Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21]CC)[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:24]3[CH:25]=[N:26][CH:27]=[C:28]([CH2:30][OH:31])[CH:29]=3)=[CH:5][C:4]=2[N:3]=1.B(Br)(Br)Br.CO>ClCCl>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][OH:21])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:24]3[CH:25]=[N:26][CH:27]=[C:28]([CH2:30][OH:31])[CH:29]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(-c4cncc(CO)c4)cnc3c2n1CC(C)(C)O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CC(C)(O)Cn1c(CO)nc2c(N)nc3cc(-c4cncc(CO)c4)cnc3c21
Temperature: -78 °C
Reaction time: 3.5 h
Yield: 30 %

Procedure:
A suspension of 1-{4-amino-2-(ethoxymethyl)-7-[5-(hydroxymethyl)pyridin-3-yl]-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl}-2-methylpropan-2-ol (627 mg, 1.48 mmol), obtained from the filtrate from the trituration in Example 68, in dichloromethane (25 mL) was cooled to −78° C. Boron tribromide (15 mL of a 1 M solution in dichloromethane) was added dropwise, and the reaction was allowed to warm to room temperature and stirred for 3.5 hours. Methanol (50 mL) was carefully added, and the resulting solution was stirred at room temperature for 30 minutes and concentrated under reduced pressure. A solution of ammonia in methanol (50 mL of 1 M) was added, and the mixture was stirred for 30 minutes. Silica gel was added, and the mixture was concentrated under reduced pressure. The resulting mixture was purified by automated flash chromatography (FLASH 40+M cartridge, eluting with 15% to 30% methanolic ammonia in dichloromethane). All fractions containing product were combined and concentrated, and the residue was dissolved in methanol (50 mL) and treated with 6 M hydrochloric acid. The solution was heated at 50° C. for two hours, concentrated under reduced pressure, and diluted with 2 N ammonia in methanol. Silica gel was added, and the mixture was concentrated under reduced pressure. Chromatographic purification was carried out again as described above with the modification that the elution gradient began with 5% methanolic ammonia in dichloromethane. The resulting product was dissolved in methanol (20 mL), divided in ten equal portions, and loaded onto ten Waters Oasis Sample Extractions Cartridge MCX columns (500 mg) according to the following procedure. Each column was washed with methanol (2 volumes) and 1 N ammonia in methanol (3 volumes), and the ammonia washes were combined and concentrated under reduced pressure. The resulting solid (200 mg) was triturated with acetonitrile, isolated by filtration, washed with acetonitrile, and dried in a vacuum oven to provide 175 mg of 1-{4-amino-2-(hydroxymethyl)-7-[5-(hydroxymethyl)pyridin-3-yl]-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl}-2-methylpropan-2-ol as a light yellow solid, mp 149-151° C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([NH:6][CH2:7][C:8]2[CH:22]=[CH:21][C:11]([O:12][C:13]([CH3:20])([CH3:19])[C:14]([O:16]CC)=[O:15])=[C:10](OC)[CH:9]=2)=[CH:4][CH:3]=1.C(S)C.[H-].[Na+]>CN(C)C=O>[CH3:20][C:13]1([CH3:19])[C:14](=[O:16])[O:15][C:21]2[CH:22]=[C:8]([CH2:7][NH:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:26][CH:25]=3)[CH:9]=[CH:10][C:11]=2[O:12]1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CNc2ccc(Cl)cc2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: CN(C)C=O
Product: CC1(C)Oc2ccc(CNc3ccc(Cl)cc3)cc2OC1=O
Temperature: 100 °C
Yield: 59.5 %

Procedure:
A mixture of 500 mg of ethyl 2-[4-(4-chloroanilinomethyl)-2-methoxyphenoxy]-2-methylpropionate, 206 mg of ethanethiol, 159 mg of 50% sodium hydride and 10 ml of dimethylformamide is heated at 100° C. for 3 hours. The reaction mixture is poured into ice-water and washed with ether. The aqueous layer is adjusted to pH 2 with 10% hydrochloric acid and extracted with ether. The extract is washed with water, dried and concentrated. The residue is pulverized with a mixture of diisopropyl ether and n-hexane and the crystals are collected by filtration to give 250 mg of 3,3-dimethyl-7-(4-chloroanilinomethyl)-1,4-benzodioxan-2-one, mp 97° to 98° C. From the mother liquor 60 mg of the same compound is further obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5](=[CH2:19])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH3:2].ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:5]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:19][O:29]1)=[O:20])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(CCCCCCCC1CCCCC1)C(=O)OCC
Solvent: ClCCl
Product: CCOC(=O)C1(CCCCCCCC2CCCCC2)CO1

Procedure:
5.25 g of the title compound, in the form of a colourless oil, which is purified by chromatography on silica gel (migrating agent: 90:10 petroleum ether/ethyl acetate), are obtained by the procedure described in Example (1a) from 9.2 g of 9-cyclohexyl-2-methylenenonanoic acid ethyl ester and 11.3 g of m-chloroperbenzoic acid in 100 ml of methylene chloride.
Reaction SMILES: [NH2:1][C:2](=[O:14])[CH2:3][S:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:16]1[N:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[NH2:1][C:2](=[O:14])[CH2:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([C:16]2[N:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]3)=[CH:18][CH:17]=2)=[CH:7][CH:6]=1
Reactant: NC(=O)CSc1ccc(B(O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)nc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(SCC(N)=O)cc3)nc2)CC1
Yield: 74.6 %

Procedure:
1-Methylethyl 4-{[(6-{4-[(2-amino-2-oxoethyl)thio]phenyl}-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (0.139 g, 75%) was prepared as a light yellow solid from {4-[(2-amino-2-oxoethyl)thio]phenyl}boronic acid (0.11 g, 0.50 mmol), 1-methylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (Example 81, Step 1, 0.15 g, 0.42 mmol), 2M Na2CO3 (2 mL), Pd(PPh3)2Cl2 (30 mg, 0.04 mmol) and DME (2 mL) in a manner similar to Example 21, Step 3. 1H NMR (400 MHz, CDCl3): δ 8.36 (d, 1H, J=2.5 Hz), 7.90 (d, 2H, J=8.2 Hz), 7.65 (d, 1H, J=8.8 Hz), 7.38 (d, 2H, J=8.2 Hz), 7.35-7.25 (m, 1H), 6.65 (bs, 1H), 5.41 (bs, 1H), 4.92 (septet, 1H, J=6.2 Hz), 4.23 (bs, 2H), 3.90 (d, 2H, J=6.3 Hz), 3.67 (s, 2H), 2.85-2.70 (m, 2H), 2.10-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.35-1.20 (m, 8H); LRMS (ESI), m/z 444 (M+H).
Reaction SMILES: C[Si](C)(C)[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:15]=[N:14][C:13]2[C:12](=[O:16])[NH:11][C:10]([NH2:17])=[N:9][C:8]1=2.O.O.[O-2].[O-2].[O-2].[O:25]=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>C(O)(=O)C>[OH:25][CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:15]=[N:14][C:13]2[C:12](=[O:16])[NH:11][C:10]([NH2:17])=[N:9][C:8]1=2
Reactant: O=[Si]=O
Reactant: C[Si](C)(C)CCOCn1cnc2c(=O)[nH]c(N)nc21
Agent: [Al+3]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc2c(ncn2COCCO)c(=O)[nH]1
Temperature: 5 °C
Yield: 69 %

Procedure:
A mixture of 9-(2-trimethylsilylethoxymethyl)guanine (15.8 g), water (250 ml), and acetic acid (20 ml) was heated to reflux, giving a solution. The hot solution was treated with a small amount of Montmorillonite K10 (an acidic clay) to remove any color, filtered, and the filtrate slowly cooled to 5° C. The white crystalline solid thus produced was filtered off, to yield 9-(2-hydroxyethoxymethyl)guanine (8.8 g, 69%). 1H NMR 3.38 (4H, singlet); 4.64 (1H, broad singlet); 5.26 (2H, singlet); 6.54 (2H, broad singlet); 7.68 (1H, singlet).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[NH:10][N:9]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[S:7]1)=[O:5])[CH3:2].[CH:15]1[C:27]2[CH:26]([CH2:28][O:29][C:30](=[O:39])[NH:31][CH:32]([C:36](Cl)=[O:37])[CH:33]([CH3:35])[CH3:34])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[N:10]([C:36](=[O:37])[CH:32]([NH:31][C:30]([O:29][CH2:28][CH:26]2[C:27]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:20]3[C:25]2=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:39])[CH:33]([CH3:35])[CH3:34])[N:9]=[C:8]([C:11]([CH3:13])([CH3:12])[CH3:14])[S:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1NN=C(C(C)(C)C)S1
Reactant: CC(C)C(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)C1SC(C(C)(C)C)=NN1C(=O)C(NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reaction time: 16 h
Yield: 49.5 %

Procedure:
A stirred suspension of polyvinylpyridine (2.63 g, 25 mmol) in a solution of 5-tert-butyl-2,3-dihydro-[1,3,4]thiadiazole-2-carboxylic acid ethyl ester (36) (J. Med. Chem., 34, p. 439 (1991)), (2.16 g, 10 mmol) in dry toluene was treated with the dropwise addition of (1-chlorocarbonyl-2-methyl-propyl)-carbamic acid 9H-fluoren-9-ylmethyl ester (4.76 g, 12.1 mmol) in 20 mL of anhydrous toluene. After stirring for 16 hours, the suspension was filtered and the filtrate was washed with saturated sodium bicarbonate solution. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and evaporated to give a yellow oil. Purification by flash chromatography eluting with 9/1 hexane/ethyl acetate gave 2.66 g (49% yield) of the title compound (37) as a clear, viscous oil. 1H NMR (500 MHz, CD3OD) δ 0.89 (d, 1.5H), 0.93 (d, 1.5H), 1.00 (d, 1.5H), 1.06 (d, 1.5H), 1.22 (t, 3H), 1.28 (s, 9H), 2.12-2.22 (m, 0.5H), 2.32-2.42 (m, 0.5H), 4.18-4.28 (m, 2H), 4.31-4.45 (m, 2H), 4.96-5.01 (m, 0.5H), 5.02-5.10 (m, 0.5H), 5.52 (d, 0.5H), 5.61 (d, 0.5H), 6.10 (s, 0.5H), 6.13 (s, 0.5H), 7.27-7.34 (m, 2H), 7.35-7.42 (m, 2H), 7.56-7.64 (m, 2H), 7.73-7.78 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])=[CH:15][CH:14]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O>O1CCOCC1.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]>[Br:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[O:20])=[CH:17][CH:18]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: Brc1cc(I)c2nccn2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccc(Nc2cc(Br)cn3ccnc23)cc1)N1CCOCC1
Temperature: 25 °C
Yield: 44 %

Procedure:
6-Bromo-8-iodo-imidazo[1,2-a]pyridine (500 mg, 1.53 mmol), (4-aminophenyl)(morpholino)-methanone (348 mg, 1.69 mmol) and CsCO3 (998 mg, 3.06 mmol) were dissolved in dioxane (10 ml). Under N2 atmosphere, Pd2(dba)3 (70 mg, 0.077 mmol) and Xantphos (89 mg, 0.153 mmol) were added and the mixture was stirred at reflux temperature overnight. After the completion of the reaction, the mixture was cooled to room temperature, poured into water (100 mL) and extracted with DCM (100 ml). The organic extracts were washed with saturated aqueous solution of sodium chloride (100 ml), dried over sodium sulfate and concentrated. The residue was purified by silica gel column (petroleum ether:ethyl acetate 1:2) to afford the desired product as a yellow solid (270 mg, yield 44%). LC-MS: 401[M+1]+, tR=1.257 min.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].N1C=CC=CC=1.[C:13]([C:21]1[CH:22]=[CH:23]C(C)=[C:25]([N:27]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C:28](=[O:30])[CH3:29])[CH:26]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.[C:40]([O:43]CC)(=[O:42])[CH3:41]>O>[C:13]([C:21]1[CH:22]=[CH:23][C:41]([C:40]([OH:43])=[O:42])=[C:25]([N:27]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[C:28](=[O:30])[CH3:29])[CH:26]=1)(=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)N(c1ccc(F)cc1)c1cc(C(=O)c2ccccc2)ccc1C
Reactant: CCOC(C)=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)N(c1ccc(F)cc1)c1cc(C(=O)c2ccccc2)ccc1C(=O)O
Temperature: 25 °C

Procedure:
Potassium permanganate 0.24 g was added to a mixed solution of pyridine 5.0 mL and water 5.0 mL of N-(5-benzoyl-2-methylphenyl)-N-(4-fluorophenyl)acetamide 0.52 g at room temperature, and it was heated and refluxed for 30 minutes. After the reaction mixture was cooled to room temperature, potassium permanganate 0.24 g was added to it, it was heated and refluxed for 30 minutes. After the reaction mixture was cooled to room temperature, potassium permanganate 0.24 g was added to it, it was heated and refluxed for 30 minutes. After the reaction mixture was cooled to room temperature, furthermore, potassium permanganate 0.24 g was added to it, and it was heated and refluxed for 30 minutes. After the reaction mixture was cooled, ethyl acetate was added to it, it was adjusted to pH2.3 with 6.0 mol/L hydrochloric acid, and insoluble matter was filtrated. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 1.0 mol/L hydrochloric acid and saturated sodium chloride aqueous solution, the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [eluent; hexane:ethyl acetate=1:2] to give 4-benzoyl-2-(N-(4-fluorophenyl)acetamido)benzoic acid 0.39 g of white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:14]1[O:16][C@@H:15]1[CH2:17][OH:18]>>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([O:18][CH2:17][CH:15]2[CH2:14][O:16]2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: OC[C@@H]1CO1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Product: O=[N+]([O-])c1cccc(S(=O)(=O)OCC2CO2)c1
Temperature: -20 °C
Reaction time: 96 h
Yield: 97 %

Procedure:
m-Nitrobenzensulfonylchloride (12.6 g; 57 mmol) was added to a cold (−20° C.) solution of (R)-(+)-glycidol (5.5 g; 74 mmol) and TEA (10.3 mL; 74 mmol). The reaction mixture was stirred at −20° C. for 96 h. The solution was filtered and the filtrate washed with tartaric acid (10% w/w), brine, H2O and concentrated giving the title compound in a 97% yield.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10](Cl)(=O)[CH3:11]>>[CH3:10][CH:11]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1][NH:9]1
Reactant: NCCc1ccccc1
Reactant: CC(=O)Cl
Product: CC1NCCc2ccccc21

Procedure:
In accordance with the same procedures as in Steps 1, 2, and 3 of Preparation 21, except for using phenethylamine and acetyl chloride, 1-methyl-1,2,3,4-tetrahydroisoquinoline was obtained. In accordance with the same procedures as in Preparation 20, the titled compound was obtained as pale yellow oil. (Yield: 91%) The product was used in the subsequent step without further purification.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][C:5]=1[S:13](=[O:16])(=[O:15])[NH2:14])([CH3:3])[CH3:2].S(Cl)([Cl:19])=O>>[CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([Cl:19])=[O:9])=[CH:6][C:5]=1[S:13](=[O:16])(=[O:15])[NH2:14])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(C(=O)O)cc1S(N)(=O)=O
Reactant: O=S(Cl)Cl
Product: CC(C)c1ccc(C(=O)Cl)cc1S(N)(=O)=O

Procedure:
5 g of 4-isopropyl-3-sulfamoylbenzoic acid were boiled under reflux in 50 ml of thionylchloride until completely dissolved and the reaction mixture was then concentrated to 25 ml under reduced pressure. After allowing to dwell over night at 0° C., the crystals were filtered off over a sinter glass frit and washed with petroleum ether. Colorless body, melting point: 177° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]([CH3:24])([CH3:23])[C:20]([NH2:22])=[O:21])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.C1(S([N:40]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42](B(O)O)=[CH:41]2)(=O)=O)C=CC=CC=1.[OH-].[K+]>>[NH:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:42]([C:2]2[N:3]=[C:4]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:18][CH2:17][N:16]([C:19]([CH3:24])([CH3:23])[C:20]([NH2:22])=[O:21])[CH2:15][CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[CH:41]1
Reactant: O=S(=O)(c1ccccc1)n1cc(B(O)O)c2ccccc21
Reactant: CC(C)(C(N)=O)N1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C(N)=O)N1CCN(Cc2ccc3nc(-c4c[nH]c5ccccc45)nc(N4CCOCC4)c3n2)CC1

Procedure:
2-(4-((2-Chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide from Example 121 (115 mg) was reacted with 1-(phenylsulfonyl)-3-indoleboronic acid via General Procedure A to yield 31.8 mg 123 following phenylsulfonyl group deprotection with aqueous potassium hydroxide at 50° C. for 2 hours then reverse phase HPLC purification. MS (Q1) 515.3 (M)+
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][NH:6][C:7]=1[C:8]#[N:9])#[N:2].[Br:10]Br>[OH-].[Na+]>[Br:10][C:5]1[NH:4][C:3]([C:1]#[N:2])=[C:7]([C:8]#[N:9])[N:6]=1
Reactant: BrBr
Reactant: N#Cc1nc[nH]c1C#N
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1nc(Br)[nH]c1C#N

Procedure:
4,5-Dicyanoimidazole (23.6 g) was dissolved in sodium hydroxide solution (0.1N, 500 ml) with stirring and then bromine (36 ml) was added dropwise with stirring at room temperature. The mixture was stirred at room temperature overnight and the resulting solid was filtered, washed with water and dried to give 2-bromo-4,5-dicyanoimidazole m.p. 141°-144°. This compound (20 g) in dimethylformamide (100 ml) was added with stirring to a suspension of sodium hydride (80% dispersion in oil, 3.05 g) in dimethylformamide (100 ml) at room temperature. The mixture was cooled to 5° and chloromethyl 2-trimethylsilylethyl ether (18 ml) was added dropwise with stirring. This mixture was allowed to stand at room temperature overnight and was then poured into water and extracted with ethyl acetate. Evaporation of solvent gave an oil which was purified by column chromatography to give 1-(2-trimethylsilylethoxymethyl)-2-bromo-4,5-dicyano-1H-imidazole m.p.47°-52°.
Reaction SMILES: [CH3:1][C:2]1([C:21]([OH:23])=O)[CH2:17][C:10]2([N+:18]([O-:20])=[O:19])[C:11]3[C:16]([CH:3]1[C:4]1[C:9]2=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.CCN=C=NCCCN(C)C.[C:54]1([C:64]2[NH:68][N:67]=[C:66]([NH2:69])[N:65]=2)[C:63]2[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=2)[CH:57]=[CH:56][CH:55]=1>C(#N)C>[CH3:1][C:2]1([C:21]([N:67]2[C:66]([NH2:69])=[N:65][C:64]([C:54]3[C:63]4[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=4)[CH:57]=[CH:56][CH:55]=3)=[N:68]2)=[O:23])[CH2:17][C:10]2([N+:18]([O-:20])=[O:19])[C:11]3[C:16]([CH:3]1[C:4]1[C:9]2=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3
Reactant: Nc1n[nH]c(-c2cccc3ccccc23)n1
Reactant: CC1(C(=O)O)CC2([N+](=O)[O-])c3ccccc3C1c1ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C(=O)n2nc(-c3cccc4ccccc34)nc2N)CC2([N+](=O)[O-])c3ccccc3C1c1ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
To a stirred solution of 15-methyl-8-nitrotetracyclo[6.6.2.02,7.09,14]hexadeca-2,4,6,9,11,13-hexaene-15-carboxylic acid (22 mg, 0.07 mmol, prepared according to WO04009017), 1-hydroxybenzotriazole (14 mg, 0.11 mmol), and N-ethyl-N,N-diisopropylamine (0.25 mL) in anhydrous acetonitrile (2 mL) was added EDCI (34 mg, 0.18 mmol) at RT under argon. After the mixture was stirred at RT for 10 min, 5-(naphthalen-1-yl)-1H-1,2,4-triazol-3-amine (22 mg, 0.1 mmol) was added. The reaction mixture was stirred at RT overnight and at 80° C. for 1 h. After the solvents were removed, the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The aqueous solution was extracted with methylene chloride. The combined organic solutions were dried (Na2SO4), concentrated and purified by silica gel chromatography to give 33 mg (94% yield) of the title compound as a white solid. (M+H)+=502.26.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH:28]1[C:33]([C@H:34]([OH:37])[CH2:35][NH2:36])=[CH:32][C:31]([OH:38])=[C:30]([OH:39])[CH:29]=1>>[OH:38][C:31]1[CH:32]=[C:33]([C@@H:34]([OH:37])[CH2:35][NH:36][CH:2]2[CH2:3][CH2:4][N:5]([C:8]3[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]4[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=4)(=[O:16])=[O:17])=[CH:12][CH:13]=3)[CH2:6][CH2:7]2)[CH:28]=[CH:29][C:30]=1[OH:39]
Reactant: NC[C@@H](O)c1ccc(O)c(O)c1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)c4ccc(O)c(O)c4)CC3)cc2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and L-norepinephrine according to the procedure of Example 255 as a grey solid; 1H NMR (300 MHz, DMSO-d6) δ 1.50–1.72 (m, 2 H), 1.95–2.10 (m, 2 H), 2.06 (s, 3 H), 2.50–3.20 (m, 5 H), 3.55–3.70 (m, 2 H), 4.05–4.20 (brs, 1), 4.60–4.75 (m, 1 H), 5.75–5.90 (brs, 1 H), 6.60–6.90 (m, 7 H), 7.59 (d, J=9.0 Hz, 2 H), 7.70 (d, J=9.0 Hz, 2 H), 8.93 (brs, 1 H), 10.42 (s, 1 H); MS (ES) m/z: 541.6 (MH+); HRMS Calcd. for C27H33N4O6S (MH+): 541.2121. Found: 541.2133.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH:30]1[C:35]([OH:37])=[O:36].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:26]([O:25][C:23]([C:4]1[CH:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]=1[CH2:2][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH:30]1[C:35]([OH:37])=[O:36])=[O:24])[CH3:27]
Reactant: O=C(O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nccs2)=NC1c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 41.4 %

Procedure:
A mixture of ethyl 6-(bromomethyl)-4-(2-nitrophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (2.4 g, 5.3 mmol), morpholine-3-carboxylic acid hydrochloride (0.9 g, 5.37 mmol) and potassium carbonate (1.48 g, 10.74 mmol) in ethanol (60 mL) was stirred at 25° C. for 12 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V)=25/1) to give the title compound as a light yellow solid (1.1 g, 41%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH:4]=[N:3][CH:2]=1.[S:13]1[CH2:19][C:17](=[O:18])[NH:16][C:14]1=[S:15].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[C:19]3[S:13][C:14](=[S:15])[NH:16][C:17]3=[O:18])=[CH:8][CH:9]=2)[CH:4]=[N:3][CH:2]=1
Reactant: O=Cc1ccc2ncncc2c1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1ccc2ncncc2c1
Temperature: 130 °C
Reaction time: 12 h
Yield: 100.1 %

Procedure:
The suspension of 6-quinazolinecarboxaldehyde (example 1a, 1.5 g, 9.5 mmol), rhodanine (1.26 g, 9.5 mmol) and sodium acetate (3.11 g, 38 mmol) in acetic acid (10 mL) was stirred at 130° C. for 12 h. After cooling to room temperature, water (40 mL) was added. The solid was collected by filtration, washed with water and dried to obtain 5-quinazolin-6-ylmethylene-2-thioxo-thiazolidin-4-one (2.6 g, 100%) as a solid. LC-MS m/e 274 (MH+).