Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:3]=1.[CH3:22][NH:23][NH2:24].C(O)CO>O>[NH2:9][C:8]1[C:7]2[C:2](=[N:3][C:4]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:5][C:6]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:23]([CH3:22])[N:24]=1
Reactant: CNN
Reactant: N#Cc1c(-c2ccccc2)cc(N2CCOCC2)nc1Cl
Solvent: O
Solvent: OCCO
Product: Cn1nc(N)c2c(-c3ccccc3)cc(N3CCOCC3)nc21
Temperature: 170 °C

Procedure:
A mixture consisting of 3.0 gm (0.01 mol) of 2-chloro-6-morpholino-4-phenyl-3-cyano-pyridine, 1.4 gm (0.03 mol) of methyl-hydrazine and 4 ml of ethylene glycol was refluxed for 3 hours at 170° C. (bath temperature). The resulting solution was then taken up in 50 ml of water, whereupon the reaction product initially separated out as a pasty precipitate. The pasty product was collected and digested with water, and after it has solidified it was suction-filtered off, washed and dried, yielding 2.8 gm (91% of theory) of the compound of the formula ##STR7## After recrystallizing the product over from methanol it had a melting point of 149°-152° C.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6]([CH2:9][OH:10])=[CH:7][O:8][C:4]=2[CH:3]=1.[CH3:13][CH2:14][O:15][C:16]([C:18]1[N:19]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:20]2[C:25]([CH:26]=1)=[C:24](O)[CH:23]=[CH:22][CH:21]=2)=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCN(C(C)C)C(C)C.N(C(OCC)=O)=NC([O-])=O>C1COCC1>[CH3:13][CH2:14][O:15][C:16]([C:18]1[N:19]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[C:20]2[C:25]([CH:26]=1)=[C:24]([O:10][CH2:9][C:6]1[C:5]3[CH:11]=[CH:12][C:2]([F:1])=[CH:3][C:4]=3[O:8][CH:7]=1)[CH:23]=[CH:22][CH:21]=2)=[O:17]
Reactant: CCOC(=O)c1cc2c(O)cccc2n1C(=O)OC(C)(C)C
Reactant: OCc1coc2cc(F)ccc12
Agent: CCOC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2c(OCc3coc4cc(F)ccc34)cccc2n1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h

Procedure:
111 (2 g, 12 mmol), 102 (3.7 g, 12 mmol), triphenylphosphine (9.4 g, 36.1 mmol) and DIPEA (6.2 ml, 36.1 mmol) are dissolved in 50 ml of THF and cooled to 0° C. Then 40% ethyl azodicarboxylate solution in THF (15.7 ml, 36.1 mmol) is added dropwise. After completed addition the mixture is stirred for 16 h (TLC control) at rt. Then the mixture is evaporated under reduced pressure. The residue is diluted with ethyl acetate, washed sat. NaHCO3- and NaCl-solution, and dried over Na2SO4. The crude product is purified by Flash-chromatography (ethyl acetate/hexanes (1:9), silicagel).
Reaction SMILES: [ClH:1].Cl.NCCCC1N=C(N)NC=1.C(OC([N:20]1[CH:24]=[C:23]([CH2:25][CH2:26][CH2:27][C:28](=O)[NH:29]C2CCCC2)[N:22]=[C:21]1[NH2:36])=O)(C)(C)C>>[ClH:1].[ClH:1].[NH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:23]1[N:22]=[C:21]([NH2:36])[NH:20][CH:24]=1
Reactant: CC(C)(C)OC(=O)n1cc(CCCC(=O)NC2CCCC2)nc1N
Agent: Cl
Agent: NCCCc1c[nH]c(N)n1
Product: NCCCCc1c[nH]c(N)n1
Yield: 18 %

Procedure:
Using the same general procedure as used for the synthesis of 4-(3-amino-propyl)-1H-imidazol-2-ylamine dihydrochloride 16, 12.5 g of lysine methyl ester dihydrochloride 28 afforded 2.25 g (18%) of the target compound 29 as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 6.09 (s, 1H), 4.96 (s, 2H), 2.56 (t, 2H, J=6.3 Hz), 2.27 (t, 2H, J=6.9 Hz), 1.35-1.51 (m, 4H); 13C NMR (100 MHz, DMSO-d6) δ 149.11, 132.29, 110.59, 40.75, 31.41, 26.62, 26.12; HRMS (ESI) calcd for C7H15N4 (MH+) 155.1291, found 155.1293.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]2[C@@H:11](I)[C@H:7]([C@@H:8]([C:21]([O:23][CH3:24])=[O:22])[N:9]2[C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[CH2:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:4][C@H:5]1[C@H:10]2[CH2:11][C@H:7]([C@@H:8]([C:21]([O:23][CH3:24])=[O:22])[N:9]2[C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: COC(=O)[C@@H]1[C@@H]2C[C@@H](OC(C)=O)[C@@H]([C@H]2I)N1[C@H](C)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1[C@H]2C[C@H]([C@H](OC(C)=O)C2)N1[C@H](C)c1ccccc1

Procedure:
A solution of methyl (1S,3S,4S,6R,7S)-6-acetyloxy-7-iodo-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate obtained in Example 42-3 (1.73 g) in methanol (20 mL) containing 20% Pd(OH)2 (173 mg) and triethylamine (0.6 mL) was stirred at room temperature for 1.5 hrs under 1 atm pressure with hydrogen.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.Cl.[CH2:18]([NH:20][C:21](=[O:35])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][C:23]=1[F:34])[CH3:19].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[CH2:18]([NH:20][C:21](=[O:35])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][C@H:8]5[C:7](=[O:16])[NH:6][C:5]=4[CH:4]=3)[CH2:30][CH2:29]2)=[CH:24][C:23]=1[F:34])[CH3:19]
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Reactant: CCNC(=O)c1ccc(N2CCNCC2)cc1F
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1F
Temperature: 120 °C
Yield: 18.1 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (76 mg, 0.348 mmol), N-ethyl-2-fluoro-4-(piperazin-1-yl)benzamide hydrochloride (100 mg, 0.348 mmol), (cyanomethyl)trimethylphosphonium iodide (127 mg, 0.521 mmol) and N,N-diisopropylethylamine (0.303 ml, 1.738 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 120° C. for 3 h. The reaction mixture became a dark brown suspension. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 10-95% ACN in water). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-methanol (5:1, 6 mL) and dried in vacuum to afford (S)—N-ethyl-2-fluoro-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (28.5 mg, 0.063 mmol, 18.12% yield) as a brownish solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (t, J=7.20 Hz, 3H) 1.83-2.02 (m, 3H) 2.18 (dd, J=6.44, 4.17 Hz, 1H) 2.44-2.49 (m, 4H) 2.81-3.01 (m, 4H) 3.23-3.32 (m, 2H) 3.34-3.44 (m, 3H) 3.52-3.64 (m, 1H) 3.93-4.01 (m, 1H) 6.91 (td, J=8.21, 2.53 Hz, 1H) 6.97 (d, J=1.77 Hz, 1H) 7.00 (dd, J=11.37, 2.53 Hz, 1H) 7.62 (d, J=1.52 Hz, 1H) 7.67 (dd, J=8.46, 7.20 Hz, 1H) 8.86 (t, J=5.43 Hz, 1H) 10.45 (s, 1H). [M+H] calc'd for C24H29FN6O2, 453; found, 453.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[N:17]=[CH:16][C:10]3[N:11]=[CH:12][NH:13][C:14](=O)[C:9]=3[CH:8]=2)=[N:4][N:3]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:14]1[C:9]2[CH:8]=[C:7]([C:5]3[O:6][C:2]([CH3:1])=[N:3][N:4]=3)[N:17]=[CH:16][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nnc(-c2cc3c(=O)[nH]cnc3cn2)o1
Product: Cc1nnc(-c2cc3c(Cl)ncnc3cn2)o1

Procedure:
6-(5-Methyl-1,3,4-oxadiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-one (0.5 g) was treated with phosphorus oxychloride in the usual manner to give the title compound (0.17 g) as an orange solid; δH CDCl3 9.68 (1H,s), 9.30 (1H,s), 8.96 (1H,s), 2.75 (3H,s); m/z (M+1+) 248.
Reaction SMILES: Cl.Cl.[O:3]=[C:4]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[CH:20]=[N:21][CH:22]=[C:23]([CH:27]=3)[C:24]([NH2:26])=[O:25])[CH:17]=2)[O:12][C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5]1.[CH:28]1([C:31]2[N:32]=[CH:33][CH:34]=[C:35]3[C:40]=2[N:39]=[C:38]([C:41](O)=[O:42])[CH:37]=[C:36]3[O:44][CH2:45][CH2:46][OH:47])[CH2:30][CH2:29]1.C1(C2C3C(=C(OC)C=C(C(O)=O)C=3)C=CN=2)CC1>>[CH:28]1([C:31]2[N:32]=[CH:33][CH:34]=[C:35]3[C:40]=2[N:39]=[C:38]([C:41]([N:9]2[CH2:10][CH2:11][C:6]4([CH2:5][C:4](=[O:3])[C:18]5[C:13](=[CH:14][CH:15]=[C:16]([C:19]6[CH:20]=[N:21][CH:22]=[C:23]([CH:27]=6)[C:24]([NH2:26])=[O:25])[CH:17]=5)[O:12]4)[CH2:7][CH2:8]2)=[O:42])[CH:37]=[C:36]3[O:44][CH2:45][CH2:46][OH:47])[CH2:29][CH2:30]1
Reactant: NC(=O)c1cncc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)c1
Reactant: O=C(O)c1cc(OCCO)c2ccnc(C3CC3)c2n1
Agent: COc1cc(C(=O)O)cc2c(C3CC3)nccc12
Agent: Cl
Product: NC(=O)c1cncc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)c4cc(OCCO)c5ccnc(C6CC6)c5n4)CC2)O3)c1

Procedure:
The intended compound was produced according to the procedure described in reference Example 37 but using 5-{4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinamide di-hydrochloride and 8-cyclopropyl-4-(2-hydroxy-ethoxy)-[1,7]naphthyridine-2-carboxylic acid in place of methyl 5-{4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinate di-hydrochloride and 1-cyclopropyl-5-methoxyisoquinoline-7-carboxylic acid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[CH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]=2[C:21](O)=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.[CH3:44][O:45][C:46](=[O:51])[C:47]([NH2:50])([CH3:49])[CH3:48]>CN(C=O)C>[CH3:44][O:45][C:46](=[O:51])[C:47]([CH3:49])([NH:50][C:21]([C:12]1[CH:13]=[CH:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]=1[CH:10]=[CH:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:22])[CH3:48]
Reactant: COC(=O)C(C)(C)N
Reactant: O=C(O)c1ccc2ccccc2c1C=CCCc1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1C=CCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
At 0° C. to a solution of 165 mg of a mixture of the (E)- and (Z)-isomers of 1-(4-phenyl-but-1-enyl)-naphthalene-2-carboxylic acid in 2 ml abs. DMF under inert atmosphere 95 mg 1-hydroxybenzotriazole, 110 μl N,N′-diiospropylcarbodiimide and 98 μl N,N-diisopropylethylamine were added. After 15 min at 0° C. 86 mg amino-isobutyric acid methyl ester hydrochloride and 98 μl N,N-diisopropylethylamine were added and the reaction was stirred for 0.5 h at 0° C. and for 4 h at room temperature. Then, the reaction mixture was concentrated, the residue was taken up in ethyl acetate and washed with 2 M HCl, aqueous sat. sodium hydrogen carbonate solution and brine. The organic layer was dried over sodium sulphate, concentrated and purified by chromatography on silica (ethyl acetate/heptane) to yield 85 mg of a mixture of the (E)- and (Z)-isomers of 2-methyl-2-{[1-(4-phenyl-but-1-enyl)-naphthalene-2-carbonyl]-amino}-propionic acid methyl ester.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.[C:24]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:25]([C:30]([NH:32][C:33]2[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][C:34]=2[O:42][CH3:43])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=1.[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>C(Cl)Cl>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:37]([C:36]3[CH:40]=[CH:41][C:33]([NH:32][C:30]([C:25]4[C:24]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:31])=[C:34]([O:42][CH3:43])[CH:35]=3)=[O:38])[CH2:6][C:5]=12
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: COc1cc(C(=O)Cl)ccc1NC(=O)c1ccccc1-c1ccccc1
Agent: [Mg+2]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1NC(=O)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.1 %

Procedure:
To a solution of 0.70 g of 10, 11-dihydro-5H-pyrrolo [2, 1-c][1, 4]benzodiazepine and 0.56 g of N, N-diisopropylethylamine in 50 ml of methylene chloride is added 1.35 g of 4-[([1, 1'-biphenyl]-2-carbonyl)amino]-3-methoxybenzoyl chloride followed by stirring at room temperature for 18 hours. The reaction mixture is washed with water and saturated aqueous NaHCO3 and the organic layer dried(Na2SO4). The organic layer is passed through hydrous magnesium silicate and the filtrate concentrated in vacuo to give a residue which is dissolved in methylene chloride and passed through a pad of hydrous magnesium silicate two additional times to give upon concentration in vacuo to give 1.5 g of amorphous solid. M+=512.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:18][CH2:19][C:20](Cl)=[O:21]>C(#N)C>[Cl:18][CH2:19][C:20]([NH:9][NH:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:11][CH:10]=1)=[O:21]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(C(=O)NN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(C(=O)NNC(=O)CCl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.1 %

Procedure:
To a mixture of 4-methylbenzohydrazide 14 (10 g, 66.59 mmol) and K2CO3 (16.57 g, 119.86 mmol) in acetonitrile (100 mL) was added 2-chloroacetyl chloride (9.02 g, 79.9 mmol) dropwise at ambient temperature. The resulting mixture was stirred at ambient temperature for 16 hours. The solid was collected, washed with H2O and ether, and dried to afford N′-(2-chloroacetyl)-4-methylbenzohydrazide 15 (13 g, 82%) which was used for the next step without further purification. A mixture of N′-(2-chloroacetyl)-4-methylbenzohydrazide 15 (6.0 g, 26.47 mmol) and phosphorous oxychloride (5.0 g, 32.84 mmol) in acetonitrile (20 mL) was stirred under reflux for 16 hours and concentrated. The residue was subjected to flush column chromatography eluting with 10-25% acetone/hexanes to give compound 16 (4 g). Yield: 72%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1>C(O)C.C(OCC)(=O)C.[Pd]>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[CH3:14]
Reactant: CCOC(=O)C=C(c1ccc(O)cc1)c1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(c1ccc(O)cc1)c1ccc(F)cc1
Yield: 90.3 %

Procedure:
A solution of 45.1 (385 mg) in ethanol (12 mL) and ethyl acetate (10 mL) was stirred with 10% Pd—C (50 mg) under a hydrogen atmosphere at room temperature for 3 h. The reaction mixture was filtered and concentrated to provide 45.2 (350 mg).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([CH2:8][NH:9][C:10](=[O:40])[CH2:11][CH2:12][NH:13][C:14](=[O:39])[CH2:15][NH:16][C:17](=[O:38])[CH2:18][C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:3]1.[Na]>O1CCCC1.CC(CC)C=O.C(OCC)(=O)C>[CH3:3][CH:4]([CH2:5][CH3:6])[CH2:8][N:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([CH2:8][NH:9][C:10](=[O:40])[CH2:11][CH2:12][NH:13][C:14](=[O:39])[CH2:15][NH:16][C:17](=[O:38])[CH2:18][C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:3]1
Reactant: O=C(CCNC(=O)CNC(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1)NC[C@H]1CCCNC1
Agent: CCC(C)C=O
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(C)CN1CCC[C@H](CNC(=O)CCNC(=O)CNC(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reaction time: 2 h
Yield: 149.1 %

Procedure:
To a solution of 200 mg of N-(2-{3-((3S)-3-piperidylmethyl)amino-3-oxopropyl}amino-2-oxoethyl)-3,3,3-triphenylpropanamide monohydrochloride in 10 ml of tetrahydrofuran, 0.10 ml of 2-methylbutanal and 230 mg of sodium triacetoxyborohydrate were successively added at room temperature, followed by 2 hours' stirring at the same temperature. The reaction liquid was diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate solution and saturated saline solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resultant residue was purified by means of silica gel column chromatography (eluting solvent: chloroform/methanol=19/1-4/1), to provide 158 mg of the title compound as a colorless solid.
Reaction SMILES: Br[CH:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:16])[C:9](=[O:17])[C:8]2[C:7]([Cl:18])=[CH:6][CH:5]=[CH:4][C:3]1=2.C(=O)([O-])[O-].[Ca+2].[CH2:24]([OH:28])[CH:25]([CH3:27])[CH3:26].O>C1COCC1>[CH2:24]([O:28][CH:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:16])[C:9](=[O:17])[C:8]2[C:7]([Cl:18])=[CH:6][CH:5]=[CH:4][C:3]1=2)[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)CO
Reactant: O=C1c2cccc(Cl)c2C(Br)c2cccc(Cl)c21
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)COC1c2cccc(Cl)c2C(=O)c2cccc(Cl)c21

Procedure:
To a solution of compound (6) (2.0 mmol) and anhydrous calcium carbonate (0.5 g) in dry THF (20 ml) was added dropwise a solution of an appropriate iso-butanol (10 ml) in dry THF (10 ml) under N2. The reaction mixture was refluxed for 3 hours. Water (250 ml) was added and then extracted with dichloromethane. The combined organic extracts were washed with water, dried (MgSO4), and concentrated. The resulting precipitate was collected by filtration, washed with water and further purified by crystallization (CH3CN).
Reaction SMILES: Cl[C:2]([C:28](=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)([Cl:27])[C:3]([N:5]([C:12]([O:14][CH:15]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:16][CH2:17][CH2:18][CH3:19])=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[C:38]([C:41]1[CH:42]=[C:43]([N:47]2[C:51]([SH:52])=[N:50][N:49]=[N:48]2)[CH:44]=[CH:45][CH:46]=1)([OH:40])=[O:39].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:36][O:35][C:32]1[CH:33]=[CH:34][C:29]([C:28]([C:2]([S:52][C:51]2[N:47]([C:43]3[CH:44]=[CH:45][CH:46]=[C:41]([C:38]([OH:40])=[O:39])[CH:42]=3)[N:48]=[N:49][N:50]=2)([Cl:27])[C:3]([N:5]([C:12]([O:14][CH:15]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:16][CH2:17][CH2:18][CH3:19])=[O:13])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:4])=[O:37])=[CH:30][CH:31]=1
Reactant: O=C(O)c1cccc(-n2nnnc2S)c1
Reactant: CCCCCCCC(CCCC)OC(=O)N(C(=O)C(Cl)(Cl)C(=O)c1ccc(OC)cc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCC(CCCC)OC(=O)N(C(=O)C(Cl)(Sc1nnnn1-c1cccc(C(=O)O)c1)C(=O)c1ccc(OC)cc1)c1ccccc1
Yield: 84.7 %

Procedure:
33 g of α-chloro-α-(4-methoxybenzoyl)-2-chloro-5-dodecyloxycarbonylacetanilide and 16 g of 1-(3-carboxyphenyl)-5-mercaptotetrazole were dispersed in 200 ml of chloroform and to which was added dropwise 10 ml of triethylamine at room temperature over a period of about 30 minutes. After stirring for 3 hours the chloroform solution washed with water and concentrated under reduced pressure. The residue was crystallized from methanol to obtain 37.4 g of α-(4-methoxybenzoyl)-α-[1-(3-carboxyphenyl)-5-tetrazolylthio]-2-chloro-5-dodecyloxycarbonylacetanilide. Yield: 85%. Melting Point: 155° to 162° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6][N:7]2[CH3:16].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][CH2:28][CH2:29][NH2:30].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:30][CH2:29][CH2:28][NH:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6][N:7]2[CH3:16]
Reactant: NCCNc1ccccn1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C)c12
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1c(NCCNc2ccccn2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C)c12
Temperature: 0 °C
Yield: 59.2 %

Procedure:
A solution 5-amino-1-methyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (170 mg, 0.598 mmol), N-2-pyridyl-1,2-ethanediamine (123 mg, 0.897 mmol) and triethylamine (0.125 mL, 0.897 mmol) in DMSO (2 mL) was stirred at 100° C. After 4 h the reaction mixture was poured into ice water and the resulting precipitate was removed by filtration, washed with ethanol, and dried to yield 5-amino-6-fluoro-1,4-dihydro-8-methoxy-1-methyl-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-3-carboxylic acid (142 mg, 59%) as a pale yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43]>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:42](=[O:44])[CH3:43])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[N:12]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole (70 mg, 0.13 mmol, example 2) and triethylamine (92 uL, 0.65 mmol) in methylene chloride (3 mL) was added acetyl chloride (59 uL, Aldrich). The reaction mixture was stirred at room temperature overnight then concentrated. Purification of the crude residue by flash chromatography (12 g of silica gel, eluting with 5-30% ethyl acetate in hexane) gave the title compound (56.1 mg, 80%). HR-MS (ES, m/z) calculated for C31H34N2O2Cl2 [(M+H)+] 537.2070, observed 537.2068.
Reaction SMILES: [SH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][O:14][CH2:15][CH2:16][N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27].C(N(CC)CC)C>C(O)C>[C:18]1(=[O:27])[N:17]([CH2:16][CH2:15][O:14][CH2:13][CH2:12][S:1][C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]12
Reactant: O=C1c2ccccc2C(=O)N1CCOCCBr
Reactant: Sc1cccc2nccn12
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCOCCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.4 %

Procedure:
To a suspension of 5-mercaptoimidazo[1,2-a]pyridine (3.00 g, 20 mmoles) and N-[2-[2-(bromo)ethyloxy]ethyl]phthalimide (5.96 g, 20 mmoles) in ethanol (200 ml) was added triethylamine (4.2 ml, 30 mmoles) and the mixture was stirred at room temperature for 12 hours and heated at reflux for 3 hours. After the solvent was distilled off, chloroform was added to the residue, which was washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off. Then, the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 4.00 g of the desired product (54.5%, light tan solid).
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]([F:14])([F:13])[S:10]([O-:12])=[O:11])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[Na+:15].[OH:16]O>O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+].O>[C:1]([O:7][CH2:8][C:9]([F:14])([F:13])[S:10]([O-:16])(=[O:12])=[O:11])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[Na+:15]
Reactant: CCCCC(=O)OCC(F)(F)S(=O)[O-]
Reactant: OO
Agent: O=[W](=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCC(=O)OCC(F)(F)S(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88 %

Procedure:
A 100 mL reactor was charged with 6.6 g (purity 28%, 7.3 millimoles) of sodium 2-valeryloxy-1,1-difluoroethanesulfinate, 60 mL of water, 0.0047 g (0.014 millimoles/0.0019 equivalents) of sodium tungstate dihydrate, and 1.9 g (16.4 millimoles/2.25 equivalents) of 30% hydrogen peroxide solution, followed by stirring at room temperature for 1.5 hours. The reaction liquid was heated under reduced pressure, followed by distilling volatile component to dryness, thereby obtaining 6.6 g of the target sodium 2-valeryloxy-1,1-difluoroethanesulfonate. Upon this, purity was 26%, and yield was 88%.