Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:17]3[CH2:18][C:19]4[S:20][C:21]([C:24]5[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=5)=[CH:22][C:23]=4[C:16]=3[NH:15][N:14]=2)=[CH:9][CH:8]=1>C(Cl)Cl>[NH2:30][C:27]1[N:28]=[CH:29][C:24]([C:21]2[S:20][C:19]3[CH2:18][C:17]4[C:13]([C:10]5[CH:11]=[CH:12][C:7]([OH:6])=[CH:8][CH:9]=5)=[N:14][NH:15][C:16]=4[C:23]=3[CH:22]=2)=[CH:25][CH:26]=1
Reactant: COc1ccc(-c2n[nH]c3c2Cc2sc(-c4ccc(N)nc4)cc2-3)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1ccc(-c2cc3c(s2)Cc2c(-c4ccc(O)cc4)n[nH]c2-3)cn1
Reaction time: 2 h
Yield: 84 %

Procedure:
BBr3 (1.25 g, 5.0 mmol) was added to a solution of 5-[6-(4-Methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-pyridin-2-ylamine (0.18 g, 0.5 mmol) in CH2Cl2 (8.0 mL). After 2 hours, the solution was evaporated and washed with EtOAc, filtered, and concentrated to give the corresponding 4-[2-(6-Amino-pyridin-3-yl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl]-phenol (0.14 g, 0.42 mmol) as brown solid in 84% yield.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O.Cl>C=CCCC.C1COCC1.CN(C=O)C.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>[CH2:15]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)[CH2:16][CH2:7][CH2:8][CH3:9]
Reactant: O=S(=O)(Oc1ccc2ncccc2c1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: C=CCCC
Solvent: C1CCOC1
Product: CCCCCc1ccc2ncccc2c1
Temperature: 5 °C
Reaction time: 3 h
Yield: 148.9 %

Procedure:
In a 5 liter-three necked flask, 21.8 g (311 mM) of 1-pentene and 170 ml of THF were placed for dissolution, and under stirring in a nitrogen gas stream atmosphere, 673.4 ml of 0.5M-THF solution of 9-BBN(9-borabicyclo[3.3.1]nonane) was added dropwise at −25 to −20° C. over 15 minutes, followed by stirring for 1 hour at −10° C. and further for 3 hours at 5° C. Under stirring on an ice bath, to the reaction mixture, 6.75 g (5.84 mM) of Pd (PPh3)4 was added, and a solution of 79.6 g (287 mM) of 6-trifluoromethylsulfonyloxyquinoline in 1010 ml of DMF (methylformamide) was added dropwise, followed by the addition of 62.1 g of anhydrous potassium carbonate and then stirring for 10 minutes. The system was warmed and stirred at 50-54° C. for 3 hours. After the reaction, the reaction mixture was left standing for cooling and gradually poured into 3 liters of cool water, followed by extraction four times with 500 ml of toluene and washing of the organic layer with water. The organic layer was evaporated or condensed into ca. 1 liter thereof, followed by the addition of HCl so as to provide pH=1 and washing of the water layer (phase) with toluene. The water layer was alkalinized with 10% NaOH to pH=11 and extracted with toluene. The organic layer was dried and evaporated into a black liquid. The black liquid was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=5/1) to obtain 42.6 g (yield: 74.4%) of 6-pentylquinoline.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:39])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[O:35][C:34]([C:36](O)=[O:37])=[CH:33][CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.[NH4+].[Cl-].CC[N:44]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C)C=O>[Cl:1][C:2]1[C:3]([F:39])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[O:35][C:34]([C:36]([NH2:44])=[O:37])=[CH:33][CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)o2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(N)=O)o2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 75 °C
Yield: 52.1 %

Procedure:
To a solution of rac-5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-furan-2-carboxylic acid prepared in Example 145 (60 mg, 0.1 mmol) in N,N-dimethylformamide (2 mL) was added NH4Cl (28 mg, 0.5 mmol), EDCI (40 mg, 0.2 mmol), HOBT (28 mg, 0.2 mmol) and NEt3 (0.029 mL, 0.2 mmol). The reaction mixture was heated at 75° C. for 20 h. The mixture was cooled to room temperature, and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc) to give rac-5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-furan-2-carboxylic acid amide as a white solid (30 mg, 50%).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10]CC)=O.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][NH2:23])[CH2:16][CH2:15]1>>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][NH:23][C:8](=[O:10])[CH2:7][N:3]2[CH2:4][CH2:5][CH2:6][C:2]2=[O:1])[CH2:16][CH2:15]1
Reactant: CN1CCN(CCCN)CC1
Reactant: CCOC(=O)CN1CCCC1=O
Product: CN1CCN(CCCNC(=O)CN2CCCC2=O)CC1

Procedure:
From 8.5 g. of ethyl 2-oxo-1-pyrrolidineacetate and 10.2 g. of 3-(4-methyl-1-piperazinyl)propylamine [J.A.C.S. 82, 2386 (1960)], following the procedure of Example 9, there is obtained N-[3-(4-methyl-1-piperazinyl)propyl]-2-oxo-1-pyrrolidineacetamide; m.p. 93° C. after recrystallization from cyclohexane.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:6]([O:7][CH3:8])[C:4]=1[OH:5].[OH-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[C:14]1([S:20]([O:5][C:4]2[C:6]([O:7][CH3:8])=[CH:9][CH:10]=[CH:11][C:3]=2[CH:2]=[O:1])(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1cccc(C=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cccc(C=O)c1OS(=O)(=O)c1ccccc1
Yield: 76 %

Procedure:
o-Vanillin (350 g, 2.3 mols) was added to a solution of NaOH (166 g, 4.15 mols) in 2 1 water. Benzenesulfonyl chloride (485 g, 2.74 mols) was added to the slurry at 20°-25° C. over 1 hour. The solid which formed was collected on a filter, washed with 2 1 water, and redissolved in CH2Cl2. That solution was dried (MgSO4) and evaporated to a slurry. The solid was collected on a filter, the filtrate was further evaporated and filtered. The solid was washed with MeOH and dried in vacuo to afford the desired product, (511 g, 81.4%), mp 120°-122° C.
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[CH2:5][CH2:4][CH:3]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[N:2]1C(OCC1C=CC=CC=1)=O.[H][H].Cl.CCOCC>CO.[Pd]>[NH:1]1[CH2:5][CH2:4][CH:3]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[NH:2]1
Reactant: CC(C)(C)OC(=O)C1CCN(C(=O)OCc2ccccc2)N1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)OC(=O)C1CCNN1
Reaction time: 0.08 h

Procedure:
3-(1,1-Dimethylethyl) 1,2-bis(phenylmethyl) 1,2,3-pyrazolidinetricarboxylate (5.30 g, 12.03 mmol) was dissolved in methanol (100 mL) and 10% Pd/C (degussa type) (1.06 g, 0.996 mmol) was added. The mixture was stirred under a balloon of hydrogen for 60 min. LCMS showed clean deprotection. HCl in ether (6.02 mL, 12.03 mmol) was added, and the mixture was stirred 5 min. The catalyst was filtered off and the filtrate was evaporated, yielding 1,1-dimethylethyl 3-pyrazolidinecarboxylate.HCl (2.45 g, 11.74 mmol, 98% yield) as an orange solid.
Reaction SMILES: [C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15](O)=[O:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:22]([NH:29][C:30](=[O:37])[C@H:31]([CH2:33][CH2:34][CH2:35][CH3:36])[NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl>[C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([N:29]([CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:30](=[O:37])[C@H:31]([CH2:33][CH2:34][CH2:35][CH3:36])[NH2:32])=[O:16])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=C(O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Reactant: CCCC[C@H](N)C(=O)NCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Yield: 80.3 %

Procedure:
Using the procedure described previously, a solution of 1-(2-adamantan-1-yl-2-oxoethyl) L-proline (154 mg, 0.53 mmol, 1.0 eq), L-norleucine N-benzylamide (234 mg, 1.07 mmol, 2.0 eq) and dichloromethane (1.0 mL), was treated with triethylamine (446 uL, 3.2 mmol, 6.0 eq), and a 50% solution of 1-n-propylphosphonic acid cyclic anhydride in dichloromethane (680 uL, 1.07 mL, 2.0 eq), to provide 210 mg (80%) of L-norleucine, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-Prolyl] benzylamide as a white foam.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH3:10].[Cl:11][C:12]1[CH:35]=[CH:34][C:15]([CH2:16][C:17]2[NH:18][C:19](=[O:33])[C:20]3[N:25]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=4)[O:23][C:21]=3[N:22]=2)=[CH:14][CH:13]=1.CCCCCCC>CN(C)C=O.CCCCCCC.C(OCC)(=O)C>[Cl:11][C:12]1[CH:35]=[CH:34][C:15]([CH2:16][C:17]2[N:18]=[C:19]([O:33][CH2:8][CH2:9][CH3:10])[C:20]3[N:25]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=4)[O:23][C:21]=3[N:22]=2)=[CH:14][CH:13]=1
Reactant: CCCBr
Reactant: O=c1[nH]c(Cc2ccc(Cl)cc2)nc2oc(-c3cccc(F)c3)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cccc(F)c3)nc12
Temperature: 60 °C
Reaction time: 16 h
Yield: 22.4 %

Procedure:
28 mg of potassium carbonate and 21 mg of 1-bromo-propane were added to a solution of 60 mg of 5-(4-chloro-benzyl)-2-(3-fluoro-phenyl)-6H-oxazolo[5,4-d]pyrimidin-7-one in 3 ml of dimethylformamide, and the reaction mixture was stirred at 60° C. for 16 h. After cooling, the mixture was subjected to chromatography (silica gel, gradient from heptane to heptane/ethyl acetate 3:1). 15 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7](=[O:19])[C:8]3[NH:9][CH:10]=[N:11][C:12]=3[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:5]2=[N:4][N:3]=1.[Cl:20]N1C(=O)CCC1=O>C1COCC1>[Cl:20][C:10]1[NH:9][C:8]2[C:7](=[O:19])[N:6]3[C:2]([CH3:1])=[N:3][N:4]=[C:5]3[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:12]=2[N:11]=1
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(C)nnc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Cl)[nH]c2c(=O)n2c(C)nnc12
Temperature: 70 °C
Yield: 18.7 %

Procedure:
To a solution of 3-methyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (0.10 g, 0.38 mmol) in THF (5 mL) in a microwave reaction tube was added N-chlorosuccinimide (0.046 g, 0.42 mmol). The mixture was heated at 70° C. in a microwave oven for 20 min. After cooling to room temperature, it was purified using preparative LCMS to provide the product (0.021 g). 1HNMR (300 MHz, CD3OD): δ 4.39 (t, J=7.5 Hz, 2H), 2.46 (s, 3H), 1.91 (m, 2H), 1.39 (m, 4H), 0.92 (m, 3H). LCMS calculated for C12H16ClN6O (M+H): 295.1. found: 295.1.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([N+:8]([O-])=O)[C:5]([O:11][CH2:12][C:13]([O:15]CC)=O)=[CH:4][CH:3]=1>CC(O)=O.CCOC(C)=O.C(Cl)(Cl)Cl.[Fe]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:12][C:13](=[O:15])[NH:8][C:6]=2[N:7]=1
Reactant: CCOC(=O)COc1ccc(Br)nc1[N+](=O)[O-]
Agent: [Fe]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C1COc2ccc(Br)nc2N1
Temperature: 77 °C
Yield: 71.1 %

Procedure:
Ethyl (6-bromo-2-nitropyridin-3-yloxy)acetate (41 g, 0.132 mole) was dissolved in glacial AcOH (400 mL) and the solution was heated to 77° C. with mechanical stirring. Iron powder (50 g, 0.89 mole) was added portionwise over 2 hr, so that the temperature did not rise above 90° C. The mixture was mechanically stirred and heated at 77° C. for 10 hr then was cooled to room temperature and diluted with 1:4 EtOAc/CHCl3 (1 L). The mixture was filtered through a pad of celite® and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (1 kg; 0-10% EtOAc/CHCl3) to afford the title compound (21.5 g, 70%): MS (ES) m/e 229 (M+H)+.
Reaction SMILES: [O:1]1CCCC1.[F:6][C:7]1[C:12]([N:13]2[C:17]([CH3:18])=[C:16]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[C:24](=[O:28])[CH:23](OC(C)=O)[CH2:22]4)[N:15]=[N:14]2)=[CH:11][CH:10]=[CH:9][N:8]=1>[OH-].[Na+].C(Cl)(Cl)Cl>[F:6][C:7]1[C:12]([N:13]2[C:17]([CH3:18])=[C:16]([C:19]3[C:20]([OH:1])=[C:21]4[C:25](=[CH:26][CH:27]=3)[C:24](=[O:28])[CH2:23][CH2:22]4)[N:15]=[N:14]2)=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: CC(=O)OC1Cc2cc(-c3nnn(-c4cccnc4F)c3C)ccc2C1=O
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1c(-c2ccc3c(c2O)CCC3=O)nnn1-c1cccnc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Three drops of 2 M sodium hydroxide aqueous solution was added at room temperature to 1 ml solution of tetrahydrofuran with 6 mg of 1-(2-fluoropyridine-3-yl)-4-(1-oxo-2-methylcarbonyloxy-indane-5-yl)-5-methyl-1H-[1,2,3]triazole, obtained in Example 45. After stirring at room temperature for 1 hour, the resultant was diluted with chloroform, washed with water and saturated saline solution, and dried with anhydrous sodium sulfate. The solvents were distilled outunder reduced pressure, and the obtained residues were purified by silicagel column chromatography (hexane:ethyl acetate=80:20) to obtain 1.3 mg of the above compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH3:27])[CH2:22][CH2:21]3)=[O:19])=[C:14]([CH3:28])[CH:13]=1)[CH:8]=[N:7]2.[CH3:29][C:30]([N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1)([C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][C:33]=1[CH3:47])[CH3:31].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:26]([N:23]1[CH2:24][CH2:25][N:20]([C:18]([C:15]2[CH:16]=[CH:17][C:12]([C:9]3[CH:8]=[N:7][C:6]4[C:11](=[C:2]([C:35]5[CH:36]=[CH:37][C:32]([C:30]([CH3:29])([N:48]6[CH2:53][CH2:52][O:51][CH2:50][CH2:49]6)[CH3:31])=[C:33]([CH3:47])[CH:34]=5)[CH:3]=[CH:4][CH:5]=4)[N:10]=3)=[CH:13][C:14]=2[CH3:28])=[O:19])[CH2:21][CH2:22]1)[CH3:27]
Reactant: CCN1CCN(C(=O)c2ccc(-c3cnc4cccc(Br)c4n3)cc2C)CC1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1C(C)(C)N1CCOCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Product: CCN1CCN(C(=O)c2ccc(-c3cnc4cccc(-c5ccc(C(C)(C)N6CCOCC6)c(C)c5)c4n3)cc2C)CC1
Temperature: 105 °C

Procedure:
A microwave tube is charged with of [4-(8-Bromo-quinoxalin-2-yl)-2-methyl-phenyl]-(4-ethyl-piperazin-1-yl)-methanone (step 80.1, 49 mg, 0.112 mmol), 4-{1-Methyl-1-[2-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-morpholine (40.4 mg, ca. 0.117 mmol), S-Phos (4.25 mg, 0.01 mmol), K3PO4 (72.5 mg, 0.33 mmol) and Pd(OAc)2 (0.75 mg, 0.0033 mmol). After several cycles of vacuum/purge with argon, 3 ml of a mixture consisting of 28 μl deionized water in 12 ml 1,2-dimethoxy-ethane, are added. The reaction mixture is then heated to 105° C. for 5 h 30. After cooling, the reaction mixture is diluted with CH2Cl2, poured onto a saturated solution of Na2CO3 and extracted 3× with CH2Cl2. The combined organic layers are washed with water, brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography (silicagel, CH2Cl2/CH2Cl2:EtOH:NH3 90:9:1 from 1:0=>0:1) to afford the title compound as a pale yellow foam, Rt=1.777 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 578 (M+1)+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[CH2:53]([O:60][C:61]1[CH:76]=[CH:75][C:74](Br)=[CH:73][C:62]=1[C:63]([O:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)=[O:64])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.[CH3:78][N:79]1[CH2:84][CH2:83][NH:82][CH2:81][CH2:80]1>CCOCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:78][N:79]1[CH2:84][CH2:83][N:82]([C:74]2[CH:75]=[CH:76][C:61]([O:60][CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[C:62]([CH:73]=2)[C:63]([O:65][CH2:66][C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)=[O:64])[CH2:81][CH2:80]1
Reactant: O=C(OCc1ccccc1)c1cc(Br)ccc1OCc1ccccc1
Reactant: CN1CCNCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CN1CCN(c2ccc(OCc3ccccc3)c(C(=O)OCc3ccccc3)c2)CC1
Temperature: 25 °C

Procedure:
Caesium carbonate (574 mg, 1.76 mmol) was finely ground in a nitrogen-filled glovebox and weighed into an oven-dried Schlenk flask. The flask was quickly capped with a rubber septum and purged with argon. Pd2(dba)3 (2.88 mg, 3.15 μmol) and BINAP (5.88 mg, 9.44 μmol) were added into the flask, followed by benzyl 2-(benzyloxy)-5-bromobenzoate (may be prepared as described in Description 4; 500 mg, 1.26 mmol), 1-methylpiperazine (126 mg, 1.26 mmol), and toluene (10 ml). The solution was refluxed for 10 h. The solution was then cooled to room temperature, diluted with ether, filtered, and concentrated in vacuo to yield the title compound which was not further purified. 100 mg.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH:21]2[C:26](=[O:27])[NH:25][C:24](=[O:28])[NH:23][C:22]2=[O:29])=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]2([C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]=[CH:4][CH:3]=3)[C:22](=[O:29])[NH:23][C:24](=[O:28])[NH:25][C:26]2=[O:27])=[CH:15][CH:14]=1
Reactant: Clc1ccnc2ccccc12
Reactant: O=C1NC(=O)C(CCc2ccc(Cl)cc2)C(=O)N1
Product: O=C1NC(=O)C(CCc2ccc(Cl)cc2)(c2ccnc3ccccc23)C(=O)N1
Temperature: 150 °C

Procedure:
A mixture of 3.63 g of 4-chloroquinoline and 5.3 g of 5-[2-(4-chlorophenyl)ethyl]barbituric acid was heated to 150° C. for 11/4 hours, to form 5-[2-(4-chlorophenyl)ethyl]-5-(4-quinolinyl)barbituric acid. This compound was hydrolyzed, without isolation, by adding 4 g of NaOH in 40 ml of water and refluxing for four hours. The mixture was cooled, acidified with HCl and refluxed for several hours, cooled, and neutralized with dilute NaOH. The desired product was extracted into CH2Cl2, which was then filtered through phase separating paper and evaporated to dryness. The residue was absorbed onto silica gel and chromatographed over silica gel using CH2Cl2. Fractions containing product were combined to give 2.69 g of crystalline material. This was recrystallized from a petroleum ether/CH2Cl2 mixture to give 2.35 g of the title product. Yield: 39%. M.P. 97° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][C:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23](OC)=[O:24])(=[O:16])=[O:15])=[O:12])[N:4]=1.C[Al](C)C.C.[NH2:32][C:33]1[N:37]=[CH:36][NH:35][N:34]=1.Cl>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][C:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([NH:32][C:33]2[N:37]=[CH:36][NH:35][N:34]=2)=[O:24])(=[O:15])=[O:16])=[O:12])[N:4]=1
Reactant: Nc1nc[nH]n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)nc(OC)n1
Agent: C
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)Nc2nc[nH]n2)n1

Procedure:
To a slurry of 4.0 g of N-[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)aminocarbonyl]-2-methoxycarbonylbenzenesulfonamide in 100 ml of methylene chloride was added by syringe 10 ml of a 2M solution of trimethylaluminum in toluene (1.44 g of Al(CH3)3). Evolution of methane gas was seen. 3-Amino-1,2,4-triazole (1.7 g) was then added and the mixture was heated at reflux for 18 hours. The reaction mixture was then treated with aqueous hydrochloric acid and the precipitated product was purified by trituration in methylene chloride, 0.63 g, m.p. 176°-179° C. NMR in TFA 2.9 ppm s, CH3 on triazine, 4.4 ppm s, OCH3 on triazine, 7.8-8.0 ppm and 8.2-8.5 ppm M, aromatic.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([N+:12]([O-:14])=[O:13])=[CH:5][C:4]=1[O:15]C.Br>C(O)(=O)C>[OH:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([N+:12]([O-:14])=[O:13])=[CH:5][C:4]=1[OH:15]
Reactant: COc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1OC
Agent: Br
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(O)c(O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 4 h
Yield: 9869.8 %

Procedure:
88, FIG. 8. In a dry 500 mL round bottom flask, 1,2-dimethoxy-4,5-dinitrobenzene (3.2 g, 0.12 mmol) 8A was stirred vigorously in 40 mL of glacial acetic acid at 30° C. Once a homogeneous solution 200 mL of 48% HBr was added to the flask and the reaction was slowly heated to reflux. The reaction was complete as indicated by TLC after 4 hours. The work up involved pouring the cooled solution into 800 mL of ice water and then extracting the aqueous phase with CHCl3 (3×150 mL) in order to remove any organic impurities. The dinitro catechol was extracted out of the aqueous layer with ethyl acetate (3×150 mL). The combined ethyl acetate extracts were washed with water and brine (3×100 mL), then dried over MgSO4 and concentrated to an orange residue. Approximately 100 mL of dichloromethane was added to the residue and then placed in the freezer for several hours. The light yellow needles that formed were filtered and washed with dichloromethane to yield 2.37 g of product (84%). 1H NMR (d6 -acetone): δ3.45 (OH), 7.42 (Ar-H); 13C NMR (d6 -acetone): δ112.44, 137.00, 149.97, EI MS M+ 200.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[NH:8][N:7]=[CH:6][C:5]=1[CH3:9].[CH3:10][Si:11]([CH3:18])([CH3:17])[CH2:12][CH2:13][O:14][CH2:15]Cl>C1COCC1>[I:3][C:4]1[N:8]([CH2:15][O:14][CH2:13][CH2:12][Si:11]([CH3:18])([CH3:17])[CH3:10])[N:7]=[CH:6][C:5]=1[CH3:9]
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1cn[nH]c1I
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cnn(COCC[Si](C)(C)C)c1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
NaH (0.48 g, 12.2 mmol, 60%) was added to a solution of 5-iodo-4-methyl-1H-pyrazole (compound 250.1, 2.3 g, 11.1 mmol) in THF (20 mL) at 0° C. The mixture was stirred at 0° C. for 30 minutes, then 2-(trimethylsilyl)ethoxymethyl chloride (2.15 mL, 12.2 mmol) was added. The resulting mixture was stirred at room temperature for 3 hours, and then carefully quenched with a small amount of water and partitioned between EtOAc (200 mL) and water (50 mL). The organic layer was washed with brine (50 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified with by silica gel column chromatography (hexanes:EtOAc, 10:1) to yield the title compound as a light yellow oil (3.15 g, 84%). m/z (ES+) 339 (M+H)+.