Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].C(N(CC)C(C)C)(C)C.[CH3:21][O:22][CH2:23]Cl>CN(C)C=O>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:21][O:22][CH3:23])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10]
Reactant: COCCl
Reactant: CC(=O)c1ccc(O)cc1O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc(C(C)=O)c(O)c1
Reaction time: 0.33 h
Yield: 87.8 %

Procedure:
In 60 ml of dimethylformamide were dissolved 5.0 g of 2',4'-dihydroxyacetophenone and 6.37 g of N,N-diisopropylethylamine, and 2.72 ml of chloromethyl methyl ether was gradually added to the solution under ice cooling. The mixture was stirred under ice cooling for 20 minutes and a reaction was carried out at room temperature for 1.5 hours. After the reaction, the reaction mixture was extracted with 300 ml of diethyl ether, and the diethyl ether layer was washed with water (100 ml×2 times), shaken with a saturated aqueous solution of sodium chloride (50 ml×2 times), dried with anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate by distillation and the residue was subjected to the silica gel chromatography (3.5 cm in diameter; 72.8 g; n-hexane/ethyl acetate=4/1; 0.3 kg/cm2) to obtain 5.66 g (yield=87.8%) of 2'-hydroxy-4'-methoxymethoxyacetophenone in the form of a colorless oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[C:27]([CH3:28])=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][C:19]=2[CH3:29])=[O:16])[C:12]([CH3:30])=[CH:11][CH:10]=1.O>CN1CCCC1=O>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:9]2[N:14]=[C:13]([C:15]([NH:17][C:18]3[C:19]([CH3:29])=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:26][C:27]=3[CH3:28])=[O:16])[C:12]([CH3:30])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: OC1CCNCC1
Reactant: COC(=O)c1cc(C)c(NC(=O)c2nc(Cl)ccc2C)c(C)c1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc(N2CCC(O)CC2)nc1C(=O)Nc1c(C)cc(C(=O)O)cc1C
Temperature: 150 °C
Reaction time: 4 h
Yield: 63.9 %

Procedure:
4-Hydroxypiperidine (171.2 g, 1660 mmoles) is added to a solution of methyl 4-[(6-chloro-3-methyl-pyridine-2-carbonyl)amino]-3,5-dimethyl-benzoate (69 g, 207.3 mmoles) in N-methylpyrrolidone (483 mL) and the mixture is stirred at 150° C. for 4 hours. The mixture is cooled to ambient temperature and poured into water (1000 mL). The mixture is washed with methyl t-butyl ether (300 mL). The aqueous layer is then acidified to pH 2 with aqueous 36% HCl. The mixture is extracted with a solution of 1/1 ethyl acetate/methyl-t-butyl ether (3×250 mL). The organic layer is evaporated to dryness. Water (500 mL) is added to the residue and the resulting mixture is stirred for 30 minutes, filtered and the filtered material dried in an oven vacuum at 45° C. overnight. The dried light brown solid is dissolved in acetone (500 mL) and heated to 50° C. Water (1000 mL) is slowly added and the mixture is stirred at 50° C. for 2 hours. The mixture is cooled to ambient temperature, filtered, and the filtered material dried under reduced pressure at 45° C. The dried material is stirred in ethyl acetate (600 mL) at 50° C. for two hours. The mixture is cooled to ambient temperature, filtered, and the filtered material dried under reduced pressure at 45° C. overnight to give the title compound as a white solid (50.8 g, 64%). Mass spectrum (m/z): 384.2 (M+1). 1H NMR (300 MHz, DMSO): 12.85 (s, 1H), 9.87 (s, 1H), 7.71 (s, 2H), 7.49 (d, J=8.7 Hz, 1H), 7.01 (d, J=8.7 Hz, 1H), 4.68 (d, J=4.1 Hz, 1H), 4.11-4.04 (m, 2H), 3.70 (m, 1H), 3.15-3.07 (m, 2H), 2.41 (s, 3H), 2.27 (s, 6H), 1.81-1.77 (m, 2H), 1.44-1.32 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][CH2:13][CH2:14][NH:15][C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN([CH2:27][CH3:28])CC.ClCC(Cl)=[O:32].[H-].[Na+]>C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:12]2[CH2:28][CH2:27][N:15]([C:16]3[N:17]=[CH:18][CH:19]=[CH:20][N:21]=3)[CH2:14][C:13]2=[O:32])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(NCCNc2ncccn2)C1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)CCl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(N2CCN(c3ncccn3)CC2=O)C1
Temperature: 25 °C
Yield: 19.6 %

Procedure:
To a solution of intermediate 2b (210 mg, 0.72 mmol) and Et3N (0.50 mL, 3.58 mmol) in CH2Cl2 (8 mL) at 0° C. was added chloroacetyl chloride (0.086 mL, 1.07 mmol). The reaction was slowly warmed up to room temperature in 3 h. It was quenched with aq. NaHCO3 and extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated. To a solution of the above crude product (150 mg, 0.41 mmol) in DMF (3 mL) at 0° C. was added NaH (60% in oil, 24 mg, 0.60 mmol). The reaction was slowly warmed up to room temperature in 3 h. It was quenched with H2O and extracted with EtOAc. The organic solution was washed with aq. NaCl, dried over Na2SO4 and concentrated. Purification by column chromatography (silica gel, 3% MeOH/CH2Cl2) gave intermediate 2c as white solid (47 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]([O:12]C)=[O:11])=[CH:7][C:6]=2[CH:14]=1.[CH3:15][S:16][CH2:17][S:18]([CH3:20])=[O:19].CN(C)[CH:23]=[O:24]>>[O:12]=[C:10]([C:8]1[S:9][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:14][C:6]=2[CH:7]=1)[C:23]([O:19][S:18][CH3:17])=[O:24].[O:11]=[C:10]([C:8]1[S:9][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:14][C:6]=2[CH:7]=1)[CH:17]([S:16][CH3:15])[S:18]([CH3:20])=[O:19]
Reactant: CSCS(C)=O
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc2cc(Cl)ccc2s1
Product: CSC(C(=O)c1cc2cc(Cl)ccc2s1)S(C)=O
Product: CSOC(=O)C(=O)c1cc2cc(Cl)ccc2s1

Procedure:
Methylthio α-oxo-α-(5-chloro-2-benzothienyl)acetate was prepared by reacting 26.8 g of methyl (5-chloro-2-benzothienyl)formate with 21.4 g of methyl methylthiomethyl sulfoxide in 500 ml of N,N-dimethylformamide to give 1-oxo-1-(5-chloro-2-benzothienyl)-2-methylthio-2-methylsulfinylethane, which was then reacted with sodium para periodate in acetic anhydride and formic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]([CH2:10][CH3:11])=[CH:5][O:6][CH2:7][CH2:8][Cl:9].[H][H]>CO.[C].[Pd]>[CH3:1][O:2][C:3](=[O:12])[CH:4]([CH2:10][CH3:11])[CH2:5][O:6][CH2:7][CH2:8][Cl:9]
Reactant: [H][H]
Reactant: CCC(=COCCCl)C(=O)OC
Agent: [Pd]
Solvent: CO
Product: CCC(COCCCl)C(=O)OC
Yield: 87 %

Procedure:
346.8 g 3-(2-Chloroethoxy)-2-ethyl-acrylic acid methyl ester was hydrogenated in 1200 ml methanol in the presence of 27 g 5% palladium-carbon catalyst at atmospheric pressure. The amount of hydrogen required to saturate the double bond was absorbed within approximately 90-120 minutes, whereupon the catalyst was filtered off, and the filtrate was partly evaporated. The residue was distilled in a vacuum to produce 305 g 3-(2-chloroethoxy)-2-ethyl-propionic acid methyl ester (87% yield) boiling at 110°-112° C./14 torr.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)=[O:7].[OH-:15].[Na+].C(Cl)(Cl)Cl.[OH2:21]>CC(C)=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:8]([CH3:13])([CH3:9])[C:6]([OH:21])=[O:15])=[CH:10][CH:9]=1)=[O:7]
Reactant: O=C(c1ccc(O)cc1)c1ccco1
Reactant: O
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)(Oc1ccc(C(=O)c2ccco2)cc1)C(=O)O

Procedure:
2-Furyl(4-hydroxy-phenyl)ketone (10 g) is dissolved in anhydrous acetone (80 g) and sodium hydroxide (13.2 g) is added thereto; the resulting mixture is stirred for 30 minutes after which anhydrous chloroform (20 g) is added dropwise thereto. On completion of the addition, the mixture is refluxed for 10 hrs. After cooling, the suspension is poured over 2 volumes water and the acetone is evaporated under reduced pressure. The aqueous phase is made acidic, and is then extracted with ethyl ether. The ether phase is neutralized, dried, and the solvent is evaporated off. The resulting solid is recrystallized from benzene, to give 9 g of acid which melts at 127° C. (B)
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-])=O)[C:4]([OH:6])=[O:5].[H][H]>O.[Pd]>[NH2:2][CH:3]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15])[C:4]([OH:6])=[O:5]
Reactant: [H][H]
Reactant: NC(CCc1ccccc1[N+](=O)[O-])C(=O)O
Agent: [Pd]
Agent: Cl
Solvent: O
Product: Nc1ccccc1CCC(N)C(=O)O

Procedure:
Alternatively, a solution of 2-amino-4-(2-nitrophenyl)butyric acid hydrochloride (2.5 g) in water (200 ml) was hydrogenated at room temperature and atmospheric pressure, using 10% Pd-C (0.5 g) as catalyst. After uptake of hydrogen ceased, the catalyst was filtered off, and the filtrate evaporated to dryness. The residue was dissolved in water (50 ml) and the pH adjusted to 7 by the addition of 10% sodium hydroxide. The solid was filtered off, washed with water, and dried to give 2-amino-4-(2-aminophenyl)butyric acid. A solution of the 2-amino-4-(2-aminophenyl)butyric acid (1.0 g), hexamethyldisilazane (5.4 g), and chlorotrimethylsilane (0.1 g) in xylene (125 ml) was refluxed for 65 hours. The reaction mixture was cooled, poured into ethanol (200 ml) and evaporated under reduced pressure. Water (100 ml) was added, and the solution extracted with dichloromethane (2×125 ml). The combined dichloromethane solutions were washed with water (50 ml), dried over magnesium sulfate, and evaporated under reduced pressure to give 3-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one as above.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:12][N:11]([C:13]([C:15]2[S:23][C:22]3[C:17](=[N:18][CH:19]=[CH:20][C:21]=3Cl)[CH:16]=2)=[O:14])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:25][C:26]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:27]=1[OH:35].C([O-])([O-])=O.[K+].[K+].O(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)Cl>[Si:1]([O:8][CH:9]1[CH2:12][N:11]([C:13]([C:15]2[S:23][C:22]3[C:17](=[N:18][CH:19]=[CH:20][C:21]=3[O:35][C:27]3[CH:28]=[CH:29][C:30]([N+:32]([O-:34])=[O:33])=[CH:31][C:26]=3[F:25])[CH:16]=2)=[O:14])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CN(C(=O)c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)C1
Temperature: 170 °C
Reaction time: 1.5 h
Yield: 34.2 %

Procedure:
A mixture of (3-(tert-butyldimethylsilyloxy)azetidin-1-yl)(7-chlorothieno[3,2-b]pyridin-2-yl)methanone 272 (749.7 mg, 1.96 mmol) (WO 2006/010264), 2-fluoro-4-nitrophenol (461 mg, 2.94 mmol), K2CO3 (518 mg, 3.92 mmol) and Ph2O (2.6 mL) was stirred in a sealed tube for 1.5 h at 170° C. The mixture was diluted with DCM, extracted with water, the organic phase dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography (eluted successively with: EtOAc/hexanes 1:1, EtOAc, EtOAc/MeOH 4:1) affording 273 (336 mg, 0.67 mmol, 34% yield). MS (m/z): (M+1) 504.1 (100%).
Reaction SMILES: [C:1]([N:4]([C:8]1[C:13]([CH3:14])=[C:12]([Cl:15])[CH:11]=[C:10]([C:16](=O)[CH3:17])[C:9]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)C(=O)C)(=[O:3])[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:32].[Na+]>CO.C(#N)C>[NH2:32][CH:16]([C:10]1[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)=[C:8]([NH:4][C:1](=[O:3])[CH3:2])[C:13]([CH3:14])=[C:12]([Cl:15])[CH:11]=1)[CH3:17]
Reactant: CC(=O)c1cc(Cl)c(C)c(N(C(C)=O)C(C)=O)c1-c1cccc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(=O)Nc1c(C)c(Cl)cc(C(C)N)c1-c1cccc(F)c1
Temperature: 65 °C

Procedure:
A mixture of N-acetyl-N-(6-acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-yl)acetamide (57 mg, 0.16 mmol), ammonium acetate (120 mg, 1.6 mmol) and sodium cyanoborohydride (20 mg, 0.32 mmol) in methanol (0.6 mL) and acetonitrile (0.6 mL) was heated at 65° C. overnight in a sealed tube. The mixture was then cooled to room temperature and quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step. LCMS calculated for C17H19ClFN2O (M+H)+: m/z=321.1. found: 321.0.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=1.C(N(CC)CC)C.[NH2:26][N:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:3]=[C:2]([NH:26][N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: CP(C)(=O)c1ccc(Nc2ncnc(Cl)n2)cc1
Reactant: CN1CCN(N)CC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN1CCN(Nc2ncnc(Nc3ccc(P(C)(C)=O)cc3)n2)CC1

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine (prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added 50 L of triethylamine and 1-Amino-4-methyl-piperazine (13 mg, 0.12 mmol). The mixture is microwaved at 120 degrees until formation of the desired compound. The reaction mixture is filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: CC(C)([O-:4])C.[K+].[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[CH2:15][C:16]#N.C(O/[CH:21]=[CH:22]/[C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])C>C1COCC1>[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C:15]1[C:16](=[O:4])[O:28][C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=1
Reactant: CCO/C=C/C(=O)C(F)(F)F
Reactant: CC(C)(C)[O-]
Reactant: N#CCc1ccc(F)cc1F
Agent: [K+]
Solvent: C1CCOC1
Product: O=c1oc(C(F)(F)F)ccc1-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.9 %

Procedure:
7.7 g (69 mmol) of potassium tert-butoxide was dissolved in 200 ml of THF, and 10 g (65 mmol) of 2,4-difluorophenyl acetonitrile was dropwise added thereto under cooling with ice. Ten minutes later, 13.5 g (69 immol) of (E)-4-ethoxy-1,1,1-trifluoro-3-buten-2-one was dropwise added thereto, followed by stirring at room temperature for 4 hours. THF was distilled off under reduced pressure. Then, the obtained residue was poured into water, acidified to pH 1 with 1N hydrochloric acid and then extracted with ethyl acetate. After washing with water and an aqueous sodium hydrogencarbonate solution, the organic layer was dried over anhydrous magnesium sulfate. And then, the ethyl acetate was distilled off under reduced pressure. To the obtained residue, 150 ml of concentrated hydrochloric acid was added, followed by stirring for 4 hours under heating and refluxing. This reaction solution was poured into ice water and extracted with ethyl acetate, followed by washing with water. The organic layer was dried over anhydrous magnesium sulfate, and then, ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 13.8 g (yield: 76%) of the desired product. Melting point: 98-100° C. 1H-NMR (400 MHz, CDCl3) δ value: 6.78(1H,d), 6.95(2H,m), 7.52(1H,d), 7.56(1H,q)ppm.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[Br:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([O:15][CH3:16])=[CH:10][C:9]=1[CH3:17].[OH2:18]>N1C=CC=CC=1>[Br:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([O:15][CH3:16])=[CH:10][C:9]=1[C:17]([OH:2])=[O:18]
Reactant: O
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1cc(C)c(Br)cc1F
Agent: [K+]
Solvent: c1ccncc1
Product: COc1cc(C(=O)O)c(Br)cc1F
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Potassium permanganate (53 g, 3.4 mol) was added to a solution of 1-bromo-5-fluoro-4-methoxy-2-methylbenzene (37 g, 1.7 mol) in 75 ml of pyridine and 150 ml of water at 60° C. The solution was stirred at 60° C. degrees for 24 hours. The solution was filtered and the solids were washed with a solution of water/methanol (50:50). The filtrate was concentrated to approximately 100 ml, then acidified (pH 1) with concentrated HCl. The solid was collected by filtration and dried under vacuum to afford 2-bromo-4-fluoro-5-methoxybenzoic acid as an off white solid. MS m/z=248.9 [M+H].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.CN(C1CCNCC1)C.CCN=C=NCCCN(C)C.[CH3:35][CH:36]([CH2:40][CH3:41])[C:37](O)=[O:38]>C(Cl)Cl>[CH3:35][CH:36]([CH2:40][CH3:41])[C:37]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1)=[O:38]
Reactant: CCC(C)C(=O)O
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C1CCNCC1
Solvent: ClCCl
Product: CCC(C)C(=O)N1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
tert-butyl piperidin-4-ylcarbamate (1 g, 5 mmol), 4-(N,N-dimethylamino)piperidine (0.73 g, 6 mmol) and EDCI (1.15 g, 6 mmol) were added into a solution of 2-methylbutanoic acid (0.612 g, 6 mmol) in CH2Cl2 (200 mL). The reaction was stirred overnight at rt. The reaction was quenched with the addition of 0.1 M HCl. The organic layer was further washed with sat. NaHCO3 solution followed by sat. NaCl solution. The organic layers was concentrated under vacuo. The product was purified by flash chromatography (Hex:EtOAc/1:1) yielding final product 15 (1.3 g, 4.6 mmol, 91.5% yield). H-NMR (DMSO-d6) ∂ 0.79 (q, J=5 Hz, 3H), 0.95 (m, 3H), 1.2-1.3 (m, 2H), 1.38 (s, 9H), 1.50 (m, 2H), 1.73 (t, J=15 Hz, 1H), 2.6-2.7 (m, 2H), 3.06 (t, J=12 Hz, 1H), 3.46 (m, 1H), 3.88 (d, J=12 Hz, 1H), 4.26 (m, 1H), 6.85 (d, J=8 Hz, 1H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]2[CH:30]=[CH:29][C:28]([OH:31])=[C:27]3[C:22]=2[CH2:23][CH2:24][CH2:25][NH:26]3)[CH2:15][CH2:14]1.C(N(CC)CC)C>O1CCCC1>[C:1]([N:26]1[C:27]2[C:22](=[C:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][N:13]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[O:6][CH3:5])[CH2:14][CH2:15]3)[CH:30]=[CH:29][C:28]=2[OH:31])[CH2:23][CH2:24][CH2:25]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COc1ccccc1N1CCN(CCc2ccc(O)c3c2CCCN3)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1N1CCN(CCc2ccc(O)c3c2CCCN3C(C)=O)CC1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A solution of 1.45 ml of acetyl chloride is 20 ml of tetrahydrofuran is added at 5° C. to a solution of 7.34 g of 5-{2-[4-(2-methoxyphenyl)piperazinyl]ethyl}-8-hydroxy-1,2,3,4-tetrahydro quinoline in 140 ml of anhydrous tetrahydrofuran containing 2.8 ml of triethylamine. This is stirred for 2 hours at 5° C. and then for 1 hour at room temperature. Then, the insoluble substance is filtered off and concentrated to dryness under reduced pressure. The residue is purified by chromatoflash on 750 g of silica (70-230 mesh) by eluating with the mixture CH2Cl3 /CH3OH (95/5).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:30][O:31][C:32](=[O:36])[CH2:33][CH2:34][NH2:35].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:30][O:31][C:32](=[O:36])[CH2:33][CH2:34][NH:35][C:18](=[O:19])[C:17]1[CH:16]=[CH:15][C:14]([CH:9]([S:8][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:22][CH:21]=1
Reactant: COC(=O)CCN
Reactant: CC(C)CC(Sc1ccc(Br)cc1)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Sc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To a mixture of 4-[1-(4-bromo-phenylsulfanyl)-3-methyl-butyl]-benzoic acid (379 mg, 1 mmol) in methylene chloride (10 mL) are added triethyl amine (0.42 mL, 3 mmol), DMAP (5.0 mg), 3-amino-propionic acid methyl ester (209 mg, 1.5 mmol) and EDCI (577 mg, 3.0 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a gradient from 0% of ethyl acetate to 100% of ethyl acetate giving 3-{4-[1-(4-Bromo-phenylsulfanyl)-3-methyl-butyl]-benzoylamino}-propionic acid methyl ester (350 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.[NH2:21][CH2:22]CN.O>CN(C)C=O>[C:22]([C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1)#[N:21]
Reactant: CCOC(=O)C=Cc1ccc(Cn2ccnc2)c(Br)c1
Reactant: NCCN
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(Cn2ccnc2)c(C#N)c1

Procedure:
A mixture of ethyl 3-[3-bromo-4-(imidazol-1-ylmethyl)phenyl]prop-2-enoate (0.2 g) and cuprous cyanide (0.07 g) in dry N,N-dimethylformamide (1 ml) was stirred and heated under reflux for 8 h. The hot reaction mixture was poured into a stirred solution of 1,2-diaminoethane (0.3 ml) and water (1.5 ml). The reaction mixture was filtered, and the residue was washed with hot benzene 2×8 ml. The organic layer was separated, and the residue was washed with more hot benzene (10 ml). The benzene solutions were combined, dried (MgSO4) and concentrated to afford a brown oil. The oil was purified using `flash` chromatography and chloroform/methanol 9:1 as eluant. The product fractions were combined and concentrated to afford ethyl 3-[3-cyano-4-(imidazol-1-ylmethyl)phenyl]prop-2-enoate as a brown oil. I.R. (CHCl3 film) vC=N: 2230 cm-1
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[CH:10]=[C:9]([CH:20]3[CH2:22][CH2:21]3)[N:8]=2)[CH:6]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)O1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:10]=[C:9]([CH:20]3[CH2:22][CH2:21]3)[N:8]=[C:7]([N:5]3[CH:6]=[C:2]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[N:3]=[CH:4]3)[N:12]=2)=[CH:14][CH:15]=1
Reactant: Clc1ccc(-c2cc(C3CC3)nc(-n3cnc(Br)c3)n2)cc1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Product: Clc1ccc(-c2cc(C3CC3)nc(-n3cnc(-c4cccnc4)c3)n2)cc1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-(4-chloro-phenyl)-6-cyclopropyl-pyrimidine (example E.14) (0.15 g, 0.4 mmol) and commercially available 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.08 g, 0.4 mmol) according to the general procedure VI. Obtained as an off-white solid (0.015 g, 10%). MS (ISP) 374.0 [(M+H)+]; mp 180-182° C.
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[C:9]3[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:8]3=[CH:7][C:6]=2[C:5](Cl)=[N:4][N:3]=1.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22]>>[CH2:19]([NH:23][C:2]1[C:11]2[CH:10]=[C:9]3[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:8]3=[CH:7][C:6]=2[C:5]([NH:3][CH2:2][CH2:11][CH2:6][CH3:5])=[N:4][N:3]=1)[CH2:20][CH2:21][CH3:22]
Reactant: COc1cccc2cc3c(Cl)nnc(Cl)c3cc12
Reactant: CCCCN
Product: CCCCNc1nnc(NCCCC)c2cc3c(OC)cccc3cc12
Temperature: 25 °C
Yield: 48 %

Procedure:
A mixture of 1,4-dichloro-6-methoxybenzo[g]phthalazine (3.94 mmol) and n-butylamine (25 mL) was treated in an autoclave at 130° C. for 6 h. After cooling to room temperature, the excess n-butylamine was evaporated to dryness under vacuum and the residue was extracted with chloroform (2×50 mL). The resulting extracts were concentrated and purified by flash chromatography on silica gel 60 Merck (200-400 mesh), using a mixture of chloroform, benzene, methanol (v/v, 1:0.5:0.2) as eluent. The removal of the solvents from the fraction of Rf=0.11 afforded 0.67 g (48%) of 1,4-bis(n-butylamino)-6-methoxy-benzo[g]phthalazine as a brown solid, melting at 178°-180° C., which shows the following physical properties: