Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1[CH3:8].[Cu](C#N)[C:11]#[N:12]>CN(C)C=O>[Br:9][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:7]=1[CH3:8])[C:11]#[N:12]
Reactant: N#C[Cu]C#N
Reactant: Cc1c(Br)cncc1Br
Solvent: CN(C)C=O
Product: Cc1c(Br)cncc1C#N
Temperature: 150 °C

Procedure:
To a stirred solution of 3,5-dibromo-4-methylpyridine (2.0 g, 7.97 mmol) in dry N,N-dimethylformamide (10 mL) was added copper cyanide (1.07 g, 11.95 mmol) at room temperature. The reaction mixture was heated at 150° C. for 6 h, cooled it, quenched with water (5 mL) and extracted with 50% ethyl acetate/hexane (2×100 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to obtain the title compound. MS (M+1): 199.1.
Reaction SMILES: [S:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([NH:16]C(=O)C)=[CH:12][CH:11]=1)(=[O:9])=[O:8].C([O-])([O-])=O.[Na+].[Na+]>Cl>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([S:7]([NH:6][C:2]2[S:1][CH:5]=[N:4][N:3]=2)(=[O:9])=[O:8])=[CH:11][CH:12]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2nncs2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Nc1ccc(S(=O)(=O)Nc2nncs2)cc1
Yield: 50 %

Procedure:
Compound 102 (1.0 g, 3.6 mmol) was suspended in 3N HCl (10 mL) and heated to reflux for 30 min. The acidic mixture was neutralized with Na2CO3 solution. The precipitated product was collected by filtration, washed with water, and dried to give the product (450 mg, 1.8 mmol, 49%), mp 226° C. (lit1 mp 221-222° C.); 1H NMR (250 MHz, CDCl3) δ 5.95 (2, s), 6.57 (2, d, J=6.5 Hz), 7.41 (2, d, J=6.5 Hz), 8.68 (1, s), 14.03 (1, br s).
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].C(#N)C.C1(C)C=CC=CC=1.[Cl:15][C:16]([Cl:21])([Cl:20])[C:17](Cl)=[O:18]>O>[Cl:15][C:16]([Cl:21])([Cl:20])[C:17]([N:3]=[C:2]=[O:1])=[O:18]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: N#C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC#N
Product: O=C=NC(=O)C(Cl)(Cl)Cl

Procedure:
To a 500 ml three neck flask equipped with a reflux condenser, thermometer, 250 ml addition funnel, magnetic stirrer, and water bath was charged 43.9 grams (0.675 mole) sodium cyanate, 75 ml acetonitrile, and 125 ml toluene. To the addition funnel was added 123 grams (0.675 mole) trichloroacetyl chloride. The trichloroacetyl chloride was added under nitrogen atmosphere at a rate to maintain the reaction temperature between 30°-40° C. After the addition was complete (30 min) the water bath was replaced with an electric heating mantle and the mixture was maintained at 65°-70° C. for 1.5 hour and then cooled to room temperature with the water bath, giving a solution of trichloroacetyl isocyanate containing slurried sodium chloride.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](I)[CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[NH:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>CN(C)C=O.[OH-].[Na+].[Cu]I>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:14]3[CH2:18][CH2:17][CH2:16][C:15]3=[O:19])[CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1
Reactant: O=C1CCCN1
Reactant: Cc1cc(Cl)c2cc(I)ccc2n1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1cc(Cl)c2cc(N3CCCC3=O)ccc2n1
Yield: 38.2 %

Procedure:
4-Chloro-6-iodo-2-methylquinoline (0.61 g; see step (ii) above), 2-pyrrolidinone (0.24 g), copper (I) iodide (0.038 g), potassium phosphate (0.5 g) and N,N′-dimethylethylenediamine (0.035 g) in dimethylformamide (3 mL) were heated in a microwave at 100° C. for 1 hour. The reaction mixture was diluted with 1 N sodium hydroxide and extracted with ethyl acetate, washed with water, dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica eluting with a mixture of dichloromethane, and methanol. The desired fractions were concentrated and the sample evaporated to dryness. Trituration from ether gave the title compound as a white powder (0.2 g).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl.[C:14]1([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(N(CC)CC)C>[C:14]1([N:20]2[CH2:25][CH2:24][N:23]([CH2:8][C:7]3[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(CN2CCN(c3ccccc3)CC2)cc1

Procedure:
In the manner given in Example 1A, p-nitrobenzyl chloride is reacted with phenylpiperazine dihydrochloride in the presence of triethylamine to give 1-phenyl-4-(p-nitrobenzyl)piperazine
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]3[C:16]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)=[C:15]([C@H:24]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:14]([CH3:35])=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[N:36]1[CH:41]=[C:40](B(O)O)[CH:39]=[N:38][CH:37]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[C:31]([O:30][C@@H:24]([C:15]1[C:14]([CH3:35])=[CH:13][C:11]2[N:12]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:40]4[CH:41]=[N:36][CH:37]=[N:38][CH:39]=4)[CH:3]=3)[S:9][C:10]=2[C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26])([CH3:34])([CH3:33])[CH3:32]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cccc(Br)c3)sc2c1-c1ccc(Cl)cc1
Reactant: OB(O)c1cncnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cccc(-c4cncnc4)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
The reaction mixture of (S)-ethyl 2-(2-(3-bromophenyl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (12 mg, 0.025 mmol), 5-pyrimidineboronic acid (5 mg, 0.0375 mmol), 2N K2CO3 (60 μL), Pd(PPh3)4 (3 mg, 0.0025 mmol) in dioxane (1 mL) was heated at 120° C. in sealed tube. After the reaction was finished, the reaction was washed by sat. NaHCO3, extracted by EtOAc, the organic phase was dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in hexanes to give the product. LCMS-ESI+: calc'd for C32H30ClN3O3S: 572.2 (M+H+); Found: 572.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].[F:9][C:10]([F:38])([F:37])[C:11]1[CH:12]=[C:13]([CH:34]=[CH:35][CH:36]=1)[CH2:14][NH:15][C:16](=[O:33])[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23]2[CH:28]=[C:27](F)[CH:26]=[CH:25][C:24]=2[N+:30]([O-:32])=[O:31])[CH:18]=1>O1CCCC1.O>[F:37][C:10]([F:9])([F:38])[C:11]1[CH:12]=[C:13]([CH:34]=[CH:35][CH:36]=1)[CH2:14][NH:15][C:16](=[O:33])[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23]2[CH:28]=[C:27]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[CH:26]=[CH:25][C:24]=2[N+:30]([O-:32])=[O:31])[CH:18]=1
Reactant: OCC(F)(F)F
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(F)ccc2[N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(OCC(F)(F)F)ccc2[N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 2,2,2-trifluoroethanol (150 mg, 1.50 mmol, 2.00 equiv) in tetrahydrofuran (10 mL). This was followed by the addition of sodium hydride (180 mg, 7.50 mmol, 10.00 equiv), in portions at 0° C. The resulting solution was stirred for 20 min at 0° C. in an ice/salt bath. To this was added N-(3-(trifluoromethyl)benzyl)-2-(5-fluoro-2-nitrophenyl)isonicotinamide 14d (300 mg, 0.72 mmol, 1.00 equiv). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 20 mL of water. The resulting solution was extracted with 3×20 mL of dichloromethane and the organic layers combined and dried over sodium sulfate and concentrated under vacuum. This resulted in 200 mg (crude) of N-(3-(trifluoromethyl)benzyl)-2-(2-nitro-5-(2,2,2-trifluoroethoxy)phenyl)isonicotinamide as a yellow solid.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[C:12]([CH3:14])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([CH3:15])[C:4]=1[NH:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])=O.[NH3:26]>C(O)C>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]1[N:26]=[CH:1][C:3]2[C:4](=[C:5]([CH3:15])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:12]([CH3:14])[CH:13]=2)[N:16]=1
Reactant: N
Reactant: CCOC(=O)c1c(C)cc(C=O)c(NC(=O)c2ccccc2Cl)c1C
Solvent: CCO
Product: CCOC(=O)c1c(C)cc2cnc(-c3ccccc3Cl)nc2c1C
Reaction time: 8 h
Yield: 30 %

Procedure:
504 mg of ethyl 4-formyl-2,6-dimethyl-3-(o-chlorobenzoylamino)benzoate was dissolved in 50 ml of ethanol saturated with ammonia and the solution was left to stand overnight at room temperature. The solvent was evaporated, and the residue was separated and purified by silica gel column chromatography. Fractions eluted with diethyl ether/n-hexane (volume ratio 2:8) were collected and the solvent was evaporated. The residue was recrystallized from methanol/n-hexane to give 150 mg (yield 30%) of 2-(o-chlorophenyl)-7-ethoxycarbonyl-6,8-dimethylquinazoline having a melting point of 69.5° to 70.5° C.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=O.[NH:11]1[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH2:1][N:11]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12]2)=[CH:4][CH:5]=1)#[N:8]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: COC(=O)C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(=O)C1CN(Cc2ccc(C#N)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
A mixture of 4-formylbenzonitrile (510 mg, 3.89 mmol), methyl azetidine-3-carboxylate (590 mg, 3.89 mmol), acetic acid (0.245 mL, 4.28 mmol) and ˜1 gm of powdered 4 Angstrom molecular sieves in DCE (15 mL) was stirred briskly at RT for 1 hr. At this time, sodium triacetoxyborohydride (907 mg, 4.28 mmol) was added and the reaction mixture was stirred at RT for 2 hr. After filtering through a sintered glass funnel, the filtrate was concentrated to a residue that was partitioned between EtOAc (50 mL) and saturated sodium bicarbonate solution (50 mL). The organic layer was washed with brine (50 mL), dried (MgSO4) and concentrated to afford a colorless oil that was chromatographed on a 12 gm Isco silica gel cartridge, eluting with a 0-100% EtOAc/Hex gradient. The essentially pure fractions were concentrated to afford methyl 1-(4-cyanobenzyl)azetidine-3-carboxylate (765 mg, 3.32 mmol). HPLC retention time=0.49 minutes [broad peak] (PHENOMENEX® Luna 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1% TFA over a 2 minute gradient. MS:(M+H)=231.23. 1H NMR (400 MHz, CDCl3) δ ppm 3.32-3.36 (m, 3H) 3.49-3.58 (m, 2H) 3.67 (s, 2H) 3.72 (s, 3H), 7.39 (d, J=8.6 Hz, 2H) 7.60 (d, J=8.3 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[C:3]=1[NH:22][C:23](=[O:34])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[C:25]=1Cl.[F-:35].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[C:3]=1[NH:22][C:23](=[O:34])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[C:25]=1[F:35]
Reactant: O=C(Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F)c1cccc([N+](=O)[O-])c1Cl
Reactant: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F)c1cccc([N+](=O)[O-])c1F
Temperature: 130 °C
Reaction time: 10 h
Yield: 19.8 %

Procedure:
To a solution of N-(2-bromo-4-(heptafluoropropan-2-yl)-6-(trifluoromethyl)phenyl)-2-chloro-3-nitrobenzamide 4.89 g (8.27 mmol) in 50 ml of anhydrous DMF was added 2.40 g (41.3 mmol) of potassium fluoride (spray-dried product) under a flow of nitrogen, followed by stirring at 130° C. for 10 hours. Liquid separation was carried out by adding ethyl acetate, hexane, and water to the reaction mixture, and then the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent solvent; hexane:ethyl acetate=10:1) to prepare 0.940 g (yield 20%) of a target compound.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20](Cl)=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=[N:23]2)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[O:30]([CH2:37][CH2:38][NH2:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>ClCCl>[CH2:8]([O:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([NH:39][CH2:38][CH2:37][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=[N:23]2)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCCOc1ccccc1
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1NCCOc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
Triethylamine (8.93 mL, 64.1 mmol) was added to a solution of 7-benzyloxy-4-chloro-3-nitroquinoline (13.45 g, 42.7 mmol), prepared in Parts A-D of Example 1, in dichloromethane (250 mL). 2-Phenoxyethylamine (6.15 mL, 47.0 mmol) was added dropwise over a period of ten minutes, and the reaction mixture was stirred for three hours at ambient temperature. Distilled water (200 mL) was added to the solution, and the aqueous layer was washed with dichloromethane (2×200 mL). The combined organic solutions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide a solid. The solid was washed with hexanes, isolated by filtration, and dried under reduced pressure to provide 17.14 g of (7-benzyloxy-3-nitroquinolin-4-yl)-(2-phenoxyethyl)amine as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1.[C:11]([NH:13][C:14](=[N:17]CCSCC1N=CNC=1)SC)#[N:12]>C(O)C>[C:11]([NH:13][C:14]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)=[NH:17])#[N:12]
Reactant: CSC(=NCCSCc1c[nH]cn1)NC#N
Reactant: NCCSCc1c[nH]cn1
Solvent: CCO
Product: N#CNC(=N)NCCSCc1c[nH]cn1

Procedure:
4-((2-Aminoethyl)thiomethyl)imidazole is reacted with dimethyl-N-cyanoimidodithiocarbonate according to the procedure of Example 3(c)(i) and the resultant N-cyano-N'-[2-(4-imidazolylmethylthio)ethyl]-S-methylisothiourea treated with ammoniacal ethanol according to the procedure of Example 5 to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:16][C:13]1[CH:14]=[CH:15][C:10]([S:8][C:4]2[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=2)=[C:11]([N+:17]([O-:19])=[O:18])[CH:12]=1
Reactant: Nc1cccc(S)c1
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Sc2cccc(N)c2)c([N+](=O)[O-])c1
Temperature: 100 °C
Yield: 33 %

Procedure:
The title compound was prepared from 3-Amino-benzenethiol (5.034 g, 40.21 mmol), 1-Chloro-4-methyl-2-nitro-benzene (4.600 g, 26.81 mmol) and K2CO3 (6.484 g, 46.92 mmol) dissolved in DMF and heated to 100° C. for 16 hrs. At this time the reaction mixture was cooled to room temperature and diluted with water, extracted with ethyl acetate. Dried over Na2SO4, filtered and concentrated under vacuum giving the title compound (2.3 g, 32%).
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:19]1([C:25]2[S:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9]([N:22]2[CH2:23][CH2:24][N:19]([C:25]3[S:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=3)[CH2:20][CH2:21]2)=[O:11])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Reactant: N#Cc1cnc(N2CCNCC2)s1
Product: N#Cc1cnc(N2CCN(C(=O)c3cc([N+](=O)[O-])ccc3N3CCOCC3)CC2)s1
Yield: 24 %

Procedure:
Prepared in analogy to example 1 (b) from 2-morpholin-4-yl-5-nitro-benzoic acid (Example A27) and 2-piperazin-1-yl-thiazole-5-carbonitrile (Example 6(a)). The crude material was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as a yellow solid (yield 24%). MS (m/e): 429.5 (M+H+, 100%).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14]([O:18][C@H:19]([CH3:24])[C:20]([F:23])([F:22])[F:21])=[N:13][N:12]=[CH:11]3)[CH:7]=1.[Cu](C#N)[C:27]#[N:28]>CN(C=O)C.C(Cl)Cl>[CH3:25][C:5]1[CH:4]=[CH:3][C:2]([C:27]#[N:28])=[CH:7][C:6]=1[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14]([O:18][C@H:19]([CH3:24])[C:20]([F:21])([F:22])[F:23])=[N:13][N:12]=[CH:11]2
Reactant: Cc1ccc(I)cc1-c1ccc2c(O[C@H](C)C(F)(F)F)nncc2c1
Reactant: N#C[Cu]C#N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(C#N)cc1-c1ccc2c(O[C@H](C)C(F)(F)F)nncc2c1
Temperature: 120 °C

Procedure:
A mixture of 6-(5-iodo-2-methylphenyl)-1-((R)-1,1,1-trifluoropropan-2-yloxy)phthalazine (100 mg, 0.22 mmol) and copper cyanide (98 mg, 1.09 mmol) in 1.0 mL of DMF in a sealed glass tube was heated at 120° C. in a microwave synthesizer for 20 min. The cooled reaction was diluted with CH2Cl2 and washed with water and brine. The organic layer was dried (MgSO4), filtered, and concentrated. Purification on a silica gel column (20-50% of EtOAc in Hexanes) afforded 4-methyl-3-(1-((R)-1,1,1-trifluoropropan-2-yloxy)phthalazin-6-yl)benzonitrile as a white solid. MS (ESI, pos. ion) m/z: 358.4 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28](Br)[C:27]=2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[N:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:42]1(B(O)O)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>O.O1CCOCC1.C(OCC)(=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>[CH:7]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[C:27]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[C:28]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:29]=[CH:30][CH:31]=2)[N:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Fc1ccc(COc2c(Br)cccc2-c2cccc(C(c3ccccc3)c3ccccc3)n2)cc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Fc1ccc(COc2c(-c3ccccc3)cccc2-c2cccc(C(c3ccccc3)c3ccccc3)n2)cc1
Temperature: 25 °C
Yield: 85 %

Procedure:
Potassium carbonate (2.1 g, 15.0 mmol, 3.0 equiv) was dissolved in water (20 mL) and added to compound 5 (2.6 g, 5.0 mmol, 1.0 equiv) and phenylboronic acid (0.73 g, 6.0 mmol, 1.2 equiv) in dioxane (20 mL). A stream of nitrogen was bubbled through the solution for 15 min and tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.025 mmol, 0.005 equiv) was added to the reaction. The reaction was refluxed for 4 hr at which point LC/MS and TLC indicated the reaction to be complete. The reaction was allowed to cool to room temperature, diluted with ethyl acetate (50 mL), the organic layer was separated and washed with saturated brine (50 mL). The organic layer was dried over sodium sulfate and absorbed onto silica gel (7 g) by concentration under reduced pressure. This material was purified on a silica gel column (60 g) by eluting with heptanes (500 mL), ethyl acetate (1%) in heptanes (500 mL), ethyl acetate (2%) in heptanes (500 mL) and ethyl acetate (3%) in heptanes (500 mL). The desired product was isolated pure in 85% yield (2.2 g).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>C(Cl)(Cl)Cl.CN(C)C=O>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(I)cc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(I)cc1

Procedure:
A round bottom flask was charged with 4-iodobenzoic acid (3.0 g, 12.1 mmol) in chloroform (100 mL). To the solution was added thionyl chloride (5.0 mL) in chloroform (10 mL) and 2-3 drops of dimethylformamide (DMF). The slurry was heated at reflux for 2 hours, while monitoring the reaction through an oil bubbler. A clear solution of 4-iodobenzoyl chloride was obtained. The volatiles were removed and a colorless oil was obtained which solidified upon cooling.
Reaction SMILES: [CH3:1][C:2]1(C)[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:36])[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]3[CH:27]=[C:28]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=3)=[CH:11][C:5]=2[CH2:4][O:3]1.C(O)(=O)C>O>[C:2]([OH:7])(=[O:3])[CH3:1].[OH:36][C@H:12]([C:10]1[CH:9]=[CH:8][C:6]([OH:7])=[C:5]([CH2:4][OH:3])[CH:11]=1)[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1
Reactant: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCCCc3cccc(S(N)(=O)=O)c3)ccc2O1
Solvent: CC(=O)O
Solvent: O
Product: NS(=O)(=O)c1cccc(CCCCOCCCCCCNC[C@H](O)c2ccc(O)c(CO)c2)c1
Yield: 216.6 %

Procedure:
3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide (0.283 g) was stirred with acetic acid (8 ml) and water (4 ml) at 70° for 35 min before evaporating to dryness. The residue was re-evaporated twice with toluene to give the title compound (0.318 g) LCMS RT=2.34 min, ES+ve 495 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[NH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].I[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].N1CCOCC1.Cl>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.CCOC(C)=O>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:4]=2[N:3]=1
Reactant: CCCCCCCCI
Reactant: O=c1[nH]c(=O)c2[nH]c(Cl)nc2[nH]1
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: CCOC(C)=O
Solvent: C1COCCN1
Product: CCCCCCCCn1c(=O)[nH]c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 65 h

Procedure:
8-Chloro-3,7-dihydro-1H-purine-2,6-dione (100 mg, 0.44 mmol) was stirred with sodium carbonate (52 mg, 0.49 mmol) in dry DMF (3 ml) for 20 min., then 1-iodooctane (118 mg, 0.49 mmol) was added and the mixture was stirred under nitrogen at 40 C for 65 h. After cooling to room temperature, the mixture was thoroughly degassed by evacuating the vessel and refilling with nitrogen several times. Tetrakis(triphenylphosphine)palladium(0) (102 mg, 0.09 mmol) was added, the mixture degassed again and then morpholine (0.385 ml, 4.4 mmol) added and stirring continued for 6.5 h. 2M HCl and EtOAc were added, and the 2-phase system was filtered. The product was present predominantly in the filtered solid, which was recrystallised from THF-acetonitrile, followed by MeOH, with filtration, to afford the pure title compound.