Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([F:18])=[C:12]([I:17])[CH:13]=2)[N:8]([C@H:19]([CH2:23][OH:24])[CH:20]([CH3:22])[CH3:21])[CH:7]=1)=[O:5])[CH3:2].N1C=CN=C1.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].O>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([F:18])=[C:12]([I:17])[CH:13]=2)[N:8]([C@H:19]([CH2:23][O:24][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH:20]([CH3:21])[CH3:22])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)c1cn([C@H](CO)C(C)C)c2cc(F)c(I)cc2c1=O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn([C@H](CO[Si](C)(C)C(C)(C)C)C(C)C)c2cc(F)c(I)cc2c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
The compound (150 g, 335 mmol) obtained in Step 3 was dissolved in dimethylformamide (500 ml), imidazole (30 g, 0.436 mmol) and tert-butyldimethylsilyl chloride (56 g, 369 mmol) were added, and the mixture was stirred at room temperature for 1.5 hr. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed successively with water, saturated aqueous ammonium chloride solution and saturated brine, and dried over sodium sulfate. The organic layer was filtered and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:3 to 1:2) to give 1-((S)-1-tert-butyldimethylsilyloxymethyl-2-methylpropyl)-7-fluoro-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (173 g, yield 92%) as a colorless amorphous form.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:26])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12](=[O:25])(=[O:24])[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([F:23])([F:22])[F:21].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C>[CH3:3][O:4][C:5](=[O:26])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12](=[O:25])(=[O:24])[N:13]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([F:23])([F:21])[F:22]
Reactant: COC(=O)CBr
Reactant: COC(=O)c1ccccc1S(=O)(=O)Nc1ccccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN(c1ccccc1C(F)(F)F)S(=O)(=O)c1ccccc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.4 %

Procedure:
To the suspension of NaH (60% in mineral oil, 2.0 g, 50 mmol) in 45 mL of DMF at 0° C. was added a solution of 2-(2-trifluoromethyl-phenylsulfamoyl)-benzoic acid methyl ester (12.0 g, 33.3 mmol) in 22 mL of DMF dropwise. After about 10 minutes, 11.22 g (66.8 mmol) of methyl bromoacetate was added, and reaction solution was warmed to room temperature in 3 hours. The light yellow reaction mixture was poured into ice water. The mixture was then extracted with EtOAc 3×(˜400 mL) and washed with brine. The organic layer was dried over MgSO4 and evaporated down to a sick light orange oil. White crystals were formed upon treatment with Et2O and hexane. It was collected and dried over the vacuum oven to give pure 2-[methoxycarbonylmethyl-(2-trifluoromethyl-phenyl)-sulfamoyl]-benzoic acid methyl ester (13.85 g, 96%).
Reaction SMILES: C([O:4][CH:5]([CH2:17][CH2:18][S:19]([CH3:21])=[O:20])[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7])(=O)C.[OH-].[Na+]>CO>[OH:4][CH:5]([CH2:17][CH2:18][S:19]([CH3:21])=[O:20])[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7]
Reactant: CCCCCCCCNC(=O)C(CCS(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCNC(=O)C(O)CCS(C)=O
Reaction time: 8 h
Yield: 65.2 %

Procedure:
To a solution of 4-(methylsulfinyl)-1-(octylamino)-1-oxobutan-2-yl acetate (5.7 g, 17.87 mmol) in methanol (75 mL) was added 1M NaOH (26.8 mL, 26.8 mmol) and the resulting solution was stirred overnight. The reaction was evaporated to a small volume and treated with EtOAc (100 mL) and 1N HCl (100 mL). The layers were separated and the organic layer was dried over magnesium sulfate, filtered and evaporated. The crude material was purified by silica gel chromatography with 0-5% methanol/dichloromethane. The desired fractions were collected and evaporated to give a white solid (3.23 g, 65%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.85 (t, J=6.83 Hz, 3 H) 1.24 (br. s., 10 H) 1.33-1.47 (m, 2 H) 1.73-1.89 (m, 1 H) 1.95-2.10 (m, 1 H) 2.51 (d, J=0.64 Hz, 3 H) 2.58-2.87 (m, 2 H) 2.99-3.14 (m, 2 H) 3.95 (dd, J=7.15, 4.29 Hz, 1 H) 5.69 (d, J=5.09 Hz, 1 H) 7.76 (t, J=5.40 Hz, 1 H). m/z 278 (MH+).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]([OH:33])([CH2:8][CH2:9][CH2:10][C@H:11]([C@@H:13]1[C@:31]2([CH3:32])[C@H:16]([C@H:17]3[C@H:28]([CH2:29][CH2:30]2)[C@:26]2([CH3:27])[C:20]([CH2:21][C@H:22]([CH2:24][CH2:25]2)[OH:23])=[CH:19][CH2:18]3)[CH2:15][CH2:14]1)[CH3:12])[C:4]([F:7])([F:6])[F:5].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1>[F:1][C:2]([F:34])([F:35])[C:3]([OH:33])([CH2:8][CH2:9][CH2:10][C@H:11]([C@@H:13]1[C@:31]2([CH3:32])[C@H:16]([C@H:17]3[C@H:28]([CH2:29][CH2:30]2)[C@:26]2([CH3:27])[C:20](=[CH:21][C:22](=[O:23])[CH:24]=[CH:25]2)[CH:19]=[CH:18]3)[CH2:15][CH2:14]1)[CH3:12])[C:4]([F:5])([F:7])[F:6]
Reactant: C[C@H](CCCC(O)(C(F)(F)F)C(F)(F)F)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: C[C@H](CCCC(O)(C(F)(F)F)C(F)(F)F)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of (2) (893 mg) and DDQ (2.2 g) in dioxane (50 ml) was stirred for 15 hr at 80°-90° C. and then refluxed for 4 hr. After cooling to room temperature the precipitate was filtered off and the filtrate was diluted with ether which was successively washed with 1 N-KOH and brine. The extract was purified by silica gel column (AcOEt-n-hexane, 1:20 to give 490 mg (55%) of the trienone (3); mp 166°-168° C. (from AcOEt-cyclohexane), MS m/e 504(M+), 489; IR(KBr), 3180, 1650, 1595 cm-1 ; NMR(CDCl3)δ0.72(s, 18-H3), 0.95(d, J=6 Hz, 21-H3), 1.18 (s, 19-H3), 5.88-6.33(4H, m, 2-,4-,6- and 7-H), 7.04(1H, d, J=10 Hz, 1-H). Anal. Calcd., For C27H34F6O2 ; C, 64.27; H, 6.79; F, 22.59. Found, C, 64.17; H, 6.81; F, 22.34.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)=[O:4].[NH2:15][C@@H:16]1[CH2:25][CH2:24][C:23]2[C:18](=[C:19]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)[CH:20]=[CH:21][CH:22]=2)[CH2:17]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:32][N:29]1[CH2:30][CH2:31][N:26]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[CH2:17][C@H:16]([NH:15][C:9](=[O:11])[C:8]2[CH:7]=[CH:6][C:5]([C:3]([N:2]([CH3:1])[CH3:14])=[O:4])=[CH:13][CH:12]=2)[CH2:25][CH2:24]3)[CH2:27][CH2:28]1
Reactant: CN(C)C(=O)c1ccc(C(=O)O)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(C(=O)N(C)C)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-(N,N-Dimethylaminocarbonyl)benzoic acid (100 mg, 0.54 mmol; described in: U.S. Pat. No. 3,607,918, 1971) was dissolved in thionyl chloride (5 mL). When the acid was dissolved, the excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. The crude acid chloride was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazine-1-yl)-1,2,3,4-tetrahydronaphthalene (120 mg, 0.49 mmol) and triethylamine (100 μL, 0.73 mmol) in methylene chloride (20 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with dilute aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using using chloroform/methanol/concentrated ammonium hydroxide (95:4:0.5) as the eluent. Yield: 160 mg (79%) of the title compound as white foam: [α]21D -30° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 420 (10, M+).
Reaction SMILES: C(NC1C=CC=CC=1C1CCC2C(=CC=C(OC)C=2)C1)C.Cl.N1(CCOC2C=CC(C(O)=O)=CC=2)CCCC1.[CH2:40]([N:42]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[CH:64]1[CH2:73][CH2:72][C:71]2[C:66](=[CH:67][CH:68]=[C:69]([O:74]C)[CH:70]=2)[CH2:65]1)[CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH2:51][CH2:52][N:53]2[CH2:57][CH2:56][CH2:55][CH2:54]2)=[CH:46][CH:45]=1)[CH3:41]>>[CH2:40]([N:42]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH2:51][CH2:52][N:53]2[CH2:57][CH2:56][CH2:55][CH2:54]2)=[CH:46][CH:45]=1)[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[CH:64]1[CH2:73][CH2:72][C:71]2[CH:70]=[C:69]([OH:74])[CH:68]=[CH:67][C:66]=2[CH2:65]1)[CH3:41]
Reactant: CCN(Cc1ccc(OCCN2CCCC2)cc1)c1ccccc1C1CCc2cc(OC)ccc2C1
Agent: CCNc1ccccc1C1CCc2cc(OC)ccc2C1
Agent: Cl
Agent: O=C(O)c1ccc(OCCN2CCCC2)cc1
Product: CCN(Cc1ccc(OCCN2CCCC2)cc1)c1ccccc1C1CCc2cc(O)ccc2C1
Yield: 70 %

Procedure:
Synthesized from ethyl[2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine and 4-(2-pyrrolidin-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, ethyl [2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl][4-(2-pyrrolidin-1-ylethoxy)benzyl]amine (446 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (303 mg).
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:23]=[CH:22][C:14]([O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#N.[N+:24](C1C=CC(N=NC2C=CC(O)=CC=2)=CC=1)([O-:26])=[O:25].BrCC(OCC)=O>>[N+:24]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:23]=[CH:22][C:14]([O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(N=Nc2ccc(O)cc2)cc1
Reactant: CCOC(=O)COc1ccc(N=Nc2ccc(C#N)cc2)cc1
Agent: CCOC(=O)CBr
Product: CCOC(=O)COc1ccc(N=Nc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
Ethyl 2-[4-(4-nitrophenylazo)phenoxy]-ethanoate was prepared in a manner similar to ethyl 2-[4-(4-cyanophenylazo)phenoxy]-ethanoate starting from 4-(4-nitrophenylazo)phenol and ethyl bromoacetate.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[CH:14]1[CH2:16][CH2:15]1)=[O:6].[H-].[Na+].CO>C1COCC1.C(Cl)(Cl)Cl>[CH:14]1([C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[N:7]2[CH2:2][CH2:3][NH:4][C:5]2=[O:6])[CH2:16][CH2:15]1
Reactant: O=C(NCCCl)Nc1cnccc1C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: C1CCOC1
Product: O=C1NCCN1c1cnccc1C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
1-(2-Chloroethyl)-3-(4-cyclopropylpyridin-3-yl)urea (I-1c: 200 mg, 0.836 mmol) in dry THF was added drop wise to a stirred mixture of NaH (40.16 mg, 1.67 mmol) in dry THF (5 mL) at 0° C. over a period of 10 minutes. The resulting mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC (10% methanol in CHCl3). The reaction mixture was quenched with methanol and concentrated to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3) afforded 140 mg of the product (94% yield).
Reaction SMILES: [CH3:1][C:2]1([C:15]([O:17]C)=O)[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][NH:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[CH3:19][NH2:20]>C(O)C>[CH3:1][C:2]1([C:15]([NH:20][CH3:19])=[O:17])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][NH:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: COC(=O)C1(C)NCCc2c1[nH]c1ccccc21
Reactant: CN
Solvent: CCO
Product: CNC(=O)C1(C)NCCc2c1[nH]c1ccccc21
Reaction time: 48 h

Procedure:
4.8 g (0.02 mol) of methyl 1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxylate are dissolved in 100 ml of ethanol saturated with methylamine. The solution is left at ambient temperature for 48 hours. The solvent is removed and the residue is then taken up in 20 ml of ethanol. The product is filtered off and washed with ethanol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:18]([O-])=O)=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C@H:13]([CH3:17])[C:14]([NH2:16])=[O:15])[CH:6]=[CH:5]2.C(O)C.[Cl-].[NH4+].O>[Fe].C(OC(=O)C)C>[NH2:18][C:3]1[C:2]([Cl:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]([C@H:13]([CH3:17])[C:14]([NH2:16])=[O:15])[C:8]2=[O:12]
Reactant: C[C@H](C(N)=O)n1ccc2c([N+](=O)[O-])c(Cl)ccc2c1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: C[C@H](C(N)=O)n1ccc2c(N)c(Cl)ccc2c1=O
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
A round bottom flask was charged with (R)-2-(6-chloro-5-nitro-1-oxoisoquinolin-2(1H)-yl)propanamide (120 mg, 0.00040 mol), ethanol (4 mL, 0.07 mol) and ammonium chloride (200 mg, 0.004 mol) in water (4 mL, 0.2 mol) was added and the reaction heated at 85° C. and iron (90 mg, 0.002 mol) was added in two portions 5 minutes apart. The reaction was stirred at that temperature for 30 minutes and ethylacetate was added and decanted. The solvent was removed to get the product as yellow solid. MS m/z=266.2 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:15]=[CH:14][N:13]([CH2:16][C:17]4[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=4)[N:12]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][C:38]=1[NH:52][S:53]([CH3:56])(=[O:55])=[O:54].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:21]1[CH:22]=[C:17]([CH:18]=[C:19]([F:24])[CH:20]=1)[CH2:16][N:13]1[CH:14]=[CH:15][C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:40]4[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[C:38]([NH:52][S:53]([CH3:56])(=[O:54])=[O:55])[CH:39]=4)[CH:3]=3)[N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:26])=[O:27])[CH:9]=2)=[N:12]1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccn(Cc4cc(F)cc(F)c4)n3)c3cc(Br)cnc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cnc3c(c2)c(-c2ccn(Cc4cc(F)cc(F)c4)n2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Yield: 37.7 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3,5-difluorobenzyl)-1H-pyrazol-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Intermediate 63) (100 mg, 0.184 mmol) was coupled with N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (Intermediate 17) (65 mg, 0.22 mmol) using sodium carbonate (58 mg, 0.552 mmol) and Pd(PPh3)4 (10 mg, 0.0092 mmol) in toluene/ethanol/water (2/2/1 ml) to afford 46 mg (37.7% yield) after purification by preparative TLC (silicagel-1000 micron) using 40% ethyl acetate in hexane as eluent. MS: m/z=664.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([S:25]([CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])(=[O:27])=[O:26])[C:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]3[S:22][CH:23]=[CH:24][C:13]=23)=[O:11])=[CH:5][CH:4]=1.O1CCN(CC[N+]#[C-])CC1.O[N:45]1[C:49](=[O:50])[CH2:48][CH2:47][C:46]1=[O:51]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([S:25]([CH2:28][CH2:29][CH2:30][C:31]([O:33][N:45]2[C:49](=[O:50])[CH2:48][CH2:47][C:46]2=[O:51])=[O:32])(=[O:26])=[O:27])[C:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]3[S:22][CH:23]=[CH:24][C:13]=23)=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(N(C(=O)c2c3ccccc3nc3sccc23)S(=O)(=O)CCCC(=O)O)cc1
Reactant: O=C1CCC(=O)N1O
Agent: [C-]#[N+]CCN1CCOCC1
Product: COc1ccc(N(C(=O)c2c3ccccc3nc3sccc23)S(=O)(=O)CCCC(=O)ON2C(=O)CCC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.5 %

Procedure:
A mixture of 66 mg (0.12 mmol) N-(4-Methoxy-phenyl)-N-(carboxypropyl-sulfonyl)-thieno[2,3-b]quinoline-4-carboxamide 17, 25 μl (0.17 mmol) 2-Morpholino-ethyl-isocyanide (MEI) and 21 mg (0.17 mmol) N-Hydroxysuccinimide (HOSu) was stirred overnight at room temperature. The solvent was removed under vacuum and the oily residue was purified by silica gel column chromatography (eluent: methylene chloride/acetone 9:1+0.1% acetic acid). The appropriate fractions were combined and evaporated to yield 75 mg of 18.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:11])[O:10][C:8](=[O:9])[CH2:7][CH2:6]1.[S:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1.Cl>C(Cl)Cl>[O:11]=[C:5]([C:13]1[S:12][CH:16]=[CH:15][CH:14]=1)[CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: O=C1CCC(=O)O1
Reactant: c1ccsc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(O)CCC(=O)c1cccs1
Temperature: 0 °C
Reaction time: 8 h
Yield: 37.5 %

Procedure:
Anhydrous aluminium chloride (15.8 g, 0.12 mol) was added to a solution of succinic anhydride (11.9 g, 0.12 mol) in dry CH2Cl2 (50 MI) and the reaction mixture was cooled to 0° C. A solution of thiophene (10.0 g, 0.12 mol) in CH2Cl2 (50 MI) was then added dropwise maintaining the same temperature. The reaction mixture was allowed to warm up to room temperature and stirred for 8 h. The mixture was then cooled to 0° C. and the Ph was adjusted to ˜3 using 6N HCl. The organic product was extracted with CH2Cl2. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 5-10% MeOH in CH2Cl2), to get 4-oxo-4-(thiophen-2-yl)butanoic acid (8.3 g, yield 38%). 1H NMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H), 8.00-7.98 (m, 2H), 7.26-7.23 (m, 1H), 3.21-3.18 (m, 2H), 2.58-2.55 (m, 2H). MS (ESI) m/z: Calculated for C8H8O3S: 184.02. found: 184.9 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[CH2:6][NH:7][CH2:8][CH2:9][CH2:10][OH:11])([O-:3])=[O:2].N1C=CN=C1.[C:21]([Si:25](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:24])([CH3:23])[CH3:22]>ClCCl>[Si:25]([O:11][CH2:10][CH2:9][CH2:8][NH:7][CH2:6][C:5]1[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=1[N+:1]([O-:3])=[O:2])([C:21]([CH3:24])([CH3:23])[CH3:22])([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1CNCCCO
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCCNCc1ccccc1[N+](=O)[O-])(c1ccccc1)c1ccccc1
Temperature: 23 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
A solution of 3-[(2-nitrobenzyl)amino]propan-1-ol (1.1 g, 5.0 mmol) in dichloromethane (50 mL) was treated with imidazole (0.68 g, 10 mmol) and tert-butylchlorodiphenylsilane (1.4 mL, 5.5 mmol) and stirred at 23° C. for 2 hours. The reaction mixture was quenched by the addition of H2O (50 mL) and 2 M aqueous NaOH (10 mL), and extracted with dichloromethane (2×50 mL), dried (Na2SO4), and evaporated. Flash chromatography (SiO2, 5-50% ethyl acetate/hexanes) provided 3-{[tert-butyl(diphenyl)silyl]oxy}-N-(2-nitrobenzyl) propan-1-amine (1.8 g, 80%) as a yellow oil:
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([N:12]3[CH:16]=[CH:15]C=N3)[N:9]=[CH:8]2)[CH:2]=1.[NH:23]1C=CN=[CH:24]1>>[C:1]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([N:12]3[CH:16]=[CH:15][N:23]=[CH:24]3)[N:9]=[CH:8]2)[CH:2]=1
Reactant: c1ccc(-c2cccc(-n3cnc(-n4cccn4)c3)c2)cc1
Reactant: c1c[nH]cn1
Product: c1ccc(-c2cccc(-n3cnc(-n4ccnc4)c3)c2)cc1
Yield: 60 %

Procedure:
The title compound was prepared by a method analogous to the synthesis of 1-(1-Biphenyl-3-yl-1H-imidazol-4-yl)-1H-pyrazole and using imidazole to give 60% yield. HRMS (ESI+): m/z=286.3366 [M+H]
Reaction SMILES: N([O-])=O.[Na+].[C:5]([N:8]1[C:17]2[C:12](=[CH:13][C:14](N)=[CH:15][CH:16]=2)[C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH3:19])[CH2:10][C:9]1([CH3:27])[CH3:26])(=[O:7])[CH3:6].S(=O)(=O)(O)O.[I-:33].[K+]>O.ClCCl>[C:5]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([I:33])=[CH:15][CH:16]=2)[C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH3:19])[CH2:10][C:9]1([CH3:27])[CH3:26])(=[O:7])[CH3:6]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1c2ccc(I)cc2C(C)(c2ccccc2)CC1(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A sodium nitrite solution (31 mg) was added dropwise to a cooled (0° C.) solution of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (128 mg) and sulfuric acid (82 mg) in water (2 ml). After stirring at 0° C. for 15 min, a potassium iodide solution (105 mg) was added. After stirring for 18 h, the reaction mixture was poured into dichloromethane. The organic layer was separated and washed with 5% aq. sodium thiosulfate and water, dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:5]([CH2:25][CH3:26])[CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[CH:13][C:14]([NH:18]C(=O)C(F)(F)F)=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[CH3:4]>CO>[CH2:25]([N:5]([CH2:3][CH3:4])[CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[CH:13][C:14]([NH2:18])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[CH3:26]
Reactant: CCN(CC)CCN1CCCc2cc(NC(=O)C(F)(F)F)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN(CC)CCN1CCCc2cc(N)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.1 mL 6 M aqueous NaOH solution was added to a solution of 0.75 g (2.184 mmol) of N-[1-(2-diethylamino-ethyl)-1,2,3,4-tetrahydro-quinolin-6-yl]-2,2,2-trifluoro-acetamide in 5 mL MeOH at 0° C. and the mixture was stirred for 15 minutes at 0° C. and for 1 hour at RT. The reaction mixture was evaporated down i. vac., sat. aqueous sodium bicarbonate solution was added and the mixture was exhaustively extracted with EtOAc. The combined org. extracts were dried over magnesium sulphate, evaporated down i. vac. and the residue was purified by column chromatography (silica gel, dichloromethane/MeOH/conc. aqueous ammonia 90:10:1).
Reaction SMILES: [C:1]1(=[O:7])[NH:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:10]([O:12][C:13](=[O:16])[CH2:14]Br)[CH3:11].O>CN(C)C=O.C(Cl)Cl>[O:7]=[C:1]1[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:14][C:13]([O:12][CH2:10][CH3:11])=[O:16]
Reactant: CCOC(=O)CBr
Reactant: O=C1CCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)CN1CCCCC1=O
Reaction time: 0.5 h

Procedure:
9.9 parts of δ-valerolactam (purchased from Aldrich Chemical Co., Milwaukee, Wisc. 53233) were dissolved in 100 part of dimethylformamide. To this solution was added 4.8 parts of a 50% dispersion of sodium hydride in mineral oil (purchased from Callgary Chemical Company, Callgary, Pa.). The reaction mixture was stirred for a period of 30 minutes. To the above reaction mixture 16.7 parts of ethylbromoacetate was added dropwise keeping the temperature less than 25° C during the addition. After the addition was completed, the reaction was stirred at room temperature for an additional 30 minutes. The reaction mass was poured into 200 parts of water. The product was isolated by extraction from the aqueous solution with three successive 200-part portions of methylene chloride. The combined organic extracts of the product were dried with anhydrous sodium sulfate. The solution of the product was filtered and the solvent was removed by evaporation at a reduced pressure of 50-300 mm on a rotary evaporator. The crude product obtained was further purified by vacuum distillation at 115° -120° C at 1.5 mm; 8.2 parts of product were obtained.