of 6-chloro-DL-tryptophan, suspended in 5 ml of methanol, are added, at room temperature, 0,230 ml of triethylamine and the mixture is stirred for approximately 10 minutes. Then, rapidly and under stirring, pyridine-4-carboxyaldehyde (0,240 ml) is added. After approximately 5 minutes, total dissolution of the suspension is obtained. Stirring is continued for 10 minutes. 122 mg of anhydrous ZnCl2 are then added, stirred for 10 minutes, followed by 0,490 ml of 1,8-diazabicyclo-(5,4,0)-undec-7-ene. The solution becomes orange-red in colour. It is left under stirring for approximately 80-90 minutes at room temperature. The limpid red solution is then quickly added dropwise and under rapid stirring to 100 ml of HCl 1N preheated to 50° C. After approximately 10 minutes from completion of the addition a spontaneous precipitation occurs, increasing in time, of a yellowish solid. The mixture is left for a further 20 minutes at 55° C., then for approximately 3 hours it is cooled to room temperature. The abundant precipitate is filtered, washed with acidic water and dried. 195 mg are recovered, with a yield of 54%.
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([O:10][CH3:11])=[CH:5][C:4]=1F)#[N:2].[CH:13]1([OH:17])[CH2:16][CH2:15][CH2:14]1>>[C:1]([C:3]1[C:4]([O:17][CH:13]2[CH2:16][CH2:15][CH2:14]2)=[CH:5][C:6]([O:10][CH3:11])=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: COc1cc(F)c(C#N)c(F)c1
Reactant: OC1CCC1
Product: COc1cc(F)c(C#N)c(OC2CCC2)c1
Yield: 92 %

Procedure:
The subtitle compound was prepared from 4-cyano-3,5-difluoroanisole and cyclobutanol following the procedure described in Example 14(a). The crude product was purified on silica gel eluting with dichloromethane:hexane (60:40 v/v) to give the subtitle compound as a white solid (92%). Rf 0.26 (dichloromethane:hexane 1:2, v/v). MS m/z 239 (MNH4)+.
Reaction SMILES: C([O-])=O.[NH4+].[C:5]([O:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([N+:21]([O-])=O)=[CH:18][CH:19]=2)[C:14]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].CO>[Pd].O>[NH2:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[N:12]([C:10]([O:9][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:11])[N:13]=[C:14]2[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)n1nc(-c2ccccc2)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)n1nc(-c2ccccc2)c2cc(N)ccc21
Temperature: 20 °C
Reaction time: 18 h
Yield: 82.3 %

Procedure:
5-Amino-N-tert-butoxycarbonyl-3-phenyl-1H-indazole can be obtained in the following way: 0.12 g of 10% palladium-on-charcoal and 0.68 g of ammonium formate are added to a solution of 0.8 g of N-tert-butoxycarbonyl-5-nitro-3-phenyl-1H-indazole and of 14 ml of methanol. The suspension is maintained with stirring for 18 hours at a temperature in the region of 20° C. 50 ml of distilled water are added to the reaction medium which is extracted with 50 ml and 25 ml of ethyl acetate. The organic phases are pooled, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure. The residue obtained is purified by chromatography on a silica column with dichloromethane as eluent. 0.6 g of 5-amino-N-tert-butoxycarbonyl-3-phenyl-1H-indazole is thus obtained in the form of an off-white solid melting at 191° C.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@H:14]([CH3:15])[CH2:13][N:12]([C:16]2[C:21]([NH:22][C:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]4[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=4[F:39])[N:26]=3)=[O:24])=[CH:20][N:19]=[C:18]3[O:40][CH2:41][CH2:42][C:17]=23)[CH2:11][C@H:10]1[NH:43]C(=O)OC(C)(C)C)(C(C)(C)C)(C)C.[H+].[H+].F[Si-2](F)(F)(F)(F)F.O.[NH4+].[OH-]>CC#N>[NH2:43][C@H:10]1[C@H:9]([OH:8])[C@@H:14]([CH3:15])[CH2:13][N:12]([C:16]2[C:21]([NH:22][C:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]4[C:33]([F:39])=[CH:34][CH:35]=[CH:36][C:37]=4[F:38])[N:26]=3)=[O:24])=[CH:20][N:19]=[C:18]3[O:40][CH2:41][CH2:42][C:17]=23)[CH2:11]1
Reactant: C[C@H]1CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [H+]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: C[C@H]1CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCO3)C[C@@H](N)[C@@H]1O
Temperature: 50 °C
Reaction time: 2 h
Yield: 16.1 %

Procedure:
To a solution of tert-butyl {(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-[5-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-2,3-dihydrofuro[2,3-b]pyridin-4-yl]-5-methylpiperidin-3-yl}carbamate (24.9 mg, 0.0349 mmol) in MeCN (2.0 mL) was added a 1.7 M dihydrogen hexafluorosilicate solution in water (200 μL, 0.340 mmol). The mixture was stirred at 50° C. for 2 h. After cooling to room temperature, the reaction mixture was neutralized with a 14.8 M NH4OH solution in water (200 μL, 2.96 mmol), and was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (2.8 mg, 16%). LCMS calc. for C25H25F3N5O3 (M+H)+: m/z=500.2. found 500.1.
Reaction SMILES: [CH:1]1([CH:6]2[CH2:14][C:13]3[C:8](=[C:9]([Cl:18])[C:10]([Cl:17])=[C:11]([S:15][CH3:16])[CH:12]=3)[C:7]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:22]I>COCCOC>[CH:1]1([C:6]2([CH3:22])[CH2:14][C:13]3[C:8](=[C:9]([Cl:18])[C:10]([Cl:17])=[C:11]([S:15][CH3:16])[CH:12]=3)[C:7]2=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CSc1cc2c(c(Cl)c1Cl)C(=O)C(C1CCCC1)C2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CSc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2

Procedure:
2-Cyclopentyl-2-methyl-5-methylthio-6,7-dichloro-1-indanone is prepared following substantially the same procedure described in Example 5, Step A, using the following substances: 2-cyclopentyl-5-methylthio-6,7-dichloro-1-indanone (7.9 g., 0.025 mole), 1,2-dimethoxyethane (200 ml.), sodium hydride (660 mg., 0.0275 mole) and methyl iodide (7.5 ml.).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:5]=1[NH2:6])([O-:3])=[O:2].[Br:14]Br>C(O)(=O)C>[Br:14][C:9]1[CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([NH2:6])=[C:7]([N+:11]([O-:13])=[O:12])[CH:8]=1
Reactant: BrBr
Reactant: Nc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: Nc1c([N+](=O)[O-])cc(Br)cc1[N+](=O)[O-]
Yield: 86 %

Procedure:
A mixture comprising 247.5 g (1.35 mol) 2,6-dinitroaniline, 2.5 L acetic acid and 250 mL bromine was heated to 100° C. for a few minutes. After cooling, the formed crystals were filtered and washed with n-hexane to give 304 g (86%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([CH:24]=[C:25]([CH2:27]Cl)[N:26]=2)[CH:23]=1.C(N(CC)CC)C>C(O)CO>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([CH:24]=[C:25]([CH2:27][N:12]3[CH2:11][CH2:10][N:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][N:7]=4)[CH2:14][CH2:13]3)[N:26]=2)[CH:23]=1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Solvent: OCCO
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)nc1
Reaction time: 2 h
Yield: 66.8 %

Procedure:
A mixture of 1-(5-trifluoromethylpyridin-2-yl)piperazine (0.4803 g), 6-chloro-2-(chloromethyl) imidazo[1,2-a]pyridine (Example 4, Step 1; 0.4177 g), triethylamine (0.231 g), and ethylene glycol (1 mL) is stirred at 80° C. for 70 min. after which additional 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (0.072 g) is added; thirty minutes later another portion (0.0517 g) is added. After stirring for a total of 2 h, the mixture is cooled and partitioned between dichloromethane and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate and concentrated. Chromatography on silica gel using methanol/dichloromethane (4/96) and crystallization from ethyl ether/hexane gives 0.549 g of the title compound; mp 81-82° C.; MS m/z 395; IR (mineral oil) 1617, 1332, 1328, 1112, 1082 cm-1. 1H NMR (CDCl3) δ2.68, 3.69, 3.77, 6.62, 7.14, 7.52, 7.55, 7.61, 8.14, 8.38.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH:14]([CH3:16])[CH3:15])=[N:5][S:6][C:7]=1[N:8]=[C:9](Cl)[N:10]([CH3:12])[CH3:11])#[N:2].[C-:17]#[N:18].[K+]>C(#N)C>[C:1]([C:3]1[C:4]([CH:14]([CH3:16])[CH3:15])=[N:5][S:6][C:7]=1[N:8]=[C:9]([C:17]#[N:18])[N:10]([CH3:12])[CH3:11])#[N:2]
Reactant: CC(C)c1nsc(N=C(Cl)N(C)C)c1C#N
Reactant: [C-]#N
Agent: [K+]
Solvent: CC#N
Product: CC(C)c1nsc(N=C(C#N)N(C)C)c1C#N
Yield: 63.8 %

Procedure:
In the manner of Example VII, 7 g of N'-(4-cyano- 3-isopropyl-5-isothiazolyl)-N,N-dimethylchloroformamidine, 3.6 g of anhydrous potassium cyanide, and a catalytic amount of 2,3,11,12-dibenzo-1,4,7,10,13,16-hexaoxacycloocta- 2,11-diene in 200 ml of dry aceto-nitrile were allowed to react for several days. After solvents were removed under reduced pressure, the residue was recrystallized from methylcyclohexane to yield 4.3 g of N'-(4-cyano-3-isopropyl-5-isothiazolyl)-N,N-dimethylcyanoformamidine, mp 78°-79°. The ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:7]2[O:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[Br:32]N1C(=O)CCC1=O>C1COCC1>[Br:32][CH2:2][C:1]([C:4]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:7]2[O:8][CH2:9][C:10]([CH3:11])([CH3:12])[C:6]=2[CH:5]=1)=[O:3]
Reactant: CC(=O)c1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)[N-]C(C)C
Agent: C[Si](C)(C)Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(=O)CBr)cc2c1OCC2(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 87.6 %

Procedure:
A solution of 5-acetyl-7-tert-butyl-2,3-dihydro-3,3-dimethylbenzo[b]furan (2.46 g, 10.0 mmol) in 25 mL of anhydrous THF is added dropwise to lithium diisopropylamide (6.0 mL, 12.0 mmol, 2.0M solution in heptane-THF-ethyl benzene) at -78° C. The resulting solution in stirred at -78° C. for 15 min, and chlorotrimethylsilane (1.5 mL, 12.0 mmol) is introduced. The reaction mixture is stirred at -78° C. for 15 min, warmed to room temperature, stirred for 1.5 h, quenched with water, and extracted with ether. The extract is dried over anhydrous sodium sulfate and concentrated in vacuo; the residue is dissolved in 25 mL of anhydrous THF and reacted at 0° C. with N-bromosuccinimide (1.78 g, 10.0 mmol). The resulting yellowish solution is kept at 0° C. for 0.5 h, warmed to room temperature, stirred for 0.5 h, quenched with water, and extracted with ether. The extract is dried over anhydrous magnesium sulfate and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (5%→20% ether-hexane) affords about 2.85 g (88%) of 5-bromoacetyl-7-tert-butyl-2,3-dihydro-3,3-dimethyl-benzo[b]furan as a yellowish solid: mp 54-56° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].Cl[C:11]1[N:16]=[C:15]([S:17][C:18]#[N:19])[C:14]([N+:20]([O-:22])=[O:21])=[CH:13][N:12]=1>C(O)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:11]2[N:16]=[C:15]([S:17][C:18]#[N:19])[C:14]([N+:20]([O-:22])=[O:21])=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: N#CSc1nc(Nc2ccc(Cl)c(Cl)c2)ncc1[N+](=O)[O-]
Reaction time: 16 h

Procedure:
2.47 g of 3,4-dichloroaniline in 12 ml ethanol are added to 3.00 g of 2-chloro-4-thiocyanato-5-nitro-pyrimidine in 40 ml toluene at ambient temperature. The mixture is stirred for another 16 hours, the solid is suction filtered, washed twice with 30 ml toluene and then once with 30 ml of ethanol and dried.
Reaction SMILES: O.S.[Na].[N+:4]([C:7]1[CH:8]=[C:9]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)([O-])=O>CO>[NH2:4][C:7]1[CH:8]=[C:9]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1
Reactant: NS(=O)(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: S
Agent: [Na]
Solvent: O
Solvent: CO
Product: Nc1cc([N+](=O)[O-])cc(S(N)(=O)=O)c1
Temperature: 25 °C

Procedure:
A suspension of sodium hydrogensulfide hydrate (3.88 g; 49 mmol) in Methanol (200 ml) was added to a solution of 3,5-dinitro-benzenesulfonamide (6 g; 24.27 mmol) in Methanol (500 ml). The reaction mixture was refluxed for 3 h then cooled to room temperature, filtered and concentrated in vacuo. The crude was washed with water, filtered and dried in vacuo. 3.2 g (15 mmol; 61% yield) of orange powder were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11]C)=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:19][C:20]1([O:23][CH2:22]1)[CH3:21]>CN(C=O)C>[OH:23][C:20]([CH3:22])([CH3:21])[CH2:19][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: CC1(C)CO1
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(O)COc1ccc(CC(=O)O)cc1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
Methyl (4-hydroxyphenyl)acetate (500 mg, 3.0 mmol) was dissolved in DMF (3 mL). K2CO3(829 mg, 6.0 mmol) was added followed by isobutylene oxide (800 μL, 9.0 mmol). The mixture was heated to 150° C. by microwave irradiation for 30 min and concentrated. The residue was dissolved in a 1:1 mixture of methanol and water (20 mL). NaOH (1 g) was added and the mixture was stirred for 30 min. Methanol was removed by rotary evaporation. The aqueous phase was acidified by 4 M HCl and extracted with dichloromethane (2×50 mL). The combined organic phases were extracted with 2 M NaOH (2×50 mL). The combined aqueous phases were subsequently acidified by 4 M HCl and extracted with dichloromethane (2×50 mL). The combined organic phases were dried over Na2SO4, filtered and evaporated to afford [4-(2-hydroxy-2-methylpropoxy)phenyl]acetic acid (106MBT52-D, 470 mg, 70%) as a colourless solid. 1H-NMR (CDCl3): δ 7.19 (m, 2H), 6.88 (m, 2H), 3.78 (s, 2H), 3.57 (s, 2H), 1.34 (s. 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]3)=[O:15])[CH2:11][CH:10]2[C:26](=O)[CH3:27])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[NH2:30][OH:31].C([O-])(=O)C.[Na+].O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]3)=[O:15])[CH2:11][CH:10]2[C:26](=[N:30][OH:31])[CH3:27])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NO
Reactant: CC(=O)C1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)CC1c1ccc(Cl)c(Cl)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=NO)C1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)CC1c1ccc(Cl)c(Cl)c1
Yield: 79.8 %

Procedure:
1-[(3SR,4RS)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-ethanone (0.87 g, 2 mmol), hydroxylamine hydrochloride (0.28 g, 2.05 mmol) and sodium acetate (0.33 g, 2.06 mmol) were dissolved in ethanol (9.0 mL) and heated to reflux for 2 h. After cooling to ambient temperature water (20 mL) was added. The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was subjected to column chromatography (silica gel, ethyl acetate) to yield the title compound as a colorless foam (0.74 g, 82%). ES-MS m/e: 437.5 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Br:1][C:2]1[CH:10]=[C:6]([C:7]([NH:18][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cncc(Br)c1
Reactant: NCc1ccccc1
Product: O=C(NCc1ccccc1)c1cncc(Br)c1
Yield: 90 %

Procedure:
5-bromo-N-(phenylmethyl)pyridine-3-carboxamide was synthesized according to the procedure described above from 5-bromonicotinic acid and benzylamine. Yield 90%. 1H NMR (400 MHz, CDCl3): 8.83 (d, 1H), 8.72 (d, 1H), 8.25 (t, 1H), 7.30 (m, 5H), 6.58 (br s, 1H), 4.62 (d, 2H); MS (EI) for C13H11N2OBr: 291 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][N:5]1[CH2:11][C:10]([CH2:12][N:13]=[N+]=[N-])=[CH:9][CH2:8][CH:7]([NH:16][C:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][N:20]=2)=[O:18])[C:6]1=[O:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[CH3:1][O:2][C:3](=[O:30])[CH2:4][N:5]1[CH2:11][C:10]([CH2:12][NH2:13])=[CH:9][CH2:8][CH:7]([NH:16][C:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][N:20]=2)=[O:18])[C:6]1=[O:29]
Reactant: COC(=O)CN1CC(CN=[N+]=[N-])=CCC(NC(=O)c2nccc3ccccc23)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CN1CC(CN)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Reaction time: 18 h

Procedure:
A solution of {6-azidomethyl-3-[(isoquinoline-1-carbonyl)-amino]-2-oxo-2,3,4,7-tetrahydro-azepin-1-yl}-acetic methyl ester, 28, (0.46 g, 1.12 mmol) in THF (10 mL) and 5 drops of water is treated with triphenylphosphine (0.6 g, 2.25 mmol) at room temperature. The solution is stirred for 18 hours after which the solvent is solvent is removed in vacuo and the resulting residue is purified by HPLC to afford the desired product which is immediately used for the next step.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:40])[C@@H:15]([NH:25][C:26]([C:28]2[CH:32]=[C:31]([OH:33])[N:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:29]=2)=[O:27])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].Br[CH2:42][C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:40])[C@@H:15]([NH:25][C:26]([C:28]2[CH:32]=[C:31]([O:33][CH2:42][C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:44])[N:30]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:29]=2)=[O:27])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 7.00 g 4-{(S)-4-tert-butoxycarbonyl-2-[(5-hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid butyl ester in 45 ml DMF were added 2.1 ml benzyl bromoacetate and 8.2 g cesium carbonate. After stirring at RT for 12 h the reaction mixture was diluted with ethyl acetate and extracted with aqueous LiCl (4% w/w) and saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was not further purified. Yield: 7.02 g yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.C(N(CC)CC)C.ClC(OCC)=O.[NH2:26][CH2:27][CH2:28][C:29]1[CH:43]=[CH:42][C:32]([O:33][C:34]([CH3:41])([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][CH:30]=1>O1CCCC1>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([NH:26][CH2:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:33][C:34]([CH3:40])([CH3:41])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:42][CH:43]=1)=[O:8]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN)cc1
Reactant: O=C(O)C=Cc1ccccc1Cl
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1ccc(CCNC(=O)C=Cc2ccccc2Cl)cc1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a mixture of 11.50 g. (63 mMol) o-chlorocinnamic acid, 200 ml. anhydrous tetrahydrofuran and 6.38 g. (63 mMol) anhydrous triethylamine, there are added dropwise at -15° C., 7.50 g. (69 mMol) ethyl chloroformate. The reaction mixture is then stirred for 15 minutes at -15° C. Subsequently, a solution of 15.80 g. (63 mMol) ethyl 2-[4-(2-aminoethyl)phenoxy]-2-methylpropionate in 50 ml. anhydrous tetrahydrofuran is added dropwise thereto and the reaction mixture is stirred for a further 2 hours at -10° C. and then left to stand for a day at ambient temperature. Thereafter, the tetrahydrofuran is distilled off in a vacuum and the residue is taken up in methylene chloride. The methylene chloride phase is extracted with 0.5 N aqueous sodium hydroxide solution, filtered, dried over anhydrous sodium sulphate and evaporated. After recrystallization of the residue from a mixture of ligroin and acetone (30:5 v/v), there is obtained, in a yield of 65% of theory, ethyl 2-{4-[2-(2-chlorocinnamoylamino)-ethyl]-phenoxy}-2-methylpropionate, which melts at 76° C.