Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([OH:26])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[C:11]([F:29])[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][CH2:45]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:39][CH2:38]1>CN(C=O)C.O>[Cl:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH2:45][CH2:44][CH2:43][N:40]4[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]4)=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[C:11]([F:29])[CH:10]=1
Reactant: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: Cc1ccc(S(=O)(=O)OCCCN2CCN(C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1OCCCN1CCN(C)CC1
Temperature: 90 °C
Reaction time: 5 h
Yield: 48.1 %

Procedure:
A mixture of the trifluoroacetic acid salt of 4-(4-chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (3.2 g, 7.4 mmol), potassium carbonate (6.1 g, 44.2 mmol) and 3-(4-methyl-1-piperazinyl)propyl-4-toluene sulphonate (3.0 g, 9.6 mmol) in DMF (60 ml) was stirred at 90° C. for 5 hours and allowed to cool to ambient temperature. The reaction mixture was poured into water (700 ml) and extracted 5 times with ethyl acetate. The combined extracts were washed with water, saturated aqueous sodium hydrogen carbonate, water and saturated brine. The ethyl acetate solution was dried over magnesium sulphate, filtered and the solvent removed under vacuum to give a residue which was purified by silica column chromatography, eluting with dichloromethane/methanol/0.880 aqueous ammonia (100/8/1). The relevant fractions were combined and evaporated under vacuum to give a residue which was triturated with ether, filtered and dried to give 4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline (1.64 g, 48%).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])C.[OH-].[Na+]>Cl>[OH2:3].[ClH:17].[Cl:18][C:13]1[CH:12]=[C:11]([C:10]([CH:7]2[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]2)=[O:19])[CH:16]=[CH:15][C:14]=1[Cl:17].[Cl:18][C:13]1[CH:12]=[C:11]([C:10]([CH:7]2[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]2)=[O:19])[CH:16]=[CH:15][C:14]=1[Cl:17].[ClH:17]
Reactant: CC(=O)N1CCC(C(=O)c2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O
Product: O=C(c1ccc(Cl)c(Cl)c1)C1CCNCC1

Procedure:
A slurry of 15 g (0.05 mol) of 1-acetyl-4-(3,4-dichlorobenzoyl)piperidine in 150 mL of 6N hydrochloric acid was heated at mild reflux for 23 hr. The mixture was cooled and neutralized using 50% sodium hydroxide solution and ice. The mixture was extracted several times with benzene and the collected extracts were dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue obtained weighed 11.1 g (86%). The hydrochloride salt was made in the usual manner on 5 g of the free base. Recrystallization from isopropyl alcohol-ether gave a crystalline solid, mp 221-223.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)#N.Cl.CC[O:23]CC>O1CCCC1>[CH3:11][C:8]1[CH:9]=[CH:10][C:5]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[O:23])=[CH:6][CH:7]=1
Reactant: Cc1ccc(Br)cc1
Reactant: CCOCC
Reactant: N#Cc1ccccn1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
In a 250 mL flask were placed 1.425 g (58.5 mmol) of magnesium turnings, 35 mL of anhydrous ether and a iodine crystal. Next, 10 g (58.8 mmol) of 4-bromotoluene dissolved in 70 mL of ether was added dropwise. After the addition was complete, the resulting mixture was heated at reflux for 30 min. Then a solution of 6 g (58.5 mmol) of 2-cyanopyridine in 35 mL of anhydrous tetrahydrofuran was added dropwise and the reaction mixture was stirred at room temperature overnight. The resulting mixture was poured into 1N HCl and extracted several times with ethyl acetate. The organic phase was dried and the solvent was removed, to afford a crude product that was chromatographed on silica gel (hexane-ethyl acetate mixtures of increasing polarity) to give 7.2 g of the desired product (yield: 62%).
Reaction SMILES: C([C:3]1[C:8](=[O:9])[C:7]2[CH:10]=[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:6]=2[O:5][CH:4]=1)=O.[Cl:26][O-].[Na+]>>[Cl:26][C:3]1[C:8](=[O:9])[C:7]2[CH:10]=[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:6]=2[O:5][CH:4]=1
Reactant: CS(=O)(=O)Nc1cc2occ(C=O)c(=O)c2cc1Oc1ccccc1
Reactant: [O-]Cl
Agent: [Na+]
Product: CS(=O)(=O)Nc1cc2occ(Cl)c(=O)c2cc1Oc1ccccc1

Procedure:
3-Formyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was reacted with sodium hypochlorite to obtain 3-chloro-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH3:26][N:27]([CH3:32])[CH:28]1[CH2:31][NH:30][CH2:29]1>>[CH3:26][N:27]([CH3:32])[CH:28]1[CH2:31][N:30]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:20])[CH2:29]1
Reactant: CN(C)C1CNC1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CC(N(C)C)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 301 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and N,N-dimethylazetidin-3-amine. 1H NMR (500 MHz, DMSO-d6) δ ppm 2.33 (d, J=1.95 Hz, 3H) 2.81 (s, 6H) 4.07-4.21 (m, 1H) 4.29 (br. s., 2H) 4.47-4.59 (m, 1H) 4.66 (m, J=7.80 Hz, 1H) 7.63 (br. s., 1H) 7.71-7.78 (m, 1H) 7.91-8.81 (m, 4H). ESI-MS m/z [M+H]+ 421.3.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:12][N:13]([O:16]C2CCCCO2)[CH:14]=[O:15])[C:5]([F:30])=[C:4]([N:31]2[CH2:35][C@@H:34]([OH:36])[C:33]([CH3:38])([CH3:37])[CH2:32]2)[N:3]=1>CC(O)=O.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:12][N:13]([OH:16])[CH:14]=[O:15])[C:5]([F:30])=[C:4]([N:31]2[CH2:35][C@@H:34]([OH:36])[C:33]([CH3:38])([CH3:37])[CH2:32]2)[N:3]=1
Reactant: CC1(C)CN(c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(C=O)OC3CCCCO3)c2F)C[C@H]1O
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)CN(c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(O)C=O)c2F)C[C@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A solution of [(2R)-3-(2-{2-chloro-5-fluoro-6-[(4S)-4-hydroxy-3,3-dimethyl-1-pyrrolidinyl]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (0.1294 g, 0.232 mmol) in 4:1 HOAc-water (5 mL) was heated at 30° C. and stirred overnight. The solution was cooled to room temperature, concentrated in vacuo, and purified directly by Gilson RPLC to give [(2R)-3-(2-{2-chloro-5-fluoro-6-[(4S)-4-hydroxy-3,3-dimethyl-1-pyrrolidinyl]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide (69.1 mg, 63% yield) as a yellow solid. LCMS: (M+H)+: 473.2.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[O:5][C:6]1[CH:30]=[CH:29][C:9]([C:10]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:13]=2)=[O:11])=[CH:8][CH:7]=1.[CH3:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:31]1([CH:4]([O:5][C:6]2[CH:30]=[CH:29][C:9]([C:10]([C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:13]=3)=[O:11])=[CH:8][CH:7]=2)[CH2:3][CH2:2][N:48]2[CH2:47][CH2:46][N:45]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=3[O:38][CH3:37])[CH2:50][CH2:49]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(OC(CCBr)c3ccccc3)cc2)c2ccccc21
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1cc(C(=O)c2ccc(OC(CCN3CCN(c4ccccc4OC)CC3)c3ccccc3)cc2)c2ccccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
Ethyl 4-{3-[4-(3-bromo-1-phenylpropoxy)benzoyl]indol-1-yl}butanoate (1.97 g) obtained in Step 2 was dissolved in N,N-dimethylformamide (20 ml). 1-(2-Methoxyphenyl) piperazine (0.83 g) and potassium carbonate (0.75 g) were added to the resultant solution and stirred overnight at 60° C. After cooling, water was added to the reaction mixture, followed by extraction with ethyl acetate. The resultant extract was washed with brine and then dried. The solvent was distilled off. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), obtaining 1.95 g of ethyl 4-{3-{4-{1-phenyl-3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy}benzoyl}indol-1-yl}butanoate as a colorless oily substance.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][OH:15])=[CH:10][C:9]([O:16][CH3:17])=[CH:8][C:7]=1[CH:18]([NH:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[NH:37])=[CH:34][CH:33]=1)[C:19]1[NH:23][C:22](=[O:24])[N:21]([C:25]2[N:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[N:20]=1.CN(C=O)C.[N+](C1C=CC([O:55][C:56](=O)[C:57]2[CH:62]=[CH:61][C:60]([CH3:63])=[CH:59][CH:58]=2)=CC=1)([O-])=O>C(N(CC)CC)C>[NH2:37][C:36](=[N:38][C:56](=[O:55])[C:57]1[CH:62]=[CH:61][C:60]([CH3:63])=[CH:59][CH:58]=1)[C:35]1[CH:34]=[CH:33][C:32]([NH:31][CH:18]([C:7]2[CH:8]=[C:9]([O:16][CH3:17])[CH:10]=[C:11]([O:12][CH2:13][CH2:14][OH:15])[C:6]=2[F:5])[C:19]2[NH:23][C:22](=[O:24])[N:21]([C:25]3[N:26]=[CH:27][CH:28]=[CH:29][N:30]=3)[N:20]=2)=[CH:40][CH:39]=1
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Reactant: Cc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)c3ccc(C)cc3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-({[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl}amino)benzamidine acetic acid salt (1.6 g) and DMF (120 mL), 4-methylbenzoic acid 4-nitrophenyl ester [CAS No. 15023-67-3] (815 mg) and triethylamine (1.21 mL) were added, and the resulting mixture was stirred overnight at room temperature. The solvent in the reaction solution was distilled off under reduced pressure. The residue obtained was purified by NAM silica gel column chromatography (mixed solvent of methanol-ethyl acetate) to obtain the captioned compound (1.01 g).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][NH:6][C:7]1[N:8]=[C:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:10]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]=2[N:12]=1)C.[Li+].[OH-].Cl>C1COCC1.O>[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:9]1[C:10]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]=2[N:12]=[C:7]([NH:6][CH2:5][C:4]([OH:32])=[O:3])[N:8]=1
Reactant: CCOC(=O)CNc1nc(-c2ccccc2Cl)c2ccc(=O)n(-c3ccccc3Cl)c2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CNc1nc(-c2ccccc2Cl)c2ccc(=O)n(-c3ccccc3Cl)c2n1
Reaction time: 1 h

Procedure:
To a solution of the product of Example 83 (20 mg, 0.43 mmol) in THF (2 mL) was added LiOH (40 mg, 1.67 mmol) dissolved in H2O (1 mL). The reaction mixture was stirred 1 h at 23° and then neutralized with 1 M HCl, extracted with EtOAc (5 mL) and the layers were separated. The organic layer was washed with H2O, satd. aq NaCl, and dried (MgSO4). The solution was filtered and evaporated to give the title compound [4,8-bis-(2-chloro-phenyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-acetic acid. LC MS (m/e)=441 (MH+). Rt=1.85 min.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([C:11]([O-:13])=[O:12])[C:5]=2[CH:4]=[N:3]1.[Li+].[OH-].Cl>CO.C1COCC1.O>[CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([C:11]([OH:13])=[O:12])[C:5]=2[CH:4]=[N:3]1
Reactant: Cn1ncc2c1CCCC2C(=O)[O-]
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cn1ncc2c1CCCC2C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
To a solution of 1-methyl-4,5,6,7-tetrahydro-1H-indazole-4-carboxylate (7 g, 36 mmol) in methanol (100 mL), THF (50 mL) and H2O (50 mL) was added LiOH (2.5 g, 108 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was acidified with 1N HCl solution to pH=5-6, and extracted with EA three times. The combined organic layers were washed with brine, dried over Na2SO4. The solvent was concentrated to give 1-methyl-4,5,6,7-tetrahydro-1H-indazole-4-carboxylic acid (6 g, 94%), which was used in the next step directly.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]=O)=[C:8]2[C:3]=1[C:4](=[O:15])[CH:5]=[C:6]([CH3:14])[O:7]2.[C:16]([CH:18]=[C:19]([O-])[CH3:20])#[N:17].[Na+].[NH2:23]/[C:24](/[CH3:30])=[CH:25]\[C:26]([O:28][CH3:29])=[O:27].C(O)(=O)C>CC(O)C>[C:16]([C:18]1[CH:12]([C:9]2[CH:10]=[CH:11][C:2]([F:1])=[C:3]3[C:8]=2[O:7][C:6]([CH3:14])=[CH:5][C:4]3=[O:15])[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([CH3:30])[NH:23][C:19]=1[CH3:20])#[N:17]
Reactant: Cc1cc(=O)c2c(F)ccc(C=O)c2o1
Reactant: CC([O-])=CC#N
Reactant: COC(=O)/C=C(/C)N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C#N)C1c1ccc(F)c2c(=O)cc(C)oc12

Procedure:
A solution of 100 mg (0.49 mmol) of 5-fluoro-2-methyl-4-oxo-4H-chromene-8-carbaldehyde in 5 ml of 2-propanol is mixed with 50.96 mg (0.49 mmol) of sodium 1-cyanoprop-1-en-2-olate, 55.84 mg (0.49 mmol) of methyl 3-aminocrotonate and 0.04 ml (0.73 mmol) of acetic acid and stirred under reflux for 3 h. After cooling, the mixture is concentrated. The residue is taken up in dichloromethane and washed with water. The organic phase is dried over sodium sulfate and concentrated. The resulting residue is crystallized from diethyl ether. The beige-colored crystals are filtered off with suction and dried at 40° C. in a vacuum drying oven. 128.3 mg (71.8% of theory) of the title compound are obtained.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:14]=[C:13]([C:15](OCC)=[O:16])[C:12]([N+:20]([O-])=O)=[C:11]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])[N:10]=2)[CH2:4][CH2:3]1.ClC1N=C([C:39](OCC)=[O:40])C([N+]([O-])=O)=C(NC2C=CC=CC=2OC)N=1.[NH2:56][C@@H]1CC[C@H](O)CC1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:10]=[C:11]3[C:12]([NH:20][C:39](=[O:40])[N:23]3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[C:13]([C:15]([NH2:56])=[O:16])[N:14]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1nc(N[C@H]2CC[C@@H](O)CC2)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Reactant: CCOC(=O)c1nc(Cl)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Reactant: N[C@H]1CC[C@@H](O)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(N[C@H]3CC[C@@H](O)CC3)nc21

Procedure:
Ethyl 2-(cis-4-hydroxycyclohexylamino)-6-(2-methoxyphenylamino)-5-nitropyrimidine-4-carboxylate. Ethyl 2-chloro-6-(2-methoxyphenylamino)-5-nitropyrimidine-4-carboxylate (See Example 30.A) (0.300 g, 0.852 mmol), cis-4-aminocyclohexanol (0.155 g, 1.022 mmol) and diisopropylethylamine (0.274 g, 2.13 mmol) were reacted according to General Procedure C, except at room temperature and in dimethylformamide (5 mL). The crude reaction mixture was condensed and purified using Biotage chromatography (0-100% ethyl acetate in hexanes) to afford the title compound (0.342 g, 93%). MS (ESI) m/z 432.0 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.BrC1C=CC(Cl)=CC=1[CH2:21][O:22][CH2:23]OC>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[CH2:4][O:6][CH2:21][O:22][CH3:23]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: COCOCc1cc(Cl)ccc1Br
Product: COCOCc1cc(OC)ccc1Br

Procedure:
This compound was made from 2-bromo-5-methoxybenzoic acid in the same manner as compound 18d: 1H NMR (300 MHz, DMSO-d6): δ 3.30 (s, 1H), 3.74 (s, 3H), 4.50 (s, 2H), 4.69 (s, 2H), 6.83 (dd, J=8.8, 2.9 Hz, 1H), 7.40 (d, J=2.9 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H).
Reaction SMILES: [C:1](=[O:16])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:2][CH:3](Cl)[CH2:4][CH2:5][CH2:6][CH3:7].[C:17]([NH:20][C:21]1[C:22]([I:37])=[C:23]([N:32]([C:34](=[O:36])[CH3:35])[CH3:33])[C:24]([I:31])=[C:25]([C:28]([O-:30])=[O:29])[C:26]=1[I:27])(=[O:19])[CH3:18].[K+].[I-].[Na+]>CN(C=O)C>[C:17]([NH:20][C:21]1[C:22]([I:37])=[C:23]([N:32]([C:34](=[O:36])[CH3:35])[CH3:33])[C:24]([I:31])=[C:25]([C:28]([O:30][CH:3]([O:2][C:1]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH2:4][CH2:5][CH2:6][CH3:7])=[O:29])[C:26]=1[I:27])(=[O:19])[CH3:18]
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Reactant: CCCCC(Cl)OC(=O)Oc1ccccc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(OC(=O)Oc1ccccc1)OC(=O)c1c(I)c(NC(C)=O)c(I)c(N(C)C(C)=O)c1I
Temperature: 50 °C
Reaction time: 48 h

Procedure:
1-Chloropentyl phenyl carbonate (0.14 g, 0.58 mmol) was added at room temperature to a solution of potassium 5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate (0.35 g, 0.53 mmol) and sodium iodide (0.008 g, 0.053 mmol) in dry DMF (3 ml). After stirring at 50° C. for 5 hours and at room temperature for 2 days the solvent was removed at reduced pressure. The residue was suspended in chloroform (15 ml) and washed four times with a saturated sodium hydrogen carbonate solution and finally twice with water. After drying with magnesium sulfate the solution was evaporated to drynes. Yield: 0.04 g. Purity by HPLC: 94.8% 1H-NMR (DMSO-d6): delta=0.92(CH3CH2); 1.31-1.55 (CH3CH2CH2); 1.68 (NCH3COCHhd 3); 2.04 (CH2CH); 2. 05 (NHCOCH3); 2.97 (NCH3); 6.95 (CH); 7.27-7.49 (phenyl); 10.13 ppm (NH). FAB/MS: 835 ((M+H)+).
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:22]2[C:17](=[CH:18][C:19](Br)=[CH:20][CH:21]=2)[C:16]=1[O:27][S:28]([C:31]([F:34])([F:33])[F:32])(=[O:30])=[O:29])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:35](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1>[C:1]([O:7][CH2:8][C@@H:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:15]1[C:24]([CH3:25])=[CH:23][C:22]2[C:17](=[CH:18][C:19]([CH3:35])=[CH:20][CH:21]=2)[C:16]=1[O:27][S:28]([C:31]([F:34])([F:33])[F:32])(=[O:30])=[O:29])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1cc2ccc(Br)cc2c(OS(=O)(=O)C(F)(F)F)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccc2cc(C)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(OS(=O)(=O)C(F)(F)F)c2c1
Temperature: 125 °C

Procedure:
To a solution of (S)-2-(7-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-tert-butoxyethyl pivalate (825 mg, 1.45 mmol) in 1,4-dioxane (7 mL) was added potassium carbonate (601 mg, 4.35 mmol), trimethylboroxine (220 mg, 1.74 mmol), and PdXPhos catalyst (107 mg, 0.145 mmol). The mixture was heated in a sealed vial in the microwave at 125° C. for 1 h. The mixture was filtered and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexanes) to give the desired product. 1H-NMR: 400 MHz, (CDCl3) δ: 7.84 (s, 1H), 7.66 (d, J=8 Hz, 1H), 7.62 (s, 1H), 7.36 (d, J=8 Hz, 1H), 5.48 (dd, J=9, 3 Hz, 1H), 4.65 (dd, J=12, 9 Hz, 1H), 4.16 (dd, J=12, 3 Hz, 1H), 2.75 (s, 3H), 2.54 (s, 3H), 1.23 (s, 9H) 1.12 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[S:9](Cl)(=[O:11])=[O:10].[CH2:15]([NH2:18])[C:16]#[CH:17]>O1CCOCC1.Cl>[CH2:15]([NH:18][S:9]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:3]=1[C:2]([F:14])([F:13])[F:1])(=[O:11])=[O:10])[C:16]#[CH:17]
Reactant: O=S(=O)(Cl)c1cnccc1C(F)(F)F
Reactant: C#CCN
Agent: Cl
Solvent: C1COCCO1
Product: C#CCNS(=O)(=O)c1cnccc1C(F)(F)F
Reaction time: 8 h

Procedure:
4-Trifluoromethyl-pyridine-3-sulfonyl chloride (0.45 g) was dissolved in dioxane (3 ml), and pro-pargylamine (0.63 ml) was added to the mixture and allowed to stand at ambient temperature overnight. The reaction was diluted with 0.5% HCl and 37% HCl was added drop-wise until the mixture became acidic. This was extracted three times with-ethyl acetate. The ethyl acetate portions were combined, washed with saturated sodium bicarbonate and dried with magnesium sulfate. The drying agent was filtered away and the solvent evaporated to give 0.13 g of crude 4-tri-fluoromethyl-pyridine-3-sulfonic acid prop-2-ynylamide, which was chromatographed an silica gel using ethyl acetate and methylene chloride to yield 0.08 g of purified 4-Trifluoromethyl-pyridine-3-sulfonic acid prop-2-ynylamide. LC/ms analysis with RT=1.36 min yielded a purity of 98% m+/m− of 264.8/262.9. Melting-point of the purified compound tested as 97-98° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([CH2:15]O)([CH2:13]O)[CH2:10][C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([CH2:15][S:23]([C:20]3[CH:21]=[CH:22][C:17]([CH3:9])=[CH:18][CH:19]=3)(=[O:25])=[O:24])([CH2:13][S:33]([C:30]3[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=3)(=[O:35])=[O:34])[CH2:10][C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CS(=O)(=O)c1ccc(C2=C(c3ccc(F)cc3)CC(CO)(CO)C2)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)CC2(CS(=O)(=O)c3ccc(C)cc3)CC(c3ccc(F)cc3)=C(c3ccc(S(C)(=O)=O)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 138.8 %

Procedure:
Under nitrogen, a solution of 2.34 mmol of the crude 1-[2-(4-fluorophenyl)-4,4-di(hydroxymethyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene (prepared in Step 9) in 8 mL of pyridine at ambient temperature was treated with 1.2 g (6.3 mmol) of p-toluenesulfonyl chloride (tosyl chloride). The resulting solution was stirred at room temperature for 17 hours, concentrated in vacuo, and chromatographed on silca gel to give 1.06 g (66% overall yield from Step 9) of 1-[2-(4-fluorophenyl)-4,4-di(tosylmethyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene as a colorless solid: NMR (CDCl3) δ 2.46 (s, 6H), 2.73 (s, 3H), 3.04 (s, 3H), 4.05 (s, 4H), 6.85-7.0 (m, 4H), 7.20 (d, J=8 Hz, 2H), 7.34 (d, J=8 Hz, 4H), 7.75 (d, J=8 Hz, 6H).
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([NH2:8])[CH:2]=1.Cl[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1>>[NH2:7][C:6]1[CH:5]=[CH:4][C:3]([N:8]([C:3]2[CH:2]=[CH:1][C:6]([NH2:7])=[CH:5][CH:4]=2)[C:10]2[CH:15]=[CH:14][C:13]([N:16]([C:10]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=3)[C:10]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=3)=[CH:12][CH:11]=2)=[CH:2][CH:1]=1
Reactant: Nc1ccc(N)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Product: Nc1ccc(N(c2ccc(N)cc2)c2ccc(N(c3ccc(N)cc3)c3ccc(N)cc3)cc2)cc1

Procedure:
Such a diimonium compound can be synthesized, for example, as follows. That is, an Ullmann reaction product of p-phenylenediamine and 1-chloro-4-nitrobenzene, is reduced to obtain N,N,N′,N′-tetrakis(p-aminophenyl)-p-phenylenediamine which is then dissolved in N,N-dimethylformamide, and an alkyl bromide is added thereto, followed by a reaction, for example, at 130° C. for 10 hours.