Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12>CN(C=O)C>[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH:64][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[Br:10])=[O:24])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Reactant: O=C(O)c1cc2cccc(Br)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[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: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2cccc(Br)c2oc1=O
Temperature: 25 °C

Procedure:
DIEA (35.6 μL, 0.2 mmol) was added to 8-bromo-3-carboxy-coumarin (50 mg, 0.19 mmol) and HATU (77.73 mg, 0.2 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (38.89 mg, 0.19 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to the final product: LCMS (ESI) m/z 461 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[N:35]=[N:36][C:37]([NH2:40])=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[N:35]=[N:36][C:37]([NH:40][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:20])[CH3:1])[N:14]([CH:15]5[CH2:19][CH2:18][CH2:17][CH2:16]5)[C:8]=4[N:9]=3)=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nn2)CC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nn3)nc2n1C1CCCC1
Yield: 41.2 %

Procedure:
Following General Procedure D, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (200 mg, 0.68 mmol) and 4-(6-amino-pyridazin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (210 mg, 0.75 mmol) to give 4-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridazin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (150 mg, 46%). MS(ESI) m/z 536.3 (M+H)+
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH:10][C:11]3[O:12][CH2:13][C:14]4[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.[CH:22]([C:24]1[NH:25][CH:26]=[CH:27][N:28]=1)=O>>[CH:1]1([C:4]2[CH:5]=[C:6]([NH:10][C:11]3[O:12][CH2:13][C:14]4[CH:20]=[C:19]([NH:21][CH2:22][C:24]5[NH:25][CH:26]=[CH:27][N:28]=5)[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1ncc[nH]1
Reactant: Nc1ccc2c(c1)COC(Nc1cccc(C3CC3)c1)=N2
Product: c1cc(NC2=Nc3ccc(NCc4ncc[nH]4)cc3CO2)cc(C2CC2)c1
Yield: 39.2 %

Procedure:
Prepared from N2-(3-cyclopropyl-phenyl)-4H-benzo[d][1,3]oxazine-2,6-diamine (197 mg, 0.71 mmol) and 2-formylimidazole (81 mg, 0.84 mmol) according to the procedure described for example 88. Obtained the title compound as a white solid (100 mg, 39%), MS (ISP) m/e=358.5 [(M−H)+].
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)=[N:6][CH:5]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[Cl:22])[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl.[NH:29]1[CH2:34][CH2:33][O:32][CH:31]([CH2:35][C:36]([OH:38])=[O:37])[CH2:30]1>>[Cl:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[CH:5]1[N:6]=[C:7]([C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[NH:8][C:3]([CH2:2][N:29]2[CH2:34][CH2:33][O:32][CH:31]([CH2:35][C:36]([OH:38])=[O:37])[CH2:30]2)=[C:4]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C1=C(CBr)NC(c2cnccn2)=NC1c1ccc(F)cc1Cl
Reactant: O=C(O)CC1CNCCO1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOC(CC(=O)O)C2)NC(c2cnccn2)=NC1c1ccc(F)cc1Cl
Yield: 31.6 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(pyrazin-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1 g, 2.2 mmol) was reacted with 2-(morpholin-2-yl)acetic acid hydrochloride (0.4 g, 2.2 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.36 g, 32%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[OH:18][C:19]1([C:25]#[C:26][C:27]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:27]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)=[CH:26][C:25]([C:19]3([OH:18])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(NN)cc1
Reactant: Cc1ccc(C(=O)C#CC2(O)CCCCC2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(-n2nc(C3(O)CCCCC3)cc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
To a suspension of 4-methoxyphenylhydrazine (165 mg, 0.944 mmol) in ethanol (5.0 mL), triethylamine (258 μL, 1.88 mmol) was added, and the obtained solution was stirred at room temperature for 30 minutes. The resulting solution was added to a solution of 3-(1-hydroxycyclohexyl)-1-(4-tolyl)-2-propyn-1-one (Reference Example 14) (214 mg, 0.883 mmol) in ethanol (3.0 mL), and the resulting mixture was stirred at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure, and distilled water was added to the residue. The resulting solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the title compound (141 mg, 0.389 mmol, 44%) as a yellow amorphous product.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@@H:9](O)[CH2:8][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1)=[N+:2]=[N-:3].C(N(S(F)(F)[F:24])CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[N:1]([CH2:4][C@@H:5]1[C@@H:9]([F:24])[CH2:8][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC[C@H]1CN(Cc2ccccc2)C[C@@H]1O
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: [N-]=[N+]=NC[C@H]1CN(Cc2ccccc2)C[C@@H]1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(3R,4R)-3-Azidomethyl-1-benzyl-4-hydroxypyrrolidine (566 mg) was dissolved in dichloromethane (9 mL). While this solution was chilled in an ice water bath, diethylaminosulfur trifluoride (0.39 mL) was added dropwise and the mixture was stirred at room temperature for 2 hours. While the reaction vessel was chilled in an ice water bath, a saturated aqueous solution of sodium bicarbonate (9 mL) was added and the mixture was diluted with dichloromethane (15 mL). The dichloromethane layer was separated, washed sequentially with a saturated aqueous solution of sodium bicarbonate (10 mL) and water (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: hexane: ethyl acetate=4:1). The first half fraction yielded (3R,4R)-3-azidomethyl-1-benzyl-4-fluoropyrrolidine as a pale brown oil (76.7 mg).
Reaction SMILES: [N+:1]([C:4]1[C:8]([C:9]2[CH:14]=[C:13]([O:15][C:16]([F:19])([F:18])[F:17])[CH:12]=[CH:11][C:10]=2[OH:20])=[CH:7][N:6]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[N:5]=1)([O-:3])=[O:2].[C:27]([O:31][C:32](=[O:51])[N:33]([S:39]([C:42]1[CH:47]=[C:46]([Cl:48])[C:45](F)=[CH:44][C:43]=1[F:50])(=[O:41])=[O:40])[C:34]1[N:35]=[CH:36][S:37][CH:38]=1)([CH3:30])([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[C:27]([O:31][C:32](=[O:51])[N:33]([S:39]([C:42]1[CH:47]=[C:46]([Cl:48])[C:45]([O:20][C:10]2[CH:11]=[CH:12][C:13]([O:15][C:16]([F:18])([F:19])[F:17])=[CH:14][C:9]=2[C:8]2[C:4]([N+:1]([O-:3])=[O:2])=[N:5][N:6]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[CH:7]=2)=[CH:44][C:43]=1[F:50])(=[O:40])=[O:41])[C:34]1[N:35]=[CH:36][S:37][CH:38]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: O=[N+]([O-])c1nn(C2CCCCO2)cc1-c1cc(OC(F)(F)F)ccc1O
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(Oc2ccc(OC(F)(F)F)cc2-c2cn(C3CCCCO3)nc2[N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-4-(trifluoromethoxy)phenol (Preparation 24, 2.00 g, 5.36 mmol) and tert-butyl[(5-chloro-2,4-difluorophenyl)sulfonyl]1,3-thiazol-4-ylcarbamate (Preparation 4, 2.20 g, 5.36 mmol) in dimethylsulfoxide (30 mL) was added potassium carbonate (1.5 g, 11 mmol). The reaction mixture was stirred for 18 hours at ambient temperature. The reaction mixture was then diluted with water and extracted with ethyl acetate (×3). The combined organic phase was washed with water (×2) then dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was triturated with ether and the solid collected by filtration and dried in vacuo to afford the title compound with a 5% de-boc impurity (3.70 g). The compound was used without further purification in the next step.
Reaction SMILES: [CH2:1]([C:8]1[NH:29][C:11]2=[N:12][C:13]([N:16]3[CH2:21][CH2:20][CH2:19][C@@H:18]([C:22]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:23])[CH2:17]3)=[CH:14][CH:15]=[C:10]2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:30]1CCOCC1>[O-2].[Mn+4].[O-2]>[C:1]([C:8]1[NH:29][C:11]2=[N:12][C:13]([N:16]3[CH2:21][CH2:20][CH2:19][C@@H:18]([C:22]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:23])[CH2:17]3)=[CH:14][CH:15]=[C:10]2[N:9]=1)(=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCO1
Reactant: O=C([C@@H]1CCCN(c2ccc3nc(Cc4ccccc4)[nH]c3n2)C1)N1CCCC1
Agent: [Mn+4]
Agent: [O-2]
Product: O=C(c1ccccc1)c1nc2ccc(N3CCC[C@@H](C(=O)N4CCCC4)C3)nc2[nH]1
Temperature: 120 °C

Procedure:
Manganese (IV) oxide (2 g) was added to a solution of (R)-(1-(2-benzyl-3H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (200 mg, 0.51 mmol) in dioxane (30 mL). After heating at 120° C. for 48 h in a sealed tube, the mixture was filtered through a pad of Celite and washed with ethyl acetate. The filtrate was concentrated in vacuo and the resulting residue was purified via preparative TLC to afford (R)-(1-(2-benzoyl-3H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (80 mg). MS (ES+APCI) (M+H) 404.1; LCMS retention time 2.855 min (Method G).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)[CH:5]=2)[CH2:3][CH2:2]1.[H][H]>[Pt]=O.C(O)C>[NH2:7][C:6]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)=[CH:5][C:4]([CH:1]1[CH2:2][CH2:3]1)=[O:8]
Reactant: c1cc(-c2cc(C3CC3)on2)ccn1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: NC(=CC(=O)C1CC1)c1ccncc1

Procedure:
A solution of 3 g. of 4-(5-cyclopropyl-3-isoxazolyl)pyridine in 50 ml. of ethanol is treated with 0.5 g. of platinum oxide and the mixture is treated with hydrogen on a Parr apparatus at 44 psi for 5 hours at 25° C. The mixture is filtered and the filtrate is evaporated to dryness under reduced pressure to give a semi-solid residue which is recrystallized from ethyl acetate to give light tan crystals, melting point 159°-166° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]([N:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:6])[CH3:2].[C:28](Cl)(=[O:39])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]=[CH2:38]>>[O:6]=[C:5]([N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=1)[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:28](=[O:39])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]=[CH2:38])=[CH:24][CH:25]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:27]
Reactant: CCOC(=O)C(=O)N(Cc1ccc(N)cc1)Cc1ccc(C(F)(F)F)cc1
Reactant: C=CCCCCCCCCC(=O)Cl
Product: C=CCCCCCCCCC(=O)Nc1ccc(CN(Cc2ccc(C(F)(F)F)cc2)C(=O)C(=O)OCC)cc1
Yield: 71 %

Procedure:
The same procedure as employed in the preparation of Example 15, step d using ethyl{(4-aminobenzyl)[4-(trifluoromethyl)benzyl]amino}(oxo)acetate and undec-10-enoyl chloride gave the title compound as a colorless oil (71%). HPLC (Condition A), Rt: 6.7 min (HPLC purity: 99%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>C(OCC)(=O)C>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:20])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C1CC2(CCN1)OCCO2
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(Oc1ccccc1)N1CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 95.1 %

Procedure:
To a stirred solution of 1,4-dioxa-8-azaspiro[4.5]decane (2.00 g, 13.9 mmol) and triethylamine (2.90 mL, 20.9 mmol) in ethyl acetate (50 mL) at 0° C. was added phenyl chloroformate (2.10 mL, 13.9 mmol). The mixture was allowed to warm to room temperature overnight. Then, the mixture was filtered to remove triethylamine hydrochloride salts. The filtrate was concentrated, and the obtained residue was chromatographed (silica gel, hexanes to 50:50 hexanes/ethyl acetate) to give the title compound (3.48 g, 95%) as a white solid:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([C:11](=[O:13])[CH3:12])[C@@H:9]([CH3:14])[CH2:8][NH:7][C:6]=2[N:15]=1.C(N(CC)C(C)C)(C)C.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[C:11]([N:10]1[C@@H:9]([CH3:14])[CH2:8][N:7]([C:33]([NH:32][C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)=[O:34])[C:6]2[N:15]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]1=2)(=[O:13])[CH3:12]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CC(=O)N1c2ccc(Br)nc2NC[C@@H]1C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(Br)nc2N(C(=O)Nc2ccc(F)cc2)C[C@@H]1C
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A reaction vial was charged with (S)-1-(6-bromo-2-methyl-3,4-dihydropyrido[2,3-b]pyrazine-1(2H)-yl)ethanone (0.1 M solution in 1,2-dichloroethane, 0.30 mL, 0.03 mmol) and N,N-diisopropylethylamine (0.052 mL, 0.300 mmol) was added. 1-Fluoro-4-isocyanatobenzene (0.017 mL, 0.150 mmol) was added neat, followed by the addition of a catalytic amount of DMAP (˜1 mg), and the reaction was shaken at 50° C. overnight. The reaction was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The aqueous layer was separated and extracted with ethyl acetate, and the combined organic layers were concentrated under a stream of nitrogen and vacuum to yield (S)-1-acetyl-6-bromo-N-(4-fluorophenyl)-2-methyl-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide. The crude product was dissolved in 1,4-dioxane (100 μL and 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.2 M solution in 1,4-dioxane, 0.27 mL, 0.054 mmol), potassium carbonate (1.0 M solution in water, 0.090 mL, 0.090 mmol) and [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) dichloromethane adduct (0.02 M solution in 1,2-dichloroethane, 150 μL, 0.003 mmol) were added. The reaction was purged with nitrogen, and heated to 80° C. on a heater shaker for 4 hours. The reaction was diluted with ethyl acetate and washed with 1 N aqueous sodium hydroxide solution and brine. The combined organic layers were concentrated in a Genevac. The crude product was purified by mass triggered preparatory HPLC. The product-containing fractions were combined and concentrated to afford (S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-N-(4-fluorophenyl)-2-methyl-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide. MS (ESI, pos. ion) m/z 435 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([CH:17]([CH3:39])[C:18](=[O:38])[NH:19][CH2:20][C:21]2[C:22]([C:31]3[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=3)=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)[CH:14]=[CH:13][C:3]=1[CH2:4][NH:5]C(=O)OC(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[NH2:5][CH2:4][C:3]1[CH:13]=[CH:14][C:15]([CH:17]([CH3:39])[C:18]([NH:19][CH2:20][C:21]2[C:22]([C:31]3[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=3)=[N:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=2)=[O:38])=[CH:16][C:2]=1[Cl:1]
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(CNC(=O)OC(C)(C)C)c(Cl)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(CN)c(Cl)c2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a stirred solution of tert-butyl 2-chloro-4-(1-oxo-1-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methylamino)propan-2-yl)benzylcarbamate (132 mg, 0.234 mmol) in dichloromethane (4 mL), cooled to 0° C., were added trifluoroacetic acid (2 ml). The resulting reaction mixture was stirred for 1 h at 0° C. and 1 hour at room temperature, then basified to pH 8-9 with aq. NaHCO3. The mixture was filtered using celite pad. The filtrate dissolved in dichloromethane and extracted with NaHCO3. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. 2-(4-(aminomethyl)-3-chlorophenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (90 mg) was obtained as 83% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:32][N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22]C(C)C)=[C:18]([O:26][CH3:27])[CH:17]=1)=[CH:13][C:12]([O:28][CH3:29])=[C:11]([O:30][CH3:31])[CH:10]=2)=[O:5])[CH3:2].O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:32][N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:26][CH3:27])[CH:17]=1)=[CH:13][C:12]([O:28][CH3:29])=[C:11]([O:30][CH3:31])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cn2cncn2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC(C)C)c(OC)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1c(Cn2cncn2)nc2cc(OC)c(OC)cc2c1-c1ccc(O)c(OC)c1
Reaction time: 6 h
Yield: 48.1 %

Procedure:
To a solution of 6,7-dimethoxy-4-(4-isopropoxy-3-methoxyphenyl)-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylic acid ethyl ester (55.6 mg) in dichloromethane (2 ml), titanium tetrachloride (TiCl4) (125 mg) was added at 0° C., followed by stirring at the same temperature for 6 hours. The reaction mixture was poured over water and extracted with chloroform. The chloroform layer was washed by sequential additions of a saturated aqueous sodium hydrogen carbonate solution and water and then dried (MgSO4), after which the solvent was distilled off. The residual oily substance was subjected to silica gel column chromatography and eluted with ethyl acetate-chloroform (3:2, v/v) to yield 6,7-dimethoxy-4-(4-hydroxy-3-methoxyphenyl)-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylic acid ethyl ester (24.5 mg, 48%) which was then recrystallized from ethyl acetate-hexane having a melting point of 176 to 178° C.
Reaction SMILES: Cl.Cl.[N:3]1([CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19]C)[CH:15]=3)[CH2:10]2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[BrH:21]>>[BrH:21].[BrH:21].[N:3]1([CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=3)[CH2:10]2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1
Reactant: COc1ccc2c(c1)CCC(N1CCNCC1)C2
Agent: Br
Agent: Cl
Product: Oc1ccc2c(c1)CCC(N1CCNCC1)C2
Reaction time: 2.5 h

Procedure:
The product from Example 29 (0.30 g) and 48% hydrobromic acid (12 ml) were warmed for 3 hours and heated at reflux with stirring under nitrogen for 2.5 hours. The reaction mixture was evaporated to dryness, and the residue, in ethanol, was heated on a steam bath. After standing at room temperature for two days, the mixture was filtered, and the solid was dried to obtain 0.37 g of the title compound, m.p. 192°-194° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:25]=[CH:24][C:8]2[N:9]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=4)[N:12]=[C:10]3[S:11][C:7]=2[CH:6]=1.[H][H]>CO.C1COCC1.[Pd]>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:25]=[CH:24][C:8]2[N:9]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=4)[N:12]=[C:10]3[S:11][C:7]=2[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(-c2cn3c(n2)sc2cc(OCCCl)ccc23)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(-c2cn3c(n2)sc2cc(OCCCl)ccc23)cc1
Temperature: 25 °C

Procedure:
A mixture of 7-(2-chloro-ethoxy)-2-(4-nitro-phenyl)-benzo[d]imidazo[2,1-b]thiazole (1 equivalent) and 10% Pd/C (0.05-0.1 equivalents) in a mixture of MeOH and THF under 1 atmosphere of hydrogen gas is stirred at rt until the reaction is substantially complete as monitored by LCMS or TLC. The mixture is filtered through Celite and concentrated under reduced pressure. The residue is purified by silica gel flash chromatography to afford 7-(2-chloro-ethoxy)-2-(4-amino-phenyl)-benzo[d]imidazo[2,1-b]thiazole.
Reaction SMILES: C(OC([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=1[C:29]([F:32])([F:31])[F:30])=O)C1C=CC=CC=1.[CH:33]([C:35]1[N:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[N:41]=[CH:40][C:39]([C:45]#[N:46])=[C:38]2[O:47][CH:48]([CH3:50])[CH3:49])=O.N1CCCCC1>CC(O)C>[F:32][C:29]([F:30])([F:31])[C:20]1[CH:21]=[C:22]([C:25]([F:26])([F:28])[F:27])[CH:23]=[CH:24][C:19]=1[CH2:18][NH:17][C:12]1[NH:11][C:15](=[CH:33][C:35]2[N:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[N:41]=[CH:40][C:39]([C:45]#[N:46])=[C:38]3[O:47][CH:48]([CH3:50])[CH3:49])[C:14](=[O:16])[N:13]=1
Reactant: CC(C)Oc1c(C#N)cnc2ccc(C=O)nc12
Reactant: O=C1CN(C(=O)OCc2ccccc2)C(NCc2ccc(C(F)(F)F)cc2C(F)(F)F)=N1
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: CC(C)Oc1c(C#N)cnc2ccc(C=C3NC(NCc4ccc(C(F)(F)F)cc4C(F)(F)F)=NC3=O)nc12
Temperature: 25 °C

Procedure:
To a mixture of 2-(2,4-bis-trifluoromethyl-benzylamino)-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (82.7 mg, 0.18 mmol) (prepared as described in C-H Kwon et al. J. Med. Chem. 1991, 34, 1845-1849), 6-formyl-4-isopropoxy-[1,5]naphthyridine-3-carbonitrile (45.6 mg, 0.19 mmol) (see Example 1) and iPrOH (5 mL) in a 25-mL round bottom flask was added piperidine (0.05 mL) and the suspension was then heated under refluxing for 5 h to give a brown solution. The reaction mixture was cooled to r.t. and concentrated to give a light yellow solid, 66.3 mg, which was purified by flash column purification to give 6-[2-(2,4-bis-trifluoromethyl-benzylamino)-5-oxo-3,5-dihydro-imidazol-4-ylidenemethyl]-4-isopropoxy-[1,5]naphthyridine-3-carbonitrile, as a light yellow solid, 20.6 mg (20.9%). HR-ES (+) m/e calcd for C25H18F6N6O2 (M+H)+ 549.1468. found 549.1472.