Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.O>C1COCC1.Cl[Ti](Cl)(Cl)Cl>[C:1]1(/[CH:7]=[CH:8]\[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C(#Cc1ccccc1)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C(=C\c1ccccc1)\c1ccccc1
Product: c1ccc(CCc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 91 %
Yield: 0.4 %

Procedure:
To the solution of one equivalent of TiCl4 (1.1 ml, 10 mmol) and 0.5 equivalent of diphenylacetylene (0.89g, 5 mmol) in THF (40 ml) at −78° C. 2 equivalents of n-butyllithium (12.5 ml, 20 mmol, 1.6M solution in hexane) was slowly added and the resulting red-brown reaction mixture stirred at −78° C. for 1 h. The reaction mixture was then allowed to warm up to room temperature over 0.5 h followed by hydrolysis with 20 ml of H2O. Extraction of the organic products was accomplished with ether anhydrous ether. cis-Stilbene (91%) and bibenzyl (0.4%) were obtained as the products.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=3)[CH2:18][CH:17]([NH2:29])[CH2:16]2)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1.[Br:30][C:31]1[CH:32]=[CH:33][C:34]([C:37](O)=[O:38])=[N:35][CH:36]=1>>[Br:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]([NH:29][CH:17]2[CH2:18][CH:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=3)[CH2:20][N:15]([C:13]([CH:8]3[CH2:9][CH2:10][CH2:11][CH2:12]3)=[O:14])[CH2:16]2)=[O:38])=[N:35][CH:36]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: CCc1ccc(C2CC(N)CN(C(=O)C3CCCC3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)c3ccc(Br)cn3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
139 mg (0.34 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-amine trifluoroacetate (Example 8A) and 68 mg (0.34 mmol, 1.0 eq.) of 5-bromopyridine-2-carboxylic acid were reacted according to General Method 1. Yield: 75 mg (44% of theory)
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11](Cl)=[O:12]>ClCCl>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[C:11]([C:7]1[O:6][CH:10]=[CH:9][CH:8]=1)=[O:12]
Reactant: CNCCO
Reactant: O=C(Cl)c1ccco1
Solvent: ClCCl
Product: CN(CCO)C(=O)c1ccco1
Yield: 57.6 %

Procedure:
A one liter, three necked flask was equipped with overhead stirrer, nitrogen atmosphere and an addition funnel. The flask was charged with 115 g of 2-(methylamino)ethanol (1.53 mol.) and 500 ml of dichloromethane. The reaction flask was cooled with an ice bath. Next, 100 g of furoyl chloride (0.77 mol.) was slowly added via the addition funnel over 2.5 hours. The dichloromethane was washed with NaCl(aq.). Next, the NaCl(aq.) layer was extracted with dichloromethane and the two dichloromethane layers were combined and dried over MgSO4. The dichloromethane was removed with a rotoevaporator to yield 75 g (44%) of N-(2-hydroxyethyl)-N-methylfuranamide.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.N1C=CC=CC=1.C(OCC)(=O)C>C1COCC1>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:19])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=C(Cl)C1CCCCC1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 56.3 %

Procedure:
To a solution of 4-fluoro-3-nitro aniline (1.41 g, 9.0 mmol) in THF (50 mL) was added cyclohexanecarbonyl chloride (1.46 g, 9.6 mmol) and pyridine (0.97 mL, 12 mmol), and the mixture stirred for 22 h at room temperature. Ethyl acetate (100 mL) was added, and the solution was washed in turn with 1M HCl (50 mL) and saturated sodium bicarbonate (50 mL). The organic layer was dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography, eluting with hexane/ethyl acetate (7:3) to give cyclohexanecarboxylic acid (4-fluoro-3-nitro-phenyl)amide (1.35 g, 56%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][C:12]3[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[NH:14][N:13]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH:36]([C:42](=O)[CH2:43][CH2:44][CH3:45])[C:37](OCC)=[O:38])=[CH:31][CH:30]=1)#[N:22].N12CCCN=C1CCCCC2>C(N(CC)C1C=CC=CC=1)C.C(OCC)(=O)C>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:37](=[O:38])[C:36]([CH2:35][C:32]4[CH:33]=[CH:34][C:29]([C:24]5[C:23]([C:21]#[N:22])=[CH:28][CH:27]=[CH:26][CH:25]=5)=[CH:30][CH:31]=4)=[C:42]([CH2:43][CH2:44][CH3:45])[N:13]4[N:14]=[C:15]([C:17]([F:20])([F:18])[F:19])[N:16]=[C:12]34)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)c1nc(NC2CCC3(CC2)OCCO3)n[nH]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)c1ccccc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2nc(C(F)(F)F)nn12
Yield: 40.6 %

Procedure:
A solution of N-(1,4-dioxaspiro[4.5]dec-8-yl)-5-(trifluoromethyl)-1H-1,2,4-triazol-3-amine (9.87 g), ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (23.59 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (5.05 mL) in N,N-diethylaniline (50 mL) was stirred at 180° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with 1 N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=80/20→60/40 (volume ratio)], and crystallized from diisopropyl ether to give the title compound as a colorless solid (7.91 g, 41%).
Reaction SMILES: Cl.[NH2:2][C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)([CH:6]([F:8])[F:7])[CH2:4][OH:5].C([O-])([O-])=O.[Na+].[Na+].[Cl:22][CH2:23][C:24](Cl)=[O:25].CO>ClCCl.CC(OC)(C)C>[Br:15][C:11]1[CH:10]=[C:9]([C:3]([NH:2][C:24](=[O:25])[CH2:23][Cl:22])([CH2:4][OH:5])[CH:6]([F:7])[F:8])[CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)CCl
Reactant: NC(CO)(c1cccc(Br)c1)C(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CO
Solvent: ClCCl
Product: O=C(CCl)NC(CO)(c1cccc(Br)c1)C(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Amino-2-(3-bromo-phenyl)-3,3-difluoro-propan-1-ol hydrochloride (6.5 g, 24.43 mmol) was put between 60 ml aqueous 2 M Na2CO3 solution and 60 ml dichloromethane and cooled to 0° C. under strong stirring. Then chloroacetylchloride (2.94 ml, 36.6 mmol), diluted in 8 ml dichloromethane, was added dropwise to the biphasic solution. After the complete addition, the reaction was stirred for 30 minutes at r.t. After completion 10 ml MeOH were added and stirring was continued for 10 minutes. Then TBME und water were added. The phases were separated, and the aqueous phase was extracted with TBME. The organic phases were washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to yield the title compound as off-white solid. 1H-NMR (360 MHz, DMSO-d6): 8.72 (s, 1H), 7.53 (m, 2H), 7.35 (m, 2H), 6.48 (t, 1H, CHF2), 5.39 (t, 1H), 4.18 (m, 2H), 3.10 (s, 2H); MS: 342 [(M+H)+].
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:15])=[CH:17][CH:18]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 60.6 %

Procedure:
To a mixture of 4-(N-Boc-aminomethyl)benzoic acid (500 mg, 1.99 mmol), DMAP (catalytic amount), benzyl alcohol (226 μl, 2.19 mmol) and dichloromethane (20 ml) was added dicyclohexylcarbodiimide (1M solution in dichloromethane, 2.19 ml, 2.19 mmol) and the mixture stirred at room temperature for 60 hours. The precipitate was removed by filtration and the filtrate concentrated in vacuo. Diethyl ether (50 ml) was added to the residue, the resulting precipitate removed by filtration and the filtrate concentrated in vacuo. Purification by flash column chromatography (petrol/EtOAc, 3:1) gave the title compound (412 mg, 61%) as a solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:12][C:13]1[N:14]=[CH:15][C:16]([CH2:19][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7])=[CH:17][CH:18]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
(3,3,3-Trifluoropropyl)malononitrile (0.6 g) and 2-chloro-5-chloromethylpyridine (0.6 g) were dissolved in N,N-dimethylformamide (15 ml), potassium carbonate (0.51 g) was added thereto, and the mixture was stirred overnight at room temperature. Then, to the reaction mixture was added water, and extracted with ethyl acetate. The organic layer was washed successively with water, saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue obtained was subjected to silica gel column chromatography to give 0.62 g of 2-((6-Chloro-3-pyridyl)methyl)-2-(3,3,3-trifluoropropyl)malononitrile represented by the following formula (hereinafter referred to as the present invention compound (4)).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](C)([C:14](OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[Na+].[Cl-]>CS(C)=O.O>[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1ccc(Cl)nn1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C(C)c1ccc(Cl)nn1
Temperature: 175 °C
Yield: 35.2 %

Procedure:
A solution of diethyl 2-(6-chloropyridazin-3-yl)-2-methylmalonate (11 g, 38.4 mmol) and NaCl (2.69 g, 46.0 mmol) in DMSO (91 mL) and H2O (1.382 ml) was divided into eight separate microwave vials and each reaction was heated in a microwave at 175° C. for 90 mins on high absorbance. The reactions were combined and then poured into H2O (300 mL). The aqueous phase was extracted with EtOAc (2×100 mL) and then the organic phase was washed with brine (2×100 mL). The organic phase was dried over MgSO4, filtered and concentrated to dryness via rotary evaporation. The resulting oil was purified via MPLC (3:1, Hex:EtOAc) to provide the title compound, ethyl 2-(6-chloropyridazin-3-yl)propanoate (54A, 2.9 g, 35%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (s, 3 H) 1.49 (d, J=7.33 Hz, 3 H) 4.09 (dd, J=7.07, 2.02 Hz, 2 H) 4.23 (d, J=7.33 Hz, 1 H) 7.83 (d, J=8.84 Hz, 1 H) 7.93 (d, J=8.84 Hz, 1 H). ESI-MS:m/z 215.0 (M+H)+.
Reaction SMILES: CS([Cl:5])(=O)=O.[CH3:6][O:7][C:8]1[C:17]2[C:12](=[C:13]([O:18][CH3:19])[CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([CH2:20]O)[CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:5][CH2:20][C:10]1[CH:9]=[C:8]([O:7][CH3:6])[C:17]2[C:12](=[C:13]([O:18][CH3:19])[CH:14]=[CH:15][CH:16]=2)[CH:11]=1
Reactant: COc1cc(CO)cc2c(OC)cccc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(CCl)cc2c(OC)cccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.9 %

Procedure:
A solution of 3.92 g of methanesulphonyl chloride in 20 ml of methylene chloride was added dropwise to a solution, cooled to -10° C., of 7.7 g (35.3 mmol) of (4,8-dimethoxy-naphthalen-2-yl)-methanol and 4.4 g (38.8 mmol) of triethylamine in 50 ml of methylene chloride. The reaction mixture was stirred at room temperature for 18 hours. For the working-up, the mixture was extracted with 50 ml of ice-cold sodium hydrogen carbonate solution and the aqueous phase was separated and back-extracted with 25 ml of methylene chloride. The combined organic phases were dried over sodium sulphate and subsequently evaporated under reduced pressure. For purification, the residue was filtered over a layer of silica gel using methylene chloride as the eluent. There were obtained 7.2 g of 2-chloromethyl-4,8-dimethoxy-naphthalene as a beige solid; MS: 296 (M)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]1[CH:19]=[C:18]([CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[OH:21])[CH:17]=[CH:16][N:15]=1.[C:32]([O:36][C:37](=[O:51])[CH2:38][CH2:39][S:40][CH2:41][C:42]1[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=1)[C:45](O)=[O:46])([CH3:35])([CH3:34])[CH3:33].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[OH:21][CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1)[C:18]1[CH:17]=[CH:16][N:15]=[C:14]([C:3]2[CH:4]=[C:5]([N:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[CH:6]=[CH:7][C:2]=2[NH:1][C:45]([C:44]2[CH:43]=[C:42]([CH:50]=[CH:49][CH:48]=2)[CH2:41][S:40][CH2:39][CH2:38][C:37]([O:36][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:51])=[O:46])[CH:19]=1
Reactant: Nc1ccc(N2CCCCC2)cc1-c1cc(C(O)c2cccc(C(F)(F)F)c2)ccn1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(O)c3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of mg of (2-(2-amino-5-(piperidin-1-yl)phenyl)pyridin-4-yl)(3-(trifluoromethyl)phenyl)-methanol 5.2c, and 41 mg of 3-((3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid 1.1c, 67 mg of diisopropylethylamine in 1.5 mL of DMF was treated with 57 mg of HATU. After stirring at 60° C. for 2 h the mixture was diluted with ethyl acetate and washed once with a saturated aqueous solution of sodium bicarbonate, three times with water, and once with brine. After drying (Na2SO4) the solvent was evaporated to give 107 mg of product. MS (ES, m/z) 706.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[N:32]1([S:38](Cl)(=[O:40])=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:38]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)(=[O:40])=[O:39]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: O=S(=O)(Cl)N1CCOCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)N1CCOCC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (50 mg, 0.120 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. morpholine-4-sulfonyl chloride (24 mg, 0.130 mmol) and pyridine (11 uL, 0.130 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 59 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)morpholine-4-sulfonamide (percentage yield: 86%), was obtained.
Reaction SMILES: [C:1](#[N:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[Cl:10]N1C(=O)CCC1=O>C(#N)C>[Cl:10][C:7]1[CH:6]=[CH:5][C:3]([NH2:4])=[C:2]([C:1]#[N:9])[CH:8]=1
Reactant: N#Cc1ccccc1N
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: N#Cc1cc(Cl)ccc1N
Temperature: 50 °C
Yield: 46.3 %

Procedure:
A 2 L round bottom flask was charged with 138 g (1.168 mol) of anthranilonitrile (Aldrich) and 1.05 L of acetonitrile. The flask was heated to 50° C. and 172.5 g (1.29 mol) of N-chlorosuccinimide (Aldrich) was added in one portion. The reaction was heated at reflux for 2.0 h (HPLC monitoring), cooled to approx. 35° C., and the solvent is removed by rotovap at reduced pressure. The residue was partitioned between 1.5 L ethyl acetate and 1 L cold water. The aqueous layer was extracted with ethyl acetate and the combined organic layers washed with 3 portions of cold water, brine, dried over MgSO4 and treated with activated carbon. The solvent was removed by rotovap at reduced pressure to give a pale orange solid which was crystallized from 430 mL of hot 1-chlorobutane and allowed to cool to room temp. overnight. After filtration, the resulting crystals were washed with cold butylchloride and air dried to give 82.5 g of off-white crystals (94% pure by HPLC). This material was recrystallized from 140 mL of s chlorobutane and 125 mL hexane to give 73 g (41%) of the title compound as a colorless solid. An additional 18.8 g (10.5%) was obtained from two recrystallizations of material from the mother liquors.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[CH:21])=[CH:16][CH:15]=2)[N:13]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: C#Cc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(C#Cc2ccc(C(F)(F)F)cn2)cc1
Yield: 20.5 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 using 5-(2-chloro-6-fluorophenyl)-2-(4-ethynylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate-2, 0.100 g, 0.319 mmol), 2-bromo-5-(trifluoromethyl)pyridine (0.108 g, 0.479 mmol), TBAF (0.201 g, 0.638 mmol), bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.028 mmol) and DMSO (3.0 mL). The obtained product was purified with column chromatography on silica gel eluting with 1.0% MeOH:DCM to afford 0.030 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.51 (t, J=8.7 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.70 (t, J=6.3 Hz, 1H), 7.79 (d, J=8.7 Hz, 2H), 7.89 (d, J=8.1 Hz, 1H), 8.06 (d, J=8.4 Hz, 2H), 8.29 (d, J=7.8 Hz, 1H), 9.00 (s, 1H), 12.75 (br s, 1H). MS (m/z): 459.37 (M+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[N:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=2)[CH:6]=1.[Cl:20][C:21]1[NH:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1.C([O-])([O-])=O.[K+].[K+]>C(C#N)(C)=O>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([N:22]3[C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[N:25]=[C:21]3[Cl:20])[N:15]=[CH:14][N:13]=2)[CH:6]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: COC(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Agent: CC(=O)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)Cc1cccc(Nc2ncnc(-n3c(Cl)nc4ccccc43)n2)c1
Temperature: 407.5 °C

Procedure:
[3-(4-Chloro-[1,3,5]triazin-2-ylamino)phenyl]acetic acid methyl ester (3.530 g, 12.67 mmol) is combined with 2-chlorobenzimidazole (1.933 g, 12.67 mmol) and K2CO3(2.101 g, 15.20 mmol) in AcCN (50 ml) and heated at 65-750° C. for 2 to 20 hours. The reaction mix is cooled to RT. The inorganic salts are filtered off. The AcCN solution is concentrated down under reduced pressure. The crude is purifired by chromatography with an EtOAc/hexane elution gradient, giving {3-[4-(2-chloro-benzimidazol-1-yl)-[1,3,5]triazin-2-ylamino]phenyl}acetic acid methyl ester.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[N:8]=[CH:7][C:6]([C:9](=[N:11][OH:12])[NH2:10])=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21](Cl)=O>>[Cl:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21]1[O:12][N:11]=[C:9]([C:6]2[CH:7]=[N:8][C:3]([C:2]([F:13])([F:1])[F:14])=[CH:4][CH:5]=2)[N:10]=1
Reactant: NC(=NO)c1ccc(C(F)(F)F)nc1
Reactant: O=C(Cl)c1sccc1Cl
Product: FC(F)(F)c1ccc(-c2noc(-c3sccc3Cl)n2)cn1

Procedure:
The title compound was prepared from 6-trifluoromethyl-pyridine-3-amidoxime (418 mg, 2.04 mmol) and 3-chloro-thiophene-2-carbonyl chloride (369 mg, 2.04 mmol) similar to Example 16, and yielded 538 mg (80%) of white solid. 1H NMR (CDCl3): 9.49 (m, 1H), 8.63 (m, 1H), 7.85 (dd, J=8.24, 0.82 Hz, 1H), 7.66 (d, J=5.49 Hz, 1H), 7.17 (d, J=5.22 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][NH2:13].Cl>C(O)C.O>[OH2:5].[ClH:1].[CH3:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:13][CH3:12])[N:10]=1.[CH3:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:13][CH3:12])[N:10]=1.[OH2:5]
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Reactant: CN
Agent: Cl
Solvent: CCO
Solvent: O
Product: CNc1nc(C)ccc1C(=O)O
Temperature: 100 °C

Procedure:
A mixture of 2-chloro-6-methylnicotinic acid (25.00 g) and 33% methylamine in ethanol (100 ml) was heated in a pressure vessel at 100° C. for 18 hours. The mixture was cooled, diluted with water (200 ml) and acidified to pH 2-3 with concentrated hydrochloric acid. The mixture was cooled in an ice bath and filtered to give 6-methyl-2-methylaminonicotinic acid hemihydrochloride hydrate, m.p. 195°-197° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=3)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39]>C(Cl)Cl>[C:38]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=3)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]2)[CH2:3][CH2:2]1)(=[O:40])[CH3:39]
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C2CCNCC2)cn1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C2CCN(C(C)=O)CC2)cn1
Reaction time: 12 h

Procedure:
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (1-piperidin-4-yl-1H-imidazol-4-yl)-amide (200 mg, 4.8 mmol) was dissolved in 5 mL of methylene chloride, charged with 0.08 mL of triethylamine, and 0.03 mL of acetylchloride at 0° C. The reaction was stirred for 12 h, quenched with sodium bicarbonate, extrated with methylene chloride and concentrated. The compound was purified by silica gel chromatography to afford the title compound: C13 NMR (100 MHz, CDCl3) 13.9, 18.9, 21.6, 32.8, 33.7, 36.0, 40.7, 43.0, 45.4, 53.1, 55.5, 102.6, 102.8, 103.1, 105.6, 105.7, 112.3, 112.4, 112.5, 131.5, 137.8, 169.1, 169.3, 169.5; MS 462.25 m/z (M+1).