Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.CO[CH:16]([O:19]C)[CH2:17][NH2:18]>>[Cl:13][C:7]1[CH:8]=[C:9]2[C:4]([NH:3][C:16](=[O:19])[C:17]3[N:10]2[CH:11]=[CH:2][N:18]=3)=[CH:5][CH:6]=1
Reactant: Clc1ccc2nc(Cl)c(Cl)nc2c1
Reactant: COC(CN)OC
Product: O=c1[nH]c2ccc(Cl)cc2n2ccnc12

Procedure:
By reaction of 2,3,6-trichloroquinoxaline with aminoacetaldehyde dimethyl acetal, according to a procedure that is similar to that followed in example 1, there is obtained 8-chloroimidazo[1,2-a]quinoxaline-4(5H)-one (m.p. >300° C.). By reacting this product with 1-ethyl propylamine according to the method described in example 9, there is obtained 8-chloro-4-(1-ethylpropylamino)imidazo[1,2-a]quinoxaline. m.p. (DSC)=125.1° C.(onset); IR (KBr): 3406, 3105, 2964, 1532 cm-1 ; 1H-NMR (CDCl3 /CD3OD): δ8.4 (1H,s), 8.05 (1H,d, J=2 Hz), 7.8÷7.4 (3H,m), 3.85 (1H,m), 1.65 (4H,m), 0.95 (6H,t); UV (EtOH): λmax =230, 245, 289, 301, 326 nm. Elementary analysis for C15H17ClN4 (m.w. 288.78): calcd. C 62.39, H 5.93, N 19.40%; found C 62.17, H 6.02, N 19.46%.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][CH2:4][CH:5]([NH:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:7]=1[CH3:21].Cl[C:36]1[N:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][N:37]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[F:33][C:2]([F:1])([F:34])[CH2:3][CH2:4][CH:5]([NH:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:36]2[N:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][N:37]=2)=[CH:8][C:7]=1[CH3:21]
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2C)cc1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(-c3ncc(C(F)(F)F)cn3)cc2C)cc1
Temperature: 130 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
A reaction mixture of methyl 4-((4,4,4-trifluoro-1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butyl)amino)benzoate (0.300 g) obtained in Example 10, step A, 2-chloro-5-(trifluoromethyl)pyrimidine (0.108 g), tetrakistriphenylphosphinepalladium (0.0726 g), sodium carbonate (0.200 g), DME (3 mL) and water (1 mL) was stirred at 130° C. for 1 hr under microwave irradiation under a nitrogen atmosphere. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.259 g).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.P.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:17][C:18]([CH3:20])=[O:19]>C(Cl)C=CC1C=CC=CC=1.[Pd]>[O:19]=[C:18]([CH3:20])[CH2:17][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: N#Cc1ccc(Cl)cc1
Agent: [Pd]
Agent: ClCC=Cc1ccccc1
Agent: O=C([O-])[O-]
Product: CC(=O)Cc1ccc(C#N)cc1
Yield: 80 %

Procedure:
This reaction is carried out in the same manner as the reaction in example 3. The difference is that, the reactants are 4-chlorobenzonitrile (137.6 mg, 1.0 mmol), palladium cinnamyl chloride (7.9 mg, 0.015 mmol), 2-Methoxy-6-(N-methyl-N-phenyl-amino) henyldicyclohexyl)phosphine (24.5 mg, 0.060 mmol), Cs2CO3 (651.9 mg, 2.0 mmol) in 4.0 mL acetone at 90° C. for 12 h. 4-(2′-Oxopropyl)benzonitrile (127.6 mg) was obtained with a yield of 80% as solid. m.p.: 79.8-80.1° C. (n-Hexane:Ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.66-7.60 (m, 2H, ArH), 7.34-7.27 (m, 2H, ArH), 3.81 (s, 2H, CH2), 2.23 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3) δ 204.3, 139.3, 132.3, 130.3, 118.6, 111.0, 50.3, 29.8; IR (KBr) v (cm−1) 3060, 3006, 2954, 2893, 2225, 1708, 1608, 1420, 1504, 1407, 1356, 1334, 1313, 1212, 1163, 1019; MS (70 eV, EI) m/z (%): 160 (M++1, 1.05), 159 (M+, 9.09), 43 (100).
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[O:11][CH3:12].[Li+].[OH-].Cl>C1COCC1.O>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:13])=[O:2])=[C:5]([O:11][CH3:12])[CH:6]=1
Reactant: COC(=O)c1ccc(N)cc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(N)ccc1C(=O)O
Yield: 72.2 %

Procedure:
To a solution of 4-amino-2-methoxy benzoic acid methyl ester (5 g; 27 mmol) in THF/H2O (125 mL/25 mL) was added LiOH (4.8 g; 200 mmol) and the slurry was refluxed for 3.5 hours. The reaction mixture was neutralized using 4 M HCl (aq) and the resulting precipitate isolated by filtration and washed with H2O (2×15 mL) to give 3.26 g (80%) of an off-white solid. Mp. 144-146° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH:4](C(=O)C1C=CC=CC=1)[CH2:5][C:6]([C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[Br:16])([CH3:8])[CH3:7].C(=O)([O-])[O-:27].[K+].[K+].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].CI.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.CC(OC)(C)C>[CH3:1][O:2][C:3](=[O:25])[CH:4]([OH:27])[CH2:5][C:6]([C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[Br:16])([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)(C)c1cc(F)ccc1Br)C(=O)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Cs+]
Solvent: CI
Solvent: CO
Solvent: COC(C)(C)C
Product: COC(=O)C(O)CC(C)(C)c1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.8 %

Procedure:
A solution of 0.9 g (2.13 mmol) of 2-benzoyl-4-(2-bromo-5-fluorophenyl)-4-methylvaleric acid-methyl ester in 50 ml of MeOH is mixed with 1.47 g (10.6 mmol) of potassium carbonate and stirred for 3 hours at room temperature. The batch is acidified (pH 3) with 10% sulfuric acid, and it is extracted with ethyl acetate. The combined extracts are washed with saturated NaCl, dried (Na2SO4) and concentrated by evaporation in a vacuum. The residue is taken up in 8 ml of DMF and stirred with 1.92 g (5.9 mmol) of cesium carbonate and 0.38 ml. (5.9 mmol) of methyl iodide for 3 hours at room temperature. The batch is mixed with 10% citric acid and extracted-with MTBE. The organic phase is washed with saturated NaCl, dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography on silica gel with hexane-ethyl acetate yields 250 mg of product.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[C:28]([C:31]([NH:33][CH2:34][C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)=[O:32])=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:11][CH:10]=1)=[O:2].C[Mg]Br.[CH2:44](OCC)[CH3:45]>O1CCCC1>[OH:2][CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[C:28]([C:31]([NH:33][CH2:34][C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)=[O:32])=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:13][CH:14]=1)[CH2:44][CH3:45]
Reactant: CCOCC
Reactant: O=Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)c1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 27.9 %

Procedure:
To a solution of 10-[(2′-formyl-1,1′-biphenyl-4-yl)carbonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 56 (0.132 g, 0.251 mmol) in dry tetrahydrofuran (15 mL) was added 3.0 Methylmagnesium bromide in diethyl ether (0.68 mL, 2.04 mmol) and the reaction mixture stirred at room temperature under nitrogen for 17 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (20 mL) and then the mixture partitioned between ethyl acetate (100 mL) and half saturated aqueous ammonium chloride solution (100 mL). The organic phase was separated, washed with brine (100 ml), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a cream foam. Purification by flash chromatography using a solvent gradient of 1 to 6% methanol in dichloromethane gave a colorless glass that was triturated with diethyl ether to afford the title compound (0.039 g, 28%) as a white solid, m.p. 111-115° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]([C:15]1[CH:16]=[C:17]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:18]([NH:20][CH:21]1[CH2:23][CH2:22]1)=[O:19])[C:8]2=[O:28].[I-].[K+].Cl.[O:32]1[CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(N(CC)C(C)C)(C)C>CC(N(C)C)=O.C(OCC)(=O)C>[CH:21]1([NH:20][C:18](=[O:19])[C:17]2[CH:24]=[CH:25][C:26]([CH3:27])=[C:15]([N:9]3[C:8](=[O:28])[C:7]4[C:12](=[CH:13][CH:14]=[C:5]([O:4][CH2:3][CH2:2][N:35]5[CH2:36][CH2:37][CH2:38][O:32][CH2:33][CH2:34]5)[CH:6]=4)[N:11]=[CH:10]3)[CH:16]=2)[CH2:23][CH2:22]1
Reactant: C1CNCCOC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OCCCl)cc2c1=O
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OCCN3CCCOCC3)cc2c1=O
Temperature: 140 °C
Yield: 63.7 %

Procedure:
3-[6-(2-Chloroethoxy)-4-oxoquinazolin-3(4H)-yl]-N-cyclopropyl-4-methylbenzamide (0.15 g), potassium iodide (0.13 g), 1,4-oxazepane hydrochloride (0.32 g), and N,N-diisopropylethylamine (0.8 ml) were stirred in DMA (3 ml) and heated under microwave irradiation conditions (Personal Chemistry Emrys Optimizer with 300 W magnetron) at 140° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water (5×), brine (2×), dried (magnesium sulfate) and concentrated. Purification by column chromatography on a silica column eluting with 10% methanol/ethyl acetate gave the title compound (0.111 g) as a white solid; NMR Spectrum: (DMSOd6) 0.55 (m, 2H), 0.70 (m, 2H), 1.80 (m, 2H), 2.13 (s, 3H), 2.76 (m, 4), 2.86 (m, 1H), 2.93 (t, 2H), 3.60 (t, 2H), 3.65 (t, 2H), 4.20 (m, 2H), 7.52 (m, 2H), 7.60 (s, 1H), 7.72 (d, 1H), 7.83 (s, 1H), 7.91 (d, 1H), 8.19 (s, 1H), 8.43 (d, 1H); Mass Spectrum: M+H+ 463.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:15]([CH3:32])[C:16](=[O:31])[CH2:17][N:18]2[C:23]3[CH:24]=[C:25]([Cl:29])[C:26]([Cl:28])=[CH:27][C:22]=3[O:21][CH2:20][C:19]2=[O:30])[CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH3:33][O:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][C:40]=1[O:41][CH3:42].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:33][O:34][C:35]1[CH:36]=[C:37]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([N:15]([CH3:32])[C:16](=[O:31])[CH2:17][N:18]3[C:23]4[CH:24]=[C:25]([Cl:29])[C:26]([Cl:28])=[CH:27][C:22]=4[O:21][CH2:20][C:19]3=[O:30])[CH2:9][N:10]3[CH2:11][CH2:12][CH2:13][CH2:14]3)=[CH:4][CH:3]=2)[CH:38]=[CH:39][C:40]=1[O:41][CH3:42]
Reactant: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCCC1)c1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1OC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(C(CN3CCCC3)N(C)C(=O)CN3C(=O)COc4cc(Cl)c(Cl)cc43)cc2)cc1OC
Reaction time: 0.25 h
Yield: 38.7 %

Procedure:
To a solution of N-[1-(4-bromophenyl)-2-(1-pyrrolidinyl)ethyl]-2-(6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-methylacetamide (70 mg, 0.13 mmol) and 3,4-dimethoxyphenylboronic acid (26 mg, 0.14 mmol) in DMF (1 mL) was added Pd(dppf)Cl2 (5.3 mg, 0.0065 mmol) followed by a 2M aqueous solution of Na2CO3 (0.26 mL, 0.52 mmol). The resultant mixture was stirred at 80° C. for 16 h. The mixture was filtered through a 0.45 um polypropylene filter and purified by Gilson Preparation HPLC (Xterra Prep RP, 19×150 mm, 18 mL/min, PH 10 with NH4OH, A: acetonitrile B: water, A: 40 to 99% over 15 min, UV detection at 214 nm) to give 30.1 mg (39%) of the title compound as an off white solid. MS (ES) m/e 598.1 [M+H]+.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].[CH:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(OCC)C>O1CCCC1.O>[CH3:11][Si:12]([C:15]#[C:16][CH:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[OH:24])([CH3:14])[CH3:13]
Reactant: C#C[Si](C)(C)C
Reactant: O=Cc1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: C[Si](C)(C)C#CC(O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
Place lithium hexamethyldisilazane (20 mL of a 1 M solution in tetrahydrofuran, 20 mmol) under an argon atmosphere and cool to 0° C. Add, by dropwise addition, trimethylsilylacetylene (2.83 mL, 20 mmol) and stir for 1 hour at 0° C. Add benzaldehyde (2.03 mL, 20 mmol) in tetrahydrofuran (10 mL). Allow to warm to room temperature and stir for 1 hour. Pour the mixture into ethyl ether and water, separate the organic phase and evaporate the solvent in vacuo. Filter the oil through silica gel (20% ethyl acetate/hexane) and evaporate the solvent in vacuo to yield 4.09 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[O:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17].Cl[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][N:21]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:17][O:16][CH2:15][CH2:14][O:13][CH2:12][O:11][C:5]1[C:6]([NH:10][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][N:21]=2)=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:18]
Reactant: COc1ccc(Cl)nc1
Reactant: COCCOCOc1c(N)cccc1C(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COCCOCOc1c(Nc2ccc(OC)cn2)cccc1C(=O)OC
Temperature: 90 °C
Reaction time: 12 h
Yield: 67.6 %

Procedure:
To a solution of 3-amino-2-((2-methoxyethoxy)methoxy)benzoic acid methyl ester 1.25 g (4.9 mmol) of step 2 in 1,4-dioxane 10 mL were added 2-chloro-5-methoxypyridine 0.70 g (4.9 mmol), Pd(OAc)2 0.11 g (0.49 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl 0.31 g (0.49 mmol) and Cs2CO3 3.85 g (9.8 mmol), followed by stirring at 90° C. for 12 hrs. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, diluted with ethylacetate, and washed with a saturated sodium bicarbonate solution and a saturated NaCl solution. After drying over magnesium sulfate and concentration in a vacuum, purification by column chromatography (developing solvent: ethylacetate/hexane=1/2) afforded 1.2 g of the title compound (yield 68%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:15])[N:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=2)[CH:7]=1.[CH3:16][N:17](C=O)C>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:16]([C:2]1[CH:3]=[CH:4][C:5](=[O:15])[N:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=2)[CH:7]=1)#[N:17]
Reactant: Cc1ccc(-n2cc(Br)ccc2=O)nc1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1ccc(-n2cc(C#N)ccc2=O)nc1
Temperature: 95 °C

Procedure:
To a suspension of 5-bromo-5'-methyl-[1,2']bipyridinyl-2-one (0.29 g, 1.09 mmol) and zinc cyanide (0.154 g, 1.30 mmol) in degassed DMF (3 ml) was added tetrakis (triphenylphosphine) palladium (151 mg, 0.13 mmol) and the reaction warmed to 95° C. for 4 hrs. The reaction was cooled and quenched with NH4OH (10 ml) and water (30 ml). The aqueous phase was extracted with CH2Cl2, dried (MgSO4), and evaporated in vacuo. The residue was chromatographed (silica gel, EtOAc: CH2Cl2 10:90 to 12:88 gradient elution) to afford the title compound.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](Cl)=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[N:14]2)=[N:9][CH:8]=1>ClCCl>[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[N:14]2)=[N:9][CH:8]=1
Reactant: CC(C)CN
Reactant: O=[N+]([O-])c1cnc2cc(Br)cnc2c1Cl
Solvent: ClCCl
Product: CC(C)CNc1c([N+](=O)[O-])cnc2cc(Br)cnc12
Temperature: 25 °C
Yield: 95.7 %

Procedure:
Isobutylamine (16.2 mL, 163 mmol) was added dropwise to a 0° C. solution of 7-bromo-4-chloro-3-nitro[1,5]naphthyridine (approximately 74.1 mmol) in dichloromethane (350 mL). The reaction mixture was allowed to stir and warm to room temperature for 3 hours, then was diluted with dichloromethane (50 mL) and washed with saturated aqueous sodium bicarbonate (300 mL). The aqueous layer was back-extracted with dichloromethane (2×75 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated to afford 23.06 g of 7-bromo-N-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine as a yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]3[C:21]=2[CH:22]=[CH:23][NH:24]3)[C:11]1=[O:30])[CH2:7][CH2:8][CH3:9])C.[C:32]([O-])([O-])=O.[K+].[K+].CI>C(#N)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:29][C:27]1[CH:26]=[C:25]2[C:21]([CH:22]=[CH:23][N:24]2[CH3:32])=[C:20]([CH2:19][N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:10]([CH:6]([CH2:7][CH2:8][CH3:9])[CH2:5][C:4]([OH:3])=[O:31])[C:11]2=[O:30])[CH:28]=1
Reactant: CCCC(CC(=O)OCC)n1c(=O)n(Cc2cc(Cl)cc3[nH]ccc23)c2ccccc21
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CCCC(CC(=O)O)n1c(=O)n(Cc2cc(Cl)cc3c2ccn3C)c2ccccc21
Temperature: 65 °C
Reaction time: 18 h
Yield: 9 %

Procedure:
3-[3-(6-Chloro-1H-indol-4-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester (300 mg, 0.68 mmol), prepared as described in example 72 using the appropriate reagents, was dissolved in acetonitrile (5 mL) and treated with K2CO3 (700 mg, 5.1 mmol), methyl iodide (0.31 mL, 5 mmol) and tetrabutylammonium bromide (161 mg, 0.5 mmol). The resulting mixture was heated at 65° C. for 60 h, filtered, and the solution was treated directly with Amberlyst® A26 (OH— form) (1.5 g, 2 mmol). This mixture was agitated for 18 h, filtered and the resin was washed with several portions of methanol. The product was eluted from the resin with 20% formic acid in methanol (2×2 mL). The eluant was concentrated and the residue was purified by preparative HPLC to provide 26 mg (9%) of the title compound. LCMS (ESMS): m/z 426 (M+H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[CH2:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:19][O:20][C:21](=[O:32])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27](Br)=[CH:26][C:25]=1[CH3:31].C([O-])(=O)C.[Na+].CN(C)CC(O)=O>CN1CCCC1=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:19][O:20][C:21](=[O:32])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH:16]=[CH:15][C:12]2[CH:13]=[CH:14][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:18])[F:1])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)=[CH:26][C:25]=1[CH3:31]
Reactant: COC(=O)COc1ccc(Br)cc1C
Reactant: C=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)CC(=O)O
Solvent: CN1CCCC1=O
Product: COC(=O)COc1ccc(C=Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1C
Temperature: 130 °C

Procedure:
A mixture of 4-trifluoromethyl-4′-vinyl-biphenyl (1.9 g, 7.7 mmol), (4-Bromo-2-methyl-phenoxy)-acetic acid methyl ester (2.0 g, 7.7 mmol), anhydrous sodium acetate (1.2 g, 14.6 mmol), N,N-dimethylglycine (0.23 g, 2.2 mmol), and palladium acetate (0.025 g, 0.11 mmol) in 10 ml of 1-methyl-pyrrolidin-2-one was heated at 130° C. for 10 h. The reaction mixture was partitioned between 250 ml of brine and 300 ml of ethyl acetate. The total mixture was filtered through a bed of Celite filter-aid. The organic layer was washed with 5% aqueous sodium carbonate solution (3×250 ml) and brine (2×250 ml), then dried over anhydrous sodium sulfate and concentrated. The residue was purified by normal phase chromatography to give {2-methyl-4-[2-(4′-trifluoromethyl-biphenyl-4-yl)-vinyl]-phenoxy}-acetic acid methyl ester; MS m/z 427 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1C[CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]2[CH:18]=[C:19]([CH2:23][S:24]([NH2:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:11]=1.ClC1N=CN=C(NC2C=C(CS(N)(=O)=[O:44])C=CC=2)N=1.Cl.COC(=O)[C@@H]1CCCN1>>[S:24]([CH2:23][C:19]1[CH:18]=[C:17]([NH:16][C:12]2[N:13]=[CH:14][N:15]=[C:10]([N:5]3[CH2:6][CH2:7][CH2:8][C@H:4]3[C:3]([O:2][CH3:1])=[O:44])[N:11]=2)[CH:22]=[CH:21][CH:20]=1)(=[O:26])(=[O:25])[NH2:27]
Reactant: COCC1CCCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Agent: COC(=O)[C@@H]1CCCN1
Agent: Cl
Product: COC(=O)[C@@H]1CCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1

Procedure:
B22 was obtained as a white crystalline solid by following the procedure reported for B4 using A1 and (S)-proline methyl ester hydrochloride; yield: 169 mg (48%). MS (ES) C16H20N6O4S requires: 392. found: 393 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O>>[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: O=Cc1cccc(Br)c1
Product: O=c1cc(N2CCN(Cc3cccc(Br)c3)CC2)nc[nH]1

Procedure:
6-[4-(3-Bromo-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 3-bromobenzaldehyde. Mass spectrum (ES) MH+=349.
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:10]=[N:9][NH:8][N:7]=1)([O-:5])=[O:4].CCN(C(C)C)C(C)C.Cl[CH2:21][C:22]1[O:26][C:25]([C:27]2([CH3:32])[O:31][CH2:30][CH2:29][O:28]2)=[CH:24][CH:23]=1>CN(C=O)C.CC(=O)OCC.O>[CH3:32][C:27]1([C:25]2[O:26][C:22]([CH2:21][N:8]3[N:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:10]=[N:9]3)=[CH:23][CH:24]=2)[O:28][CH2:29][CH2:30][O:31]1
Reactant: CC1(c2ccc(CCl)o2)OCCO1
Reactant: O=[N+]([O-])c1cn[nH]n1
Agent: N#N
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(c2ccc(Cn3ncc([N+](=O)[O-])n3)o2)OCCO1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-nitro-2H-[1,2,3]triazole (875 mg, 7.67 mmol) in DMF (7.0 mL) was treated at rt with DIPEA (2.63 mL, 15.34 mmol). After 30 min, a solution of 2-(5-chloromethyl-furan-2-yl)-2-methyl-[1,3]dioxolane (1.87 g, 9.21 mmol) in DMF (7.0 mL) was added and the reaction mixture was stirred for 16 h at 50° C. Water (100 mL), followed by EA (100 mL) were added. The aq. layer was extracted with EA (100 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (2:1 hept-EA) gave the title compound as an orange oil: TLC:rf (2:1 hept-EA)=0.26. LC-MS-conditions 02: tR=0.95 min; [M+H]+=281.01.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]=12.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCOCC1>[C:17]1([N:16]2[C:8](=[O:10])[C:7]3=[C:2]([Cl:1])[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]3[C:11]2=[O:12])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: Nc1ccccc1
Solvent: C1COCCO1
Product: O=C1c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)N1c1ccccc1
Yield: 90 %

Procedure:
In 1.2 l of dioxane was dissolved 286 g (1 mol) of tetrachlorophthalic anhydride, and while refluxing the solution, 93 g (1 mol) of aniline was added dropwise to the solution. Thereafter, the mixture was refluxed for 2 hours. The reaction mixture was allowed to cool, whereby tabular crystals were precipitated. The crystals were collected by filtration, washed with dioxane, and dried to provide 325 g of N-phenyltetrachlorophthalimide having a melting point of 251° C. to 253° C. (yield 90%).