Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O(C(C)(C)C)[K].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:15]#[C:16][CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH:20]2[CH3:24])[CH:9]=1>CN1C(=O)CCC1>[Br:7][C:8]1[CH:9]=[C:10]2[C:11](=[CH:12][CH:13]=1)[NH:14][C:16]([CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH3:24])=[CH:15]2
Reactant: CC1CCCN1CCC#Cc1cc(Br)ccc1N
Agent: CC(C)(C)O[K]
Solvent: CN1CCCC1=O
Product: C[C@@H]1CCCN1CCc1cc2cc(Br)ccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
To a cooled (0° C.) suspension of KO-tBu (95%, 7.8 g, 66 mmol) in NMP (150 mL) was added a solution of 4-bromo-2-[4-(2-methyl-pyrrolidin-1-yl)-but-1-ynyl]-phenylamine (10 g, 33 mmol) in NMP (50 mL) dropwise keeping the temperature below 5° C. The resulting mixture was then stirred at room temperature for 3 hours under nitrogen. HPLC indicated that all the starting material was consumed. H2O (400 mL) was added slowly to the reaction mixture followed by addition of IPAc (500 mL). The resulting mixture was stirred for 5 min. and the organic layer was separated. The organic layer was then washed with 20% brine (3×200 mL), dried over Na2SO4 and treated with activated carbon. After filtration, the filtrate was concentrated under reduced pressure to give the title compound as a thick oil (6.2 g), which was used in the next coupling reaction without further purification. 1H NMR (400 MHz, CDCl3) δ 10.21 (s, 1H), 7.73 (s, 1H), 7.27 (s, 2H), 6.24 (s, 1H), 3.42-3.50 (m, 1H), 3.21-3.28 (m, 1H), 2.97-3.10 (m, 2H), 2.49-2.60 (m, 2H), 2.33 (q, J=8.78 Hz, 1H), 2.10-2.17 (m, 1H), 1.87-2.02 (m, 2H), 1.58-1.67 (m, 1H), 1.24 (d, J=6.2 Hz, 3H). 13C NMR (400 MHz, CDCl3) δ 140.89, 133.92, 129.91, 122.98, 121.77, 112.16, 111.75, 98.32, 60.47, 53.60, 53.34, 33.19, 26.30, 22.14, 19.56. [M+H]+ at m/z 307.
Reaction SMILES: [CH:1]1[C:10]2[C@@H:11]3[CH2:16][NH:15][CH2:14][CH2:13][C@@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.[NH2:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25](=[O:30])[CH2:26][CH2:27][CH2:28]Cl>>[CH:1]1[C:10]2[C@@H:11]3[CH2:16][N:15]([CH2:28][CH2:27][CH2:26][C:25]([C:19]4[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=4[NH2:17])=[O:30])[CH2:14][CH2:13][C@@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1
Reactant: Nc1cc(F)ccc1C(=O)CCCCl
Reactant: c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCC2
Product: Nc1cc(F)ccc1C(=O)CCCN1CC[C@H]2[C@@H](C1)c1cccc3c1N2CCC3

Procedure:
The title compound was prepared by the method of Example 402 as a yellow oil (35 mg, 20%) from (7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (100 mg, 0.47 mmol) and 1-(2-amino-4-fluorophenyl)-4-chloro-1-butanone (202 mg, 0.93 mmol). The title compound was spectroscopically identical to Example 415.
Reaction SMILES: Cl[S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].S(Cl)(Cl)(=O)=O.[CH2:29]([NH2:31])[CH3:30]>C1COCC1>[CH2:29]([NH:31][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3])[CH3:30]
Reactant: CCOC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN
Solvent: O=S(=O)(Cl)Cl
Solvent: C1CCOC1
Product: CCNS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)OCC)cc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Ethyl(4-nitrophenyl)acetate (25.0 g, 119.5 mmol) was alkylated with 4-iodomethyltetrahydropyran (32.4 g, 143.4 mmol), according to the protocol described in Preparation 41, to give ethyl 2-(4-nitrophenyl)-3-(tetrahydropyran-4-yl)propionate: δH (CDCl3): 1.21 (3H, t), 1.25-1.45 (3H, m), 1.55-1.65 (2H, m), 1.70-1.80 (1H, m), 2.05-2.15 (1H, m), 3.25-3.35 (2H, m), 3.79 (1H, t), 3.90-3.95 (2H, m), 4.10-4.20 (2H, m), 7.49 (2H, d), 8.19 (2H, d). The nitro group of this compound (6.55 g, 18.1 mmol) was reduced utilising the procedure described in EXAMPLE 145 to give ethyl 2-(4-aminophenyl)-3-(tetrahydropyran-4-yl)propionate: m/z (ES+)=278.2 [M+H]+. This compound (30.5 g, 110 mmol) was transformed into ethyl 2-(4-chlorosulfonylphenyl)-3-(tetrahydropyran-4-yl)propionate employing the protocol described in Preparation 59. A solution of this sulfonyl chloride (33.6 g, 93.2 mmol) in anhydrous THF (100 mL) was added over 30 min at 0° C. to EtNH2 (116.5 mL of a 2.0M solution in THF, 233.0 mmol). The mixture was warmed up to 20° C., before being stirred for 16 h. The suspension was filtered through a Celite pad, which was washed with THF (3×50 mL). The combined THF solutions were concentrated to furnish crude ethyl 2-(4-ethylsulfamoylphenyl)-3-(tetrahydropyran-4-yl)propionate: m/z (ES+)=370.2 [M+H]+. Hydrolysis of this ester (33.7 g, 91.2 mmol), utilising the procedure outlined in Preparation 41, followed by purification via RP-HPLC afforded the title compound: m/z (ES+)=342.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([C:12]1[CH:13]=[C:14]([CH3:29])[C:15]([CH3:28])=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][C:23]([CH:26]=[O:27])=[CH:24][N:25]=1)=[CH:17]2)[S:4]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)(=[O:6])=[O:5])[CH3:2].CO.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH2:1]([N:3]([C:12]1[CH:13]=[C:14]([CH3:29])[C:15]([CH3:28])=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][C:23]([CH2:26][OH:27])=[CH:24][N:25]=1)=[CH:17]2)[S:4]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:6])[CH3:2]
Reactant: CCN(c1cc(C)c(C)c2cc(-c3ncc(C=O)s3)[nH]c12)S(=O)(=O)c1cccs1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(c1cc(C)c(C)c2cc(-c3ncc(CO)s3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 2 h
Yield: 98.4 %

Procedure:
A mixed solution of N-ethyl-N-[2-(5-formyl-1,3-thiazol-2-yl)-4,5-dimethyl-1H-indol-7-yl]thiophene-2-sulfonamide (85 mg), methanol (10 mL) and tetrahydrofuran (15 mL) was added sodium borohydride (10 mg) under ice-cooling, and the mixture was stirred at the same temperature for 2 hr. Aqueous citric acid solution was added to the reaction mixture, and the organic solvent was evaporated under reduced pressure. The obtained mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (84 mg, yield 99%) as pale-yellow crystals, melting point 189-190° C.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.[CH2:16]([NH2:24])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[N:24][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:9][CH:8]=1
Reactant: CN(C)CCCOc1ccc(C=O)cc1
Reactant: NCCc1ccccc1
Solvent: Cc1ccccc1
Product: CN(C)CCCOc1ccc(C=NCCc2ccccc2)cc1
Yield: 91.2 %

Procedure:
4-(3-Dimethylaminopropoxy)benzaldehyde (30.0 g) is reacted with 18 g of phenethylamine in 150 ml of toluene as described under Example 1 to give 41 g of an oil; boiling point 184°-189° C./0.1-0.2 mm of Hg.
Reaction SMILES: [CH3:1][N:2]1CCCC1=O.Br[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:17][N:16]=2)=[CH:11][CH:10]=1.[Cu]C#N.Cl>[Fe](Cl)Cl.O>[C:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:17][N:16]=2)=[CH:11][CH:10]=1)#[N:2]
Reactant: CCCCCCCCc1ccc(-c2ccc(Br)cc2)nc1
Reactant: CN1CCCC1=O
Agent: Cl[Fe]Cl
Agent: N#C[Cu]
Agent: Cl
Solvent: O
Product: CCCCCCCCc1ccc(-c2ccc(C#N)cc2)nc1

Procedure:
94 ml of N-methylpyrrolidone was added to the 47.6 g (0.138 mol) of the 2-(p-bromophenyl)-5-octylpyridine. Then 19.3 g (0.216 mol) of copper (I) cyanide was added and the solution was refluxed for 2 hours. A mixture of 69 g of iron (II) chloride, 13.8 ml of concentrated hydrochloric acid and 69 ml of water was added to the mixture solution and the organic layer was extracted with chloroform. The extract was washed with a 10% aqueous solution of potassium hydroxide and then three times with water. Chloroform was removed by distillation. The residue was distilled under reduced pressure (210° to 220° C./2 mmHg) and recrystallized from methanol to obtain 33 g (0.1113 mol) of 2-(p-cyanophenyl)-5-octylpyridine.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:21]1([CH2:27][CH2:28][CH2:29][C:30](O)=[O:31])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:30](=[O:31])[CH2:29][CH2:28][CH2:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:10][CH:9]=1
Reactant: COc1ccc(CC(N)C(O)c2ccc(F)cc2)cc1
Reactant: O=C(O)CCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: COc1ccc(CC(NC(=O)CCCc2ccccc2)C(O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(methyloxy)phenyl)-1-propanol (450 mg, 1.64 mmol) in acetonitrile (30 ml) were added 4-phenyl-n-butyric acid (268 mg, 1.64 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (470 mg, 2.45 mmol) and 1-hydroxy-1H-benzotriazole (250 mg, 1.64 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:acetone=1:1). Recrystallization from ethyl acetate-hexane gave the title compound (575 mg, 83%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:9][CH2:8]1.[Na+].[I-:29]>CC(=O)CC>[I:29][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:9][CH2:8]1
Reactant: CN([C@H]1CC[C@H](C#CCCCCl)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CN([C@H]1CC[C@H](C#CCCCI)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 80 °C

Procedure:
A solution of 250 mg (0.59 mmol) of trans-N-[4-(5-Chloro-pent-1-ynyl)-cyclohexyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide in 10 ml butan-2-one was treated with 136 mg of NaI (0.91 mmol) and heated at 80° C. for 48 h. Evaporation gave 330 mg of crude trans-N-[4-(5-Iodo-pent-1-ynyl)-cyclohexyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide which was used directly for the next step, MS: 514 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[N:10]3[C:11](=[N:16][C:17]([CH3:18])=[C:9]3[C:8]1=[O:19])[CH:12]=[CH:13][CH:14]=2.C(N(CC)CC)C.[F:27][C:28]([F:35])([F:34])[CH2:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:18][C:17]1[N:16]=[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[N:10]2[C:9]=1[C:8](=[O:19])[N:7]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:30]([CH2:29][C:28]([F:35])([F:34])[F:27])(=[O:32])=[O:31]
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: Cc1nc2cccc3n(CCCCCN)c(=O)c1n23
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2cccc3n(CCCCCNS(=O)(=O)CC(F)(F)F)c(=O)c1n23
Yield: 65.4 %

Procedure:
To a solution of 1.630 g (6.31 mmol) of 1-[5-(amino)pentyl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one and 1.32 ml (9.47 mmol) of triethylamine in 30 ml of methylene chloride was added, while stirring under ice-cooling, 1.38 g (7.56 mmol) of 2,2,2-trifluoroethanesulfonylchloride. The mixture was stirred for 30 minutes at the same temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, which was then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to give 1.669 g of the desired compound (65.4%, pale brown solid substance).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([NH:11][C:12]1[CH:43]=[CH:42][C:15]([C:16]([N:18]([CH3:41])[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=2[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)=[O:33])=[O:17])=[CH:14][C:13]=1[O:44][CH3:45])=[O:10].[CH:46]([CH:48]=O)=O.S([O-])(O)=O.[Na+]>C(O)C.C(Cl)(Cl)Cl>[CH3:45][O:44][C:13]1[CH:14]=[C:15]([CH:42]=[CH:43][C:12]=1[NH:11][C:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:2]=1[N:1]=[CH:46][CH:48]=[N:8]2)=[O:10])[C:16]([N:18]([CH3:41])[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([N:34]1[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]1)=[O:33])=[O:17]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc(N)c1N
Reactant: O=CC=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2nccnc12
Yield: 63.2 %

Procedure:
A mixture of 4-(2,3-diaminophenyl)carbonylamino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (200 mg), glyoxal (47 mg) and sodium hydrogen sulfite (169 mg) in ethanol (15 ml) was refluxed for 5 hours. The solution was diluted with chloroform (30 ml) and the solution was washed with water and brine. The organic solution was dried over magnesium sulfate and the solvent was evaporated in vacuo to give an oil. The crude product was purified by silica gal column (1% methanol in chloroform) to give 3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]-4-(quinoxalin-5-yl)carbonylaminobenzamide (131 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH2:29])[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=1.CN(C)C=O>C(#N)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH:29][C:2]2[C:11]3[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:14])[CH:3]=2)[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=1
Reactant: NC(c1ccncc1)c1ccc(Cl)cc1
Reactant: COc1cccc2c(Cl)cc(C)nc12
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1cccc2c(NC(c3ccncc3)c3ccc(Cl)cc3)cc(C)nc12

Procedure:
Preparation was made using a similar procedure as described in example 19, method 19.2. Starting materials were 4-chloro-8-methoxy-2-methylquinoline and C-(4-chlorophenyl)-C-pyridin-4-yl-methylamine. Acetonitrile was used as solvent instead of dimethylformamide.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[N+:10]([CH:13]=[C:14](SC)[S:15]([CH3:17])=O)([O-:12])=[O:11]>CO>[N+:10]([CH:13]=[C:14]([S:15][CH3:17])[NH:6][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2])([O-:12])=[O:11]
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Reactant: CCOC(CN)OCC
Solvent: CO
Product: CCOC(CNC(=C[N+](=O)[O-])SC)OCC
Yield: 49 %

Procedure:
A solution of aminoacetaldehyde diethylacetal (11g, 0.08 mol) and 1-nitro-2-methylthio-2-methylsulphinyl-ethylene (15g, 0.08 mol) in methanol (200 ml) was stirred for 21/2 hours at room temperature. The solvent was removed in vacuo leaving a yellow oily residue which after trituration with propan-2-ol gave 1-nitro-2-methylthio-2-(2,2-diethoxy-ethylamino)ethylene (9.8, 49%) m.p. 72-74°.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([C:21]1[CH:25]=[CH:24][S:23][CH:22]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].O>CN(C=O)C>[Br:1][C:22]1[S:23][CH:24]=[CH:25][C:21]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCCCCCCCCc1ccsc1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCc1ccsc1Br
Reaction time: 24 h
Yield: 94.8 %

Procedure:
A solution of N-bromosuccinimide (NBS) (48 g; 0.27 mol) dissolved in DMF (160 ml) was slowly added to a solution of 3-dodecylthiophene (68 g; 0.27 mol) dissolved in DMF (110 ml). After the reaction solution was stirred for one day, 750 ml of water was added thereto. An organic material was extracted by using ethyl ether (3×300 ml), and washed with brine and water, and then the residual moisture was removed over anhydrous magnesium sulfate. After removing the solvent, the residue was distilled off under reduced pressure at 125° C./˜5 mmHg to obtain a product (84.85 g, yield of 94%).
Reaction SMILES: C1(C([NH:20][CH:21]2[C:34](=[O:35])[N:23]3[CH:24]([P:29]([OH:33])([O:31][CH3:32])=[O:30])[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]23)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[C:37]1([CH3:47])[CH:42]=[CH:41][C:40]([S:43]([OH:46])(=[O:45])=[O:44])=[CH:39][CH:38]=1>CC(C)=O>[C:37]1([CH3:47])[CH:38]=[CH:39][C:40]([S:43]([OH:46])(=[O:44])=[O:45])=[CH:41][CH:42]=1.[NH2:20][CH:21]1[C:34](=[O:35])[N:23]2[CH:24]([P:29]([OH:33])([O:31][CH3:32])=[O:30])[C:25]([CH3:27])([CH3:28])[S:26][C@H:22]12
Reactant: COP(=O)(O)C1N2C(=O)C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2SC1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: COP(=O)(O)C1N2C(=O)C(N)[C@H]2SC1(C)C
Reaction time: 0.25 h

Procedure:
To a stirred slurry of 4.72 g. (0.010 mole) 6-triphenylmethylamino-2,2-dimethyl-3-(O-methylphosphono)penam in 50 ml. of dry acetone was added 1.90 g. (0.010 mole) of p-toluenesulfonic acid monohydrate at ambient temperature. The solids dissolved slowly to afford a clear solution. After stirring for about 15 minutes the product started to precipitate. After stirring for about one hour the product was removed by filtration and washed with acetone. 1H-nmr (DMSO-d6) ppm (δ): 1.62 (s,3,CH3), 1.70 (s,3, CH3), 3.62 (d, J=11,3, OCH3), 3.88 (d, J=11,1,C-3), 5.05 (m,1,C-6), 5.37 (d, J=4,1, C-5). IR(Nujol mull): 1765 cm-1 (β-lactam).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[N:19]=[C:20](/[CH:23]=[CH:24]/[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:21][CH:22]=2)=[CH:12][CH:11]=1)(=O)=O.[NH:31]1[CH:35]=[CH:34][N:33]=[C:32]1[C:36]([O:38][CH2:39][CH3:40])=[O:37].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:25]1(/[CH:24]=[CH:23]/[C:20]2[O:21][CH:22]=[C:18]([CH2:17][O:16][C:13]3[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:31]4[CH:35]=[CH:34][N:33]=[C:32]4[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:15][CH:14]=3)[N:19]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CS(=O)(=O)OCCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Reactant: CCOC(=O)c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Reaction time: 2 h
Yield: 59 %

Procedure:
A mixture of 4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butyl methanesulfonate (430 mg), ethyl 2-imidazolecarboxylate (155 mg), potassium carbonate (305 mg) and N,N-dimethylformamide (10 ml) was stirred for two hours at temperatures ranging from 80 to 90° C. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated. The residue was subjected to a silica gel column chromatography. The crystalline product obtained from the fraction eluted with ethyl acetate-hexane (2:1, v/v) was recrystallized from ethyl acetate-hexane to give ethyl 1-[4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butyl]-2-imidazolecarboxylate (280 mg, 60%) as colorless prisms, mp 96-97° C.
Reaction SMILES: [C:1](=[S:3])=S.[OH-].[K+].C(O)C.[F:9][C:10]1[CH:38]=[CH:37][C:13]([O:14][C:15]2[C:23]3[N:22]=C(C4C=CC=CN=4)[NH:20][C:19]=3[CH:18]=[C:17]([O:30][C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH:16]=2)=[CH:12][CH:11]=1>C(OCC)(=O)C>[F:9][C:10]1[CH:38]=[CH:37][C:13]([O:14][C:15]2[C:23]3[N:22]=[C:1]([SH:3])[NH:20][C:19]=3[CH:18]=[C:17]([O:30][C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH:16]=2)=[CH:12][CH:11]=1
Reactant: Fc1ccc(Oc2cc(Oc3cccnc3)cc3[nH]c(-c4ccccn4)nc23)cc1
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Fc1ccc(Oc2cc(Oc3cccnc3)cc3[nH]c(S)nc23)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
0.06 ml of carbon disulfide and 54 mg of potassium hydroxide were added to an ethanol (2.0 ml) solution of 273 mg of 3-(4-fluoro-phenoxy)-5-(pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 68, and the reaction liquid was stirred overnight at 80° C. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure to obtain the entitled compound.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH:31]=[C:30]([CH3:38])[C:29]4=[O:39])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH:31]=[C:30]([CH3:38])[C:29]4=[O:39])[CH2:24][CH2:25]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Cc1cc2ccccc2n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1cc2ccccc2n(CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To 2 mL of a chloroform solution containing 97 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(3-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 2 mL of trifluoroacetic acid was added and stirred at room temperature for 4 hours. After the solvent was removed under reduced pressure and the residue was alkalized by aqueous saturated sodium hydrogen carbonate solution, it was extracted with ethyl acetate. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 78 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-3-methylquinolin-2(1H)-one as a pale yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[C:12]([C:17]([OH:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[N:7]([C:20]2[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:27])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[Cl:32]CCl.ClN1C(=O)CCC1=O.[OH-].[K+]>O>[C:1]([C:5]1[C:9]([Cl:32])=[C:8]([NH:10][C:11]2[C:12]([C:17]([OH:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[N:7]([C:20]2[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:27])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(C)c1-n1nc(C(C)(C)C)cc1Nc1cccnc1C(=O)O
Reactant: ClCCl
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccc(C)c1-n1nc(C(C)(C)C)c(Cl)c1Nc1cccnc1C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 76 %

Procedure:
To a solution of 3-{[3-tert-butyl-1-(2,6-dimethylphenyl)-1H-pyrazol-5-yl]amino}pyridine-2-carboxylic acid (Example 10, 50 mg, 0.14 mmol) in an acetic acid/dichloromethane mixture (1 mL of each) was added N-chlorosuccinimide (18 mg, 0.14 mmol). The solution was stirred at rt for 12 h, and then water (10 mL) was added. The reaction mixture was basified to pH 9 using KOH (1.0 M ice cold solution). The water layer was extracted with dichloromethane (50 mL), and the organic phase was subsequently washed with saturated sodium sulfite, brine, and concentrated to dryness. The crude material was subjected to HPLC purification to give the desired product (42 mg, 76%). 1H NMR (300 MHz, CD2Cl2) δ 10.45 (s, 1H), 9.30 (s, 1H), 8.04 (d, 1H), 7.50 (m, 1H), 7.25 (m, 2H), 7.15 (m, 2H), 2.02 (s, 6H), 1.43 (s, 9H). ES-MS m/z 399.0 (MH+); HPLC RT (min) 3.33.