Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:18]2[C:23](=[O:24])[NH:22][C:21](=[O:25])[CH:20]=[N:19]2)[CH:5]=[CH:6][C:7]=1[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])O.S(Cl)([Cl:28])=O>ClC(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:18]2[C:23](=[O:24])[NH:22][C:21](=[O:25])[CH:20]=[N:19]2)[CH:5]=[CH:6][C:7]=1[CH:8]([Cl:28])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17]
Reactant: O=c1cnn(-c2ccc(C(O)c3ccc(Cl)cc3Cl)c(Cl)c2)c(=O)[nH]1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=c1cnn(-c2ccc(C(Cl)c3ccc(Cl)cc3Cl)c(Cl)c2)c(=O)[nH]1
Reaction time: 3 h

Procedure:
To a stirred mixture of 16 parts of 2-[3-chloro-4-[(2.4-dichlorophenyl) hydroxymethyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione and 150 parts of trichloromethane are added dropwise, during a period of 5 minutes, 16 parts of thionyl chloride. Upon completion, stirring is continued for 3 hours at reflux temperature. The reaction mixture is 10 evaporated in vacuo. Methylbenzene is added and the whole is evaporated again, yielding 2-[3-chloro-4-[chloro(2,4-dichlorophenyl) methyl]phenyl]1,2,4-triazine-3,5(2H,4H)-dione.
Reaction SMILES: C([NH:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH:18][C:19]3[CH:24]=[C:23]([C:25](=[O:37])NC4C=CC=C(C(F)(F)F)C=4)[CH:22]=[CH:21][C:20]=3[CH3:38])=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1)(C)(C)C.[CH3:39][C:40]1[N:41]=[CH:42][N:43]([C:45]2[CH:46]=[C:47]([CH:49]=[C:50]([C:52]([F:55])([F:54])[F:53])[CH:51]=2)[NH2:48])[CH:44]=1.NC1C=CC=CC=1>>[NH2:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH:18][C:19]3[CH:24]=[C:23]([C:25](=[O:37])[NH:48][C:47]4[CH:49]=[C:50]([C:52]([F:55])([F:53])[F:54])[CH:51]=[C:45]([N:43]5[CH:44]=[C:40]([CH3:39])[N:41]=[CH:42]5)[CH:46]=4)[CH:22]=[CH:21][C:20]=3[CH3:38])=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1cccc2c(NC(C)(C)C)nccc12
Reactant: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Solvent: Nc1ccccc1
Product: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(NC(=O)c4cccc5c(N)nccc45)c3)cc(C(F)(F)F)c2)cn1
Yield: 7.5 %

Procedure:
The procedures of Steps (1), (2) and (3) of Example 2 and Step (4) of Example 1 were repeated step by step, except for using 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline obtained in Step (1) above instead of aniline in Step (1) of Example 2 to obtain the title compound (3.0 mg, 7.5%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:21]=[CH:20][C:19]2[O:18][C:17]3[C:12](=[CH:13][C:14]([C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26]Cl)=[CH:15][CH:16]=3)[CH2:11][C:10]=2[CH:9]=1)=[O:7].[I-].[K+].[CH2:31]([NH:34][CH2:35][CH:36]=[CH2:37])[CH:32]=[CH2:33]>O1CCCC1>[CH2:31]([N:34]([CH2:35][CH:36]=[CH2:37])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:21]=[CH:20][C:19]2[O:18][C:17]3[C:12](=[CH:13][C:14]([C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][N:34]([CH2:35][CH:36]=[CH2:37])[CH2:31][CH:32]=[CH2:33])=[CH:15][CH:16]=3)[CH2:11][C:10]=2[CH:9]=1)=[O:7])[CH:32]=[CH2:33]
Reactant: C=CCNCC=C
Reactant: O=C(CCCCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCCCl)ccc1O2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCN(CC=C)CCCCC(=O)c1ccc2c(c1)Cc1cc(C(=O)CCCCN(CC=C)CC=C)ccc1O2
Temperature: 120 °C
Reaction time: 24 h

Procedure:
A mixture of 41.9 g (0.1 mole) of 2,7-bis(5-chlorovaleryl)-xanthene, 2 g of potassium iodide, 100 ml of diallylamine and 200 ml. of tetrahydrofuran was heated and stirred at 120°C. for 24 hours. After cooling, the reaction mixture was filtered and the filtrate evaporated to dryness. The resulting residue was cooled, dissolved in 10% HCl, extracted with diethyl ether and made alkaline. The product was extracted with methylene chloride, evaporated to dryness, recrystallized six times from heptane and dried in vacuo to give the desired product. M.P. 54°-55°C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([CH2:34][CH:35]=[CH2:36])[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[Cl:25])[C:21]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[OH2:38].C[N+]1([O-])CCOCC1.[OH2:47]>CC(C)=O.C(O)(C)(C)C.[Os](=O)(=O)(=O)=O>[C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([CH2:34][CH:35]([OH:47])[CH2:36][OH:38])[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[Cl:25])[C:21]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCC1(NC(=O)OC(C)(C)C)CCC(Oc2cc3ccnc(OCc4ccccc4)c3cc2Cl)CC1
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: CC(C)=O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)NC1(CC(O)CO)CCC(Oc2cc3ccnc(OCc4ccccc4)c3cc2Cl)CC1
Temperature: 25 °C

Procedure:
A solution of 100 mg (0.19 mmol) of [1-allyl-4-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-cyclohexyl]-carbamic acid tert-butyl ester (52) in a mixture of 250 μL of water and 500 μL of acetone was treated with 36.2 mg (0.27 mmol) N-methylmorpholine oxide monohydrate and 24.0 μL (1.91 μmol) of a 2.5% solution of osmium tetroxide in tert-butanol. The mixture was stirred at room temperature until complete conversion was indicated by LCMS. The reaction was then quenched by addition of saturated aqueous sodium bisulfite, extracted with ethyl acetate, dried over magnesium sulfate and concentrated. 68 mg of crude [4-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-1-(2,3-dihydroxy-propyl)-cyclohexyl]-carbamic acid tert-butyl ester (56) could be isolated as mixture of stereoisomers. Rt=1.92 min (Method C). Detected mass: 557.3 (M+H+).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]([CH3:22])[C:12]3[C:17]([C:18]=2[C:19]#[N:20])=[CH:16][CH:15]=[C:14]([Cl:21])[CH:13]=3)[CH:7]=[N:8][CH:9]=1)[CH3:3].[CH2:23]([S:25](Cl)(=[O:27])=[O:26])[CH3:24].C(N(CC)CC)C>ClCCl>[Cl:21][C:14]1[CH:13]=[C:12]2[C:17]([C:18]([C:19]#[N:20])=[C:10]([C:6]3[CH:5]=[C:4]([CH:2]([NH:1][S:25]([CH2:23][CH3:24])(=[O:27])=[O:26])[CH3:3])[CH:9]=[N:8][CH:7]=3)[N:11]2[CH3:22])=[CH:16][CH:15]=1
Reactant: CC(N)c1cncc(-c2c(C#N)c3ccc(Cl)cc3n2C)c1
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)NC(C)c1cncc(-c2c(C#N)c3ccc(Cl)cc3n2C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask is charged with 2-[5-(1-amino-ethyl)-pyridin-3-yl]-6-chloro-1-methyl-1H-indole-3-carbonitrile (0.072 g, 0.209 mmol) and dichloromethane (3 mL). Ethanesulfonyl chloride (0.060 g, 0.525 mmol) and triethylamine (0.059 mL, 0.417 mmol) are added and the reaction is stirred at room temperature overnight. The reaction mixture is concentrated in vacuo to give a residue which is purified by silica gel flash chromatography (heptane-ethyl acetate, 1:1) to afford ethanesulfonic acid {1-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-ethyl}-amide as a white solid. 1H NMR (400 MHz, MeOD) δ ppm 1.32 (t, J=7.5 Hz, 3H), 1.65 (d, J=7.1 Hz, 3H), 2.96-3.15 (m, 2H), 3.84 (s, 3H), 4.75-4.86 (m, 1H), 7.39 (dd, J=8.6, 1.8 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.78 (d, J=1.5 Hz, 1H), 8.20 (t, J=2.0 Hz, 1H), 8.80 (d, J=2.0 Hz, 1H), 8.83 (d, J=2.3 Hz, 1H). HRMS (ESI) m/z 403.1005 [(M+H)+ Calcd for C19H20N4O2SCl: 403.0996].
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].Br[CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[N:24]=1)=[O:18].[H-].[Na+]>CN(C=O)C>[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[C:23]1[N:24]=[C:20]([NH:19][C:17](=[O:18])[CH2:16][N:10]2[C:6]3[C:5](=[O:12])[N:4]([CH3:13])[C:3](=[O:14])[N:2]([CH3:1])[C:7]=3[CH:8]=[CH:9]2)[S:21][CH:22]=1
Reactant: O=C(CBr)Nc1nc(-c2ccc(F)cc2F)cs1
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ccn2CC(=O)Nc2nc(-c3ccc(F)cc3F)cs2)n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (50 mg, 0.279 mmol) with 2-bromo-N-[4-(2,4-difluorophenyl)-1,3-thiazol-2-yl]acetamide (111 mg, 0.330 mmol) in the presence of NaH (16 mg, 0.666 mmol) in dry DMF (5.0 mL) to give 60 mg of the product as a white solid; 1H NMR (δ ppm, DMSO-d6, 300 MHz) 3.17 (s, 3H), 3.40 (s, 3H), 5.32 (s, 2H), 6.23 (s, 1H), 7.21-7.27 (m, 1H), 7.36-7.42 (m, 2H), 7.52 (s, 1H), 8.03-8.10 (m, 1H), 12.70 (br s, 1H); APCI-MS (m/z) 432.20 (M+H)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH3:16])=[CH:9][CH:8]=1.[Cl:17][Si:18](Cl)([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20].C(OCC)C>C1COCC1>[Cl:17][Si:18]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH3:16])=[CH:9][CH:8]=1
Reactant: COCOc1ccc(Br)cc1
Reactant: CC(C)[Si](Cl)(Cl)C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCOc1ccc([Si](Cl)(C(C)C)C(C)C)cc1
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 71.2 %

Procedure:
A solution of n-butyllithium (1.6M, 72.50 mL, 0.116 mol) was added slowly dropwise to a solution of bromo-4-methoxymethoxybenzene (25.23 g, 0.116 mol) in dry THF (110 mL) at −78° C. After stirring for 50 min at −78° C., dichlorodiisopropylsilane (21.00 mL, 0.116 mol) was charged into the flask. The reaction mixture was slowly allowed to warm to room temperature with stirring. Diethyl ether (100 mL) was added, the mixture was then stirred for 15 min and filtered. The filtrate was concentrated in vacuo to an oil. The oil was purified by short path distillation (116-128° C./0.18 mm Hg) to afford the compound (23.7 g, 71%) as a slightly cloudy pale yellow oil.
Reaction SMILES: [N:1]1C=CC=NC=1.[N:7]1[CH:15]=[C:14]2[C:10]([N:11]=C[NH:13]2)=[N:9][CH:8]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>>[NH2:13][C:14]1[C:10]([NH2:11])=[N:9][C:8]([NH2:1])=[N:7][CH:15]=1
Reactant: c1ncc2[nH]cnc2n1
Reactant: c1cncnc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: Nc1ncc(N)c(N)n1

Procedure:
The amine of the formula 69 is subsequently reacted with a substituted chloropyrimidine. The amine can be condensed, for example, with 2-amino-6-chloro-5-nitro-4-(3H)-pyrimidinone in the presence of a tertiary amine base, preferably triethylamine, in refluxing n-butanol to give a pyrimidine compound of formula 70. The pyrimidine compound of formula 70 can then be converted to a purine derivative by a two step procedure. In the first step, the nitro moiety of the pyrimidine is reduced with, for example, sodium dithionite, to give a triaminopyrimidine intermediate. Alternative reducing agents and conditions that can also successfully reduce the nitro group include NaBH4/THF, NaBH4—BiCl3, Sn/HCl, SnCl2, Mg/(NH4)2SO4/MeOH, CuBr.SMe2, TiCl2(Cp)2/Sm, iron and nickel catalyzed procedures. In the second step, treatment of the triaminopyrimidine intermediate with formic acid, hydrochloric acid, and an orthoformate derivative, e.g., triethylorthoformate, effects cyclization and provides the methylene compound of formula 71. The methylene compound of formula 71 can be converted to the compound of formula 21 by the oxidation procedure described in the final steps of Processes B and C.
Reaction SMILES: CS(C)=O.[CH3:5][O:6][C:7](=[O:23])[CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][N:14]1[C:19](=[O:20])[CH2:18][CH2:17][CH2:16][C@@H:15]1[CH2:21][OH:22].FC(F)(F)C([O-])=O.[NH+]1C=CC=CC=1>C1C=CC=CC=1>[CH3:5][O:6][C:7](=[O:23])[CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][N:14]1[C:19](=[O:20])[CH2:18][CH2:17][CH2:16][C@@H:15]1[CH:21]=[O:22]
Reactant: COC(=O)CCCC=CCN1C(=O)CCC[C@@H]1CO
Agent: O=C([O-])C(F)(F)F
Agent: c1cc[nH+]cc1
Solvent: CS(C)=O
Solvent: c1ccccc1
Product: COC(=O)CCCC=CCN1C(=O)CCC[C@@H]1C=O
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
7-((R)-2-Hydroxymethyl-6-oxo-piperidin-1-yl)-hept-5-enoic Acid Methyl ester 95% Ethanol (0.5 mL) was added to a mixture of nickel (II) chloride (105 mg, 0.81 mmol) and sodium borohydride (15 mg, 0.40 mmol). The mixture immediately turned black. After 15 min at rt, ethylene diamine (86 μL, 1.29 mmol) was added. After 15 min at rt, a solution of 7-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester (from Example 1, step 3, 43.3 mg, 0.16 mmol) in 95% ethanol (1.0 mL) was added via cannula. A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 19 h. The reaction mixture was filtered through celite, washing with ethanol, and the filtrate was concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→3% MeOH/CH2Cl2, gradient) afforded 16.7 mg (38%) of 7-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-hept-5-enoic acid methyl ester. Step 2. 7-((R)-2-Formyl-6-oxo-piperidin-1-yl)-hept-5-enoic acid methyl ester EDCI (36 mg, 0.19 mmol) and DMSO (18 μL, 0.25 mmol) were added sequentially to a solution of 7-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-hept-5-enoic acid methyl ester (16.7 mg, 0.062 mmol) in benzene (1.0 mL) at rt. The mixture was cooled to 0° C. and pyridinium trifluoroacetate (13.2 mg, 0.068 mmol) was added. The reaction was allowed to warm to rt and then was stirred at rt for 2.5 h. The solution was decanted from the oily residue and the residue was washed with benzene (3×1 mL). The combined benzene phases were concentrated in vacuo to afford crude 7-((R)-2-formyl-6-oxo-piperidin-1-yl)-hept-5-enoic acid methyl ester that was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:19](O)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1>>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[CH2:10][N:5]1[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:19]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[O:26])[N:3]=[CH:4]1
Reactant: O=C(O)c1cccnc1
Reactant: COc1cccc(Cn2cnc(N)c2C(N)=O)c1
Product: COc1cccc(Cn2cnc(NC(=O)c3cccnc3)c2C(N)=O)c1
Yield: 62 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 19, using 2.96 g (12.0 mmol) of 4-amino-1-(3-methoxybenzyl)-5-imidazole carboxamide which was prepared in the same manner as in Example 81 and nicotinic acid instead of cyclopentylacetic acid to obtain 2.61 g of 1-(3-methoxybenzyl)-4-(3-pyridylcarbonylamino)-5-imidazolecarboxamide (yield 62%).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=O)[CH3:2]>C(O)(=O)C.[Pd]>[CH2:1]([N:3]([CH2:4][CH2:5][CH2:6][C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)[CH2:17][CH3:18])[CH3:2]
Reactant: CCN(CC)CCC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCN(CC)CCCc1ccc([N+](=O)[O-])cc1
Reaction time: 20 h

Procedure:
A slurry of 5% Pd/C (2.5 g) in glacial acetic acid (30 mL) was added to a solution of 3-(diethylamino)-4′-nitro-propiophenone (14.33 g, 50 mmol) in glacial acetic acid (150 mL). The mixture was shaken on a Parr shaker under hydrogen pressure for about 20 hours. The catalyst was filtered, and the solvent was evaporated to dryness. The resulting amber liquid was dissolved in ether and washed twice with 2N NaOH (150 mL). The ether layer was dried and evaporated to give N,N-diethyl-3-(p-nitrophenyl)-propylamine as an oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6](Br)=[CH:7][CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[C:23]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:24]=[C:25]([CH:31]=2)[C:26]([O:28][CH2:29][CH3:30])=[O:27])O1.[F-].[Cs+]>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>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:21]3[CH:31]=[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:24]=[C:23]([CH:22]=3)[C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:5]=2)[CH:10]=[CH:11][C:2]=1[C:21]1[CH:31]=[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:24]=[C:23]([CH:22]=1)[C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: Brc1ccc2ccc(Br)nc2n1
Reactant: CCOC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)OCC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Product: CCOC(=O)c1cc(C(=O)OCC)cc(-c2ccc3ccc(-c4cc(C(=O)OCC)cc(C(=O)OCC)c4)nc3n2)c1
Yield: 70 %

Procedure:
To a 250 mL Schlenk flask, 2,7-dibromo-1,8-naphthyridine (2.00 g, 6.94 mmol), diethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isophthalate (6.06 g, 17.40 mmol, this compound was synthesized according to literature method: J. Natera, L. Otero, L. Sereno, F. Fungo, N.-S. Wang, Y.-M. Tsai, T.-Y. Hwu, K.-T. Wong, Macromolecules 2007, 40, 4456-4463), CsF (4.00 g) and Pd(PPh3)4 (200 mg) were added. The flask was connected to a Schlenk line and evacuated of air then refilled with nitrogen. 140 mL of 1,2-dimethoxyethane (DME) was degassed (two hours) and added to the flask through a canula. The flask was equipped with a water condenser and refluxed under nitrogen for 3 days. The solvent was removed on a rotary evaporator. 100 mL of H2O was added and then extracted with CHCl3. The organic phase was dried with MgSO4. After removal of the CHCl3 solvent, the crude product was purified by column chromatography (silica, ethyl acetate/hexane, 20% and then 50%) to give a yellow solid product with a yield of 70% (2.77 g) based on 2,7-dibromo-1,8-naphthyridine. 1H NMR (300 MHz, DMSO-d6): δ 1.42 (t, 12H), 4.46 (q, 8H), 8.43 (d, 2H), 8.60 (s, 2H), 8.69 (d, 2H), 9.07 (s, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][C:10](OS(C3C=CC=CC=3)(=O)=O)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[BrH:28].C(=O)([O-])O.[Na+]>C(O)(=O)C>[Br:28][C:10]1[CH2:11][CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]=1
Reactant: Br
Reactant: CCOC(=O)C1CC(OS(=O)(=O)c2ccccc2)=NN1c1ncccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C1CC(Br)=NN1c1ncccc1Cl
Yield: 85 %

Procedure:
A solution of ethyl 1-(3-chloro-2-pyridinyl)-4,5-dihydro-3-[(phenylsulfonyl)oxy]-1H-pyrazole-5-carboxylate (i.e. the product of Step A)(1.0 g, 2.44 mmol) in acetic acid (4 mL) was added to a solution of hydrogen bromide in acetic acid (33%, 1.2 g, 4.89 mmol). After about 1 h the reaction mixture was added to saturated aqueous sodium hydrogen carbonate solution (100 mL). The mixture was then extracted with ethyl acetate (2×50 mL), and the combined extracts were dried (MgSO4) and evaporated to provide the title product as an oil (0.69 g, 85% yield), which slowly crystallized. The 1H NMR spectrum was the same as reported for the product of Example 1, Step C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][CH:14]=[CH:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+]>C(OC(=O)C)(=O)C>[F:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[S:13][C:14]([N+:1]([O-:4])=[O:2])=[CH:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])O
Reactant: CS(=O)(=O)c1ccc(-c2ccsc2-c2ccc(F)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CS(=O)(=O)c1ccc(-c2cc([N+](=O)[O-])sc2-c2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Nitric acid (d=1.42; 1.6 ml) was added dropwise to a stirred solution of 2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]thiophene (6 g) in acetic anhydride (98 ml) at -5° to 0° C. The mixture was stirred for 1 hour at 0° C., treated with sodium bicarbonate (1 g), and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and an aqueous solution of sodium bicarbonate, and concentrated. The residue was purified by column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (20:1) to give yellow crystals of 2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-nitrothiophene (4.4 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]([C:14]1[CH:19]=[CH:18][C:17](Cl)=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1)([CH3:13])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][NH2:25]>>[C:1]([O:5][C:6]([NH:8][C@@:9]([C:14]1[CH:19]=[CH:18][C:17]([NH:25][CH3:24])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1)([CH3:13])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(C(=O)O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN
Product: CNc1ccc([C@@](C)(NC(=O)OC(C)(C)C)C(=O)O)cc1[N+](=O)[O-]

Procedure:
Prepared analogously to Example 1b from (R)-2-tert.butyloxycarbonylamino-2-(4-chloro-3-nitro-phenyl)-propionic acid and methylamine.
Reaction SMILES: N#N.[H-].[Na+].[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([N:15]([CH3:17])[CH3:16])[C:13]#N)=[CH:8][CH:7]=1.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][C:23](CCl)=[CH:22][CH:21]=1>O.CN(C)C=O>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:15]([CH3:17])[CH3:16])=[CH:13][C:23]2[CH:26]=[CH:27][C:20]([C:19]([F:29])([F:28])[F:18])=[CH:21][CH:22]=2)=[CH:8][CH:7]=1
Reactant: FC(F)(F)c1ccc(CCl)cc1
Reactant: CN(C)C(C#N)c1ccc(F)cc1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=Cc1ccc(C(F)(F)F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Yield: 88.3 %

Procedure:
Into a 200 ml four-necked flask equipped with a thermometer, a stirrer, a dropping funnel and a N2 gas supply tube, a N2 gas was introduced so that the interior of the flask became a N2 atmosphere. 40 ml of dimethylformamide and 2.4 g (61.6 mmol) of sodium hydride (62% oil suspension) were charged, and a solution comprising 10 g (56 mmol) of 2-(4-fluorophenyl)-2-(N,N-dimethylamino)acetonitrile and 10.9 g (56 mmol) of 4-(trifluoromethyl)benzyl chloride, was dropwise added over a period of one hour at from 5 to 10° C. under cooling with ice water and then further reacted at from 20 to 30° C. for one hour. After completion of the reaction, 200 ml of water was added, and the mixture was extracted with 200 ml of ethyl acetate. The extract was washed with a 5% sodium hydrogen carbonate aqueous solution and water and then dried over anhydrous sodium sulfate. Ethyl acetate was distilled off, and the obtained oily substance was distilled under reduced pressure to obtain 15.3 g (yield: 88.3%) of the desired compound (boiling point: 130-135° C./0.6 KPa). The NMR spectrum data thereof were as follows.
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([CH3:20])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][NH2:19])=[O:14])=[CH:8][CH:7]=1)[CH:3]([CH3:5])[CH3:4].CS[C:23]1[NH:24][CH2:25][CH2:26][N:27]=1>>[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([CH3:20])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:23]2[NH:27][CH2:26][CH2:25][N:24]=2)=[O:14])=[CH:8][CH:7]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CSC1=NCCN1
Reactant: CC(C)Cc1ccc([C@@H](C)C(=O)NCCCN)cc1
Agent: Cl
Product: CC(C)Cc1ccc([C@@H](C)C(=O)NCCCNC2=NCCN2)cc1

Procedure:
The (R)2-[(4-isobutylphenyl)-N-3-(aminopropyl)propionamide hydrochloride (see example 5) is converted in the free amine and treated with 2-methylthio-2-imidazoline iodohydrate (commercial reactant) according to the above cited Bodanszky procedure (J. Am. Chem. Soc., 86, 4452, 1964) to give (R)2-(4′-isobutylphenyl)-N-[3-(imidazolin-2-yl)aminopropyl]propionamide