Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCC)(=O)C.Cl.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:23][C:24]3[CH:43]=[CH:42][C:27]([CH2:28][CH:29]4[CH2:34][CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]4)=[CH:26][CH:25]=3)=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1>>[ClH:8].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][C:24]3[CH:43]=[CH:42][C:27]([CH2:28][CH:29]4[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]4)=[CH:26][CH:25]=3)=[O:22])=[CH:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(Cc2ccc(NC(=O)c3ccc(-c4ccc(Cl)cc4)cc3)cc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(CC2CCCNC2)cc1)c1ccc(-c2ccc(Cl)cc2)cc1
Yield: 111.8 %

Procedure:
4N Hydrogen chloride-ethyl acetate (3 ml) was added to tert-butyl 3-[4-[[(4′-chloro[1,1′-biphenyl]-4-yl)carbonyl]amino]benzyl]-1-piperidinecarboxylate (150 mg, 0.297 mmol)obtained in Reference Example 82. Two hours later, the solvent was distilled out under reduced pressure. Diisopropyl ether was added to the residue, to give the titled compound (73.3 mg) as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:14]([OH:16])=O)=[CH:7][N:8]2[CH2:11][C:12]#[N:13])=[CH:4][CH:3]=1.OC1C2N=NNC=2C=CC=1.ClCCl.[CH3:30][NH:31][CH3:32]>CN(C=O)C>[CH3:30][N:31]([CH3:32])[C:14]([C:6]1[C:5]2[C:9](=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2)[N:8]([CH2:11][C:12]#[N:13])[CH:7]=1)=[O:16]
Reactant: N#CCn1cc(C(=O)O)c2ccc(Br)cc21
Reactant: CNC
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cn(CC#N)c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a reaction tube was added 26 mg (94 micromol) of 6-bromo-1-cyanomethyl-1H-indole-3-carboxylic acid, 138 mg (approximately 186 micromol of carbodiimide functionality) of polystyrene carbodiimide resin (Argonaut Technologies, Foster City Calif., Product No. 800371), 21.3 mg (158 micromol) of HOBT (hydroxybenzotriazole), 1.5 mL dichloromethane, and 3 drops of DMF. The tube was capped, swirled and allowed to shake on a mechanical shaker for 1 hour at room temperature. The cap was removed, and dimethylamine (1 equivalent, 78 micromol) was added to the tube. The tube was re-capped and shaken for 24 hours at room temperature. 200 microliters of DMF was then added to the tube, and the tube was re-capped and shaken for an additional 48 hours, after which 130 mg (230 micromol) of polystyrene isocyanate resin (Argonaut Technologies, Foster City Calif., Product No. 800260) was added, followed by 1 hour of shaking, to remove excess dimethylamine. The content of the tube was filtered through a Varian liquid extraction tube (pre-washed with 20 microliters of saturated sodium bicarbonate solution), and washed 3× with 1 mL dichloromethane. The combined organic fractions were evaporated under reduced pressure to yield 6-Bromo-1-cyanomethyl-1H-indole-3-carboxylic acid dimethylamide as an oil. Step 4
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].O>C1COCC1>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][NH2:12])=[CH:13][CH:14]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(N2CCOCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Yield: 22.5 %

Procedure:
The product from Example 66A (1.24 g, 6.6 mmol) in THF (25 mL) was treated with LiAlH4 (2.5 g, 65.9 mmol) at 0° C. The mixture was allowed to warm to room temperature and then refluxed for 1 hour. The mixture was allowed to cool to room temperature and then treated with 1N NaOH carefully followed by water. The mixture was concentrated under reduced pressure and the resulting aqueous mixture was extracted with diethyl ether. The organic extracts were combined, washed with saturated NaHCO3 solution, dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to provide the title compound as a yellow oil (286 mg, 23%).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=CC=CC=3)[C:12]2=[O:21])[S:2]1.C1(=O)OC(=[O:26])CC1>C1(C)C=CC=CC=1.CO.C(N)CCC.N1C=CC=CC=1>[S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:19](=[O:20])[CH2:18][CH2:13][C:12]([OH:21])=[O:26])[S:2]1
Reactant: O=C1CCC(=O)O1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCC1CCSS1
Solvent: CCCCN
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(O)CCC(=O)NCCCCCC1CCSS1
Yield: 38 %

Procedure:
The reaction was effected as described in Example 61, but using a solution of 1.5 mmol of 2-[5-(1,2-dithiolan-3-yl)pentyl]isoindole-1,3-dione in 3 ml of toluene, 2 ml of methanol, 2 ml of butylamine, 4 ml of pyridine and 230 mg of succinic anhydride. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure and the residue was subjected to reverse phase preparative silica gel column chromatography, using 2:3, 1:1 and 3:2 by volume mixtures of acetonitrile and water as eluent. Acetonitrile was removed from the eluate so obtained by distillation under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilised, to give 166 mg of the title compound as a pale yellow amorphous substance, melting at 74° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][NH:19]C(=O)OC(C)(C)C)[CH2:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl>O1CCOCC1>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][NH2:19])[CH2:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)NCCCN1CC=C(c2cccc([N+](=O)[O-])c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NCCCN1CC=C(c2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
Into a stirred solution of 4.35 (12.0 mmol) of tert-butyl 3-(4-(3-nitrophenyl)-3,6-dihydro-1(2H)-pyridinyl)propylcarbamate in 100 ml of 1,4-dioxane at 0° C. was bubbled HCl gas for 10 minutes. The reaction mixture was allowed to warm to room temperature and the bubbling was continued for an additional 1 hour. The solvent was removed in vacuo, the residue was dissolved in 50 mL of water and was neutralized by the addition of KOH pellets. The aqueous solution was extracted with 3×80 mL of dichloromethane, the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 9:1, dichloromethane:methanol+1% isopropyl amine) to afford 3.05 g (97.0% yield) of the desired product: 1H NMR (400 MHz, CDCl3) δ 8.24 (t, 1H, J=1.8 Hz), 8.09 (dd, 1H, J=1.8, 8.2 Hz), 7.69 (dd, 1H, J=1.8, 8.2 Hz), 7.48 (t, 1H, J=8.2 Hz), 6.24 (m, 1H), 3.21 (d, 2H, J=3.6 Hz), 2.84 (t, 2H, J=6.6 Hz), 2.75 (t, 2H, J=5.8 Hz), 2.64-2.54 (m, 4H), 1.76 (m, 2H); ESMS m/e: 262.2 (M+H)+; Anal. Calc. for C14H19N3O2 (0.06 CHCl3): C, 62.90; H, 7.16; N, 15.65. Found: C, 63.20; H, 7.16; N, 15.65.
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[C:16]1([CH2:22][O:23][C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[C:30](=[O:34])[CH2:29][CH2:28][CH2:27]3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCOCC1>[OH:34][C:30]1[C:31]2[C:26](=[CH:25][C:24]([O:23][CH2:22][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:33][CH:32]=2)[CH:27]=[CH:28][C:29]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1
Reactant: COc1ccc(Br)cc1
Reactant: O=C1CCCc2cc(OCc3ccccc3)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc3cc(OCc4ccccc4)ccc3c2O)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
Twelve liters of 1,4-dioxane were vacuum degassed and then combined with sodium tert-butoxide (1523 g, 15.84 mol), 4-bromoanisole (1845 g, 9.86 mol) and 3,4-dihydro-6-(phenylmethoxy)-1(2H)-naphthalenone (1002 g, 3.97 mol). The resulting red slurry was again degassed by pulling vacuum and purging the system with nitrogen. Palladium acetate (8.90 g, 0.0396 mol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (25.9 g, 0.0416 mol) were added and the mixture was heated to 70° C. After 2.5 hours the temperature was increased to 100° C. and this temperature was maintained for an additional 5 hours. The mixture was allowed to cool to ambient temperature before quenching with 6 liters of 3 M HCl. The layers were allowed to separate and the aqueous phase was extracted with 2 liters of ethyl acetate. The organic phases were combined and dried with 500 g of sodium sulfate then concentrated to a red solid. The solid was combined with 4 liters of toluene and stirred at 60° C. for 1 hour then cooled to ambient temperature. The solids were collected by filtration, washed with toluene and dried in vacuo to provide 564 g (40%) of the title compound. H1 NMR (CDCl3, 500 MHz) 8.20 (d, J=9.1 Hz, 1H), 7.50 (d, J=7.3 Hz, 2H), 7.44 (d, J=8.7 Hz, 2H), 7.42 (t, J=7.3 Hz, 2H), 7.35 (m, 2H), 7.29 (d, J=8.5 Hz, 1H), 7.25 (dd, J=2.5, 9.1 Hz, 1H), 7.20 (d, J=2.5, 1H), 7.07 (d, J=8.7 Hz, 2H), 5.75 (s, 1H), 5.20 (s, 2H), 3.88 (s, 3H).
Reaction SMILES: C([Li])CCC.Cl[C:7]1[N:11]([C:12]2[CH:13]=[C:14]3[C:19](=[C:20]([CH3:22])[CH:21]=2)[NH:18][C:17](=[O:23])[CH:16]=[CH:15]3)[C:10]([CH3:24])=[N:9][C:8]=1[C:25]#[N:26].[Cl-].[NH4+].O>CCCCCC.O1CCCC1.C(OCC)(=O)C.CO>[C:25]([C:8]1[N:9]=[C:10]([CH3:24])[N:11]([C:12]2[CH:13]=[C:14]3[C:19](=[C:20]([CH3:22])[CH:21]=2)[NH:18][C:17](=[O:23])[CH:16]=[CH:15]3)[CH:7]=1)#[N:26]
Reactant: Cc1cc(-n2c(C)nc(C#N)c2Cl)cc2ccc(=O)[nH]c12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: Cc1cc(-n2cc(C#N)nc2C)cc2ccc(=O)[nH]c12
Temperature: 25 °C
Yield: 22.5 %

Procedure:
n-Butyllithium (17.5 cm3 of a 1.5M solution in n-hexane) was added dropwise to a stirred solution of 6-(5-chloro-4-cyano-2-methylimidazol-1-yl)-8-methyl-2-(1H)-quinolone (3.57 g) in tetrahydrofuran (THF) (100 cm3) at -70° under nitrogen. After 15 minutes saturated aqueous ammonium chloride solution (20 cm3) was added and the mixture was warmed to room temperature over 1 hour. The mixture was then poured into water (50 cm3), extracted with ethyl acetate (4×150 cm3), and the combined and dried (MgSO4) organic extracts were evaporated in vacuo to give a residue which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]). Elution with methanol:dichloromethane, 1:19 by volume, followed by combination and evaporation of the appropriate fractions, gave a solid which was boiled with ethyl acetate/methanol, then filtered and dried to afford the title compound, (0.71 g), which was shown spectroscopically to be identical to the product of Preparation 2.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[Na+:12].C(O)C>O>[CH3:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O-:10])=[O:9].[Na+:12]
Reactant: CCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCC(=O)[O-]

Procedure:
The sodium octoate was prepared by stirring 3.60 g of octanoic acid in 3 g of water and neutralizing with 2.00 g of aqueous sodium hydroxide (50%). 5 g of water was used for dilution and rinse. A waxy solid formed which was dissolved by adding about 10 ml of ethanol. pH paper indicated a pH of about 8. The total solution was evaporated on a watch glass on a steam bath under a flow of nitrogen to give 4.04 g white solid. The solid was titrated in ethanol with aqueous HCl: the titer was 5.88 mmol/g. Estimated purity was 97.6%.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([CH2:7][NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[CH2:24]([O:26][C@H:27]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:28][C:29]1[CH:39]=[CH:38][C:32]([O:33][CH2:34][C:35](O)=[O:36])=[CH:31][CH:30]=1)[CH3:25].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[F:1][C:2]([F:22])([F:23])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=2)[C:35](=[O:36])[CH2:34][O:33][C:32]2[CH:31]=[CH:30][C:29]([CH2:28][C@H:27]([O:26][CH2:24][CH3:25])[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:39][CH:38]=2)=[CH:20][CH:21]=1
Reactant: FC(F)(F)c1ccc(CNCc2ccc(C(F)(F)F)cc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](Cc1ccc(OCC(=O)N(Cc2ccc(C(F)(F)F)cc2)Cc2ccc(C(F)(F)F)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.4 %

Procedure:
To a solution of N,N-bis[4-(trifluoromethyl)benzyl]amine (0.733 g, 2.20 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.593 g, 2.00 mmol) in methylene chloride (20 mL) were added N,N-diisopropylethylamine (0.80 mL, 4.6 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.674 g, 2.10 mmol) and the reaction mixture was stirred at room temperature for 4 h. The resulting solution was diluted with methylene chloride (130 mL) and the organic phase was washed with 5% HCl (3×75 mL), saturated aqueous NaHCO3 (2×75 mL), and brine (75 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 70 g/150 mL) with methanol (0-1% gradient) in methylene chloride as the eluent yielded 0.91 g (74%) of a whitish oil.
Reaction SMILES: [C:1]([C:3]1[C:4]([S:44][CH3:45])=[N:5][C:6]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)=[C:7]([C:31]([O:33]CC)=O)[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH:11][C:10]=1[N+:28]([O-])=O)#[N:2]>C(O)(=O)C.[Fe]>[C:1]([C:3]1[C:4]([S:44][CH3:45])=[N:5][C:6]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)=[C:7]2[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:17][CH2:16]3)=[CH:11][C:10]=1[NH:28][C:31]2=[O:33])#[N:2]
Reactant: CCOC(=O)c1c(-c2ccc(OC)cc2)nc(SC)c(C#N)c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1ccc(-c2nc(SC)c(C#N)c3c2c(=O)[nH]c2cc(N4CCN(C(=O)OC(C)(C)C)CC4)ccc23)cc1
Reaction time: 4 h
Yield: 66.5 %

Procedure:
0.48 g (8.6 mmol) of iron is added to a solution of 1 g (1.7 mmol) of tert-butyl 4-(4-(3-cyano-5-(ethoxycarbonyl)-6-(4-methoxyphenyl)-2-(methylthio)pyridin-4-yl)-3-nitrophenyl)piperazine-1-carboxylate dissolved in 8.82 ml of acetic acid. The reaction medium is carried at 90° C. for 4 hours. The precipitate obtained is filtered on Dicalite and then rinsed with a 98:2 dichloroethane/methanol mixture. The filtrate is concentrated to yield 0.63 g (66%) of tert-butyl 4-(1-cyano-4-(4-methoxyphenyl)-2-(methylthio)-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)piperazine-1-carboxylate in the form of a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[CH:5]=[C:6]1[NH:10][C:9](=[O:11])[NH:8][C:7]1=[O:12]>[OH-].[Na+].[Ni]>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[CH2:5][CH:6]1[NH:10][C:9](=[O:11])[NH:8][C:7]1=[O:12]
Reactant: COc1ccccc1C=C1NC(=O)NC1=O
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Product: COc1ccccc1CC1NC(=O)NC1=O
Yield: 79 %

Procedure:
218.2 g (1 mole) of 5-(2-methoxy-benzylidene)-hydantoin are dissolved in 2 l of a N sodium hydroxide solution and 70 g of wet Raney-nickel are added. The reaction mixture is worked up according to Example 6. Thus 174 g of the desired compound are obtained, yield 79%. Mp.: 186° C.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.[C:22]1([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH:34]=[O:35])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[C:22]1([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH:34]([C:21]2[N:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[OH:35])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=CCCCCCCc1ccccc1
Reactant: c1ccnnc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(CCCCCCc1ccccc1)c1cccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 22.1 %

Procedure:
2,2,6,6-Tetramethylpiperidine (1.54 mL) was dissolved in anhydrous THF (60 mL) and treated dropwise with 2.0 M n-BuLi (4 equiv) at −40° C. The reaction mixture was stirred at 0° C. for 0.5 h, cooled to −78° C. and treated with a solution of pyridazine (165 μL, 2.26 mmol) in THF (4 mL) immediately followed by a solution of 7-phenylheptanal (435 mg, 2.29 mmol) in THF (2 mL). The reaction mixture was stirred at −78° C. for 1 h before being quenched by the addition of 1 N HCl/EtOH/THF (2/9/9, 40 mL). The reaction mixture was diluted with EtOAc, and washed with H2O, saturated aqueous NaHCO3 and saturated aqueous NaCl. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. Flash chromatography (SiO2, 3×15 cm, 1% MeOH—CH2Cl2) afforded the alcohol (135 mg, 22%) as colorless oil: 1H NMR (CDCl3, 500 MHz) δ 9.12 (dd, 1H, J=1.8, 4.7 Hz), 7.49 (m, 2H), 7.26 (m, 2H), 7.17 (m, 3H), 4.97 (td, 1H, J=4.9, 8.0 Hz), 3.60 (d, 1H(—OH), J=5.4 Hz), 2.58 (t, 2H, J=7.7 Hz), 1.88 (m, 1H), 1.77 (m, 1H), 1.43 (m, 2H), 1.34 (m, 6H).
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:9][C@H:10]1[CH:14]=[CH:13][C@H:12]([CH3:15])[NH:11]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:9][C@H:10]1[CH:14]=[CH:13][C@H:12]([CH3:15])[N:11]1[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)Br
Reactant: C[C@H]1C=C[C@H](C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)N1[C@@H](C)C=C[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.6 %

Procedure:
Ethyl 2-bromopropionate (9.8 g.) was added, dropwise, to a stirred mixture of trans-2,5-dimethyl-3-pyrroline (5 g.), potassium carbonate (6.9 g.), and dimethylformamide (12.5 cm3) maintained below 30° C. by external cooling. After addition was complete the mixture was stirred at room temperature overnight. The mixture was then diluted with water (25 cm3) and the product extracted into ether. The ether extract was dried and evaporated to give an oil which was distilled under vacuum to give ethyl 2-(trans-2,5-dimethyl-2,5-dihydro-1H-pyrrol-1-yl)propionate (2.5 g.) b.p. 90°-97° C./15 mm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[OH:15][CH2:16][CH2:17][CH2:18][C:19](=O)[CH3:20]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:19]([CH3:20])[CH2:18][CH2:17][CH2:16][OH:15])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Reactant: CC(=O)CCCO
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCCO

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 5-hydroxy-pentan-2-one.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[Si]([O:29][CH2:30][CH:31]1[CH:35]([CH2:36][O:37][Si](C(C)(C)C)(C)C)[CH2:34][C:33]([CH2:45]Br)=[CH:32]1)(C(C)(C)C)(C)C>>[OH:29][CH2:30][CH:31]1[CH:35]([CH2:36][OH:37])[CH2:34][C:33]([CH2:45][N:8]2[C:9]([C:10](=[O:19])[C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]2=[O:20])=[CH:32]1
Reactant: CC(C)(C)[Si](C)(C)OCC1C=C(CBr)CC1CO[Si](C)(C)C(C)(C)C
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2CC2=CC(CO)C(CO)C2)c1
Yield: 26.3 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and [3,4-di(t-butyldimethylsilyloxymethyl)cyclopent-1-en-1-yl]methyl bromide were reacted by the same method with example 28 to obtain the titled compound (74 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.[CH2:31]([NH:34][C:35]([NH2:37])=[O:36])[C:32]#[CH:33].C(Cl)Cl>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CCN(CC)CC.CCO>[NH2:37][C:35]([NH:34][CH2:31][C:32]1[N:12]2[C:13]3[C:18]([C:19](=[O:20])[C:10]([C:8]([NH:7][CH2:6][C:5]4[CH:29]=[CH:30][C:2]([Cl:1])=[CH:3][CH:4]=4)=[O:9])=[CH:11]2)=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3[CH:33]=1)=[O:36]
Reactant: C#CCNC(N)=O
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CN3CCOCC3)cc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)NCc1cc2cc(CN3CCOCC3)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn1c23
Temperature: 25 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (300 mg), PdCl2(PPh3)2 (19.7 mg), CuI (5.3 mg), Et3N (10.4 mL), and prop-2-ynylurea (60.3 mg) is stirred at room temperature overnight. Distilled CH2Cl2 (10.4 mL) and additional PdCl2(PPh3)2 (19.7 mg) and CuI (5.3 mg) are added. The reaction is stirred at room temperature overnight. The reaction mixture is condensed, adsorbed onto silica, and chromatographed eluting with 2% MeOH in CH2Cl2 to 6.5% MeOH in CH2Cl2. Product containing fractions are combined and condensed to afford a mixture of cyclized and uncyclized materials. To a scintillation vial is added the mixture, EtOH (4 mL), Et3N (0.1 mL), and CuI (˜1 mg). The suspension is heated at 70° C. overnight. The reaction mixture is condensed, adsorbed onto silica, and chromatographed eluting with 6% MeOH in CH2Cl2 then 7% MeOH in CH2Cl2. Product-containing fractions are combined and condensed to afford a solid. The solid is suspended in CH2CT2/hexanes and filtered to afford 19.7 mg (7%) of 2-{[(aminocarbonyl)amino]methyl}-N-(4-chlorobenzyl)-8-(4-morpholinylmethyl)-6-oxo-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]([CH3:16])[CH2:11][C:12](=[O:15])[NH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1F.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]([CH3:16])[CH2:11][C:12](=[O:15])[NH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: CC1CC(=O)NN=C1c1ccc(F)c(F)c1
Reactant: C1CNCCN1
Solvent: ClCCl
Product: CC1CC(=O)NN=C1c1ccc(N2CCNCC2)c(F)c1
Yield: 54.1 %

Procedure:
5.0 g (22.3 mmol) of 6-(3,4-difluorophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone and 19.2 g (222 mmol) of piperazine are stirred at 160° C. for 15 hours. When the reaction mixture has cooled down, it is taken up with 200 ml of dichloromethane and washed with 3×30 ml of water. After drying, the organic phase is concentrated by evaporation and the residue is crystallized with methanol. The solid obtained is suction filtered and recrystallized from ethyl acetate. 3.5 g (54%) of colourless crystals, m.p. 172°-174° C., are obtained.