Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:17][CH:16]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37]Cl)=[CH:31][CH:30]=1.Cl>O1CCCC1.CCCCCC>[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37][CH:23]([CH2:22][CH2:21][C:18]2[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:20][CH:19]=2)[C:24]([OH:26])=[O:25])=[CH:31][CH:30]=1
Reactant: COc1ccc(CCCC(=O)O)cc1
Reactant: COc1ccc(CCCCl)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: COc1ccc(CCCC(CCc2ccc(OC)cc2)C(=O)O)cc1
Temperature: 0 °C

Procedure:
A solution of diisopropylamine (15 g, 0.148 mol) in dry tetrahydrofuran (100 ml) at -78° C. was treated dropwise with a solution of butyl lithium in hexane (100 ml of a 1.6M solution 0.16 mol) under an atmosphere of dry argon. The solution was allowed to warm up to 0° C. over 2 hours, cooled back to -78° C. and treated with a solution of 4-(4-methoxyphenyl)butyric acid (14.1 g, 0.0726 mol) in dry tetrahydrofuran (50 ml). The solution was allowed to warm up to -20° C., cooled back to -78° C. and treated dropwise over 2 hours with 3-(4-methoxyphenyl)propyl chloride (13.5 g, 0.0731 mol). The solution was allowed to warm up to room temperature, poured into excess 2N hydrochloric acid and extracted with chloroform. The combined extracts were dried (MgSO4) and the solvent was evaporated off under reduced pressure to give the crude product, which was further purified by column chromatography (silica gel, 50% chloroform in hexane) to give 5-(4-methoxyphenyl)-2-[2-(4-methoxyphenyl)ethyl]pentanoic acid as a colourless crystalline solid, m.p. 91°-94° C. (from toluene).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[CH:5][C:4]=1[OH:18].[Br:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1.[F-].[Cs+]>COCCOC.CO.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>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([C:7]2[CH:6]=[CH:5][C:4]([OH:18])=[C:3]([O:2][CH3:1])[CH:8]=2)=[CH:22][CH:21]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: Brc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Product: COc1cc(-c2ccc(Br)cc2)ccc1O
Temperature: 70 °C
Yield: 54.1 %

Procedure:
A mixture of 2-methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (0.250 g, 1.00 mmol), 1,4-dibromo benzene (0.259 g, 1.10 mmol), Pd(PPh3)4 (0.0580 g, 5%), and CsF (0.456 g, 3.00 mmol) in DME/MeOH (25 mL, 1:1) was heated at 70° C. overnight. The reaction mixture was concentrated and the residue was extracted with CH2Cl2, washed with water, dried over MgSO4, filtered, concentrated, and purified by flash chromatography eluted with hexane/CH2Cl2 (1:9) to give 0.151 g (54%) of the desired product. MS (DCI/NH3) m/z: 279.9 (M+H)+; 1H NMR (300 MHz, CD3OD) δ 3.91 (s, 3H), 6.86 (d, J=8.14 Hz, 1H), 7.06 (m, 1H), 7.14 (d, J=2.03 Hz, 1H), 7.44-7.58 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][CH:10](OC)OC>C(O)C.Cl>[N:1]1[CH:9]=[CH:10][N:3]2[CH:4]=[CH:5][N:6]=[CH:7][C:2]=12
Reactant: Nc1cnccn1
Reactant: COC(CBr)OC
Agent: Cl
Solvent: CCO
Product: c1cn2ccnc2cn1
Yield: 21.4 %

Procedure:
To a solution of 2-aminopyrazine (2.0 g, 21.03 mmol) in ethanol (40 mL) was added 2-bromo-1,1-dimethoxyethane (2.5 mL, 21.03 mmol) followed by 5 drops of concentrated hydrochloric acid. After refluxing for 14 hours, the solvent was evaporated. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate (3×). The combined organic phase was washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by flash chromatography (100% ethyl acetate, 10% methanol in ethyl acetate, then 10% methanol in dichloromethane) to give 536 mg of the title compound as a solid. 1H NMR (500 MHz, CDCl3) δ 7.70 (bs, 1H), 7.82 (bs, 1H), 7.89 (d, 1H, J=4.4 Hz), 8.10 (d, 1H, J=4.6 Hz), 9.12 (s, 1H).
Reaction SMILES: [CH:1]12[CH2:13][CH2:12][CH:8]([CH2:9][NH:10][CH2:11]1)[C:7]1[C:2]2=[CH:3][C:4]([NH:14][C:15]2[N:20]=[C:19]([NH:21][C@@H:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]3[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[C:18]([Cl:33])=[CH:17][N:16]=2)=[CH:5][CH:6]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>>[Cl:33][C:18]1[C:19]([NH:21][C@@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[N:20][C:15]([NH:14][C:4]2[CH:3]=[C:2]3[C:7](=[CH:6][CH:5]=2)[CH:8]2[CH2:12][CH2:13][CH:1]3[CH2:11][N:10]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:9]2)=[N:16][CH:17]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)C2CCC3CNC2)ncc1Cl
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)C2CCC3CN(S(C)(=O)=O)C2)ncc1Cl

Procedure:
N-{(1R,2R)-2-[5-Chloro-2-(10-methanesulfonyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide was prepared from N-{(1R,2R)-2-[2-(10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-5-chloro-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide and methanesulfonyl chloride in an analogous manner to Example 278. Product isolated as a white foam as a mixture of diastereomers (14.79 mg, 42%). LCMS (m/e) 569 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.94 (s, 1H), 7.43-7.23 (m, 2H), 7.12-7.06 (m, 1H), 6.91-6.84 (m, 1H), 3.91-3.77 (m, 3H), 3.30-2.96 (m, 5H), 2.79 and 2.77 (diastereomeric singlets, 3H), 2.55 and 2.52 (diastereomeric singlets, 3H), 2.30-2.13 (m, 4H), 1.95-1.70 (m, 4H), 1.45-1.28 (m, 4H).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[C:14]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:28])[CH:25](Cl)[CH3:26])=[CH:20][CH:19]=1)(=[O:16])[CH3:15].[Cl-].[Na+].[K+].[Br-]>CN(C)C=O>[C:14]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:28])[CH:25]([CH3:26])[CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[CH:20][CH:19]=1)(=[O:16])[CH3:15]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(=O)Nc1ccc(C(=O)C(C)Cl)cc1
Agent: [Br-]
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)C(C)C(=O)c1ccc(NC(C)=O)cc1
Temperature: 0 °C

Procedure:
24.407 ml. (0.16 mol) of diethyl malonate were added dropwise to a suspension of 7.631 g (0.159 mol) of sodium hydride in 90 ml of anhydrous dimethylformamide under a nitrogen atmosphere, the mixture was heated for 90 minutes to 50° C., then 37.462 g (0.166 mol) of 1-(4-acetylaminophenyl)-2-chloro-1-propanone were added and heating was continued for a further 3 hours to 80° C. After cooling the mixture was stirred into 1 l of ice water, saturated with sodium chloride and extracted exhaustively with ethyl acetate. The combined ethyl acetate extracts were dried over sodium sulphate, filtered over activated charcoal and concentrated by evaporation in vacuo, and the residue was purified by column chromatography on silica gel. After working up in the usual way 45.0 g (80% of theoretical) of a colourless oil were obtained, Rf 0.7 (El: EE). IR (KBr): 1747, 1732, 1676 cm−1 (C═O) MS: M+349
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([F:17])([F:16])[C:9]1([C:12](OC)=[O:13])[CH2:11][CH2:10]1>C(OCC)C>[F:7][C:8]([F:17])([F:16])[C:9]1([CH2:12][OH:13])[CH2:11][CH2:10]1
Reactant: COC(=O)C1(C(F)(F)F)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC1(C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To an ice-cold suspension of lithium aluminum hydride (33.91 mmoles; 1.29 g) in diethyl ether (90 mL) is added dropwise over 25 minutes methyl 1-(trifluoromethyl)cyclopropanecarboxylate (16.95 mmoles; 3.00 g) in 30 mL of diethylether. The reaction is stirred at 0° C. for 2 hours. The mixture is quenched by slow addition of 7.5 mL of water, then 15 mL of 5 M sodium hydroxide and 9 mL of water. The thick slurry is vigourously stirred at room temperature for 3 hours. The mixture is transferred to a separatory funnel, diluted with water and extracted with diethylether. The combined organic layers are washed with brine, dried over magnesium sulfate, filtered and concentrated to dryness. 2.37 g of the title compound as a colorless oil are obtained. 2.37 g. 1H NMR (CDCl3) d (ppm): 0.762-0.807 (m, 2H), 1.018-1.055 (m, 2H), 3.732 (s, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:22]([C:26]([OH:28])=O)=[CH:21][C:20]([O:29][CH:30]([CH3:32])[CH3:31])=[C:19]([Cl:33])[C:18]=3[C:17]2=[O:34])=[C:13]([CH3:35])[CH:12]=[C:11]([CH3:36])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:37]([N:39](CC)[CH2:40]C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CNC.Cl>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:22]([C:26]([N:39]([CH3:40])[CH3:37])=[O:28])=[CH:21][C:20]([O:29][CH:30]([CH3:32])[CH3:31])=[C:19]([Cl:33])[C:18]=3[C:17]2=[O:34])=[C:13]([CH3:35])[CH:12]=[C:11]([CH3:36])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(CN2CCc3c(C(=O)O)cc(OC(C)C)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Reactant: CCN(CC)CC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(CN2CCc3c(C(=O)N(C)C)cc(OC(C)C)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Reaction time: 0.08 h
Yield: 90.4 %

Procedure:
To a solution of 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-1-oxo-7-(propan-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid (90a, 17 mg, 0.033 mmol) in DMF (1 mL) was added triethylamine (0.023 mL, 0.165 mmol) and HATU (14 mg, 0.035 mmol). The reaction mixture was stirred for 5 minutes, and then dimethylamine.HCl (4.10 mg, 0.050 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with H2O (5 mL) and the solid that precipitated was collected by filtration and dried under vacuum to give 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-N,N-dimethyl-1-oxo-7-(propan-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide (90b, 16 mg, 89% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]=[C:9]([CH2:12][NH2:13])[O:8][C:7]=2[CH:14]=1.[CH2:15]([N:18]=[C:19]=[O:20])[CH2:16][CH3:17].[N-]=C=O>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]=[C:9]([CH2:12][NH:13][C:19]([NH:18][CH2:15][CH2:16][CH3:17])=[O:20])[O:8][C:7]=2[CH:14]=1
Reactant: CCCN=C=O
Reactant: COc1ccc2c(c1)OC(CN)=CO2
Agent: [N-]=C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCNC(=O)NCC1=COc2ccc(OC)cc2O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The amine obtained in Step C of Example 24 is dissolved in 16 ml of anhydrous toluene; 0.78 g (9.17 mmol) of n-propyl isocyanate is then added to the medium. After 4 hours of stirring under an inert atmosphere and at ambient temperature, the excess of isocyanate is neutralised with a few drops of water. The solvent is then evaporated in vacuo. The residue obtained is purified on a silica column (eluant:MeOH/CH2Cl2: 10/90) to yield the title urea in the form of a white solid.
Reaction SMILES: [CH3:1]/[C:2](=[CH:6]\[C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:11]=1)/[C:3](O)=[O:4].C(N(CC)CC)C.C1(P([N:39]=[N+:40]=[N-:41])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[CH3:1][C:2](=[CH:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:11]=1)[C:3]([N:39]=[N+:40]=[N-:41])=[O:4]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: C/C(=C\c1cc(-c2ccccc2)cs1)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=Cc1cc(-c2ccccc2)cs1)C(=O)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (E)-2-methyl-3-(4-phenyl-thiophen-2-yl)-acrylic acid (924 mg, 3.78 mmol) and triethylamine (617 μl, 4.43 mmol) in THF (10 ml) was added diphenylphosphoryl azide (897 μl, 6.27 mmol) at 0° C. The reaction was next stirred for 4 h at room temperature. At which point the contents of the reaction flask were partitioned between ethyl acetate (25 ml) and sodium hydrogencarbonate (25 ml). The organic phase was separated and the solvent removed in vacuo. The crude residue was suspended between methanol (25 ml) and distilled water (25 ml), the precipitate collected and dried (MgSO4) to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=C(N)[N:4]=1.CI.[H-].[Na+].[CH3:15][N:16]([CH:18]=O)[CH3:17]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:18]([N:16]([CH3:15])[CH3:17])[N:4]=1
Reactant: CN(C)C=O
Reactant: COc1cc(C)nc(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COc1cc(C)nc(N(C)C)n1
Temperature: 23 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution containing 1.0 g (7.19 mmol) of 4-methoxy-6-methylpyrimidin-2-amine in 10 mL of anf DMF were added 1.35 mL (21.6 mmol) of methyl iodide followed by 853 mg (21.6 mmol) of 60% suspension of sodium hydride in mineral oil. The reaction mixture was stirred at 23° C. for 20 min. The reaction mixture was quenched with water and concentrated under diminished pressure in order to remove as much DMF as possible. The residue was dissolved in 70 mL of ethyl acetate and washed with 50-mL portions of water and brine respectively. The organic solution was dried (MgSO4) and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (15×5 cm). Elution with 4:1 hexanes-ethyl acetate afforded the expected product as colorless oil: yield 755 mg (63%); silica gel TLC Rf 0.25 (4:1 hexanes-ethyl acetate); 1H NMR (CDCl3) δ 2.22 (s, 3H), 3.12 (s, 6H), 3.83 (s, 3H) and 5.76 (s, 1H); 13C-NMR (CDCl3) δ 24.07, 36.76, 36.76, 52.68, 93.74, 162.24, 167.70 and 170.24; mass spectrum (APCI+), m/z 168.1135 (M+H) (C8H14N3O requires 168.1137).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]([C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1.O.[OH:31][C:32]1[CH:46]=[CH:45][CH:44]=[CH:43][C:33]=1[CH2:34]P(=O)(OCC)OCC>O1CCCC1>[OH:31][C:32]1[CH:46]=[CH:45][CH:44]=[CH:43][C:33]=1[CH:34]=[CH:26][C:25]1[CH:24]=[CH:23][C:22]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:11]2[CH:12]=[CH:13][C:8]([CH3:7])=[CH:9][CH:10]=2)=[CH:29][CH:28]=1
Reactant: CCOP(=O)(Cc1ccccc1O)OCC
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=O)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=Cc3ccccc3O)cc2)cc1
Reaction time: 2 h

Procedure:
At first, 14.8 g of potassium tert-butoxide and 50 ml of tetrahydrofuran were put in a reaction vessel having a stirrer, a thermometer and a dropping funnel. Under a nitrogen gas flow, a solution in which 9.90 g of the diethyl 2-hydroxybenzylphosphonate and 5.44 g of 4-(N,N-bis(4-methylphenyl)amino)benzaldehyde were dissolved in tetrahydrofuran was slowly dropped therein at room temperature, and the reaction is further performed for 2 hours at the same temperature. Next, water was added thereto while cooling the reaction product with water, a hydrochloric acid solution with a normal concentration of 2 (i.e., 2N) was added therein to acidize the reaction product, and then tetrahydrofuran was removed by an evaporator. Further, toluene was added thereto to extract a crude product with toluene. The toluene phase was washed with water, a sodium hydrogen carbonate solution and a saturated saline in this order, and magnesium sulfate was then added thereto to dehydrate the toluene phase.
Reaction SMILES: O=[C:2]1[N:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[NH:3]1.C(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:2]1[N:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]=1
Reactant: CCOC(=O)Cn1c(=O)[nH]c2cccnc21
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)Cn1c(Cl)nc2cccnc21
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl (2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)acetate (14.5 g) and phosphoryl chloride (100 mL) was stirred at 100° C. overnight. The mixture was poured into ice, neutralized with saturated sodium bicarbonate solution and extracted with AcOEt. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was diluted with AcOEt and insoluble crystals were removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 10%-40% AcOEt in hexane) to give the title compound (5.46 g).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:12])[NH:8][CH2:9]2)=[CH:4][CH:3]=1.[NH2:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[C:16]([Cl:21])[N:15]=1>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:12])[N:8]([C:18]3[CH:17]=[C:16]([Cl:21])[N:15]=[C:14]([NH2:13])[N:19]=3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CC1Cc2ccc(Br)cc2CN1
Product: CC1Cc2ccc(Br)cc2CN1c1cc(Cl)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 1 starting from 7-bromo-3-methyl-1,2,3,4-tetrahydroisoquinoline and 2-Amino-4,6-dichloropyrimidine (Alfa Aesar, Cat. No. A11330). LCMS (M+H)+: m/z=353.0.
Reaction SMILES: [CH2:1]([C:4]1([C:25](O)=[O:26])[N:8]2[C:9](=[O:24])[C:10]([NH:13][C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[CH:11][N:12]=[C:7]2[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[C:28]([O:32][C:33](=[O:45])[NH:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([CH2:43][NH2:44])=[CH:39][CH:38]=1)=[NH:36])([CH3:31])([CH3:30])[CH3:29]>>[CH2:17]([O:16][C:14](=[O:15])[NH:13][C:10]1[C:9](=[O:24])[N:8]2[C:4]([CH2:1][CH:2]=[CH2:3])([C:25](=[O:26])[NH:44][CH2:43][C:40]3[CH:39]=[CH:38][C:37]([C:35]([NH:34][C:33]([O:32][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:45])=[NH:36])=[CH:42][CH:41]=3)[CH2:5][CH2:6][C:7]2=[N:12][CH:11]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C=CCC1(C(=O)O)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CN)cc1
Product: C=CCC1(C(=O)NCc2ccc(C(=N)NC(=O)OC(C)(C)C)cc2)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Yield: 86 %

Procedure:
According to the procedure for the preparation of intermediate 19c, intermediate 20b (50 mg, 0.135 mmol) was coupled with [(4-aminomethyl-phenyl)-imino-methyl]-carbamic acid tert-butyl ester to afford 70 mg (86%) of intermediate 20c.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8])[CH2:2][CH3:3].[OH-].[Na+].Cl>CO>[CH2:1]([O:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([OH:9])=[O:8])[CH2:2][CH3:3]
Reactant: CCCOc1ccccc1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCOc1ccccc1C(=O)O
Temperature: 60 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To a solution of methyl 2-(propyloxy)benzoate (841 mg) in methanol (20 ml) was added 2N sodium hydroxide solution (5 ml) and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was acidified with 6N hydrochloric acid to pH 4 and organic solvent was removed by evaporation. The aqueous layer was diluted with water and extracted with chloroform. The extract was washed with brine, dried over magnesium sulfate, and evaporated in vacuo to give 2-(propyloxy)benzoic acid as colorless oil (756 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[N:4][C:3]=1[NH:9][NH2:10].[OH-].[Na+].[H][H]>CO.[Pd]>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[N:4][C:3]=1[NH:9][NH2:10]
Reactant: [H][H]
Reactant: NNc1nnc(Cl)cc1N
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NNc1nnccc1N
Reaction time: 4 h

Procedure:
A solution of 4 g of 4-amino-6-chloro-3-hydrazinopyridazine in 240 ml. of methanol and 60 ml. of 0.5 N sodium hydroxide in methanol are charged into a Paar shaker. To this solutionn, 2 g. of 10% palladium on carbon catalyst is added. The Paar shaker is charged at room temperature with hydrogen to an initial pressure of 50 psi and shaken. After about 4 hours, the reaction mixture is filtered, the solvent evaporated, and the residue extracted with chloroform. The chloroform solution is evaporated to dryness, and the 4-amino-3-hydrazino pyridazine obtained is dissolved in methanol. Hydrogen chloride gas is bubbled in, and the 4-amino-3-hydrazinopyridazine dihydrochloride (m.p. 281°-283°C.) which precipitates is separated by filtration.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][C@@H:16]([C:18]3[CH:32]=[CH:31][C:21]([O:22][CH2:23][C@@H:24]([N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[CH3:25])=[CH:20][CH:19]=3)[C@@H:15]([C:33]3[CH:38]=[CH:37][C:36]([O:39][Si](C(C)C)(C(C)C)C(C)C)=[CH:35][CH:34]=3)[S:14][C:13]=2[CH:50]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CCO.CCOC(C)=O.O.[Pd]>[OH:39][C:36]1[CH:37]=[CH:38][C:33]([C@H:15]2[S:14][C:13]3[CH:50]=[C:9]([OH:8])[CH:10]=[CH:11][C:12]=3[O:17][C@H:16]2[C:18]2[CH:32]=[CH:31][C:21]([O:22][CH2:23][C@@H:24]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH3:25])=[CH:20][CH:19]=2)=[CH:34][CH:35]=1
Reactant: CC(C)[Si](Oc1ccc([C@H]2Sc3cc(OCc4ccccc4)ccc3O[C@H]2c2ccc(OC[C@H](C)N3CCCC3)cc2)cc1)(C(C)C)C(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: C[C@@H](COc1ccc([C@@H]2Oc3ccc(O)cc3S[C@@H]2c2ccc(O)cc2)cc1)N1CCCC1
Temperature: 80 °C

Procedure:
A stirred mixture of 102 mg (0.14 mmol) of compound 10a, generated in Example 10, Step A, 30.6 mg (0.29 mmol) of palladium black and 181.2 mg (0.29 mmol) ammonium formate in 3 mL of EtOH/EtOAc/H2O (7:2:1) was heated at 80° C. for 2 h. The reaction mixture was filtered through a pad of Celite® to remove the catalyst, washed thoroughly with EtOH/EtOAc/H2O (7:2:1), and the filtrate was partitioned between water and EtOAc. The organic phase was separated, dried over Na2SO4, filtered, evaporated, and dried in vacuo to give the crude product which was used without purification.
Reaction SMILES: ClC1C=CN=C2C=CSC=12.[F:11][C:12]1[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[CH:29][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[CH:21]=[C:22](C(N(C)C)=O)[S:23][C:16]=12>>[F:11][C:12]1[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[CH:29][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[CH:21]=[CH:22][S:23][C:16]=12
Reactant: CN(C)C(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: Clc1ccnc2ccsc12
Product: O=[N+]([O-])c1ccc(Oc2ccnc3ccsc23)c(F)c1
Yield: 45 %

Procedure:
Starting from the chloride 2 (scheme 1) and following the procedure described above for the synthesis of compound 6 (scheme 1, example 1), title compound 168 was obtained in 45% yield. LRMS (M+1) 290.3 (100%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:18])[CH2:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.Cl[CH2:20][CH2:21][CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24].C(N(CC)CC)C>C(O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[O:18])[CH2:11][N:12]1[CH2:13][CH2:14][N:15]([CH2:20][CH2:21][CH2:22][C:23](=[O:24])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:16][CH2:17]1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCNCC1
Reactant: O=C(CCCCl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cccc(C)c1NC(=O)CN1CCN(CCCC(=O)c2ccccc2)CC1

Procedure:
A mixture of N-(2,6-dimethylphenyl)-2-piperazinylacetamide (4) (100 mg, 0.4 mmol), 4-chloro-1-phenylbutan-1-one (12) (100 mg, 0.55 mmol), and triethylamine (0.4 mL) in ethanol (3 mL) was heated at reflux for 16 hours. Ethanol was removed under reduced pressure and the residue was purified by preparative TLC using 10% methanol in dichloromethane as mobile phase to afford N-(2,6-dimethylphenyl)-2-[4-(4-oxo-4-phenylbutyl)piperazin-1-yl]acetamide, a compound of formula (16).