Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:19]3=[O:29])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:36][C:37]1[CH:42]=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][N:38]=1>O1CCOCC1.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>[CH3:36][C:37]1[N:38]=[CH:39][C:40]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16]([N:18]4[CH2:22][CH2:21][N:20]([CH:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)[C:19]4=[O:29])=[O:17])=[N:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)=[CH:41][CH:42]=1
Reactant: O=C(Nc1ccc(Oc2ccnc(Cl)c2)cn1)N1CCN(C2CCOCC2)C1=O
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2cc(Oc3ccc(NC(=O)N4CCN(C5CCOCC5)C4=O)nc3)ccn2)cn1
Temperature: 95 °C
Yield: 51.9 %

Procedure:
A mixture of Example C1 (0.200 g, 0.479 mmol), K2CO3 (0.132 g, 0.957 mmol) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.126 g, 0.574 mmol) in dioxane (8 mL) and water (2 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.055 g, 0.048 mmol), sparged again with Ar and heated at 95° C. overnight. The mixture was cooled to RT, treated with satd. NaHCO3 and extracted with EtOAc (4×). The combined organics were dried over Na2SO4, concentrated to dryness, suspended in MeCN and sonicated. The resulting solid was collected via filtration and dried to afford N-(5-((6′-methyl-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (118 mg, 52%). 1H NMR (400 MHz, DMSO-d6): δ 10.97 (s, 1 H), 9.09 (d, J=2.3 Hz, 1 H), 8.54 (d, J=5.7 Hz, 1 H), 8.29-8.24 (m, 2 H), 8.07 (d, J=9.0 Hz, 1 H), 7.75 (dd, J=9.0, 2.9 Hz, 1 H), 7.63 (d, J=2.4 Hz, 1 H), 7.33 (d, J=8.2 Hz, 1 H), 6.87 (dd, J=5.7, 2.4 Hz, 1 H), 3.92-3.77 (m, 5 H), 3.48-3.34 (m, 4 H), 2.50 (s, 3 H), 1.77-1.65 (m, 2 H), 1.62-1.55 (m, 2H); MS (ESI) m/z: 475.2 (M+H+).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]1[C:14]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:15]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH3:30])[CH:29]=2)[C:16]2[N:17]([C:19]([CH2:22][CH3:23])=[CH:20][CH:21]=2)[N:18]=1.O.NN>C(O)C>[NH2:3][CH2:12][C:13]1[C:14]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:15]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH3:30])[CH:29]=2)[C:16]2[N:17]([C:19]([CH2:22][CH3:23])=[CH:20][CH:21]=2)[N:18]=1
Reactant: CCOC(=O)CCCCc1c(CN2C(=O)c3ccccc3C2=O)nn2c(CC)ccc2c1-c1cncc(C)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCCCc1c(CN)nn2c(CC)ccc2c1-c1cncc(C)c1
Yield: 84 %

Procedure:
A mixture of ethyl 5-[2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (107 mg) and hydrazine monohydrate (51.1 mg) in ethanol (2 mL) was heated under reflux for 2 hours. After evaporation of solvent, the residue was partitioned between chloroform and saturated sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated in vacuo to give ethyl 5-[2-(aminomethyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate as yellow oil (67.6 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[N:30]=[CH:29][CH:28]=[CH:27]2>N1CCCNC1=O>[N:30]1[C:31]2[C:26](=[CH:25][CH:24]=[CH:23][C:22]=2[NH:21][CH2:12][C:10]([C:13]([F:16])([F:15])[F:14])([OH:11])[CH2:9][C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:19][CH3:20])([CH3:18])[CH3:17])[CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Reactant: Nc1cccc2cccnc12
Agent: O=C1NCCCN1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2cccnc12)C(F)(F)F
Yield: 77.5 %

Procedure:
200 mg (0.68 mmol) of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl)-2-(trifluoromethyl)oxirane (WO 00/32584) and 99 mg (0.68 mmol) of 8-aminoquinoline are heated in 0.2 ml of 3,4,5,6-tetrahydro-2-(1H)-pyrimidone (DMPU) for 20 hours to 130° C. After the reaction mixture is purified on silica gel with hexane-ethyl acetate (0-20%), 230 mg of the product is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18]C(C)(C)C)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O[CH2:27][CH:28]1[CH2:30][CH2:29]1>CCO.CCO.CCO.CCO.[Ti]>[Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:27][CH:28]3[CH2:30][CH2:29]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CC1
Reactant: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Agent: [Ti]
Solvent: CCO
Product: O=C(OCC1CC1)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Reaction time: 24 h

Procedure:
A mixture of 9.4 g (26.1 mmol) of tert.butyl (S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate, 30 g (416 mmol) of hydroxymethyl-cyclopropane and 1.4 g (6 mmol) of tetraethyl orthotitanate is stirred at 120° for 24 hours, a small amount of solvent being distilled off in vacuo three times. The mixture is subsequently evaporated in vacuo, the residue is taken up in 60 ml of chloroform, the chloroform solution is treated with 40 ml of water and stirred for 15 hours. The mixture is then filtered through siliceous earth while washing with chloroform, the chloroform phase is dried over magnesium sulphate and evaporated. The residue is chromatographed on silica gel while eluting with ethyl acetate. After recrystallization from ethyl acetate, there is obtained cyclopropylmethyl (S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate of melting point 193-194°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CN(C=O)C.CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCCCCCCBr
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 88.5 %

Procedure:
To a stirred solution of 4-bromo-4′-hydroxybiphenyl (5.05 g, 20.2 mmol) in DMF (100 ml) were added K2CO3 (4.20 g, 30.4 mmol) and 1 -bromoheptane (4.14 ml, 26.4 mmol), and then the mixture was heated at 80° C. After being stirred at 80° C. for 20 h, the mixture was cooled to room temperature. The mixture was diluted with Et2O (250 ml) and then the solution was washed with sat. brine (150 ml×2). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was recrystallized from CH2Cl2-petroleum ether to give 4-bromo-4′-heptyloxybiphenyl (6.21 g, 88%) as a white solid; FAB-MS: m/z 347[MH+].
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH2:38][CH3:39])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:41]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:42]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH2:38][CH3:39])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:41]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:42])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Reactant: CCCCCCOC(=O)Cl
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCCC)c4ccccc4)ccc3n2C)cc1
Yield: 31 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-n-propyloxycarbonylethyl)-amide-hydrochloride and n-hexyl chloroformate. Yield: 31% of theory, C36H44N6O5 (640.8) Rf value: 0.42 (silica gel; dichloromethane/ethanol=19:1) ##EQU69##
Reaction SMILES: C([N:8]1[CH:12]([CH:13]2[CH2:16][CH2:15][CH2:14]2)[CH2:11][C:10](=[O:17])[O:9]1)C1C=CC=CC=1.[H][H]>C(O)C.O[Pd]O>[NH2:8][CH:12]([CH:13]1[CH2:16][CH2:15][CH2:14]1)[CH2:11][C:10]([OH:17])=[O:9]
Reactant: O=C1CC(C2CCC2)N(Cc2ccccc2)O1
Reactant: [H][H]
Agent: O[Pd]O
Solvent: CCO
Product: NC(CC(=O)O)C1CCC1

Procedure:
Dihydroxypalladium (0.252 g, 1.794 mmol) was charged into a flask and flushed with nitrogen. Ethanol (30 mL) was added followed by a solution of 2-benzyl-3-cyclobutyl-isoxazolidin-5-one, 47a, (0.834 g, 3.605 mmol) in approximately 90 mL of ethanol. The reaction mixture was subjected to 50 psi of hydrogen for 4 hours. The pressure was vented and the catalyst was filtered off. All volatiles were removed at reduced pressure. 1H NMR shows the presence of starting material, 47a. The mixture was dissolved in approximately 100 mL of MeOH and added to 83 mg of 10% Pd/C that had been wet with 20 mL of MeOH. The mixture was subjected to 50 psi of H2 overnight. The pressure was vented and the catalyst was filtered off. All volatiles were removed at reduced pressure to afford 340 mg of product. The resulting crude residue was used without further purification: 1H NMR (400 MHz, d6-DMSO) δ 3.06-2.83 (m, 1H), 2.28 (ddd, J=23.7, 11.8, 7.7 Hz, 1H), 2.19-1.99 (m, 2H), 1.99-1.56 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13](Cl)(=[O:18])[CH2:14][C:15](Cl)=[O:16].[ClH:20]>C1COCC1>[Cl:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]([NH:1][C:13](=[O:18])[CH2:14][C:15]([NH:1][C:2]2[CH:7]=[C:6]([Cl:20])[C:5]([Cl:9])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])=[O:16])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: Cl
Reactant: O=C(Cl)CC(=O)Cl
Solvent: C1CCOC1
Product: O=C(CC(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-])Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
1-Amino-4,5-dichloro-2-nitrobenzene (113.84 g, 0.55 moles) was dissolved in THF (500 ml). Malonyl chloride (38.75 g, 0.27 moles) was added to the mixture heated to reflux. Another 500 ml portion of THF was added and refluxing was continued for two hours. HCl evolved during the reaction. The reaction mixture was then chilled in an ice bath, the solid was filtered off, washed with cold THF, and dried. A second yield was obtained by concentrating the filtrate, filtering off the solid, making a slurry of the solid in diethyl ether and filtering again. Yield 166.8 g (88%). Product was used as isolated for the next step in the sequence. Anal. Calcd. for C15H8Cl4N4O6 : C, 37.4; H, 1.7; Cl, 29.4; N, 11.6. Found: C, 37.4; H, 1.3; Cl, 29.4; N, 11.6
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7](O)=O.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:39][C:40]1[C:61]([NH2:62])=[CH:60][C:43]2[CH2:44][C@@H:45]3[C:50]([CH3:52])([CH3:51])[C@:49]([CH3:53])([C:42]=2[CH:41]=1)[CH2:48][CH2:47][N:46]3[C:54](=[O:59])[C:55]([F:58])([F:57])[F:56]>CN(C)C=O.CCOC(C)=O>[F:58][C:55]([F:56])([F:57])[C:54]([N:46]1[CH2:47][CH2:48][C@:49]2([CH3:53])[C:50]([CH3:52])([CH3:51])[C@H:45]1[CH2:44][C:43]1[CH:60]=[C:61]3[N:62]=[C:7]([C:2]4[CH:3]=[N:4][CH:5]=[CH:6][N:1]=4)[NH:39][C:40]3=[CH:41][C:42]=12)=[O:59]
Reactant: O=C(O)c1cnccn1
Reactant: CC1(C)[C@H]2Cc3cc(N)c(N)cc3[C@]1(C)CCN2C(=O)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1(C)[C@H]2Cc3cc4nc(-c5cnccn5)[nH]c4cc3[C@]1(C)CCN2C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of pyrazine-2-carboxylic acid (152 mg), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (397 mg), and triethylamine (0.5 mL) in dimethylformamide (5 mL) is stirred at room temperature for 30 min, before 1-[(2R,6S)-8,9-diamino-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone (300 mg) is added. The solution is stirred at room temperature overnight. Then, the solution is diluted with EtOAc and washed with water and 2 M aqueous K2CO3 solution and dried (MgSO4). The solvent is removed under reduced pressure and the residue is taken up in acetic acid (5 mL). The resulting solution is heated at 80° C. overnight. Then, the solvent is removed under reduced pressure and the residue is evaporated twice with toluene to give the crude title compound that is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:14](=O)([O-])[O-].[K+].[K+].[CH2:20]1[O:28][C:27]2[CH:26]=[CH:25][C:24]([N:29]=[C:30]=[S:31])=[CH:23][C:22]=2[O:21]1.CI.Cl>CC(C)=O>[O:28]1[C:27]2[CH:26]=[CH:25][C:24]([NH:29][C:30]([S:31][CH3:14])=[C:11]([S:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)(=[O:9])=[O:10])[C:12]#[N:13])=[CH:23][C:22]=2[O:21][CH2:20]1
Reactant: S=C=Nc1ccc2c(c1)OCO2
Reactant: O=C([O-])[O-]
Reactant: N#CCS(=O)(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CSC(Nc1ccc2c(c1)OCO2)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59 %

Procedure:
To a solution of 4-chlorophenylsulfonylacetonitrile (1.00 g, 4.64 mmol) in dry acetone (10 ml) first dry potassium carbonate (1.28 g, 9.3 mmol) and then 3,4-methylenedioxyphenyl isothiocyanate (0.87 g, 4.9 mmol) were added. The resulting mixture was stirred at room temperature under nitrogen for 4 h, and then filtered. To the filtrate methyl iodide (0.86 ml, 13.9 mmol) was added. The mixture was stirred at room temperature for 50 min. Then pH was adjusted to 1 with 1N aqueous HCl. The precipitate was filtered off and washed with water to give 1.12 g (59%) of the title compound. Mp 196-200° C. 1H NMR (200 MHz, CDCl3): δ=2.22 (s, 3H), 6.05 (s, 2H), 6.68 (m, 2H), 6.80 (d, 1H), 7.53 (d, 2H), 7.87 (d, 2H), 9.80 (br s, 1H); EI SP/MS: 408 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2].[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[C:29]([CH2:31][N+](C)(C)C)[CH:30]=1)[N:27]([CH3:36])[CH:26]=[CH:25]2.[I-].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:31][C:29]2[CH:30]=[C:22]([Br:21])[CH:23]=[C:24]3[C:28]=2[N:27]([CH3:36])[CH:26]=[CH:25]3)[C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCCC(CC(=O)OCC)n1c(=O)[nH]c2ccccc21
Reactant: Cn1ccc2cc(Br)cc(C[N+](C)(C)C)c21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(CC(=O)OCC)n1c(=O)n(Cc2cc(Br)cc3ccn(C)c23)c2ccccc21
Yield: 55 %

Procedure:
To a solution of 3-(2-Oxo-2,3-dihydro-benzimidazol-1-yl)-hexanoic acid ethyl ester (50 mg, 0.18 mmol) in DMF (10 mL) were added (5-Bromo-1-methyl-1H-indol-7-ylmethyl)-trimethyl-ammonium; iodide (111 mg, 0.27 mmol) and K2CO3 (75 mg, 0.54 mmol) at room temperature under nitrogen atmosphere. The solution was heated to 100 C for 2 hours. The solution was cooled down and water was added. The solution was extracted with EtOAc and the combined organic layer was dried with MgSO4. The solution was filtered and the filtrate was concentrated. The residue was purified by CombiFlash with 20% EtOAc in Hexane as the eluent to afford the desirable product 3-[3-(5-Bromo-1-methyl-1H-indol-7-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester (50 mg, 55%) as a colorless foam.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11](Cl)[C:10]=1[N+:18]([O-:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH2:30]([NH:33][CH2:34][CH:35]=[CH2:36])[CH:31]=[CH2:32]>C(OC(O)C)C>[CH2:30]([N:33]([CH2:34][CH:35]=[CH2:36])[C:11]1[C:10]([N+:18]([O-:20])=[O:19])=[C:9]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=1)[CH:31]=[CH2:32]
Reactant: C=CCNCC=C
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCc2ccccc2)c1C
Agent: CCOC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN(CC=C)c1nc(C)c(C)c(NCc2ccccc2)c1[N+](=O)[O-]
Temperature: 100 °C
Yield: 64.9 %

Procedure:
Benzyl-(2-chloro-5,6-dimethyl-3-nitro-pyridin-4-yl)-amine (1.2 g, 4.1 mmol) was dissolved in ethoxyethanol (60 mL) and diisopropylethylamine (1.1 mL, 6.2 mmol) and diallylamine (0.76 mL, 6.2 mmol) added in one portion. The reaction mixture was heated in a sealed vessel at 100° C. overnight, and then concentrated in vacuo to an orange residue. This residue was purified directly by column chromatography on silica gel, using a gradient of 8:1→1:1 pentane:EtOAc as eluant to provide the title compound as a bright orange oil (938 mg, 65%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([CH3:21])[NH:13][C:12]2[CH2:22][O:23][C:24](=[O:25])[C:11]1=2)([O-])=O>O1CCCC1.[Ni]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([CH3:21])[NH:13][C:12]2[CH2:22][O:23][C:24](=[O:25])[C:11]1=2
Reactant: CCOC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1ccccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1ccccc1N
Reaction time: 1.5 h
Yield: 56 %

Procedure:
58 mmol of ethyl 4-(2-nitrophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate are dissolved in 200 ml of tetrahydrofuran, and 2 g of Raney nickel are added. Hydrogenation is carried out under a pressure of 50 bar of H2 for 1.5 h. The solution is evaporated, and dilute hydrochloric acid is added and the product is filtered off with suction and dried. Yield: 56% of theory
Reaction SMILES: Br[CH:2]([C:6](=O)[CH3:7])[C:3](=[O:5])[CH3:4].[NH2:9][C:10]([NH2:12])=[O:11].C([O-])(O)=O.[Na+].[Na+].[Cl-]>CC(C)=O.O.CCOC(C)=O>[NH2:12][C:10]1[O:11][C:2]([C:3](=[O:5])[CH3:4])=[C:6]([CH3:7])[N:9]=1
Reactant: NC(N)=O
Reactant: CC(=O)C(Br)C(C)=O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)c1oc(N)nc1C
Temperature: 100 °C
Yield: 57.9 %

Procedure:
3-Bromo-2,4-pentandione (P8) (26.66 g, 148.93 mmol) obtained in Step I as described above, is dissolved in acetone (87 mL). This mixture is added to a solution of urea (22.36 g, 372 mmol, 2.5 eq) in water (20 mL). The resulting mixture is heated in order to obtain a clear solution and is distributed into 38 microwave tubes (3 ml each). The vials are heated to 100° C. for 1200 s each in the microwave oven. All vials are combined, NaHCO3 sat (100 ml) and EtOAc (100 ml) are added, the aqueous phase is saturated with NaCl and the phases are separated. The aqueous phase is extracted with EtOAc (4 times 100 ml). Combined organic layers are dried over MgSO4, filtrated and evaporated under reduced pressure to give 1-(2-amino-4-methyl-1,3-oxazol-5-yl)ethanone (P5) as an orange solid (12.09 g). It is further recrystallized in MeOH, affording a brownish solid (5.56 g, 27%). 1H NMR (DMSO-d6) δ: 2.22 (s, 3H), 2.25 (s, 3H), 7.51 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5](Cl)=[O:6].[NH2:12][CH2:13][C:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][C:19]([Cl:25])=[CH:20][CH:21]=2)[N:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:25][C:19]1[CH:18]=[C:17]2[C:22]([C:23](=[O:24])[C:14]([CH2:13][NH:12][C:5](=[O:6])[C:4]3[CH:3]=[C:2]([F:1])[CH:10]=[C:9]([F:11])[CH:8]=3)=[CH:15][N:16]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cc(F)cc(F)c1
Temperature: 25 °C

Procedure:
A 10 mL round bottom flask was charged with 3,5-difluorobenzoyl chloride (78.0 mg, 0.442 mmol) and anhydrous methylene chloride (5 mL) and was treated with 3-(aminomethyl)-7-chloro-1-phenylquinolin-4(1H)-one (intermediate D) (49.8 mg, 0.175 mmol), triethylamine (87.1 mg, 0.12 mL, 0.861 mmol), and catalytic N,N-(dimethylamino)pyridine (DMAP) (one spatula tip). The flask was capped with a glass stopper and the reaction stirred at room temperature over the weekend. The reaction was partitioned between methylene chloride (25 mL) and water (25 mL). The organic portions were dried over magnesium sulfate, filtered and rinsed with methylene chloride, concentrated on a rotary evaporator, and briefly dried on a vacuum pump. The material was then purified via Analogix Intelliflash 280 chromatography using a 12 g silica gel column and a 1%-5% MeOH/CH2Cl2 gradient elution. Two columns were required to isolate the desired product from the bis-acylation side product. Fractions containing the two products were separately combined and concentrated. The second product to elute was the desired product N-(7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-3,5-difluoro-benzamide, isolated as an off-white solid (44 mg, 60%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.91 (t, J=5.14 Hz, 1H) 8.27 (d, J=8.66 Hz, 1H) 8.03 (s, 1H) 7.38-7.73 (m, 9H) 6.90 (d, J=1.81 Hz, 1H) 4.37 (d, J=5.24 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1/[C:11](/[NH:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12]/[C:13]([O:15]C)=O.C[Si]([N:28]=[C:29]=[S:30])(C)C.CCCCCCC.CCOC(C)=O>CC1CCCO1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:17]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:29](=[S:30])[NH:28][C:13](=[O:15])[CH:12]=1
Reactant: CCOC(=O)CN/C(=C\C(=O)OC)c1ccc(OC)cc1OC
Reactant: C[Si](C)(C)N=C=S
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Product: CCOC(=O)Cn1c(-c2ccc(OC)cc2OC)cc(=O)[nH]c1=S
Temperature: 110 °C
Reaction time: 1 h

Procedure:
To a solution of (Z)-methyl 3-(2,4-dimethoxyphenyl)-3-((2-ethoxy-2-oxoethyl)amino)acrylate (4.68 g, 15.1 mmol) in 2-methyltetrahydrofuran (38 mL) was added (trimethylsilyl)isothiocyanate (12.9 mL, 90.8 mmol). The resulting solution was purged with nitrogen gas for 3 times, and the mixture was heated at 110° C. for 18 hours. The mixture was cooled down to room temperature and the solvent was removed under reduced pressure to give a red solid. This residue was suspended in a mixture of 3:1 heptane/EtOAc (200 mL), and it was stirred at room temperature for 1 hour. The solid was filtered, and triturated with CH2Cl2 (100 mL), concentrated under reduced pressure and dried under vacuum the title compound (4.42 g, 87%) as a pink solid. This material was used without further purification in the next step.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[NH2:8][CH:9]1[CH:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]2[CH:16]=[C:15]([CH2:26][NH:27][S:28]([CH2:31][CH2:32][CH3:33])(=[O:30])=[O:29])[CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10]1.C(Cl)(=O)C.C(N(C(C)C)C(C)C)C>ClCCl>[CH2:19]([CH:18]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:26][NH:27][S:28]([CH2:31][CH2:32][CH3:33])(=[O:30])=[O:29])[CH:16]=2)[CH2:11][CH2:10][CH:9]1[NH:8][C:3](=[O:5])[CH3:2])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CCCS(=O)(=O)NCc1ccc2c(c1)C(Cc1ccccc1)C(N)CC2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)Cl
Product: CCCS(=O)(=O)NCc1ccc2c(c1)C(Cc1ccccc1)C(NC(C)=O)CC2

Procedure:
N-{[7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}propane-1-sulfonamide (cf. example 42) was acetylated in dichloromethane with acetyl chloride in the presence of ethyldiisopropylamine at room temperature.