Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[F:18])=[N:5]1.[NH:20]1[CH:24]=[C:23]([C:25]2[S:26][CH:27]=[C:28]([C:30](O)=[O:31])[N:29]=2)[N:22]=[CH:21]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:17][C:11]1[C:10]([F:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:30]([C:28]3[N:29]=[C:25]([C:23]4[N:22]=[CH:21][NH:20][CH:24]=4)[S:26][CH:27]=3)=[O:31])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=C(O)c1csc(-c2c[nH]cn2)n1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1)NC(=O)c1csc(-c2c[nH]cn2)n1

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-fluorobenzonitrile (0.3 g, 1.07 mmol), 2-(1H-imidazol-4-yl)thiazole-4-carboxylic acid (0.25 g, 1.29 mmol), HOBt (0.22 g, 1.61 mmol), DIPEA (0.56 mL, 3.23 mmol) and EDCI (0.31 g, 1.61 mmol) in 10 mL DMF as solvent using the method described in Example 34(d). Yield 65 mg. 1H NMR (400 MHz; CDCl3): δ 1.27 (d, 3H), 4.40 (m, 2H), 4.60 (m, 1H), 6.80 (dd, 1H), 7.24 (d, 1H), 7.30 (m, 1H), 7.56 (m, 2H), 7.70 (d, 1H), 8.02 (s, 1H), 8.08 (m, 1H).
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[O:20])[CH:16]=[N:17][CH:18]=1.O>C1COCC1>[Br:12][C:13]1[CH:14]=[C:15]([CH:19]([C:8]2[N:7]([CH3:6])[CH:11]=[CH:10][N:9]=2)[OH:20])[CH:16]=[N:17][CH:18]=1
Reactant: Cn1ccnc1
Reactant: O=Cc1cncc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cn1ccnc1C(O)c1cncc(Br)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
At −78° C., under N2 protection, n-BuLi (0.16 mL, 1.6 M, 1.0 mmol) was added to a solution of 1-methyl-1H-imidazole (82 mg, 1.0 mmol) in THF (10 mL) and the reaction mixture was stirred at −78° C. for 0.5 hour; then, 5-bromo-pyridine-3-carbaldehyde (186 mg, 1.0 mmol) was added to the above solution and stirring continued at −78° C. for additional 2 hours. The reaction mixture was poured into water (5.0 mL) and extracted with EtOAc (2×50 mL). The organic layer was dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product (210 mg, 78.4%) as white solid. MS: 268.1 & 270.1 (M+H+).
Reaction SMILES: [CH2:1]([NH:8][CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:10](Cl)([Cl:13])([Cl:12])=[S:11]>CCOCC>[CH2:1]([N:8]([CH3:9])[P:10]([Cl:13])([Cl:12])=[S:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=P(Cl)(Cl)Cl
Reactant: CNCc1ccccc1
Solvent: CCOCC
Product: CN(Cc1ccccc1)P(=S)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
A solution of N-benzyl-N-methylamine (2.81 g, 0.32 mol) in 47 mL of ether was added dropwise with stirring to 78.6 g (0.47 mol) of thiophosphoryl chloride in 375 mL of ether at 0° C. under an argon atmosphere. After the addition was complete, the resultant slurry was stirred for 30 min at 0° C., and then for 1 h at 25° C. The amine hydrochloride was removed by filtration and the solvent was concentrated at reduced pressure to provide 28.5 g (92.5%) of a red colored oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH2:4][N:5]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:14]=[C:13]([OH:36])[CH:12]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8].Cl[CH2:39][CH2:40][CH2:41][CH2:42][C:43]1[CH:52]=[CH:51][C:50]2[C:45](=[CH:46][C:47]([O:61][CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)=[C:48]([O:53][CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[CH:49]=2)[CH:44]=1.C(=O)([O-])[O-].[I-].[Na+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:37])[CH2:4][N:5]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[C:11]1[CH:12]=[C:13]([O:36][CH2:39][CH2:40][CH2:41][CH2:42][C:43]2[CH:44]=[C:45]3[C:50](=[CH:51][CH:52]=2)[CH:49]=[C:48]([O:53][CH2:54][C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:47]([O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[CH:46]3)[CH:14]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:16]=1
Reactant: ClCCCCc1ccc2cc(OCc3ccccc3)c(OCc3ccccc3)cc2c1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(N(CC(=O)OC)CC(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCc2ccc3cc(OCc4ccccc4)c(OCc4ccccc4)cc3c2)cc(N(CC(=O)OC)CC(=O)OC)c1
Yield: 49.3 %

Procedure:
A mixture of 1.5 g (2.88 mmol) of N-[3-hydroxy-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester, 1.24 g (2.88 mmol) of 2-(4-chlorobutyl)-6,7-bis(phenylmethoxy) naphthalene, 0.8 g (5.75 mmol) ofpotassium carbonate and 0.43 g (2.88 mmol) of sodium iodide in 50 ml of acetone and 10 ml of DMF was stirred at reflux under argon for 40 hours. The acetone was removed by distillation and 50 ml of DMF, 1.24 g of 2-(4-chlorobutyl)-6,7-bis(phenylmethoxy)naphthalene, 0.8 g of potassium carbonate and 0.43 g of sodium iodide were added and the mixture was stirred and heated at 85° for 4 days. The DMF was removed using an oil pump at 55°. The residue was extracted with methylene chloride,the extract was concentrated and the product was purified by HPLC using 20%ethyl acetate-hexane to give 1.3 g (49% yield) of N-(2 -methoxy-2oxoethyl)-N-[3-(octadecyloxy)-5-[4-[2,3-bis(phenylmethoxy)-6-naphthalenyl]butoxy]phenyl]glycine methyl ester as a semisolid. The nmr and mass spectra were consistent with the structure.
Reaction SMILES: [I-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7].[C:14](#[N:16])C>>[Cl:3][C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:5]=1[C:6]([C:14]#[N:16])=[O:7]
Reactant: CC#N
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: [I-]
Agent: [Na+]
Product: N#CC(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The reaction was carried out under Argon. Cuprous cyanide (5.0 g, 56.0 mmol) and anhydrous sodium iodide (15.6 g, 104 mmol) were stirred for 2 minutes in anhydrous acetonitrile (100 ml). The resulting solution was mixed with 2,4-dichlorobenzoyl chloride (10.96 g, 52.3 mmol) whereupon an orange precipitate formed. The mixture was stirred for 30 minutes at room temperature, filtered and concentrated in vacuo. The residue was taken up in dichloromethane and the resulting precipitate was filtered off. Concentration of the filtrate under reduce pressure gave a yellow solid which was recrystallised from 60°-80° C. b.p.t. petroleum ether to give 2,4-dichlorobenzoyl cyanide as cream coloured crystals (8.36 g, 80%), melting point 73°-74° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][N+:6]([O-:8])=[O:7])[CH3:2].[CH3:10][Si:11](C)([CH3:15])[CH2:12]CO.O>C1C=CC=CC=1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[N+:6]([CH2:5][C:4]([O:3][CH2:1][CH2:2][Si:11]([CH3:15])([CH3:12])[CH3:10])=[O:9])([O-:8])=[O:7]
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: C[Si](C)(C)CCO
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: O
Solvent: c1ccccc1
Product: C[Si](C)(C)CCOC(=O)C[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
To a stirred solution of nitroacetic acid ethyl ester (5.0 g, 37.6 mmol) and 2-(trimethylsily)ethanol (7.27 g, 61 mmol) in dry benzene (100 mL) is added titanium tetraisopropoxide (1.05 q, 3.69 mmol) and the mixture is heated at reflux for 1 hour. The solution is cooled to 40° C. and water (2 mL) is added and stirring is continued for 10 minutes at room temperature. The solvents are evaporated and the residue is taken up in dichloromethane and dried over anhydrous magnesium sulfate. The mixture is filtered through a small pad of Celite and the solvent is evaporated. The residue is purified by distillation to give nitroacetic acid, 2-(trimethylsily)ethyl ester (6.10 g, 79%) as a colorless liquid. B.pt. 90°-95° C./0.3 mmHg.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[O:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16]>>[OH:10][CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([N:13]2[CH2:14][CH2:15][O:11][C:12]2=[O:16])[CH:7]=[CH:6][CH:5]=1
Reactant: OCCc1cccc(Br)c1
Reactant: O=C1NCCO1
Product: O=C1OCCN1c1cccc(CCO)c1
Yield: 48 %

Procedure:
The title compound was prepared in 48% yield according to the general procedure for the preparation of amides, ureas and carbamates (Method A) starting from 2-(3-bromophenyl)ethanol and 1,3-oxazolidin-2-one.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14](O)=[O:15])[N:10]([CH2:17][CH:18]([CH3:20])[CH3:19])[N:9]=[CH:8]2.Cl.Cl.[CH3:28][O:29][C:30](=[O:41])[C@@H:31]([NH2:40])[CH2:32][CH2:33][N:34]([CH2:36][CH2:37][O:38][CH3:39])[CH3:35].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClC(Cl)C>[CH3:28][O:29][C:30](=[O:41])[C@@H:31]([NH:40][C:14]([C:13]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:6][C:5]=1[O:4][C:3]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:2]=1[F:1])=[O:15])[CH2:32][CH2:33][N:34]([CH2:36][CH2:37][O:38][CH3:39])[CH3:35]
Reactant: COCCN(C)CC[C@H](N)C(=O)OC
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)O)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: COCCN(C)CC[C@H](NC(=O)c1cc2c(cnn2CC(C)C)cc1Oc1ccc(F)cc1F)C(=O)OC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 69.5 %

Procedure:
To a solution of 5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (prepared as in Example 110, Steps A-G) (0.094 g, 0.27 mmol), (S)-2-amino-4-[(2-methoxy-ethyl)-methyl-amino]-butyric acid methyl ester dihydrochloride (0.079 g, 0.28 mmol), EDCI (0.057 g, 0.30 mmol) and HOBt (0.045 g, 0.30 mmol) in dichloroethane (2 mL) was added dropwise triethylamine (0.23 mL, 1.62 mmol). The reaction mixture was stirred at room temperature for 2.5 hours. The mixture was concentrated under reduced pressure and chromatographed, eluting with ethyl acetate, to afford 0.100 g of product (69% yield).
Reaction SMILES: Cl.[O:2]([CH2:6][CH2:7][NH2:8])[N+:3]([O-:5])=[O:4].C[O-].[Na+].[NH2:12][C:13]1[CH:14]=[C:15]([C:19](=[N:24][C:25]#[N:26])OCCC)[CH:16]=[N:17][CH:18]=1>CN(C=O)C.CO>[NH2:12][C:13]1[CH:14]=[C:15]([C:19](=[N:8][CH2:7][CH2:6][O:2][N+:3]([O-:5])=[O:4])[NH:24][C:25]#[N:26])[CH:16]=[N:17][CH:18]=1
Reactant: NCCO[N+](=O)[O-]
Reactant: CCCOC(=NC#N)c1cncc(N)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: N#CNC(=NCCO[N+](=O)[O-])c1cncc(N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.8 %

Procedure:
To a solution of 2-nitroxyethylamine hydrochloride (140 mg, 0.98 mmol) in DMF (1 ml) was added sodium methoxide (42 mg, 0.78 mmol) followed by a solution of propyl 5-amino-N-cyano-3-pyridinecarboximidate (100 mg, 0.49 mmol) in methanol (1 ml) described in Example 6 of Experimental Example 1, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was evaporated under reduced pressure. The residue was suspended in water and extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography with a mixed solvent of methanol and chloroform as an eluent to give the title compound (77 mg, yield 63%) as colorless crystals.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][NH:7][C:6]1=[O:15].[Cl:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>ClCCl>[Cl:16][CH2:17][CH2:18][C:19]([C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[NH:5][C:6](=[O:15])[NH:7][CH2:8]2)=[O:20]
Reactant: O=C1NCc2ccccc2N1
Reactant: O=C(Cl)CCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1NCc2cc(C(=O)CCCl)ccc2N1
Temperature: 20 °C

Procedure:
20 g of aluminium chloride (0.15 mol) are taken up in 100 ml of dichloromethane. 7.43 g of 1,2,3,4-tetrahydroquinazolin-2-one (0.05 mol) are added in portions with stirring at a maximum of 20° C. The reaction mixture thus obtained is subsequently stirred for 30 minutes. A solution consisting of 6.98 g of 3-chloropropionyl chloride (0.055 mol) and 50 ml of dichloromethane is then added dropwise with stirring at a temperature of at most 25° C. and the mixture is subsequently stirred for a further hour. After completion of the reaction, the reaction mixture obtained is stirred into 300 g of ice, and the precipitate is filtered off with suction and washed with plenty of water and small amounts of methanol. The reaction forms a slightly more polar product than the starting material, which can be separated by thin-layer chromatography using an eluent consisting of chloroform and methanol in the mixture ratio 95:5. Yield: 11.37 g of 6-(3-chloro-1-oxopropyl)-1,2,3,4-tetrahydroquinazolin-2-one (95.3% of theory); m.p: >270° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[Se](O)(O)=[O:22].O1CCOCC1>O>[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:9](=[O:22])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:20])=[CH:11][CH:12]=1)(=[O:17])=[O:18]
Reactant: CS(=O)(=O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Reactant: O=[Se](O)O
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)C(=O)c2ccc(F)cc2)cc1

Procedure:
A mixture of ketone from step 3 (1 g, 3.5 mmol), selenious acid (H2SeO3) (550 mg, 1.25 equiv.), dioxane (10 ml) and water (1 ml) were heated to reflux for 4 hours and cooled. The mixture was filtered and the filtrate evaporated. The residue was triturated with cold methanol and filtered to give 620 mg (60%) of the dione: m.p. 174-175° C. Anal. Calc'd. for C15H11FO4S (M.W. 306.31): C, 58.82; H, 3.62; S, 10.47. Found: C, 58.70; H, 3.60; S, 10.70.
Reaction SMILES: [F:1][C:2]1[C:3]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[CH:32][CH:31]=2)=[C:4]([C:8]2[N:13]=[C:12]([N:14]3[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]3)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH:51]1([C:54](Cl)=[O:55])[CH2:53][CH2:52]1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH:51]1([C:54]([N:39]2[CH2:40][CH2:41][CH:36]([C:33]3[CH:32]=[CH:31][C:30]([CH2:29][O:28][C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[C:8]4[N:13]=[C:12]([N:14]5[C:18]([C:19]([F:21])([F:22])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]5)[CH:11]=[CH:10][CH:9]=4)=[CH:35][CH:34]=3)[CH2:37][CH2:38]2)=[O:55])[CH2:53][CH2:52]1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3cccc(F)c3OCc3ccc(C4CCNCC4)cc3)n2)c1C(F)(F)F
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn(-c2cccc(-c3cccc(F)c3OCc3ccc(C4CCN(C(=O)C5CC5)CC4)cc3)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the title compound from Example 5 Step C (40 mg, 0.07 mmol) in DCM (1 mL) were added diisopropyl ethyl amine (0.12 mL, 0.70 mmol) and cyclopropanecarbonyl chloride (0.02 mL, 0.21 mmol). The reaction mixture was stirred for 1 h at ambient temperature, then was diluted with sat. aq. NaHCO3 and extracted with DCM. The organic phase was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The product was used in the subsequent step without further purification: LCMS m/z 636.8 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]1=[O:26])[CH:8]=[CH:7]2)([O-])=O>[C].[Pd].CN(C)C=O>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][CH2:15][N:16]1[C:17](=[O:26])[C:18]3=[CH:25][CH:24]=[CH:23][CH:22]=[C:19]3[C:20]1=[O:21])[CH:8]=[CH:7]2
Reactant: O=C1c2ccccc2C(=O)N1CCCn1ccc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1ccc2c(ccn2CCCN2C(=O)c3ccccc3C2=O)c1
Reaction time: 7 h
Yield: 84.5 %

Procedure:
To 4.4 g of 5-nitro-1-(3-phthalimidopropyl)-indole was added 200 ml of dimethylformamide, further was added 0.15 g of 10% palladium-carbon and hydrogenized at 65° C., under the pressure of 4 kg/cm2, for 7 hours. After the reaction was finished, the reaction mixture was filtrated, and the solvent was removed by distillation under reduced pressure. The thus obtained residue was treated to a silica column chromatography (eluent: 3% methanol/dichloromethane) to obtain 3.4 g of 5-amino-1-(3-phthalimidopropyl)indole in the form of brown needle crystals.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(Cl)(Cl)Cl>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][O:11]2)=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: Cc1cc(OC2CCCCO2)cc(C)c1Br
Yield: 98.7 %

Procedure:
Pyridinium para-toluenesulfonate (0.01 g) was added to a chloroform solution containing 4-bromo-3,5-dimethylphenol (50 g) and 3,4-dihydro-2H-pyran (35 g), followed by stirring. After confirmation of the degree of reaction progress by thin-layer chromatography (hereinafter referred to as TLC), the reaction was quenched with triethylamine. The organic phase was washed with water and saturated brine in this order. The resulting organic phase was dried over anhydrous magnesium sulfate. Subsequently, the organic phase was concentrated and purified by column chromatography to obtain 70 g (yield: 980) of 2-(4-bromo-3,5-dimethylphenoxy)tetrahydropyran as a colorless liquid.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:13]([O:20][N:21]1[C:27](=[O:28])[N:26]2[CH2:29][C@H:22]1[CH2:23][CH2:24][C@H:25]2[C:30]1[O:31]C(C2CCNCC2)=N[N:34]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O/[N:42]=[C:43](\[CH:45]1[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH2:46]1)/N>CN(C=O)C.CCOC(C)=O>[CH2:13]([O:20][N:21]1[C:27](=[O:28])[N:26]2[CH2:29][C@H:22]1[CH2:23][CH2:24][C@H:25]2[C:30]1[O:31][N:42]=[C:43]([CH:45]2[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH2:46]2)[N:34]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1N2C[C@@H](CC[C@H]2c2nnc(C3CCNCC3)o2)N1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(/C(N)=N\O)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2noc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
CDI (511.3 mg, 3.1 mmol) was added to a solution of crude (2S,5R)-6-(benzyloxy)-2-(5-(piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-1,6-diazabicyclo[3.2.1]octan-7-one (726 mg, 2.6 mmol) in DMF (15 mL). The mixture was stirred at rt for 1 h, then, (E)-tert-butyl 4-(N′-hydroxycarbamimidoyl)piperidine-1-carboxylate (631.8 mg, 2.6 mmol) was added at rt. The mixture was stirred at rt for 2 hrs, and then stirred at 50° C. for another 6 hrs. The mixture was diluted with EtOAc (150 mL) and washed with 1 M HCl (2×), water (2×), and saturated sodium chloride (2×), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (1:5 to 1:1 EtOAc/hexanes) to give tert-butyl 4-(5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate (968 mg, 76%) as a white solid. ESI-MS (EI+, m/z): 506.2 [M+Na]+. 1H-NMR (400 MHz, CDCl3): δ 7.47-7.36 (m, 5H), 4.99-4.94 (m, 2H), 4.73 (d, J=6.0 Hz, 1H), 3.93 (d, J=9.6 Hz, 1H), 3.72 (s, 1H), 3.08-2.90 (m, 4H), 2.72 (d, J=9.6 Hz, 1H), 2.15 (dd, J=12.0, 5.2 Hz, 1H), 2.09-1.93 (m, 5H), 1.85-1.79 (m, 1H), 1.59-1.50 (m, 2H), 1.40 (s, 9H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[N:13]1[CH:18]=[CH:17][C:16]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]#[CH:29])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1.[F:30][C:31]([F:36])([F:35])[C:32]([CH3:34])=[O:33]>O1CCCC1>[F:30][C:31]([F:36])([F:35])[C:32]([OH:33])([CH3:34])[C:29]#[C:28][C:25]1[CH:26]=[CH:27][C:22]([S:19]([C:16]2[CH:15]=[CH:14][N:13]=[CH:18][CH:17]=2)(=[O:20])=[O:21])=[CH:23][CH:24]=1
Reactant: CC(=O)C(F)(F)F
Reactant: C#Cc1ccc(S(=O)(=O)c2ccncc2)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(O)(C#Cc1ccc(S(=O)(=O)c2ccncc2)cc1)C(F)(F)F
Temperature: -20 °C
Reaction time: 0.42 h
Yield: 49.4 %

Procedure:
To a solution of diisopropylamine (0.37 mL, 2.66 mmol) in tetrahydrofuran (11 mL) at -20° C. was added n-butyllithium (0.9 mL of 2.5M solution in hexanes, 2.25 mmol) and the resulting solution was stirred for 25 minutes at -20° C. before being cooled to -78° C. To this was added a solution of 4-(4-pyridylsulfonyl)phenylacetylene (0.5 g, 2.05 mmol) in tetrahydrofuran (3 mL) over a five minute period. The mixture was stirred for an additional 15 minutes at -78° C. To this was added 1,1,1-trifluoroacetone (0.20 mL, 2.25 mmol) in one portion. After stirring the mixture at -78° C. for 20 minutes, it was quenched with water, warmed to ambient temperature and the pH adjusted to 7.0 with saturated aqueous NH4Cl . The solution was evaporated and the resulting residue was partitioned between water and ethyl acetate. The ethyl acetate layer was separated, washed (brine), dried and evaporated. The resulting brown oil was purified by chromatography, with ethyl acetate:dichloromethane as the eluent (1:5), to give the title compound as a white solid (0.36 g, 50%); mp 122°-125° C.; NMR (CDCl3): 1.73 (s,3, CH3), 3.37 (s,1, OH), 7.61 (d,2, J=8.2, At), 7.76 (d,2, J=5.1, Ar), 7.93 (d,2, J=4); MS: m/z=356(M+ 1). Analysis for C16H12F3NO3S: Calculated: C, 54.08; H, 3.40; N, 3.94; Found: C, 53.99; H, 3.41; N, 3.75.
Reaction SMILES: [C:1](=[NH:21])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([F:20])[CH:14]=2)=[CH:8][CH:7]=1)[NH2:2].[CH:22]([CH:24]([CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[N:34][CH:35]=1)[C:25](OC)=O)=[O:23].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[F:20][C:15]1[CH:14]=[C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:25]=[C:24]([CH2:29][C:30]4[CH:35]=[N:34][CH:33]=[N:32][CH:31]=4)[C:22](=[O:23])[N:21]=3)=[CH:11][CH:10]=2)[CH:18]=[CH:17][C:16]=1[CH3:19]
Reactant: COC(=O)C(C=O)Cc1cncnc1
Reactant: Cc1ccc(Oc2ccc(CCOC(=N)N)cc2)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1ccc(Oc2ccc(CCOc3nc(=O)c(Cc4cncnc4)c[nH]3)cc2)cc1F
Temperature: 115 °C
Yield: 3.7 %

Procedure:
To the solution of 2-{4-[(3-fluoro-4-methylphenyl)oxy]phenyl}ethyl imidocarbamate (100 mg, 0.249 mmol) and methyl 2-formyl-3-(5-pyrimidinyl)propanoate (58 mg, 0.299 mmol) in NMP (2 mL) was added K2CO3 (138 mg, 0.997 mmol). The mixture was heated with a microwave reactor at 115° C. for 2 h. Purification via MDAP then afforded the title compound (4 mg, 3.71% yield). LCMS: rt=3.19 min, [M+H+]=433
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].[NH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)CN
Reactant: N#Cc1ccc(CBr)cc1
Product: CC(C)(C)OC(=O)CNCc1ccc(C#N)cc1

Procedure:
The title compound was prepared following the general procedure 10, starting from 4-cyanobenzyl bromide and tert-butyl glycinate. It was isolated as a colorless oil. 1H NMR (DMSO-d6, 300 MHz) δ 7.78 (d, J=8.3 Hz, 2H), 7.52 (d, J=8.3 Hz, 2H), 3.79 (s, 2H), 3.19 (s, 2H), 2.60 (br s, 1H), 1.41 (s, 9H). HPLC (Method A) Rt 2.17 min (Purity: 97.2%).