Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:17]([OH:19])=O)=[CH:11][N:12]([CH3:16])[C:13](=[O:15])[CH:14]=2)=[C:4]([F:20])[CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:42]([O:44][CH2:45][CH2:46][O:47][NH2:48])=[CH2:43].CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[CH:42]([O:44][CH2:45][CH2:46][O:47][NH:48][C:17]([C:10]1[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:20])=[CH:14][C:13](=[O:15])[N:12]([CH3:16])[CH:11]=1)=[O:19])=[CH2:43]
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(Br)cc2F)cc1=O
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=COCCONC(=O)c1cn(C)c(=O)cc1Nc1ccc(Br)cc1F
Reaction time: 3 h
Yield: 52 %

Procedure:
A mixture of 4-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.120 g, 0.352 mmol), EDCI (0.10 g, 0.53 mmol), and HOBt (0.071 g, 0.53 mmol) in DMF (5 mL) was stirred for 3 hours. O-(2-Vinyloxy-ethyl)-hydroxylamine (0.071 mL, 0.70 mmol) was added followed by Et3N (0.098 mL, 0.70 mmol). After 2 hours, the reaction mixture was diluted with EtOAc and washed with saturated NH4Cl solution, saturated NaHCO3 solution and brine. The organic layer was dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography (3% MeOH in methylene chloride) gave 0.078 g (52%) clean desired product.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7].[BrH:14].[C:15]1([P:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C>[Br-:14].[OH:13][C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:2][P+:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(O)c(CO)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Br
Solvent: CC#N
Product: COC(=O)c1ccc(O)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [Br-]
Yield: 92.6 %

Procedure:
The compound obtained in (b) (182 mg, 1 mmol) was mixed successfully with 2 ml of acetonitrile and triphenylphosphine hydrobromide (361 mg, 1.05 mmol). After heating at reflux for one hour fifteen minutes, the reaction medium was cooled and evaporated to dryness, ethyl ether was added, the mixture was filtered and the precipitate was washed with ethyl ether. After drying in an oven, 470 mg of a white solid were obtained, equivalent to a yield of 93%. Its properties were as follows:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Cl:13])[N:4]=1.[OH:14][CH2:15][C:16]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.CC(C)([O-])C.[K+]>O1CCCC1.O>[Cl:13][C:5]1[N:4]=[C:3]([CH2:2][O:14][CH2:15][C:16]2([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: FC(F)(F)c1cc(Cl)nc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(F)(F)F)cc(Cl)n2)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-(bromomethyl)-6-chloro-4-(trifluoromethyl)pyridine (1.1 g, 4.1 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (1.0 g, 3.4 mmol) were combined in tetrahydrofuran (20 mL) and cooled to 0° C. The reaction was treated with potassium tert-butoxide (763 mg, 6.8 mmol) portion wise. The reaction was stirred at 0° C. for 1 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over magnesium sulfate, and concentrated. Column chromatography on silica gel (10% ethyl acetate/hexanes) gave 837 mg (52%). 1H-NMR (CDCl3, 400 MHz) δ 7.31-7.38 (m, 6H), 7.18 (s, 1H), 4.48 (s, 2H), 3.74-3.79 (m, 2H), 3.50 (s, 2H), 2.99-3.06 (m, 2H), 2.21-2.25 (m, 2H), 1.83-1.86 (m, 2H), 1.42 (s, 9H). Mass spec.: 485.11 (MH)+.
Reaction SMILES: O.C(=O)([O-])[O-].[Mg+2].[N:7]#[C:8]Br.[CH2:10]([O:17][C:18](=[O:32])[C@H:19]([CH2:28][CH:29]([CH3:31])[CH3:30])[NH:20][C:21](=[O:27])[C@H:22]1[CH2:26][CH2:25][CH2:24][NH:23]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(#N)C.C(OCC)C>[CH2:10]([O:17][C:18](=[O:32])[C@H:19]([CH2:28][CH:29]([CH3:30])[CH3:31])[NH:20][C:21](=[O:27])[C@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:8]#[N:7])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H]1CCCN1)C(=O)OCc1ccccc1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [Mg+2]
Solvent: O
Solvent: CC#N
Solvent: CCOCC
Product: CC(C)C[C@H](NC(=O)[C@H]1CCCN1C#N)C(=O)OCc1ccccc1

Procedure:
A mixture of 10 mL diethyl ether, 2 mL water, and 150 mg magnesium carbonate was cooled in an ice bath and 0.83 mL (4.16 mmol) 5M cyanogen bromide in acetonitrile was added with stirring. A solution of (D)-prolyl-leucine benzyl ester (883 mg, 2.77 mmol) in 17 mL diethyl ether was added over the course of 10 minutes. Another 0.20 mL (1.0 mmol) of 5M cyanogen bromide in acetonitrile was then added and the mixture was stirred at room temperature for 30 minutes. The organic phase was decanted and the aqueous phase extracted twice with diethyl ether. The combined ether phase was washed with 1N HCl, water, and saturated sodium bicarbonate, then dried over magnesium sulfate. Filtration and evaporation of solvent gave the crude product that was purified by flash chromatography on silica gel, eluting with 2% methanol/dichloromethane. N-cyano-(D)-prolyl-leucine benzyl ester (11) was isolated as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][CH3:16])=[CH:12][C:11]([N:17]3[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]3)=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([NH2:9])=[O:8].[C:24](=[O:27])([O-])[O-:25].[K+].[K+]>CN(C=O)C.CO.O>[C:3]([O:25][C:24](=[O:27])[NH:23][CH:20]1[CH2:19][CH2:18][N:17]([C:11]2[CH:12]=[C:13]([O:14][CH2:15][CH3:16])[C:3]3[C:2]([NH2:1])=[C:6]([C:7](=[O:8])[NH2:9])[S:5][C:4]=3[CH:10]=2)[CH2:22][CH2:21]1)([CH3:13])([CH3:4])[CH3:2]
Reactant: CCOc1cc(N2CCC(N)CC2)cc2sc(C(N)=O)c(N)c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: CCOc1cc(N2CCC(NC(=O)OC(C)(C)C)CC2)cc2sc(C(N)=O)c(N)c12
Temperature: 80 °C
Yield: 50 %

Procedure:
To a solution of 0.311 g (0.856 mmol) of the above amide in DMF (5 mL) was added 0.91 mL (1.0 mmol) of a 10% solution of 2-thioacetamide in MeOH along with 0.70 g (5.1 mmol) of potassium carbonate. The mixture was heated to 80° C. for 24 h then cooled to room temperature and diluted with H2O. The mixture was washed with CH2Cl2 and the combined organic phase was washed with H2O, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to provide 0.093 g (25%) of [1-(3-amino-2-carbamoyl-4-ethoxy-benzo[b]thiophen-6-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester as a white powder.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH:8](OCC)OCC)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:30]3=[N:31][CH:32]=[CH:33][CH:34]=[C:29]3[N:28]([CH2:35][CH3:36])[C:27]2=[O:37])=[CH:22][CH:21]=1>>[CH2:35]([N:28]1[C:29]2[C:30](=[N:31][CH:32]=[CH:33][CH:34]=2)[N:26]([C:23]2[CH:22]=[CH:21][C:20]([N:19]3[C:2]4=[N:3][C:4]5[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=5[N:6]4[CH:7]=[CH:8]3)=[CH:25][CH:24]=2)[C:27]1=[O:37])[CH3:36]
Reactant: CCOC(Cn1c(Cl)nc2ccccc21)OCC
Reactant: CCn1c(=O)n(-c2ccc(N)cc2)c2ncccc21
Product: CCn1c(=O)n(-c2ccc(-n3ccn4c5ccccc5nc34)cc2)c2ncccc21
Temperature: 150 °C
Yield: 31.5 %

Procedure:
A mixture of 2-chloro-1-(2,2-diethoxyethyl)-1H-benzimidazole (860 mg) and 3-(4-aminophenyl)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (636 mg) was heated at 150° C. for 50 min. The reaction mixture was partitioned between AcOEt/THF (1/1) and 1 M NaOH aqueous solution. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with THF and recrystallized from THF to give 1-ethyl-3-[4-(1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (311 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([C@@H:13]([N:15](C(O)=O)[CH2:16]C2C=CC=CC=2)[CH3:14])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1.CCOCC>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([C@@H:13]([NH:15][CH3:16])[CH3:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]([C@@H]1CCN(Cc2ccccc2)C1=O)N(Cc1ccccc1)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN[C@@H](C)[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 0 °C

Procedure:
(S,S)-1-benzyl-2-oxo-3-[1'-(carboxybenzylamino)ethyl]pyrrolidine (0.51 g, 1.44 mmol) is dissolved in tetrahydrofuran (20 ml) under a N2 atmosphere. LAH (0.32 g, 8.43 mmol) is added and the reaction mixture is refluxed for 12 hours. The reaction mixture is cooled to 0° C., diluted with Et2O and quenched with 15% aqueous NaOH. The resulting mixture is filtered through a celite pad which is then washed carefully with Et2O. The filtrate is washed with 15% aqueous NaOH and the aqueous layer extracted with Et2O. The combined Et2O layers are dried over MgSO4, filtered and concentrated under a stream of N2 to give crude (R,S)-1-benzyl-3-[1'-(methylamino)ethyl]pyrrolidine: 1H NMR (300 MHz, CDCl3) δ 1.04 (d, J is 6 Hz, 3H), 1.52 (m, 1H), 1.93 (m, 1H), 2.17 (m, 1H), 2.25 (dd, J is 16, 8 Hz, 1H), 2.37 (s, 3H), 2.33-2.49 (m, 2H), 2.56 (dd, J is 15, 8 Hz, 1H), 2.77 (dd, J is 8, 8 Hz, 1H), 3.58 (d, J is 12.8 Hz, 1H), 3.60 (d, J is 12.8 Hz, 1H), 7.23-7.36 (m, 5H). This crude material is suitable for use in Step 5.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:29])[C:9]2[CH:28]=[CH:27][C:12]3[N:13]([CH3:26])[C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:30][C:31]1[CH:32]=[C:33]([S:37]([NH2:40])(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1>>[ClH:1].[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][NH:16][C:14]2[N:13]([CH3:26])[C:12]3[CH:27]=[CH:28][C:9]([N:8]([CH3:29])[C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:30][C:31]5[CH:32]=[C:33]([S:37]([NH2:40])(=[O:38])=[O:39])[CH:34]=[CH:35][CH:36]=5)[N:7]=4)=[CH:10][C:11]=3[N:15]=2)=[CH:19][CH:20]=1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: COc1ccc(CNc2nc3cc(N(C)c4ccnc(Cl)n4)ccc3n2C)cc1
Product: COc1ccc(CNc2nc3cc(N(C)c4ccnc(Nc5cccc(S(N)(=O)=O)c5)n4)ccc3n2C)cc1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example one with N5-(2-chloro-pyrimidin-4-yl)-N2-(4-methoxy-benzyl)-1,N5-dimethyl-1H-benzoimidazole-2,5-diamine (82 mg, 0.20 mmol) and 3-amino-benzenesulfonamide (34 mg, 0.20 mmol) as a white solid (83 mg, 72%). 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ10.28 (br s, 2H), 9.53 (br s, 1H), 8.44 (s, 1H), 7.91 (d, J=6.6 Hz, 1H), 7.73 (M, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.43 (d, J=8.4 Hz, 4H), 7.28-7.34 (m, 3H), 6.94 (d, J=8.4 Hz, 2H), 5.81 (m, 1H), 4.67 (d, J=5.7 Hz, 2H), 3.74 (s, 3H), 3.71 (s, 3H), 3.50 (s, 3H). MS (ESI) m/z=545 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[NH2:5].Cl.O1[CH2:17][CH2:16][O:15][CH2:14]C1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[N:20][N:19]=1>CO.CCOC(C)=O.N>[Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[NH:5][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:8][C:2]2[CH:3]=[CH:4][N:5]=[C:16]([O:15][CH3:14])[CH:17]=2)=[N:20][N:19]=1
Reactant: C1COCCO1
Reactant: CCc1ccc(N)cc1Br
Reactant: c1ccc2cnncc2c1
Agent: Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1ccc(Nc2nnc(Cc3ccnc(OC)c3)c3ccccc23)cc1Br
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Under N2-atmosphere, 0.73 g (3.7 mMol) 3-bromo-4-ethyl-aniline and 0.82 ml 4 N HCl/dioxane are added to 1.00 g (3.5 mMol) 1-chloro-4-[2-methoxy-pyridin-4-yl)methyl]phthalazine in 12 ml methanol, and the mixture is stirred for 2 h at 70° C. After cooling, the resulting yellow solution is diluted with EtOAc and 2.5% NH3 solution, and the aqueous phase is removed and extracted twice with EtOAct. The organic phases are washed with water and brine, dried (Na2SO4) and evaporated with a RE. After addition of DIPE to the residue, the title compound crystallizes out: M.p. 133-135° C.; FAB-MS: (M+H)+=449/451; HPLC(Grad20-100) tRet=11.4.
Reaction SMILES: [Br:1][C:2]1[C:7]([Br:8])=[CH:6][N:5]=[N:4][CH:3]=1.N1NC(=[O:15])C=CC=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[K+]>CN(C=O)C>[CH2:16]([N:4]1[C:3](=[O:15])[C:2]([Br:1])=[C:7]([Br:8])[CH:6]=[N:5]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Brc1cnncc1Br
Reactant: BrCc1ccccc1
Reactant: O=c1cccn[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=c1c(Br)c(Br)cnn1Cc1ccccc1
Temperature: 50 °C

Procedure:
A mixture of 4,5-dibromopyridazin-2H-pyridazin-3-one (10 g, 40 mmol), benzyl bromide (6.84 g, 40 mmol), 8N KOH (5 mL, 40 mmol) and DMF (40 mL) was warmed up to 50° C. and reacted for 0.5 hr. The mixture was cooled to r.t., poured over H20 (500 mL) and extracted twice with Et2O (200 mL). The combined organic layers were washed with brine, dried with MgSO4 and the solvent was removed in vacuo to give the title compound which was used for next step without further purification.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:34][C:35]1[S:36][CH:37]=[CH:38][CH:39]=1)[C:9]([N:11]1[CH2:16][CH2:15][C:14]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)([C:17](=[O:25])[NH:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:13][CH2:12]1)=[O:10])(C)(C)C.N1C=CC=CC=1S(Cl)(=O)=[O:48].C(N([CH:57]([CH3:59])C)CC)(C)C>ClCCCl>[CH:19]1([NH:18][C:17]([C:14]2([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:57](=[O:48])[CH3:59])=[CH:29][CH:28]=3)[CH2:13][CH2:12][N:11]([C:9](=[O:10])[CH:8]([NH2:7])[CH2:34][C:35]3[S:36][CH:37]=[CH:38][CH:39]=3)[CH2:16][CH2:15]2)=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)NC(Cc1cccs1)C(=O)N1CCC(Cc2ccc(N)cc2)(C(=O)NC2CCCCC2)CC1
Reactant: O=S(=O)(Cl)c1ccccn1
Solvent: ClCCCl
Product: CC(=O)Nc1ccc(CC2(C(=O)NC3CCCCC3)CCN(C(=O)C(N)Cc3cccs3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of {2-[4-(4-aminobenzyl)-4-cyclohexylcarbamoyl-piperidin-1-yl]-2-oxo-1-thiophen-2-ylmethyl-ethyl}-carbamic acid tert-butyl ester (0.352 mmol; 0.2 g) in 1,2-dichloroethane (5 mL) was added pyridine-2-sulfonyl chloride (0.422 mmol; 0.075 g) and N,N-diisopropyl-N-ethylamine (0.703 mmol; 0.123 mL) and the resulting solution was stirred for 3 hours at room temperature. The resulting mixture was evaporated and the residue was purified via reverse phase HPLC. The desired fractions were combined and lyophilized. The residue was dissolved in tetrahydrofuran (10 mL) and a 4N HCl in 1,4-dioxane solution (15 mL), and the resulting mixture was stirred for 6 hours at room temperature and evaporated. The residue was triturated with diethyl ether and dried under vacuum to yield 4-(4-acetylaminobenzyl)-1-(2-amino-3-thiophen-2-yl-propionyl)-piperidine-4-carboxylic acid cyclohexylamide as a hydrochloride salt.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:42][O:43][C:44]1[C:45]2[N:58]=[C:57]([NH2:59])[S:56][C:46]=2[C:47]([CH:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[N:48][CH:49]=1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:59][C:57]2[S:56][C:46]3[C:47]([CH:50]4[CH2:55][CH2:54][O:53][CH2:52][CH2:51]4)=[N:48][CH:49]=[C:44]([O:43][CH3:42])[C:45]=3[N:58]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: COc1cnc(C2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cnc(C2CCOCC2)c2sc(NC(=O)c3ccc(F)cc3)nc12
Reaction time: 6 h
Yield: 75.7 %

Procedure:
To a stirred solution of 42 mg (0.30 mmol) 4-fluoro-benzoic acid in 4 ml THF were added 126 mg (0.33 mmol) HATU and 0.066 ml (0.60 mmol) N-methylmorpholine and stirring continued at 50° C. for 6 h. 40 mg (0.15 mmol) 7-methoxy-4-(tetrahydro-pyran-4-yl)-thiazolo[5,4-c]pyridin-2-ylamine was then added and stirring continued at 50° C. for 16 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (ethyl acetate/heptane) followed by trituration in ether afforded 44 mg (75%) 4-fluoro-N-[7-methoxy-4-(tetrahydro-pyran-4-yl)-thiazolo[5,4-c]pyridin-2-yl]-benzamide as a white crystalline solid. ES-MS m/e (%): 388 (M+H+, 100).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C(=O)(O)[O-].[Na+].O>CO>[C:4]1([CH2:3][CH2:2][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCCc1ccccc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: c1ccc(CCn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(2-Bromoethyl)benzene (41.62 g, 0.225 mol) was added dropwise to a stirred mixture of imidazole (13.6 g, 0.2 mol) and sodium bicarbonate (16.8 g, 0.2 mol) in methanol (100 ml). Following the addition, the reaction mixture was stirred at ambient temperature for 24 h, and then stirred and heated under reflux for 6 h. After concentration of the reaction mixture under reduced pressure, the residue was treated with water (100 ml), and this mixture was extracted with chloroform (3×75 ml). The combined extracts were dried (magnesium sulphate), and the solution was then evaporated under reduced pressure. The resulting brown oil was distilled to afford 1-(2-phenylethyl)imidazole, b.p. 122°/0.2 mmHg. The slightly impure product was purified using a silica gel column and by elution with ethyl acetate/methanol (9:1). The product fractions were pooled, concentrated, under reduced pressure, and then distilled, to afford the pure product, b.p. 110°/0.1 mmHg.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][C@@H:30]1[CH3:35])([CH3:28])[CH3:27]>>[F:25][C:4]1[C:5]([CH3:24])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:32]4[CH2:33][CH2:34][N:29]([CH:26]([CH3:28])[CH3:27])[C@@H:30]([CH3:35])[CH2:31]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Reactant: CC(C)N1CCNC[C@@H]1C
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCN(C(C)C)[C@@H](C)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-1-isopropyl-2-methylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02-1.50 (m, 9 H) 2.33 (d, J=2.53 Hz, 3 H) 2.88-3.64 (m, 5 H) 3.89 (br. s., 2 H) 4.22-4.92 (m, 1 H) 7.53-7.69 (m, 1 H) 7.70-7.79 (m, 1 H) 7.84-8.79 (m, 4 H) 9.49-10.25 (m, 1 H). ESI-MS m/z [M+H]+ 463.3.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.[CH3:12][C:13]1([CH3:22])[C:15]2(CCC(C)=CC2)[O:14]1.[OH-:23].[Na+]>CO>[CH3:11][C:1]1[CH2:6][CH2:5][C:4]([C:13]([O:14][CH3:15])([CH3:22])[CH3:12])([OH:23])[CH2:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC1=CCC2(CC1)OC2(C)C
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: COC(C)(C)C1(O)CC=C(C)CC1
Reaction time: 2 h

Procedure:
To a stirred solution of 0.8 g of p-toluenesulfonic acid in 125 ml of methanol held at 3°-5° C. was added dropwise over 0.5 hour a solution of 15.2 g of 2,2,6-trimethyl-1-oxaspiro(2.5)oct-5-ene in 25 ml of methanol. After an additional 2 hours at 5° C. and 2 hours at 5°-20° C., the mixture was treated with 2 ml of 15% sodium hydroxide and concentrated at a water pump at below 60° C. The residue was dissolved in methylene chloride, washed, dried and Claisen-distilled to give 15.6 g of the desired product, b.p. 70° C. (0.2 mm).
Reaction SMILES: C(C1[N:8]=[C:7]2[N:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[NH:31][N:30]=[N:29][N:28]=4)=[CH:17][CH:16]=3)[C:10]([CH2:12][CH3:13])=[N:11][C:6]2=[C:5]([CH3:32])[CH:4]=1)#N.[Br-].[CH3:34][C:35]([OH:37])=O.[CH2:38]1COCC1>>[C:35]([C:34]1[N:8]=[C:7]2[N:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[NH:31][N:30]=[N:29][N:28]=4)=[CH:17][CH:16]=3)[C:10]([CH2:12][CH3:13])=[N:11][C:6]2=[C:5]([CH3:32])[CH:4]=1)(=[O:37])[CH3:38]
Reactant: CCc1nc2c(C)cc(C#N)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: C1CCOC1
Reactant: CC(=O)O
Agent: [Br-]
Product: CCc1nc2c(C)cc(C(C)=O)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
To 5-Cyano-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine (137 mg) at 0° C. in THF (5 mL) was added methylmagne slum bromide (0.70 mL, 3M/ether). After stirring for 6 hour, 10 % aqueous HOAc was added, the mixture was heated to 50° C. for 10 minutes then extracted w ith EtOAc. Purification (SiO2, 93/3/4 CH2Cl2 /MeOH/HOAc) gave 40 mg of the title compound. 1H NMR (300 MHz, CD3OD) 7.88 (s, 1H), 7.67-7.60 (m, 2 H), 7.58-7.50 (m, 2 H), 7.28-7.05 (AB quartet, 4H), 5.63 (s, 2H), 2.95 (q, 2H, J=7.5 Hz), 2.70 (s, 3H), 2.68 (s, 3H), 130 (t, 3H, J=7.5 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH2:13][N:14]([CH3:20])[C:15](=[N:18][CH3:19])SC)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:21]([NH:29][NH2:30])(=O)[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>C(O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH2:13][N:14]([CH3:20])[C:15]3[N:18]([CH3:19])[C:21]([C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)=[N:29][N:30]=3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNC(=O)c1ccncc1
Reactant: CN=C(SC)N(C)Cc1nc(-c2cccc(Cl)c2)no1
Solvent: CCO
Solvent: ClCCl
Product: CN(Cc1nc(-c2cccc(Cl)c2)no1)c1nnc(-c2ccncc2)n1C
Yield: 33.3 %

Procedure:
1-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-ylmethyl]-1,2,3-trimethyl-isothiourea (55 mg, 0.177 mmol) was mixed with isonicotinic hydrazide (29.1 mg, 0.212 mmol) in ethanol (1 mL) at 85° C. o.n. The reaction mixture was diluted with DCM and washed with water. The product was purified by column chromatography with 5˜7% MeOH in EA and triturated with Et2O to give the title compound (22.5 mg, 40%). 1H-NMR: 8.80 (d, 2H), 8.10 (s, 1H), 8.00 (d, 1H), 7.66 (d, 2H), 7.51 (d, 1H), 7.47(t, 1H), 4.80 (s, 2H), 3.74 (s, 3H), 3.15 (s, 3H).