Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([CH2:15][C:16](=[O:26])[NH:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)[C:9]=1[CH3:27])[CH3:6])=[O:4].N1C=CC=CC=1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([CH:5]([N:7]([C:37](=[O:38])[CH2:36][O:35][CH3:34])[C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([CH2:15][C:16](=[O:26])[NH:17][C:18]2[CH:19]=[C:20]([Cl:25])[CH:21]=[C:22]([Cl:24])[CH:23]=2)[C:9]=1[CH3:27])[CH3:6])=[O:4]
Reactant: COCC(=O)Cl
Reactant: COC(=O)C(C)Nc1c(C)ccc(CC(=O)Nc2cc(Cl)cc(Cl)c2)c1C
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COCC(=O)N(c1c(C)ccc(CC(=O)Nc2cc(Cl)cc(Cl)c2)c1C)C(C)C(=O)OC
Temperature: 25 °C

Procedure:
16.2 g of N-(1'-methoxycarbonyl-ethyl)-2,6-dimethyl-3-(3',5'-dichlorophenylcarbamoylmethyl)-aniline and 3.2 g of pyridine were placed into 120 ml of toluene; and within 15 minutes were added 4.7 g of methoxyacetic acid chloride, dissolved in 30 ml of toluene. After the exothermic reaction had subsided, stirring was maintained for 4 hours at room temperature, and the reaction suspension was then filtered with suction. The yellow filtrate was washed with water, dried over sodium sulfate, and concentrated in a rotary evaporator. The solid residue was digested with ether, and the white crystals were filtered off with suction; m.p. 126°-128° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[N:14]=[N:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:29]=1[CH2:35]Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[H-].[Na+]>CN(C=O)C.C(OCC)C>[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:29]=1[CH2:35][N:8]([C:9]1[N:14]=[N:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: BrCc1cc(Br)ccc1OCc1ccccc1
Reactant: CCOC(=O)c1ccc(NC(=O)OC(C)(C)C)nn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)c1ccc(N(Cc2cc(Br)ccc2OCc2ccccc2)C(=O)OC(C)(C)C)nn1
Reaction time: 2 h

Procedure:
A mixture of ethyl 6-(tert-butoxycarbonylamino)-3-pyridazine carboxylate (2.4 g), 1-(benzyloxy)-2-bromomethyl-4-bromobenzene (3.2 g) and sodium hydride (0.5 g of a 50% W/W dispersion in oil) in DMF was stirred for 2 hours. The mixture was diluted with diethyl ether and washed with water. The organic solution was dried (MgSO4), filtered and evaporated. Ethyl 6-[N-(2-benzyloxy-5-bromobenzyl)-N-(tert-butoxycarbonyl)amino]-3-pyridazinecarboxylate was isolated by flash chromatography, eluting with 2% ethyl acetate in CH2Cl2. Yield: 1.7 g.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH:2]1[C:7]([NH2:9])=[O:8].C(N(CC)CC)C.[C:17]1([C:23](Cl)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[C:23]([N:4]1[CH2:5][CH2:6][NH:1][CH:2]([C:7]([NH2:9])=[O:8])[CH2:3]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NC(=O)C1CNCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)C1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1.29 g (10 mmol) of piperazine-2-carboxamide were dissolved in 20 ml of absolute methylene chloride, 1.01 g (10 mmol) of triethylamine were added, a solution of 2.79 g (10 mmol) of triphenylmethyl chloride in 20 ml of absolute methylene chloride was added dropwise and the mixture was subsequently stirred at room temperature for 5 hours. The reaction solution was washed twice with water, dried and concentrated and the crude product was purified by flash chromatography on silica gel with CH2Cl2 /CH3OH 95:5.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:18]([CH3:20])[CH3:19])[CH:13]([OH:17])[C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:18]([CH3:20])[CH3:19])[CH:13]([O:17][C:27](=[O:29])[CH3:28])[C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(O)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(C(=O)O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a solution of 3-(S)-[(benzyloxycarbonyl)amino]-2-(R,S)-hydroxy-4-methylpentanoic acid (1.70 g, 6.04 mmol) and pyridine (4.9 mL) was added acetic anhydride (5.7 mL, 6.17 g, 60.4 mmol) dropwise at room temperature. The reaction was allowed to stir overnight and was diluted with ethyl acetate and washed with water (2×). The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo to give a thick oil. The residue was purified by column chromatography on silica gel with 15% methanol/dichloromethane to afford 1.56 g (80%) of 3-(S)-[(benzyloxycarbonyl)amino]-2-(R,S)-acetoxy-4-methyl pentanoic acid as a light yellow viscous oil. FAB MS [M+H] m/z; Calcd: 324, Found: 324.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1>>[NH2:15][C:10]1[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]2[C:2]([NH:16][C:17]3[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[N:9]=1
Reactant: Nc1cccc(O)c1
Reactant: Cc1nc(N)nc(-c2cccnc2F)n1
Product: Cc1nc(N)nc(-c2cccnc2Nc2cccc(O)c2)n1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 22 using 4-(2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine and 3-aminophenol, and isolated as a yellow solid (34%). LCMS (API-ES) m/z 295 (M+H)+; 1H NMR (400 MHz, d6-DMSO) δ 11.97 (s, 1H) 9.27 (s, 1H) 8.76 (dd, J=7.78, 1.76 Hz, 1H) 8.35 (dd, J=4.77, 1.76 Hz, 1H) 7.64-7.92 (m, 2H) 7.51 (s, 1H) 6.99-7.28 (m, 2H) 6.89 (dd, J=7.53, 4.52 Hz, 1H) 6.40 (d, J=7.03 Hz, 1H) 2.45 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.C[O:11][CH:12](OC)[CH2:13][CH:14](OC)OC.C(=O)(O)[O-].[Na+]>C(O)C.O>[CH:12]([CH:13]=[CH:14][NH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:11]
Reactant: COC(CC(OC)OC)OC
Reactant: Cc1cccnc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cccnc1NC=CC=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-amino-3-methylpyridine (53.9 g) and anhydrous hydrogen chloride (40 g) in anhydrous ethanol (960 ml) was treated with 1,1,3,3-tetramethoxypropane and heated at reflux for 6 hours. The solution was then concentrated to dryness under reduced pressure and the residue was triturated with diethyl ether, to give crude 9-methylpyrido[1,2-a]pyrimidinium chloride (76 g). This crude salt was dissolved in water (300 ml) and treated with sodium bicarbonate (35.4 g). The mixture was stirred at room temperature for one hour and then it was filtered, washed with water and recrystallised from water, to give 1-formyl-2-(3-methylpyrid-2-ylamino)ethene (32.7 g), m.p. 129°-131° C. (with decomposition).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([OH:29])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:37]([O:44][C:45](Cl)=[O:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)(Cl)Cl>[CH2:1]([N:8]([C:45]([O:44][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:46])[CH2:9][CH:10]([OH:29])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCCCCCCOCC(O)CNCc1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCOCC(O)CN(Cc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
21.4 g of 3-benzylamino-1-hexadecyloxy-propan-2-ol are dissolved in 100 cc. of anhydrous chloroform. At first 5.4 g of triethylamine and then a solution of 9 g of chloroformic acid benzyl ester in 50 cc. of chloroform is added dropwise with cooling and the mixture is stirred for 3 hours. The chloroform solution is washed with 5% hydrocholoric acid and water, dried over sodium sulfate, evaporated and the residue is purified by column chromatography (silicic acid gel//chloroform).
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:13]/[C:14]1[NH:15][CH:16]=[CH:17][C:18]=1[O:19][CH3:20])/[C:5](=[O:12])[NH:6]2.Cl.[CH:22](N)=N.O>C(O)C>[CH3:20][O:19][C:18]1[CH:17]=[CH:16][NH:15][C:14]=1/[CH:13]=[C:4]1\[C:5](=[O:12])[NH:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:11][CH:22]=[N:1][C:2]=3[C:3]\1=2
Reactant: N=CN
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(N)c21
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc3[nH]cnc3c21
Temperature: 25 °C

Procedure:
A mixture of (Z)-4,5-diamino-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (60 mg, 0.22 mmol) (from Example 15 above) and formamidine hydrochloride (177 mg, 2.2 mmol) (Aldrich) in ethanol (3 mL) was heated at reflux for 45 min. The mixture was cooled to room temperature, and water was slowly added to induce precipitation. The precipitate was collected by suction filtration, washed with water and dried in a vacuum oven overnight to give (Z)-8-[(3-methoxy-1H-pyrrol-2-yl)methylene]-3,6,7,8-tetrahydro-pyrrolo-[3,2-e]benzimidazol-7-one. (Yield 48 mg, 99%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[F:10][C:11]([F:21])([F:20])[O:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:13]([O:12][C:11]([F:10])([F:20])[F:21])[CH:14]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Nc1cccc(OC(F)(F)F)c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cnc(Cl)nc1Nc1cccc(OC(F)(F)F)c1

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 3-trifluoromethoxyaniline gave 2-chloro-5-fluoro-N4-(3-trifluoromethoxyphenyl)-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.12 (d, 1H, J=3 Hz), 7.68 (bs, 1H), 7.53 (dd, 1H, J=1.2 and 8.4 Hz), 7.41 9t, 1H, J=8.1 Hz), 7.04 (bdt, 2H); 19F NMR (CDCl3): −16430 and −44463; LCMS: purity: 89%; MS (m/e): 308 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][C:12](=O)[CH2:13][CH2:14][C:15]2([CH3:22])[C:19](=[O:20])[CH2:18][CH2:17][C:16]2=O)[CH:6]=[CH:7][CH:8]=1.O>C1C=CC=CC=1>[CH3:22][C@:15]12[CH2:14][CH2:13][C:12]3[C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[CH2:9][CH2:10][C:11]=3[C:16]1=[CH:17][CH2:18][C:19]2=[O:20]
Reactant: COc1cccc(CCCC(=O)CCC2(C)C(=O)CCC2=O)c1
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc2c(c1)CCC1=C2CC[C@]2(C)C(=O)CC=C12
Yield: 75.2 %

Procedure:
To 2-(6-m-methoxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione (3 g) in benzene (100 cc) add polyphosphoric acid (from orthophosphoric acid, 15 g. and phosphorus pentoxide, 6 g.) and heat the mixture at 90° for 4 minutes under such reduced pressure as the need to control frothing will allow. Cool, add water, and extract the mixture with ether and ethyl acetate; isolate the product from the resulting solution to obtain the colorless crystalline 13β-methyl-3-methoxygona-1,3,5(10), 8,14-pentaen-17-one (2 g), b.p. 115°-116°; ultraviolet absorption peak at 313 mμ (ε35,100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@@H:16]1[CH2:20][CH2:19][N:18]([C@H:21]([CH3:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]1=[O:30])(=[O:14])=[O:13])[CH:6]=[CH:5]2.[CH2:31](O)C.C(NC(C)C)(C)C>[Pd].C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][CH:16]1[CH2:20][CH2:19][N:18]([CH:21]([CH2:29][CH3:31])[C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:17]1=[O:30])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: C[C@H](C(=O)OC(C)(C)C)N1CC[C@@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Reactant: CCO
Agent: [Pd]
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CCC(C(=O)OC(C)(C)C)N1CCC(NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Reaction time: 18 h

Procedure:
A mixture of Intermediate 112 [Mixture 1] (0.051 g), 10% palladium on carbon (0.01 g) and ethanol (5 ml) was stirred under an atmosphere of hydrogen for 18 h. The reaction mixture was filtered through Celite™ and the filtrate was concentrated under reduced pressure to give a yellow gum. The gum (0.034 g) in DCM (2 ml) was treated with 6-chloronaphthylsulphonyl chloride1 (0.04 g) and N,N-diisopropylamine (0.073 ml) and stirred at room temperature for 24 h. The mixture was washed with water and concentrated under reduced pressure to yield an oil which was partially purified using SPE (silica, eluting with cyclohexane:ethyl acetate 1:1) to give the title compound (0.043 g) as a white solid.
Reaction SMILES: BrBr.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[NH:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15].[S-:17][C:18]#[N:19].[Na+].O>C(O)(=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([S:17][C:18]#[N:19])[C:7]([Cl:10])=[CH:6][C:5]=1[NH:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: N#C[S-]
Reactant: O=C(O)CCNc1cc(Cl)ccc1Cl
Agent: BrBr
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#CSc1cc(Cl)c(NCCC(=O)O)cc1Cl
Reaction time: 1 h
Yield: 103 %

Procedure:
A solution of 6 ml (0.11 mole) of bromine in 20 ml of acetic acid was added dropwise over 20 min to a stirred mixture of 25 g (0.10 mole) of N-(2,5-dichloropheyl)-β-alanine, 20.5 g (0.25 mole) of sodium thiocyanate and 100 ml of acetic acid at 15°-20°. An additional 80 ml of acetic acid was added to facilitate stirring which was continued for 1 hr. The reaction mixture was poured into 600 ml of cold water. The yellow solid was collected by filtration, washed with water and dried in an oven at 100° for 2 hrs to give 30 g (100%) of N-(2,5-dichloro-4-thiocyanatophenyl)-β-alanine. Two recrystallizations from CH3NO2 gave an analytical sample, m.p. 133°-135°.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([OH:14])=O)[N:3]1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=1.C(N(CC)CC)C.C(OC(Cl)=O)C.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>O1CCCC1>[N:35]1([C:12]([CH2:11][CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2](=[O:1])[N:3]2[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=2)=[O:14])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: C1CCNCC1
Reactant: O=C(O)CC1c2ccccc2C(=O)N1c1ccc(Cl)cn1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CC1c2ccccc2C(=O)N1c1ccc(Cl)cn1)N1CCCCC1
Temperature: 0 °C
Yield: 26.2 %

Procedure:
3-Oxo-2-(5-chloro-2-pyridyl)isoindoline-1-acetic acid (1 g) and triethylamine (0.8 g) were dissolved in 20 ml of dry tetrahydrofuran and, under ice-cooling with stirring, 0.39 g of ethoxycarbonyl chloride was added portionwise. The mixture was stirred for 3 minutes, 0.56 g of piperidine was added, and the whole mixture was stirred for an additional 30 minutes. The reaction mixture was poured into 500 ml of ice water, followed by extraction with ethyl acetate. The extract was washed with water and dried. The ethyl acetate was then distilled off and the residue was treated with ether. The resulting crystals thus obtained were collected by filtration and recrystallized from ethyl acetate to give 0.32 g of colorless crystals, melted at 165°-166° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[CH:8][C:7]=2[CH:6]=[C:5]([OH:19])[CH:4]=1.[C-:20]#[N:21].[K+].C1OCCOCCOCCOCCOCCOC1.O>CN(C)C=O>[OH:19][C:5]1[CH:4]=[C:3]([CH2:2][C:20]#[N:21])[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[CH:8][C:7]=2[CH:6]=1
Reactant: Oc1ccc(-c2cc3cc(O)cc(CBr)c3o2)cc1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
To a solution of benzyl bromide 4 (0.0758 g, 0.238 mmole) in 5 mL dimethylformamide was added pulverized potassium cyanide (0.0232 g, 0.3563 mmole) and 18-crown-6 ether (0.100 g, 0.378 mmole). After stirring at 80° C. for 2 hours, the reaction mixture was cooled and poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate, water, brine, and dried with magnesium sulfate. The organic phases were concentrated and the residue was loaded on to silica gel and chromatographed with silica gel (hexanes:ethyl acetate, 9:1) to afford 0.046 g (82%) of benzylnitrile 5 as a yellow solid: Mp=128–130° C.; 1H NMR (DMSO-d6) δ 7.85 (d, 2 H, 8.7 Hz), 7.19 (s, 1 H), 7.06 (d, 2 H, J=8.7 Hz), 7.00 (d, 1 H, J=2.5 Hz), 6.88 (d, 1 H, J=2.1 Hz), 3.82 (s, 3 Hz), 3.79 (s, 3 H); MS, 285 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:14]=[CH:15][CH:16]=3)[C:11]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:10][N:9]=2)[CH:5]=[N:6][CH:7]=1.N1C=CC=CC=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH2:25]([NH:24][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]([C:4]2[CH:3]=[C:2]([NH:1][S:39]([CH3:38])(=[O:41])=[O:40])[CH:7]=[N:6][CH:5]=2)=[N:9][N:10]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1cncc(-c2nnc(NCc3ccccc3)c3c(-c4ccccc4)cccc23)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cncc(-c2nnc(NCc3ccccc3)c3c(-c4ccccc4)cccc23)c1
Reaction time: 5 h
Yield: 69.7 %

Procedure:
To a solution of 4-(5-aminopyridin-3-yl)-N-benzyl-8-phenylphthalazin-1-amine (60.0 mg, 0.149 mmol) in DCM (20 mL) was added pyridine (0.0241 mL, 0.297 mmol) at room temperature followed by methanesulfonyl chloride (0.0120 mL, 0.149 mmol) and the reaction mixture stirred for 5 h. The volatile components were removed under reduced pressure and the resulting residue was purified by preparative HPLC (Condition 22 as described in general methods) to obtain N-(5-(4-(benzylamino)-5-phenylphthalazin-1-yl)pyridin-3-yl)methanesulfonamide (50.0 mg, 69.8%) as a white solid. LCMS (Condition 4): retention time 2.45 min, [M+1]=482.2. HPLC (Condition 28): retention time=6.83 min, purity 97.53%. 1H NMR (400 MHz, DMSO-d6) δ 2.97 (s, 3 H), 4.51 (d, J=4.8 Hz, 2 H), 5.06 (t, J=4.8 Hz, 1 H), 7.02-7.03 (m, 2 H), 7.22-7.28 (m, 3 H), 7.43-7.52 (m, 5 H), 7.68 (dd, J=2.4 Hz, J=5.6 Hz, 1 H), 7.72 (br s, 1 H), 7.87-7.90 (m, 2 H), 8.35 (br s, 1 H), 8.40 (d, J=1.6 Hz, 1 H), 10.25 (br s, 1 H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12]Br)=[CH:9][CH:10]=2)[C:5](=[O:14])[N:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>O1CCCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)=[CH:9][CH:10]=2)[C:5](=[O:14])[N:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1
Reactant: CN1CCNCC1
Reactant: CC(C)n1nc(Br)c2ccc(CBr)cc2c1=O
Solvent: C1CCOC1
Product: CC(C)n1nc(Br)c2ccc(CN3CCN(C)CC3)cc2c1=O
Reaction time: 1 h
Yield: 80 %

Procedure:
4-Bromo-7-bromomethyl-2-isopropyl-2H-phthalazin-1-one (0.2 g, 0.56 mmol) was dissolved in tetrahydrofuran (THF) (1 ml), to this was added N-Methyl piperazine (0.14 g, 1.4 mmol) as a solution in THF (1 ml) and the reaction mixture was stirred for 1 hour. Whereupon LC-MS indicated complete consumption of starting material, the solvent was removed under vacuum and the residue was purified by flash column chromatography (elution: 90% ethyl acetate, 10% methanol) to give the title compound (0.17 g, 84% yield) as a light yellow solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:14][C:15]([CH3:17])=[O:16]>>[O:7]([CH2:14][C@@H:15]1[CH2:17][O:16]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)=O
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(OC[C@@H]2CO2)cc1
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of phenol (9.4 g, 100 mmol) and (2S)-(+)glycidyl 3-nitrobenzesulfonate(25.9 g, 100 mmol) in 500 mL of acetone was treated with 3 equivalents of potassium carbonate (41.5 g, 300 mmol) and stirred at reflux for 1 day. The suspension was cooled to ambient temperature; the solid was filtered; and the filtrate concentrated to dryness. The residue was partitioned between methylene chloride and water and the aqueous layer was extracted with methylene chloride. The organic layers were combined and dried over magnesium sulfate and concentrated to give the title compound (15.0 g, 99%) as an orange oil; 1H NMR (300 MHz, CDCl3) δ 6 2.76 (dd, J=4.9, 2.6 Hz, 1 H), 2.90 (dd, J=4.9, 4.9 Hz, 1 H), 3.30-3.40 (m, 1 H), 3.95 (dd, J=11.0, 5.4 Hz, 1 H), 4.18 (dd, J=11.0, 3.0 Hz, 1 H), 6.85-7.00 (m, 3 H), 7.25-7.35 (m, 2 H); MS (ES) m/z: 151.0 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([S:27](=[O:31])(=[O:30])[NH:28][CH3:29])=[CH:23][C:19]=1[C:20](O)=[O:21]>>[C:14]([C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:20]([C:19]3[CH:23]=[C:24]([S:27]([NH:28][CH3:29])(=[O:31])=[O:30])[CH:25]=[CH:26][C:18]=3[Cl:17])=[O:21])[CH2:10][CH2:9]2)=[C:2]([F:1])[CH:3]=1)(=[O:16])[CH3:15]
Reactant: CNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: CC(=O)c1ccc(N2CCNCC2)c(F)c1
Product: CNS(=O)(=O)c1ccc(Cl)c(C(=O)N2CCN(c3ccc(C(C)=O)cc3F)CC2)c1

Procedure:
The title compound was prepared according to the procedure D described for example 2 from 1-(3-Fluoro-4-piperazin-1-yl-phenyl)-ethanone and 2-Chloro-5-methylsulfamoyl-benzoic acid (CAS: 68901-09-7; BE 620741) (69%, light yellow foam, M−H: 452.1)
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([F:13])=[C:11]([F:14])[C:10]([Br:15])=[C:9]([F:16])[C:8]=1[F:17].[C:18](=[O:20])=[O:19].Cl>O1CCCC1.O>[Br:15][C:10]1[C:11]([F:14])=[C:12]([F:13])[C:7]([C:18]([OH:20])=[O:19])=[C:8]([F:17])[C:9]=1[F:16]
Reactant: Fc1c(F)c(Br)c(F)c(F)c1Br
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1c(F)c(F)c(Br)c(F)c1F
Temperature: -70 °C
Yield: 81.5 %

Procedure:
n-Butyllithium (42 ml, 2.4M in hexane) was slowly added to a solution of 30.78 g 1,4-dibromo-2,3,5,6-tetrafluorobenzene in 200 ml tetrahydrofuran cooled to -70° C. under nitrogen. Solid carbon dioxide (about 12 g) was then added to the stirred mixture which was then allowed gradually to warm to 0° C. at which point 16 ml 6M hydrochloric acid and 16 ml water were added. The reaction mixture was concentrated and the residue extracted with methylene dichloride. The extract was washed with concentrated sodium chloride solution, dried (magnesium sulfate) and concentrated to dryness to give 22.23 g (81.5%) 4-bromo-2,3,5,6-tetrafluorobenzoic acid, m.p. 128°-135° C.