Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]([C:23]([CH:25]1[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26]1)=[O:24])[NH2:22].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:22][NH:21][C:23]([CH:25]1[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26]1)=[O:24])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)NN)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(C(=O)NNC(=O)[C@H]2CC[C@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.25 g, 0.90 mmol) in dry DCM (30 mL) were added tert-butyl 3-(hydrazinylcarbonyl)azetidine-1-carboxylate 259 (0.29 g, 1.35 mmol), 1-hydroxybenzotriazole (0.19 g, 1.35 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.26 g, 1.35 mmol) and 4-(dimethylamino)pyridine (0.16 g, 1.35 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by column chromatography to give tert-butyl 3-[(2-{[(2R,5S)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]azetidine-1-carboxylate 260 (0.35 g, 81%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH2:30])[C:13](=[O:29])[NH:14][CH2:15][CH2:16][N:17]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH3:18])([CH3:4])([CH3:3])C.CCN(C(C)C)C(C)C.[CH3:41][C:42](OC(C)=O)=[O:43]>C(Cl)(Cl)Cl>[CH:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:30][C:42](=[O:43])[CH3:41])[C:13](=[O:29])[NH:14][CH2:15][CH2:16][N:17]([C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])[CH3:18])([CH3:3])[CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: CN(CCNC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H](CCCCNC(=O)OC(C)C)C(=O)NCCN(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
To a solution of compound H (1.4 g, 3.21 mmol) in CHCl3 (10 mL) at room temperature was added DIEA (2.6 mL, 15 mmol) followed by Ac2O (0.85 mL, 9.0 mmol). The reaction mixture was stirred at room temperature for 2 h. Solvents were removed in vacuo and then the residue was dissolved in dichloromethane (100 mL). The organic layer was washed with 10% citric acid (75 mL), saturated NaHCO3 (75 mL) and brine (75 mL). The organic layer was separated, dried over Na2SO4 and solvent removed in vacuo to afford compound I (1.45 g, 99%). LC-MS [M+H] 479.5 (C24H38N4O6+H, calc: 479.5).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=2)=[CH:4][C:3]=1I.C([Sn](CCCC)(CCCC)[C:22]1[CH:27]=[CH:26][N:25]=[N:24][CH:23]=1)CCC.[F-].[Cs+]>CN(C)C=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu]I>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=2)=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][N:25]=[N:24][CH:23]=1
Reactant: N#Cc1cccc(-c2ccc(O)c(I)c2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1cccc(-c2ccc(O)c(-c3ccnnc3)c2)c1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 58.3 %

Procedure:
A mixture of 4′-hydroxy-3′-iodobiphenyl-3-carbonitrile (Preparation 120, 715 mg, 2.23 mmol), 4-(tributylstannyl)pyridazine (904 mg, 2.45 mmol) and cesium fluoride (677 mg, 4.46 mmol) in N,N-dimethylformamide (5 mL) was degassed under nitrogen. Then tetrakistriphenylphosphinepalladium (0) (258 mg, 0.22 mmol) and copper (I) iodide (85 mg, 0.45 mmol) were added, the reaction mixture was further degassed and then heated at 60° C. for 4 hours. The cooled reaction mixture was quenched with 10% ammonia (0.88M) in water (10 mL), diluted with ethyl acetate (20 mL) and then the mixture was stirred for 20 minutes. The resulting mixture was further diluted with ethyl acetate (10 mL) and the layers were separated. The organic layer was dried over anhydrous MgSO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 10% dichloromethane in ethyl acetate to give the title compound (355 mg, 55%).
Reaction SMILES: [N:1](=[C:3]1[C:9]([CH3:11])([CH3:10])[CH:8]2[C:5]([CH3:13])([CH2:6][CH:7]2[OH:12])[C:4]1=O)[OH:2].O.NN.[OH-].[K+].Cl>C(O)CO.O>[N:1](=[C:3]1[C:9]([CH3:10])([CH3:11])[CH:8]2[C:5]([CH3:13])([CH2:6][CH:7]2[OH:12])[CH2:4]1)[OH:2]
Reactant: CC1(C)C(=NO)C(=O)C2(C)CC(O)C12
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: OCCO
Solvent: O
Product: CC12CC(=NO)C(C)(C)C1C(O)C2
Reaction time: 0.5 h
Yield: 50.9 %

Procedure:
To a solution of 2050 mg of the ketoxime (VI) in 25 ml of ethylene glycol, was added 0.7 ml of 80% hydrazine hydrate. After having been kept at 40° to 50° C. for 30 minutes, the solution was admixed with 750 mg of potassium hydroxide and kept at 150° C. for 4 hours under an argon atmosphere. After cooling and adding 50 ml of water, the solution was neutralized with 1 N HCl and extracted with methylene chloride. The extract was washed with an aqueous sodium bicarbonate solution, then with an aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give 970 mg of a crystalline compound (V). M.p. 130°-133° C.; MS m/e: 183 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][C:16]2=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[CH2:30][CH2:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:32]([CH:31]=[CH2:30])(=[O:34])=[O:33])[CH2:17][C:16]2=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCNCC2=O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CS(=O)(=O)N1CCN(CC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
To a solution of 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-2-piperazinone (5.0 g) and triethylamine (6.792 g) in dichloromethane (80 ml) was added dropwise at 0° C. a solution of 2-chloroethanesulfonyl chloride (4.11 g) in dichloromethane (20 ml), and the mixture was stirred at 0° C. for 30 minutes. The reaction solution was diluted with dichloromethane, washed with water, citric acid solution, sodium bicarbonate solution and brine, dried and concentrated, and the residue was purified with silica gel column chromatography (ethyl acetate) to give colorless amorphous of 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-4-vinylsulfonyl-2-piperazinone (3.99 g).
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH:4]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][C:17]3[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][C:20]([CH2:21]Br)=[CH:19][C:18]=3[C:29]([F:32])([F:31])[F:30])[CH:14]=2)[NH:9][CH:8]=1)([CH3:6])[CH3:5]>CN(C)C=O.O>[CH:4]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][C:17]3[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][C:20]([CH2:21][C:1]#[N:2])=[CH:19][C:18]=3[C:29]([F:32])([F:31])[F:30])[CH:14]=2)[NH:9][CH:8]=1)([CH3:6])[CH3:5]
Reactant: CC(C)c1c[nH]c2ccc(Oc3c(C(F)(F)F)cc(CBr)cc3C(F)(F)F)cc12
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1c[nH]c2ccc(Oc3c(C(F)(F)F)cc(CC#N)cc3C(F)(F)F)cc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
72.9 mg (1.49 mmol) of sodium cyanide are added at 50° C. to a solution of 0.57 g (1.19 mmol) of benzyl bromide from Example VII in 3.5 ml of dimethylformamide and 0.38 ml of water and the mixture is stirred for 60 minutes at 50° C. Dimethylformamide is subsequently distilled off, the concentrate is diluted with ethyl acetate and water, and the aqueous phase is separated off and extracted again with ethyl acetate. The combined organic phases are washed with sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The purification of the crude product is carried out on silica gel 60 by means of toluene/ethyl acetate (toluene, toluene/ethyl acetate=18:1 and 18:1.5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]3[CH:23]=[N:22][C:21]([C:24](OC)=[O:25])=[CH:20][N:19]=3)[CH2:10][CH2:9]2)[CH:7]=1.[NH2:30][CH2:31][CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37]>CC(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]3[CH:23]=[N:22][C:21]([C:24]([NH:30][CH2:31][CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:25])=[CH:20][N:19]=3)[CH2:12][CH2:13]2)[CH:7]=1
Reactant: COC(=O)c1cnc(NCCCN2CCN(c3cc(Cl)ccc3OC)CC2)cn1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CC(C)O
Product: COc1ccc(Cl)cc1N1CCN(CCCNc2cnc(C(=O)NCCNC(=O)OC(C)(C)C)cn2)CC1

Procedure:
4 g (0.0095 mol) of methyl 2-[[3-[4-(5-chloro-2-methoxyphenyl)piperain-1-yl]propyl]amino]-pyrazine-5-carboxylate and 3.05 g (0.02 mol) of 1,1-dimethylethyl 2-aminoethylcarbamate are introduced into 10 ml of 2-propanol in a 0.5 l round-bottomed flask and the mixture is heated at reflux for 2 days.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH:11]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[CH3:20].CC(C)(C)C(O)=O.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.C(Cl)Cl.O.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:9]2[S:8][C:7]3[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[CH:10]=2)=[C:14]([CH3:20])[CH:15]=1
Reactant: COc1ccc2ccsc2c1
Reactant: Cc1cc(F)ccc1Br
Agent: Cl[Pd+]
Agent: CC(C)(C)C(=O)O
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: ClCCl
Product: COc1ccc2cc(-c3ccc(F)cc3C)sc2c1
Temperature: 150 °C
Yield: 44 %

Procedure:
To a 20 mL microwave vial, 6-methoxybenzo[b]thiophene (1 g, 6.09 mmol), 2-bromo-5-fluorotoluene (0.808 mL, 6.39 mmol), BrettPhos palladacycle(1 st generation) (0.243 g, 0.304 mmol), trimethylacetic acid (1.866 g, 18.27 mmol), and K2CO3 (2.52 g, 18.27 mmol) were suspended in DMA (10 mL). The reaction was heated for 90 min at 150° C. under microwave radiation. The reaction mixture was diluted with DCM and water. The organic layer was collected (phase separator) and concentrated to afford the crude product. The crude material was concentrated onto to silica gel and purified by column chromatography (SiO2, 100% Heptanes) to afford 2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophene (730 mg, 2.68 mmol, 44% yield) as a white solid. 1H NMR (400 MHz, CDCL3) δ ppm=7.69 (d, J=9.09 Hz, 1H), 7.43 (dd, J=6.06, 8.59 Hz, 1H), 7.35 (d, J=2.53 Hz, 1H), 7.14 (s, 1H), 7.00-7.10 (m, 2H), 6.90-7.00 (m, 1H), 3.92 (s, 3H), 2.47 (s, 3H).
Reaction SMILES: C(Cl)CCl.[NH2:5][CH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH:14]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH:15]([F:17])[F:16].[C:27]([N:34]1[CH2:41][CH2:40][CH2:39][C@H:35]1[C:36](O)=[O:37])([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:13][C:11]1[CH:10]=[CH:9][C:8]([CH:14]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH:15]([F:17])[F:16])=[C:7]([CH:12]=1)[CH2:6][NH:5][C:36](=[O:37])[C@@H:35]1[CH2:39][CH2:40][CH2:41][N:34]1[C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28]
Reactant: COc1ccc(NC(c2ccc(Cl)cc2CN)C(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccc(NC(c2ccc(Cl)cc2CNC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)C(F)F)cc1
Yield: 50.9 %

Procedure:
EDC (0.171 g, 1.25 mmol) was added to a stirred mixture of N-{1-[2-(aminomethyl)-4-chlorophenyl]-2,2-difluoroethyl}-N-(4-methoxyphenyl)amine (0.314 g, 0.96 mmol), N-BOC-L-proline (0.207 g, 0.96 mmol) and HOAT (0.171, 1.25 mmol) in DMF (2.0 mL). After 18 h the mixture was partitioned between EtOAc and water. The organic layer was washed with 1M citric acid, saturated aqueous NaHCO3 and brine, dried (Na2SO4) and reduced in vacuo and the residue was purified by flash column chromatography on silica (eluting with 5% methylene chloride, 10-50% ethyl acetate/hexanes gradient) to give N-(5-chloro-2-{2,2-difluoro-1-[(4-methoxyphenyl)amino]ethyl}benzyl)-1-(tert-butoxycarbonyl)-L-prolinamide (0.256 g) as a foam; LC-MS m/z=524.3.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@H:8]([CH2:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[CH2:9][N:10]([CH3:15])[S:11]([CH3:14])(=[O:13])=[O:12])(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].O>ClCCl>[CH3:15][N:10]([CH2:9][C@H:8]([NH:7][CH3:6])[CH2:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1cccs1)CN(C)S(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1cccs1)CN(C)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 66.4 %

Procedure:
A solution of of N-methyl-N-((1R)-2-(N-methyl-N-(methylsulfonyl)amino)-1-((2-thienyl)methyl)ethyl)carbamic acid tert-butyl ester (1.87 g, 7.12 mmol) in dichloromethane (7 ml) was cooled to 0° C. Trifluoroacetic acid (7 ml) was added. The reaction mixture was stirred for 45 min at 0° C. Dichloromethane (10 ml) was added. A saturated aqueous solution of sodium hydrogen carbonate (10 ml) was added. Solid sodium hydrogen carbonate was added until pH 7.Water (100 ml) was added, until a clear solution was obtained. The phases were separated. The aqueous phase was extracted with dichloromethane (2×50 ml). The combined organic phases were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (120 g), using dichloromethane/methanol/25% aqueous ammonia as eluent, to give 1.24 g of N-methyl-N-((2R)-2-(methylamino)-3-(2-thienyl)propyl)methanesulfonamide.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:11])=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=[O:6].[C:12](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[F:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=[O:6]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(F)cc(F)c1O
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COc1c(F)cc(F)cc1C=O
Yield: 66 %

Procedure:
3,5-Difluoro-2-hydroxybenzaldehyde in the form of a crude product (corresponding to 0.35 mol) was dissolved in 800 ml of acetonitrile. 110 g (0.8 mol) of potassium carbonate and 61 ml (0.96 mol) of methyl iodide were added thereto, and the mixture was heated under reflux for 5 hr. After cooling the mixture, insolubles were removed by filtration, and the mother liquor was concentrated. 1.3 l of ether was added to the concentrate, and the mixture was washed twice with 500 ml of water. Then, the mixture was washed with a saturated saline solution, and the ether layer was dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo to prepare 39.6 g (yield: 66%) of the intended product (in two states).
Reaction SMILES: [OH-].[K+].[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([S:22]C(=O)N(C)C)=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:29][CH2:30][CH2:31][N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([CH3:42])([CH3:41])[C:33]1=[O:43].O>CO>[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([S:22][CH2:29][CH2:30][CH2:31][N:32]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:34]([CH3:42])([CH3:41])[C:33]3=[O:43])=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:5])([CH3:6])[CH3:4]
Reactant: CC1(C)C(=O)N(CCCBr)c2ccccc21
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCCCN3C(=O)C(C)(C)c4ccccc43)c2CC1
Temperature: 25 °C

Procedure:
Add potassium hydroxide (170 mg, 3.03 mmol) in one portion to a solution of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (187 mg, 0.49 mmol) in methanol (10 mL). Heat the reaction at reflux under nitrogen overnight. Then add further portion of KOH (867 mg, 15.45 mmol) and heat at reflux for 3 h. Then cool to room temperature and add 1-(3-bromo-propyl)-1,3-dihydro-3,3-dimethyl-indol-2-one (274 mg, 0.97 mmol, prepared by following the procedure described in Perkin 1 2000, 769-774). Stir the reaction at room temperature overnight. Remove solvents in vacuo, add water and extract with diethyl ether (2×50 mL). Combine the organic extracts, wash with water (2×50 mL) and brine (50 mL). Dry over MgSO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 1:1 gradient over 40 min) to give 3-tert-butoxycarbonyl-7-chloro-6-[3-(3,3-dimethyl-2-oxo-2,3-dihydro-indol-1-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colourless oil (330 mg), 50% contaminated with 1-(3-methoxypropyl)-1,3-dihydro-3,3-dimethyl-indol-2-one. MS (ES+) m/z: 537 (M+Na)+.
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][C@H:13]([NH2:16])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:17]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[C:1]([N:11]1[CH2:15][CH2:14][C@H:13]([NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(OCc1ccccc1)N1CC[C@H](NC2CCCCC2)C1
Yield: 99 %

Procedure:
To a solution of (3S)-1-Cbz-3-aminopyrrolidine (4.11 g, 16.0 mmol) and cyclohexanone (2.36 g, 24.0 mmol) in DCE (50 mL) was slowly added NaBH(OAc)3 (6.78 g, 32.0 mmol) at rt. The reaction mixture was quenched after 4 h using a saturated aqueous NaHCO3 solution and extracted with DCM followed by EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (EtOAc/Hex=2/1) to give the title compound (4.79 g, 98.1%).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>COCCO>[CH2:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][CH:11]([CH2:10][NH:9][C:2]2[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:12][CH2:13]1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Fc1cccnc1Cl
Solvent: COCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CCC(CNc2ncccc2F)CC1

Procedure:
A solution of 2-chloro-3-fluoropyridine (prepared in a manner similar to that described by W. J. Link, R. F. Borne and F. L. Setliff, J. Heterocyclic Chem. 4, 641–3, 1967) (131 mg 1 mmol), benzyl 4-(aminomethyl)-piperidine-1-carboxylate (EXAMPLE 13, STEP 1) (248 mg, 1 mol) and diisopropylethylamine (129 mg, 1 mmol) were heated to reflux in 2-methoxyethanol for 2 days under nitrogen. The reaction mixture was concentrated, partitioned between ethyl acetate and water, the organic layer washed with brine, dried over anhydrous sodium sulfate and solvent evaporated to give the crude product purified by chromatography on silica. M.S. (M+1): 344.3
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=1.[NH2:12][C:13]1[NH:17][N:16]=[N:15][N:14]=1>>[NH:14]1[C:13]([NH:12][C:9]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=2)=[O:11])=[N:17][N:16]=[N:15]1
Reactant: Nc1nnn[nH]1
Reactant: COc1cccc(C(=O)O)n1
Product: COc1cccc(C(=O)Nc2nnn[nH]2)n1
Yield: 46.4 %

Procedure:
0.48 g of 6-methoxy-2-pyridinecarboxylic acid, 0.51 g of N,N'-carbonyldiimidazole and 0.29 g of 5-aminotetrazole are treated in the same manner as described in Example 2. The crude product thus obtained is recrystallized from a mixture of dimethylformamide, water and ethanol, whereby 0.32 g of N-(5-tetrazolyl)-6-methoxy-2-pyridinecarboxamide is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:23]3[CH2:28][CH2:27][C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)([OH:29])[CH2:25][CH2:24]3)=[O:22])[C:9]=2[CH3:36])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:43][N:44](C)C(=O)C>[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[K+].[K+].[K+].[K+].[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[N:12]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:43]#[N:44])=[CH:3][CH:4]=2)=[C:9]([CH3:36])[C:10]([C:21]([N:23]2[CH2:28][CH2:27][C:26]([OH:29])([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:25][CH2:24]2)=[O:22])=[N:11]1
Reactant: CC(=O)N(C)C
Reactant: Cc1c(C(=O)N2CCC(O)(c3ccccc3)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Br)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: Cc1c(C(=O)N2CCC(O)(c3ccccc3)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(C#N)cc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 10 %

Procedure:
Nitrogen gas was bubbled through a solution of 1-{[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidin-4-ol (1 eq., 45 mg, 0.077 mmol), K4[Fe(CN)6].3H2O (0.22 eq., 7.5 mg, 0.017 mmol), sodium carbonate (1 eq., 8.1 mg, 0.017 mmol), and palladium(II) acetate (0.10 eq., 1.7 mg, 0.008 mmol) in N,N-dimethylacetamide (2 mL) for 1 min. The solution is capped and stirred at 120° C. for 16 h. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-100% ethyl acetate/hexane to yield pure 4-[1-(2,4-dichlorophenyl)-3-[(4-hydroxy-4-phenylpiperidin-1-yl)carbonyl]-4-methyl-1H-pyrazol-5-yl]benzonitrile (4 mg, 10%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.75-1.94 (m, 2H) 2.07-2.32 (m, 5H) 3.25-3.43 (m, 1H) 3.55-3.76 (m, 1H) 4.31 (d, J=12.90 Hz, 1H) 4.73 (d, J=13.00 Hz, 1H) 7.01 (d, J=8.48 Hz, 2H) 7.08-7.57 (m, 10H).