Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]#[N:13])[CH:8]=[CH:9][CH:10]=1.Cl[CH2:15][CH2:16][N:17]([CH2:25][CH2:26]Cl)[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]>CS(C)=O.C1COCC1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2([C:12]#[N:13])[CH2:26][CH2:25][N:17]([C:18]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:24])[CH2:16][CH2:15]2)[CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: COc1cccc(CC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1cccc(C2(C#N)CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 87.9 %

Procedure:
This compound is prepared by the procedure described in step A of preparation 1.8, from 16.3 g of sodium hydride at a concentration of 60% in oil in 400 ml of DMSO, 30 g of 3-methoxyphenylacetonitrile in 150 ml of THF and 47 g of tert-butyl bis(2-chloroethyl)carbamate in 100 ml of DMSO. This gives 54 g of the expected product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[NH:5][C:6]([O:8]C(C)(C)C)=O.[CH2:29]([O:36][C:37]1[CH:55]=[CH:54][C:40]([CH2:41][C@@H:42](C(O)=O)[NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[CH:39][CH:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>FC(F)(F)C(O)=O.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[NH:5][C:6](=[O:8])[C@H:42]([CH2:41][C:40]1[CH:39]=[CH:38][C:37]([O:36][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:55][CH:54]=1)[NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:48])[CH3:49])=[O:45]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.1 %

Procedure:
A solution of 1.04 g (2.64 mmol) of Nε -benzyloxycarbonyl-Nα -(tert-butoxycarbonyl)-L-lysine methyl ester in 5.3 mL of trifluoroacetic acid was stirred for 2 hours at room temperature. The reaction mixture was evaporated in vacuo to give a colorless oil, which was mixed with 0.966 g (2.6 mmol) of O-benzyl-N-(tert-butoxycarbonyl)-L-tyrosine, 0.37 mL (2.6 mmol) of triethylamine and 20.8 mL of chloroform. To that mixture was added, in one portion, 0.54 g (2.6 mL) of dicyclohexylcarbodiimide at 0° C. The reaction mixture was stirred for one hour at 0° C. and then overnight at room temperature. The solvent was removed by evaporation and the residue was chromatographed on silica gel, using first methylene chloride and then 1:1 methylene chloride/ethyl acetate as eluents, to give 0.49 g (29.1%) of a colorless solid. NMR (CDCl3) δ 7.3 (10 H, m), 7.1 (2H, d), 6.85 (2H, d), 6.5 (1H, m), 5.1 (2H, s), 5.0 (1H, m), 4.7-4.1 (2H, m), 3.65 (3H, s), 3.3-2.9 (4H, m), 1.4 (9H, s). A portion of the product was recrystallized from a mixture of ethyl acetate and isopropyl ether to give crystals melting at 167°-168° C. The product has the formula ##STR118## as confirmed by elemental analysis.
Reaction SMILES: [CH3:1][O:2][C:3](=[NH:8])[NH:4][N+:5]([O-:7])=[O:6].[Cl-].[Na+].Cl.CN.[C:14](=O)([O-])O.[Na+].Cl>O>[CH3:14][NH:8][C:3](=[N:4][N+:5]([O-:7])=[O:6])[O:2][CH3:1]
Reactant: COC(=N)N[N+](=O)[O-]
Reactant: O=C([O-])O
Agent: CN
Agent: Cl
Agent: [Cl-]
Solvent: O
Product: CNC(=N[N+](=O)[O-])OC
Reaction time: 16 h
Yield: 73 %

Procedure:
Into a 100-ml, 4-necked flask equipped with a stirrer were introduced 1.5 g of O-methyl-N-nitroisourea, 11 g of water, 3 g of sodium chloride and 2 g of methylamine hydrochloride, and the resulting material was maintained at 20 degree centigrade. Thereafter, 0.1 g of sodium hydrogen carbonate was added to the mixture and the mixture was stirred at 20 degree centigrade for 16 hours. Then, while stirring the reaction mixture, 0.1 g of concentrated hydrochloric acid and 200 ml of water were added to the mixture to give a homogenious aqueous solution of N,O-dimethyl-N′-nitroisourea, which was analyzed by HPLC. In the aqueous solution, 1.2 g of N,O-dimethyl-N′-nitroisourea was contained, and the reaction yield was 73%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH:18]=[CH2:19])[CH:16]=3)[O:11][C:10](=[O:20])[CH:9]=2)[CH2:3][CH2:2]1.[O:21]1[C:26]2[CH:27]=[CH:28][C:29]([CH:31]=O)=[CH:30][C:25]=2[O:24][CH2:23][CH2:22]1>>[O:21]1[C:26]2[CH:27]=[CH:28][C:29]([CH2:31][N:1]3[CH2:6][CH2:5][CH:4]([NH:7][C:8]4[C:17]5[C:12](=[CH:13][CH:14]=[C:15]([CH:18]=[CH2:19])[CH:16]=5)[O:11][C:10](=[O:20])[CH:9]=4)[CH2:3][CH2:2]3)=[CH:30][C:25]=2[O:24][CH2:23][CH2:22]1
Reactant: C=Cc1ccc2oc(=O)cc(NC3CCNCC3)c2c1
Reactant: O=Cc1ccc2c(c1)OCCO2
Product: C=Cc1ccc2oc(=O)cc(NC3CCN(Cc4ccc5c(c4)OCCO5)CC3)c2c1

Procedure:
4-(Piperidin-4-ylamino)-6-vinyl-chromen-2-one and 2,3-dihydro-benzo{1,4}dioxine-6-carbaldehyde were allowed to react in a manner analogous to that previously described to give the title compound. 1H NMR (500 MHz, DMSO-D6) δ ppm 1.64 (m, 2H) 1.92 (m, 2H) 2.08 (m, 2H) 2.83 (m, 2H) 3.38 (s, 2H) 3.49 (m, 1H) 4.22 (m, 4H) 5.23 (s, 1H) 5.34 (m, 1H) 5.95 (m, 1H) 6.77 (m, 4H) 7.25 (m, 2H) 7.69 (m, 1H) 8.21 (m, 1H); MS (DCI/NH3) m/z 418 [M+H]+.
Reaction SMILES: CC1C=C([N+]([O-])=O)C=CC=1[N:11]=[C:12]=[S:13].N[C@H](C1CCCCC1)C.Cl[CH:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25](O)=[O:26]>>[C:28]1([CH:24]2[S:13][CH2:12][NH:11][C:25]2=[O:26])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: O=C(O)C(Cl)c1ccccc1
Agent: C[C@H](N)C1CCCCC1
Product: O=C1NCSC1c1ccccc1

Procedure:
2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-amino-1-cyclohexylethane followed by α-chloro-α-phenylacetic acid according to Method C8a to afford 2-(2-methyl-4-nitrophenylimino)-3-((]S)-1-cyclohexylethyl)-5-phenyl-1,3-thiazolidin4-one.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][P:18]([O:26][CH3:27])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])=[CH:14][CH:15]=2)[C:10](I)=[N:9]1)=O)(C)(C)C.[S:29]1[C:33](B(O)O)=[CH:32][C:31]2[CH:37]=[CH:38][CH:39]=[CH:40][C:30]1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:27][O:26][P:18]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)(=[O:19])[O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][N:9]=[C:10]2[C:33]1[S:29][C:30]2[CH:40]=[CH:39][CH:38]=[CH:37][C:31]=2[CH:32]=1
Reactant: COP(=O)(Oc1ccc2c(c1)c(I)nn2C(=O)OC(C)(C)C)c1ccccc1
Reactant: OB(O)c1cc2ccccc2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COP(=O)(Oc1ccc2[nH]nc(-c3cc4ccccc4s3)c2c1)c1ccccc1
Yield: 2.9 %

Procedure:
The title compound is prepared according to procedure L employing 30 mg of 3-iodo-5-(methoxyphenylphosphinoyloxy)indazole-1-carboxylic acid tert-butyl ester, 21.2 mg of benzo[b]thiophene-2-boronic acid, 2.23 mg of 1,1′-bis(diphenylphosphino)ferrocene palladium(II) dichloride and 71 mg of cesium carbonate in 500 μl of dimethylformamide. 0.7 mg of phenylphosphonic acid 3-benzo[b]thiophen-2-yl-1H-indazol-5-yl ester methyl ester is isolated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[I:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:32][C:31]4[CH:34]=[CH:35][C:28]([I:27])=[CH:29][CH:30]=4)[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: O=Cc1ccc(I)cc1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(Cc3ccc(I)cc3)CC2)cc1

Procedure:
Using the general procedure described in Example 3, N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (0.070 mmol) was reacted with 4-iodobenzaldehyde to provide 28 mg of the title product as the free base. Treatment with hydrochloric acid and concentration in vacuo yielded the salt of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[CH:5]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([O:11][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[C:8]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:9]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Yield: 160.4 %

Procedure:
A mixture of 25.0 g (0.15 mol) of 3,5-dihydroxybenzoic acid methyl ester, 44 ml (0.37 mol) of benzyl bromide and 82 g (0.60 mol) of potassium carbonate in 300 ml of DMF was stirred and heated at 85° under argon for 45 hours. The cooled reaction mixture was filtered and the filtrate was concentrated at reduced pressure. The residue was treated with methylene chloride and the extract was filtered again to remove salts. Crystallization from methylene chloride-methanol gave 41.9 g (81% yield, mp 64°-66°) of 3,5-bis(phenylmethoxy)benzoic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]([O:20]CC)=[O:19])[C:9]2=[O:23])[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH3:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]([OH:20])=[O:19])[C:9]2=[O:23])[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc2ccccc2n(-c2cccc(C)n2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(-n2c(=O)c(C(=O)O)nc3ccccc32)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
27.2 g (88 mmol) of ethyl 1-(6-methylpyridine-2-yl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylate was dissolved in 1,4-dioxane (50 ml) and water (50 ml), and 18.3 g (0.13 mol) of potassium carbonate was added thereto, and the solution was stirred for 1 hour at 60° C. The solvent was distilled off under reduced pressure and the aqueous layer was adjusted to pH<4. The precipitated crystals were filtered to obtain 23.3 g (yield: 94%) of 1-(6-methylpyridine-2-yl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid.
Reaction SMILES: Cl[CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3](=[O:5])[CH3:4].[S-:10][C:11]#[N:12].[Na+]>C(C(C)=O)C>[CH3:8][CH:7]([CH3:9])[CH2:6][CH:2]([S:10][C:11]#[N:12])[C:3](=[O:5])[CH3:4]
Reactant: CC(=O)C(Cl)CC(C)C
Reactant: N#C[S-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CC(=O)C(CC(C)C)SC#N

Procedure:
17.91 g (120.5 mmol) of 3-chloro-5-methylhexan-2-one were dissolved in 120 ml of methyl ethyl ketone, 10.0 g (123.4 mmol) of sodium thiocyanate were added and the reaction mixture was heated under reflux for 1 h. After cooling, the reaction mixture was filtered, the residue was washed with methyl ethyl ketone and the combined filtrates were concentrated on a rotary evaporator. The oily residue was taken up in about 400 ml of dichloromethane and washed three times with in each case 100 ml of water. The organic phase was dried over sodium sulfate and the solvent was removed on a rotary evaporator. This gave 20.07 g of the crude product, which was reacted further as such.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:11]1[C:19]2[C:14](=[CH:15][C:16]([N:20]=[C:21]([O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:22]=[CH:23]S(C3C=CC=CC=3)(=O)=O)=[CH:17][CH:18]=2)[CH2:13][CH2:12]1.COC(C)(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:23]=[CH:22][C:21](=[N:20][C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[CH2:11][CH2:12][CH2:13]3)[O:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(S)cc1
Reactant: O=S(=O)(C=CC(=Nc1ccc2c(c1)CCC2)Oc1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: Fc1ccc(SC=CC(=Nc2ccc3c(c2)CCC3)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.5 %

Procedure:
To a solution of 4-fluorothiophenol (0.22 g) in DMF (6 mL) was added 60% sodium hydride (84 mg), and the mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. The reaction mixture was added to a solution of phenyl N-(5-indanyl)-3-(phenylsulfonyl)acrylimidate (0.65 g) in anhydrous DMF (3 mL) under ice-cooling. The mixture was stirred at room temperature for 2 hours. To the reaction mixture was added tert-butyl methyl ether (50 mL), which was washed with a 1N aqueous sodium hydroxide solution, water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was isolated and purified by medium pressure preparative liquid chromatography (Yamazen SI-40B, hexane:ethyl acetate=19:1) to obtain phenyl 3-(4-fluorophenylthio)-N-(5-indanyl)acrylimidate (0.16 g).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[N:21][CH:20]=[CH:19][N:18]=2)[CH2:13][CH2:12]1)C)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]2[C:17]([N:14]3[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][NH:7][CH3:6])[CH2:16][CH2:15]3)=[N:18][CH:19]=[CH:20][N:21]=2)=[CH:24][CH:25]=1
Reactant: CN(CCN1CCN(c2nccnc2-c2ccc(F)cc2)CC1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCN1CCN(c2nccnc2-c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
Dissolve {2-[3′-(4-fluoro-phenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl]-ethyl}-methyl-carbamic acid tert-butyl ester (3.8 g, 9.16 mmol, 1 eq.) in dichloromethane (20 mL). Add trifluoroacetic acid (41.2 g, 27.8 mL, 366.4 mmol, 40 eq.). Stir at room temperature for 1.5 hr. Partition the reaction mixture between aqueous 5N NaOH (pH aqueous layer=14) and dichlormethane. Separate the layers. Extract the aqueous layer with dichloromethane (2×50 mL). Combine the organic layers, dry over anhydrous Na2SO4, filter and concentrate to afford the title preparation (3.04 g, 100% yield). MS (loop): m/z=316.3 [M+H].
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:10]([N:13]1[C:17]([NH2:18])=[N:16][N:15]=[N:14]1)[CH2:11][CH3:12]>>[CH2:10]([N:13]1[C:17]([NH:18][C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:9])=[N:16][N:15]=[N:14]1)[CH2:11][CH3:12]
Reactant: CCCn1nnnc1N
Reactant: O=C(O)C1CCCCC1
Product: CCCn1nnnc1NC(=O)C1CCCCC1
Yield: 49 %

Procedure:
Employing 0.30 g (2.3 mmol) of cyclohexane carboxylic acid and 0.29 mg (2.3 mmol) of 1-propyl-1H-tetrazol-5-amine in the procedure described above and elution with CH2Cl2/MeOH/Et31NT (9.3:0.5:0.2) gave the product in 49% yield.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]#[N:12].Cl.C1COCC1>O>[CH:3]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]#[N:12])=[O:2]
Reactant: COC(OC)c1cc(Oc2cccc(C#N)c2)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cccc(Oc2ccc([N+](=O)[O-])c(C=O)c2)c1
Temperature: 25 °C

Procedure:
A mixture of 3-(3-dimethoxymethyl-4-nitro-phenoxy)-benzonitrile (0.068 mol) in water (55 mL) was stirred at room temperature, and then 12N HCl (55 mL) and THF (140 mL) were added, and the reaction mixture was stirred overnight at room temperature. The mixture was stirred in H2O and extracted with diisopropyl ether. The organic layer was separated, washed with a 10% NaHCO3 solution, separated again, dried, filtered off and the solvent was evaporated. The obtained residue was stirred in diisopropyl ether, and then the desired product was filtered off and dried to yield the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]([Cl:7])(Cl)[C:3](Cl)=[O:4].[CH2:8]=[C:9]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.CCOCC>[Cl:1][C:2]1([Cl:7])[C:3](=[O:4])[CH2:8][C:9]21[CH2:10][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12]2
Reactant: C=C1CN(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC2(CC(=O)C2(Cl)Cl)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
28.42 mL (254.65 mmol) of trichloroacetyl chloride dissolved in 70 mL of dimethoxyethane are added dropwise, at 0° C., to a mixture containing 7.98 g (47.16 mol) of tert-butyl 3-methyleneazetidine-1-carboxylate (WO 2008/124 085) and 36.48 g (282.94 mmol) of zinc-copper amalgam suspended in 200 mL of ether. The reaction medium is stirred at room temperature for 12 hours. The mixture is then poured portionwise into a sodium carbonate solution at 0° C. The solution obtained is filtered through Celite and rinsed thoroughly with water and ether. The aqueous phase is then separated out and extracted several times with ether. The combined organic phases are dried over sodium sulfate and the filtrate is concentrated under reduced pressure. After evaporating off the solvent, the product obtained, in the form of a brown oil, is used without further purification in the following step.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13](O)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.[F:22][C:23]1([F:29])[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C)C1C=CN=CC=1.CN(C=O)C>[F:22][C:23]1([F:29])[CH2:27][CH2:26][CH:25]([NH:28][C:13](=[O:14])[C@H:12]([N:9]2[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]4[C:6]3=[C:11]([C:2]([F:1])=[CH:3][N:4]=4)[CH2:10]2)[CH:16]([CH3:17])[CH3:18])[CH2:24]1
Reactant: NC1CCC(F)(F)C1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)[C@H](C(=O)NC1CCC(F)(F)C1)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Yield: 39.8 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (15 mg, 0.051 mmol) under nitrogen. DMF (0.5 mL), 3,3-difluorocyclopentanamine (11.2 mg, 0.051 mmol), HOBt (11.83 mg, 0.077 mmol), EDC (14.81 mg, 0.077 mmol) and N,N-dimethylpyridin-4-amine (9.44 mg, 0.077 mmol) were added and the solution was stirred at 25° C. for 4 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 20-50%). The fractions were collected and lyophilized to afford the title compound as a brown oil (8 mg, 39.4%). 1H NMR (500 MHz, CD3OD) δ 0.93 (d, J=6.83 Hz, 3 H) 1.04 (dd, J=6.35, 2.93 Hz, 3 H) 1.62-1.80 (m, 1 H) 1.87-2.02 (m, 1 H) 2.14-2.28 (m, 2 H) 2.35-2.58 (m, 2 H) 3.35 (s, 1 H) 4.22-4.35 (m, 1 H) 4.94-5.10 (m, 2 H) 5.45 (dd, J=18.79, 5.13 Hz, 1 H) 7.86 (s, 1 H) 8.17 (d, J=2.93 Hz, 1 H). [M+H] calc'd for C19H21F3N4O2, 395; found, 395.4.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:11])=[O:10])=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)[CH:3]=1.[C:22]1([NH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28].CS(O)(=O)=O.C(Cl)(Cl)Cl>C1(OC2C=CC=CC=2)C=CC=CC=1>[NH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:29][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:11])=[O:10])=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)[CH:3]=1
Reactant: Nc1ccccc1N
Reactant: NC(=O)Cc1cnc(Cl)cc1NCc1cc(F)cc(F)c1
Agent: CS(=O)(=O)O
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: NC(=O)Cc1cnc(Nc2ccccc2N)cc1NCc1cc(F)cc(F)c1
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 16.4 %

Procedure:
To 89 mg of 6-chloro-4-[(3,5-difluorobenzyl)amino]pyridine-3-carboxyamide (the compound of Example 20) suspended in 3 mL of diphenylether, 65 mg of 1,2-phenylenediamine and 144 mg of methanesulfonic acid were added, and stirred in a nitrogen atmosphere at 180° C. for 30 minutes. After cooling, chloroform was added to the reaction mixture to dissolve the deposit, washed with saturated sodium bicarbonate, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform:methanol:ammonia water=10:1:0.1) to obtain 18 mg (yield 17%) of the title compound as a light brown powder.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][N:14]1[C:18](=[O:19])[CH:17]([CH3:20])[S:16][CH:15]1[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.CI.P([O-])([O-])([O-])=O>CCCCCC.O1CCCC1>[CH3:20][C:17]1([CH3:1])[S:16][CH:15]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:14]([CH3:13])[C:18]1=[O:19]
Reactant: CC(C)NC(C)C
Reactant: CC1SC(c2cccnc2)N(C)C1=O
Agent: O=P([O-])([O-])[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CI
Product: CN1C(=O)C(C)(C)SC1c1cccnc1
Reaction time: 1 h
Yield: 39.4 %

Procedure:
Dry diisopropylamine (0.95 ml, 5.3 mmol) was added to dry tetrahydrofuran (3 ml). Further a butyllithium solution (3.6 ml, 5.8 mmol) in hexane was added dropwise at -40° C. The mixture was kept at -10° C. for 1 hour. Then a solution of 3,5-dimethyl-2-(3- pyridyl)thiazolidin-4-one (1 g, 4.8 mmol) in dry tetrahydrofuran (7 ml) was added dropwise at -20 to -10° C. After this reaction mixture had been kept between those temperatures for 1 hour, methyl iodide (0.75 g, 5.3 mmol) dissolved in dry tetrahydrofuran (2 ml) was added at -20 to -10° C. This reaction mixture was heated for 2 hours up to 0° C. and then kept at the same temperature for 2 hours. The resulting mixture, after addition of a phosphate buffer (pH 7.0), was extracted with ethyl acetate. The extract was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure, and subjected to medium-pressure liquid chromatography (hexane-acetone) and then to recrystallization from a 1:1 ether-hexane mixture, giving 5,5,3-trimethyl-2-(3-pyridyl)thiazolidin-4-one (0.42 g, 39% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][O:22][CH2:23][C:24]([NH:26][NH2:27])=[O:25])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:28])[N:10]1[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[NH:35][S:36]([CH3:39])(=[O:38])=[O:37].[C:40](N1C=CN=C1)(N1C=CN=C1)=[O:41].C(N(CC)CC)C.Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][O:22][CH2:23][C:24]2[O:25][C:40](=[O:41])[NH:27][N:26]=2)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:28])[N:10]1[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[NH:35][S:36]([CH3:39])(=[O:38])=[O:37]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCC(=O)NN)C1c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2n[nH]c(=O)o2)C1c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
A solution of 343 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-(2-hydrazino-2-oxoethoxy)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 6.9 ml of THF was cooled to 0° C., and 116 mg of 1,1′-carbonyldiimidazole and 0.12 ml of triethylamine were added thereto, followed by stirring at 0° C. for 2 hours, and then stirring at room temperature overnight. 0.1 M hydrochloric acid was added thereto, followed by extraction with ethyl acetate. The solution was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to obtain 221 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-[(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methoxy]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white powder crystal.