Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([CH3:17])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:18]1([CH3:30])[CH:23]=[CH:22][C:21]([S:24]([CH2:27][N+:28]#[C-:29])(=[O:26])=[O:25])=[CH:20][CH:19]=1.[H-].[Na+]>CS(C)=O.C(OCC)C>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH3:17])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4][CH2:3][CH2:2][C:27]([N+:28]#[C-:29])([S:24]([C:21]1[CH:20]=[CH:19][C:18]([CH3:30])=[CH:23][CH:22]=1)(=[O:25])=[O:26])[CH2:2][CH2:3][CH2:4][C:5]([CH3:17])([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:10]
Reactant: CCOC(=O)C(C)(CCCBr)c1ccccc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: [C-]#[N+]C(CCCC(C)(C(=O)OCC)c1ccccc1)(CCCC(C)(C(=O)OCC)c1ccccc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 117.8 %

Procedure:
To a solution of ethyl 5-bromo-2-methyl-2-phenyl-pentanoate (25 g, 75.25 mmol), tetra-ii-butylammonium iodide (2.78 g, 7.53 mmol), and p-toluenesulphonylmethyl isocyanide (TosMIC, 7.34 g, 37.63 mmol) in anhydrous DMSO (400 mL) and anhydrous diethyl ether (I150 mL) was added sodium hydride (60% dispersion in mineral oil, 3.80 g, 95 mmol) at rt under N2 atmosphere. The reaction mixture was stirred for 24 h at rt, then carefully hydrolized with ice-water (600 mL), and extracted with diethyl ether (2×300 mL). The organic layer was washed with brine (2×300 mL) dried over anhydrous MgSO4, concentrated in vacuo to furnish crude 2,10-dimethyl-6-isocyano-6-(4-tolyl-sulfonyl)-2,10-diphenyl-undecanedioic acid diethyl ester (28 g) as a brown oil. A solution of this crude intermediate (25 g) was dissolved in CH2Cl2 (500 mL) and concd. HCl (140 mL) and stirred for 2 h at rt. The reaction mixture was diluted with water (500 mL) and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×200 mL). The combined layers were washed with saturated NaHCO3 solution (150 mL), and brine (150 mL), dried over MgSO4, and concentrated ill vacuo. The resulting crude oil was purified by flash chromatography (silica gel, ethyl acetate/hexanes=1/20, 1/10) to furnish 2,10-dimethyl-6-oxo-2,10-diphenyl-undecanedioic acid diethyl ester (9.5 g, 50.3%) as a light yellowish oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm) 7.40-7.10 (m, 10H), 4.20-4.05 (m, 4H), 2.38 (m, 4H), 2.05-1.80 (m, 4H), 1.60 (s, 6H), 1.50-1.20 (m, 4H), 1.22 (m, 6H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm) 210.24, 176.06, 143.71, 128.42, 126.72, 125.97, 60.83, 50.13, 42.97, 38.91, 22.73, 22.47, 19.09, 14.13. HRMS (LSIMS, nba): Calcd. for C29H39O5 (MH+): 467.2797, found: 467.2772.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]([CH3:23])[C:9](=[O:22])[CH2:10][N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])=[CH:6][CH:5]=[C:4]([Cl:24])[C:3]=1[CH2:25][OH:26].C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([N:8]([CH3:23])[C:9](=[O:22])[CH2:10][N:11]2[C:12](=[O:21])[C:13]3=[CH:20][CH:19]=[CH:18][CH:17]=[C:14]3[C:15]2=[O:16])=[CH:6][CH:5]=[C:4]([Cl:24])[C:3]=1[CH2:25][O:26][S:35]([CH3:34])(=[O:37])=[O:36]
Reactant: CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)c(CO)c1Cl
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)c(COS(C)(=O)=O)c1Cl
Reaction time: 1 h

Procedure:
To a mixture of 2,6-dichloro-1-hydroxymethyl-3-[N-methyl-N-(phthalimidoacetyl)amino]benzene (399 mg) and triethylamine (0.17 ml) in methylene chloride (8 ml) was added methanesulfonyl chloride (0.086 ml) under -20° C., and the mixture was stirred for 1 hour. The mixture was washed with sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo to give 2,6-dichloro-1-methylsulfonyloxymethyl-3-[N-methyl-N-(phthalimidoacetyl)amino]benzene (561 mg)
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[I:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][NH2:18])=[CH:13][CH:12]=1>C(O)(=O)C>[I:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][N:18]=[C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH3:2])=[CH:13][CH:12]=1
Reactant: NNc1ccc(I)cc1
Reactant: CC(=O)c1ccccc1
Solvent: CC(=O)O
Product: CC(=NNc1ccc(I)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.54 g (12.82 mmol) of acetophenone in 10 ml of 50% strength acetic acid is added to a solution of 2.0 g (8.546 mmol) of 4-iodophenylhydrazine in 30 ml of the same solvent. The mixture is stirred at room temperature, and a precipitate is formed. After 30 minutes, the precipitate is filtered off and thoroughly washed with water and then with cyclohexane. The residue is dried under high vacuum. This gives 1.95 g (68% of theory) of the title compound.
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1.ClC1C=CC=C(C(OO)=[O:19])C=1>ClCCl>[F:1][CH:2]([F:10])[C:3]1[C:4]([CH3:9])=[N+:5]([O-:19])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ncccc1C(F)F
Solvent: ClCCl
Product: Cc1c(C(F)F)ccc[n+]1[O-]
Temperature: 5 °C
Reaction time: 12 h
Yield: 98.4 %

Procedure:
27.26 g of 3-difluoromethyl-2-methylpyridine (XVI) was dissolved in 700 ml of anhydrous dichloromethane, and under cooling with ice, to which 45.19 g of 3-chloro-perbenzoic acid was added, and the resulting mixture was stirred at 5° C. for 12 hours. The resulting organic layer was washed with 5% sodium carbonate solution, and thereafter, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; chloroform:methanol=9:1) to obtain 29.82 g of 3-difluoromethyl-2-methylpyridine N-oxide (XVII).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:22][CH:21]=3)=[N:15][CH:16]=2)[N:11]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][CH2:41][N:42]3C(=O)C4=CC=CC=C4C3=O)[CH:35]=2)[C:10]1=[O:53].O.NN>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]([CH2:30][CH3:31])[CH2:32][CH3:33])=[CH:22][CH:21]=3)=[N:15][CH:16]=2)[N:11]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][CH2:41][NH2:42])[CH:35]=2)[C:10]1=[O:53]
Reactant: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(c2cccc(CCN4C(=O)c5ccccc5C4=O)c2)C(=O)N(c2ccc(Cl)cc2Cl)C3)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(c2cccc(CCN)c2)C(=O)N(c2ccc(Cl)cc2Cl)C3)cc1
Yield: 23 %

Procedure:
A solution of 50 mg (0.07 mmol) of 3-(2,4-dichlorophenyl)-7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydro-1-[3-(2-phthalimidoethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one in 5 ml of ethanol was treated with 0.5 ml of hydrazine hydrate. After 18 hours the mixture was evaporated and the product purified by column chromatography on silica gel using dichloromethane/methanol/acetic acid/water (60:18:2:3) for the elution. Product-containing fractions were combined, evaporated and the residue evaporated with toluene. The residue was then dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The residue was triturated with pentane and filtered to give 10 mg (23%) of 3-(2,4-dichlorophenyl)-7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydro-1-[3-(2-aminoethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 108° C.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:24][C:23]3[N:25]4[C:16](=[CH:17][N:18]=[C:19]4[CH:20]=[CH:21][CH:22]=3)[CH:15]=2)=[O:13])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:33]1([CH2:39][CH2:40][CH2:41]Br)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(O)C>[C:33]1([CH2:39][CH2:40][CH2:41][N:3]2[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][NH:11][C:12]([C:14]3[S:24][C:23]4[N:25]5[C:16](=[CH:17][N:18]=[C:19]5[CH:20]=[CH:21][CH:22]=4)[CH:15]=3)=[O:13])[CH2:5][CH2:4]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCCCc1ccccc1
Reactant: O=C(NCCC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(NCCC1CCN(CCCc2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1

Procedure:
To a solution of 0.60 g (1.49 mM) of N-[2-(4-piperidyl)ethyl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 1.0 ml (7.17 mM) of triethylamine in ethanol (6 ml) was added 0.27 ml (1.78 mM) of 3-phenyl-1-bromopropane at room temperature and the mixture was refluxed under nitrogen for 24 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over MgSO4, and purified by column chromatography (methanol/ethyl acetate 30-50-80%) to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:47][C:48]([F:63])([F:62])[C:49]1[N:53]2[CH2:54][CH2:55][NH:56][CH2:57][C:52]2=[C:51]([C:58]([O:60][CH3:61])=[O:59])[N:50]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:56]1[CH2:55][CH2:54][N:53]2[C:49]([C:48]([F:63])([F:47])[F:62])=[N:50][C:51]([C:58]([O:60][CH3:61])=[O:59])=[C:52]2[CH2:57]1)=[O:5]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: COC(=O)c1nc(C(F)(F)F)n2c1CNCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)c1cc(Cc3n[nH]c(=O)c4ccccc34)ccc1F)CC2
Reaction time: 12 h
Yield: 22.7 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (300 mg, 1 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (568 mg, 1.50 mmol), crude methyl 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate 3b (300 mg, 1.50 mmo) and N,N-diisopropylethylamine (0.4 mL, 2 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain methyl 7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxylate 3 (120 mg, yield 23.0%) as a light yellow solid.
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:9](Cl)=[O:10].[NH2:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14]1>>[C:20]1([CH2:19][CH2:18][N:15]2[CH2:16][CH2:17][CH:13]([NH:12][C:9]([C@H:2]3[CH2:3][CH:4]4[CH2:7][CH2:8][CH:1]3[CH2:6][CH2:5]4)=[O:10])[CH2:14]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Cl)C1CC2CCC1CC2
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Product: O=C(NC1CCN(CCc2ccccc2)C1)[C@H]1CC2CCC1CC2

Procedure:
2-Bicyclo[2.2.2]octanecarbonyl chloride and (S)-3-amino-1-(2-phenylethyl)pyrrolidine were reacted under the same conditions as in Example 53 to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)-2-bicyclo[2.2.2]octanecarboxamide.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH3:13]>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9]([NH2:13])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: O=S(=O)(Cl)Cc1cccc(I)c1
Solvent: C1CCOC1
Product: NS(=O)(=O)Cc1cccc(I)c1

Procedure:
A stirred solution of (3-iodophenyl)methanesulfonyl chloride (1 g) in THF (20 ml) was treated with 0.88 ammonia (25 ml) at room temperature for 30 min. The solvent was removed under reduced pressure and the residue was triturated in ether to give the title compound (0.35 g).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]3([CH2:18][NH2:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](O)=[O:26])#[N:21]>>[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([NH:19][CH2:18][C:12]1([C:9]2[S:10][CH:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)=[O:26])#[N:21]
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: NCC1(c2nc(-c3ccccc3)cs2)CCOCC1
Product: N#Cc1cccc(C(=O)NCC2(c3nc(-c4ccccc4)cs3)CCOCC2)c1
Yield: 89 %

Procedure:
This compound was synthesized from (4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-cyanobenzoic acid as described in example 8 step 6 (6.6 g, yield 89%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.11-8.10 (m, 1H), 8.02-7.99 (dt, J=7.9 Hz, 1.5 Hz, 1H), 7.91-7.88 (m, 2H), 7.78-7.74 (dt, J=7.7 Hz, 1.3 Hz, 1H), 7.71-7.68 (m, 1H), 7.53-7.46 (m, 3H), 7.42-7.36 (m, 1H), 3.97-3.90 (m, 2H), 3.85-3.83 (d, J=5.7 Hz, 2H), 3.77-3.69 (m, 2H), 2.35-2.29 (m, 2H), 2.07-1.98 (m, 2H). MS (ESI) m/z: Calculated for C23H21N3O2S: 403.14. found: 402.2 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([CH2:9][CH:10]([CH3:21])[C:11]([N:13]2[CH2:20][CH2:19][CH2:18][C@H:14]2[C:15]([OH:17])=[O:16])=[O:12])=[O:8])=[CH:4][CH:3]=1.[C:22]([O-:25])(=[S:24])[CH3:23].[Na+]>C(#N)C>[C:22]([S:24][CH:9]([C:7](=[O:8])[C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:10]([CH3:21])[C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])(=[O:25])[CH3:23]
Reactant: CC([O-])=S
Reactant: CC(CC(=O)c1ccc(Cl)s1)C(=O)N1CCC[C@H]1C(=O)O
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)SC(C(=O)c1ccc(Cl)s1)C(C)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
Bromination of the [S]-1-[3-(5-chloro-2-thenoyl)-2-methylpropionyl]-L-proline and reaction of the brominated product with sodium thioacetate in acetonitrile gives a mixture of the [R-(R*,S*)] and [R-(R*,R*)] isomers of the product of the Example as a glass.
Reaction SMILES: [O-]S([O-])(=O)=O.[Na+].[Na+].[NH2:8][C:9]1[CH:10]=[C:11]([CH:17]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:12]=[C:13]([CH2:15][CH3:16])[CH:14]=1.[CH3:32][N:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[C:30]([C:27]1[CH:28]=[CH:29][C:24]([NH:23][CH:17]([C:11]2[CH:10]=[C:9]([NH:8][CH:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)[CH:14]=[C:13]([CH2:15][CH3:16])[CH:12]=2)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:25][CH:26]=1)#[N:31]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(N)cc(CC)c1
Reactant: CN1CCC(=O)CC1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(CC)cc(NC2CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.6 %

Procedure:
Na2SO4 (1.09 g, 7.7 mmol) was added to a solution of the ethyl (RS)-(3-amino-5-ethyl-phenyl)-(4-cyano-phenylamino)-acetate (250 mg, 0.77 mmol) obtained in Example 223.4 and 1-methyl-4-piperidone (174 mg, 1.54 mmol) in acetic acid (5 ml) and the mixture was stirred for 15 min. at room temperature. The mixture was subsequently cooled to 0° C. and NaHB(OAc)3 (489 mg, 2.31 mmol) was slowly added portionwise. After 30 min. a saturated solution of NaHCO3 was added and the mixture was extracted with EtOAc. The organic phase was dried and filtered, and the filtrate was concentrated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH 9:1). There were obtained 287 mg (89%) of ethyl (RS)-(4-cyano-phenylamino)-[3-ethyl-5-(1-methyl-piperidin-4-ylamino)-phenyl]-acetate as a yellowish solid; MS: 421 ([M+H]+).
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[CH:7][CH:8]=1)[NH2:2].[CH3:19][O:20][CH2:21][C:22](Cl)=O>O1CCOCC1>[CH3:19][O:20][CH2:21][C:22]1[N:4]2[N:5]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[CH:7]=[CH:8][C:3]2=[N:1][N:2]=1
Reactant: NNc1ccc(-c2cccc(C(F)(F)F)c2)nn1
Reactant: COCC(=O)Cl
Solvent: C1COCCO1
Product: COCc1nnc2ccc(-c3cccc(C(F)(F)F)c3)nn12

Procedure:
To a mixture of 0.02 mole of 3-hydrazino-6-[3-(trifluoromethyl)phenyl]pyridazine in 50 ml. of dioxane is added 0.01 mole of methoxyacetyl chloride. The mixture is heated at reflux temperature for 4 hours, then is filtered. The filtrate is evaporated and the residue is crystallized from dichloromethane-hexane to give the product of the Example, m.p. 149°-150° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)=[O:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:20][C:17]2[CH:18]=[CH:19][C:14]([C:12](=[O:13])[CH3:11])=[CH:15][CH:16]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 90 °C
Yield: 99.8 %

Procedure:
To a mixture of 1-fluoro-4-nitrobenzene (5.0 g, 35.43 mmol) and 4-hydroxyacetophenone (4.82 g, 35.40 mmol) in DMF (40 mL) was added potassium carbonate (9.79 g, 70.86 mmol). The reaction mixture was heated at 90° C. overnight. After the completion of the reaction as confirmed by TLC, the reaction mixture was diluted with EtOAc (200 mL) and washed with water (3×30 mL). The organic layer was separated, dried over Na2SO4 and concentrated in vacuo to afford the title compound (9.09 g, 99%) as a solid which was used as such in the next step.
Reaction SMILES: [F:1][C:2]1([F:23])[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=2[C:17]2[N:18]([CH3:22])[N:19]=[CH:20][CH:21]=2)[CH2:3]1.[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][C:26]=1[CH3:34].C(N(CC)CC)C>C1COCC1>[F:23][C:2]1([F:1])[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:25]([F:24])=[C:26]([CH3:34])[CH:27]=3)=[CH:12][C:11]=2[C:17]2[N:18]([CH3:22])[N:19]=[CH:20][CH:21]=2)[CH2:3]1
Reactant: Cc1cc(C(=O)Cl)ccc1F
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCC(F)(F)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2ccc(OCCN3CCC(F)(F)C3)c(-c3ccnn3C)c2)ccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.6 %

Procedure:
A mixture of 4-[2-(3,3-Difluoro-pyrrolidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (64 mg, 0.20 mmole), 4-fluoro-3-methyl-benzoyl chloride (52 mg, 0.30 mmole), and triethylamine (56.5 μL, 0.40 mmole) in 1 mL THF was stirred at room temperature for 10 minutes. The mixture was purified by HPLC to give the title compound as a white solid (TFA salt, 29 mg, 32% yield). Exact mass calculated for C24H25F3N4O2 458.2, found 459.3 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:9]=[O:10])=[C:4]([CH3:18])[CH:3]=1.[H-].[Na+].[Br:21][CH2:22][CH2:23]Br>C1COCC1>[Br:21][CH2:22][CH2:23][O:10][CH:9]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[CH3:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: BrCCBr
Reactant: Cc1ccccc1C(C=O)c1ccc(F)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1C(=COCCBr)c1ccc(F)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(4-Fluoro-2-methylphenyl)-(2-methylphenyl)acetaldehyde (3.5 g, 0.0444 mol) was dissolved in dry THF (20 ml) and added dropwise to a suspension of sodium hydride (60% oil dispersion) (0.63 g, 0.0158 mol) in dry tetrahydrofuran (30 ml). The mixture was stirred at room temperature for 1 h and heated at reflux for 0.5 h. After cooling 1,2-dibromoethane (12.4 ml, 10 equiv.) was added, and the reaction mixture was allowed to stand at room temperature for 192 h. The reaction mixture was filtered and evaporated. The residue was pumped in vacuo, but still contained ca. 30% starting aldehyde, so the above procedure was repeated.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([Cl:23])=[CH:21][C:20]([Cl:24])=[CH:19][N:18]=4)[CH2:13][CH2:12]3)[NH:7][C:6]=2[CH:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1>>[Cl:23][C:22]1[C:17]([N:14]2[CH2:13][CH2:12][N:11]([C:8]3[NH:9][C:10]4[C:2]([C:35]5[CH:34]=[CH:33][CH:32]=[C:31]([C:30]([F:41])([F:40])[F:29])[CH:36]=5)=[CH:3][C:4]([C:25]([F:27])([F:26])[F:28])=[CH:5][C:6]=4[N:7]=3)[CH2:16][CH2:15]2)=[N:18][CH:19]=[C:20]([Cl:24])[CH:21]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: FC(F)(F)c1cc(Br)c2nc(N3CCN(c4ncc(Cl)cc4Cl)CC3)[nH]c2c1
Product: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)cc3nc(N4CCN(c5ncc(Cl)cc5Cl)CC4)[nH]c23)c1

Procedure:
The reaction of 4-bromo-2-[4-(3,5-dichloropyridin-2-yl)piperazin-1-yl]-6-trifluoromethyl-1H-benzoimidazole (99 mg, 0.2 mmol, Example 9) and 3-trifluromethylphenylboronic acid (48 mg, 0.25 mmol, Aldrich) under the conditions of Example 10 gave the title compound as a light-yellow amorphous solid. MS (ESI, pos. ion) m/z: 560 (M+1).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13]([O:15]C)[C:12]([O:17]C)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.O>ClCCl>[CH2:1]([S:8][C:9]1[NH:14][C:13](=[O:15])[C:12]([OH:17])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(SCc2ccccc2)nc1OC
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=c1[nH]c(SCc2ccccc2)ccc1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 19.7 %

Procedure:
To a solution of 6-(benzylsulfanyl)-2,3-dimethoxypyridine (Intermediate 44, 0.2 g, 0.76 mmol) in dichloromethane (1 ml) was added a solution of boron tribromide in dichloromethane (1 M, 0.77 g, 3.1 mmol) at −5° C. and reaction was stirred for 1 hour at 0° C. The temperature was gradually allowed to rise to room temperature before the mixture was stirred for a further 1 hour at room temperature. Upon cooling to 0° C. water (10 ml) was added drop-wise and the resulting mixture was filtered and the solid was washed with water (2 ml) followed by ethyl acetate (5 ml) and dried under vacuum at 40° C. to yield 6-(benzylsulfanyl)-3-hydroxypyridin-2(1H)-one (35 mg, 20%).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH3:13].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=1.[O-]CC.[Na+]>C(O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1/[CH:13]=[CH:20]/[C:16]1[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1nc2ccccn2c(=O)c1Br
Reactant: O=Cc1cccnc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1c(Br)c(/C=C/c2cccnc2)nc2ccccn12

Procedure:
The title compound was prepared from 3-bromo-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (250 mg, 1.045 mmol) and pyridine-3-aldehyde (168 mg, 1.561 mmol) in the presence of sodium ethoxide (142 mg, 2.086 mmol) in absolute ethanol (25 ml) as described in Intermediate 1 to give 203 mg of the product as a light yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.11 (t, J=6.9 Hz, 1H), 7.32-7.36 (m, 1H), 7.63-7.76 (m, 3H), 7.98-8.05 (m, 2H), 8.57 (d, J=4.8 Hz, 1H), 8.35 (s, 1H), 8.97 (d, J=6.6 Hz, 1H).