Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:19]2[C:14]([CH:15]=[N:16][C:17]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)=[CH:23][CH:22]=3)=[N:18]2)=[CH:13][CH:12]=1)C.[OH-].[Li+].CO>O>[CH3:33][N:30]1[CH2:29][CH2:28][N:27]([C:24]2[CH:23]=[CH:22][C:21]([NH:20][C:17]3[N:16]=[CH:15][C:14]4=[CH:13][CH:12]=[C:11]([C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[C:4]([OH:34])=[O:3])[N:19]4[N:18]=3)=[CH:26][CH:25]=2)[CH2:32][CH2:31]1
Reactant: CCOC(=O)c1ccccc1-c1ccc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nn12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5ccccc5C(=O)O)n4n3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
Into a 8-dram vial, 2-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-benzoic acid ethyl ester (0.250 g, 0.548 mmol), Lithium hydroxide (0.0262 g, 1.10 mmol), Methanol (15 mg), and Water (3.0 mL) were added. The reaction mixture was stirred at room temperature overnight. The solvent was removed under vacuum. The solid was acidified with 1N HCl. The reaction was partitioned DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum to give 2-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-benzoic acid as a solid (180 mg, 76%). The solid was used as is without further purification.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[C:13]1([CH:19]([NH2:21])[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[O:11]=[C:4]1[CH:5]([C:8]([OH:9])=[O:10])[CH2:7][CH2:6][N:21]1[CH:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:20]
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: CC(N)c1ccccc1
Solvent: CCO
Product: CC(c1ccccc1)N1CCC(C(=O)O)C1=O
Yield: 89.2 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g, 1.47 mmol) and 1-phenylethanamine (0.568 mL; 4.41 mmol) in ethanol (3 mL). 2-oxo-1-(1-phenylethyl)pyrrolidine-3-carboxylic acid 0.306 g (89%) was obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:17]([CH3:18])=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][N:8]=2)=[C:4]([Cl:19])[CH:3]=1>CCOC(C)=O.[Pt]>[Br:1][C:2]1[C:17]([CH3:18])=[CH:16][C:5]([O:6][C:7]2[N:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=2)=[C:4]([Cl:19])[CH:3]=1
Reactant: Cc1cc(Oc2ccc([N+](=O)[O-])cn2)c(Cl)cc1Br
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2ccc(N)cn2)c(Cl)cc1Br
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To a solution of 2-(4-bromo-2-chloro-5-methylphenoxy)-5-nitropyridine (10.0 g) in AcOEt (150 mL) was added 5% Pt/C (1.00 g) at 0° C. After stirring at room temperature for 5 hours under a hydrogen atmosphere, the reaction mixture was filtered off using celite, and the filtrate was concentrated under reduced pressure to give 6-(4-bromo-2-chloro-5-methyl-phenoxy)pyridin-3-amine as a pink solid (9.13 g).
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:20]=3[CH:21]=2)=[O:16])[CH2:9]1.[N+](C1C=CC([O:36][C:37](=O)[NH:38][C:39]2[CH:44]=[CH:43][C:42]([N:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]3=[O:51])=[CH:41][C:40]=2[F:52])=CC=1)([O-])=O>>[F:52][C:40]1[CH:41]=[C:42]([N:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]2=[O:51])[CH:43]=[CH:44][C:39]=1[NH:38][C:37]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:20]=3[CH:21]=2)=[O:16])[CH2:9]1)=[O:36]
Reactant: O=C(NC[C@H]1CCNC1)c1cc2cc(Cl)ccc2o1
Reactant: O=C(Nc1ccc(-n2ccccc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@H]1CCN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C1)c1cc2cc(Cl)ccc2o1

Procedure:
67.3 Using general method H, 5-chloro-benzofuran-2-carboxylic acid ((S)-1-pyrrolidin-3-ylmethyl)-amide trifluoro acetate was reacted with [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester (prepared according to example 54.3) to give (R)-3-{[(5-chloro-benzofuran-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. Pale yellow solid. MS 507.0 ([M−H]−)
Reaction SMILES: [OH:1][C:2]1[C:11]([CH:12]=[O:13])=[C:10]([OH:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[I-].[Na+].Br[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].Cl>O.CN(C)C=O>[CH:12]([C:11]1[C:2]([OH:1])=[C:3]([C:4]([O:6][CH3:7])=[O:5])[CH:8]=[CH:9][C:10]=1[O:14][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:13]
Reactant: CCOC(=O)CCCCBr
Reactant: COC(=O)c1ccc(O)c(C=O)c1O
Agent: Cl
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCOc1ccc(C(=O)OC)c(O)c1C=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.9 %

Procedure:
Methyl 2,4-dihydroxy-3-formylbenzoate (10.0 g, 0.051 M) was added to dimethylformamide (100 ml), then to this mixture was added sodium hydride (1.344 g, 0.056 M), portionwise. The mixture became warm and effervescence occurred. When the addition was complete the reaction mixture was left to stir at room temperature for 10 minutes. To this solution was then added sodium iodide (0.765 g), ethyl 5-bromovalerate (11.7 g, 0.056 M), and a further 20 ml of dimethylformamide. The whole was brought to 60° C. and left to stir for 5 days. The reaction mixture was cooled, poured into water (200 ml), acidified with concentrated hydrochloric acid, and extracted into ethyl acetate (2×75 ml). The combined organic layers were washed with water (2×75 ml), 5% sodium hydroxide solution (50 ml), water (50 ml) and brine (50 ml), dried (magnesium sulphate), filtered and the solvent removed in vacuo to give ethyl 5-(2-formyl-3-hydroxy-4-methoxycarbonylphenoxy)pentanoate 6.92 g, 42% as a yellow oil, purified by column chromatography and obtained as a pale-yellow solid.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:10]([C:11]([F:14])([F:13])[F:12])[CH2:9][N:8]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:7]1)=[O:5])C.[Li+].[OH-].Cl>C1COCC1.O.C(Cl)Cl>[C:18]([O:17][C:15]([N:8]1[CH2:9][CH:10]([C:11]([F:14])([F:12])[F:13])[CH:6]([C:4]([OH:5])=[O:3])[CH2:7]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CC1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(C(=O)O)C(C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.3 %

Procedure:
107.2 (3RS,4SR)-4-Trifluoromethyl-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (9.76 g) was dissolved in THF/water (1:1 10 ml) and LiOH (0.826 g) was added to the emulsion. The mixture was stirred for 18 h at 25° C. The reaction mixture was then diluted with CH2Cl2 (50 ml) and treated with HCl (1N, 20 ml). The aqueous phase was extracted twice with CH2Cl2 (20 ml) and the combined organic layers were dried over Na2SO4, filtered and evaporated to dryness to yield (3RS,4SR)-4-trifluoromethyl-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (5.8 g) as light yellow solid. MS 284.3 ([M+H]+).
Reaction SMILES: Cl[C:2]1[O:3][CH:4]=[C:5]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[CH2:22][O:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[O:8])[N:6]=1.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[C:31]1([NH:30][C:2]2[O:3][CH:4]=[C:5]([C:7]([N:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]3[CH2:22][O:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[O:8])[N:6]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2coc(Cl)n2)C(COc2cccnc2)C1
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2coc(Nc3ccccc3)n2)C(COc2cccnc2)C1
Temperature: 25 °C
Yield: 48.8 %

Procedure:
A solution of tert-butyl 4-(2-chlorooxazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (117 mg, 0.277 mmol), aniline (51 mg, 0.554 mmol) and potassium carbonate (76 mg, 0.554 mmol) in THF (2 mL) was heated to 70° C. overnight. Upon cooling to rt, the reaction mixture was filtered and concentrated under reduced pressure. The material was purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient), yielding 64.8 mg (40%) of the title compound as the TFA salt. LC-MS: RT=6.72 min, [M+H]+=480.0.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1)[CH2:3][OH:4].[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.Cl>N1C=CC=CC=1>[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29]([O:4][CH2:3][C:2]([CH3:22])([CH3:1])[CH2:5][O:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:9]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(CO)COCc1ccc(F)c(Oc2ccccc2)c1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(C)(C)COCc2ccc(F)c(Oc3ccccc3)c2)cc1
Temperature: 20 °C
Reaction time: 24 h
Yield: 53.1 %

Procedure:
A mixture of 2,2-dimethyl-3-(4-fluoro-3-phenoxybenzyloxy)propan-1-ol (5 g), p-toluenesulphonyl chloride (3.75 g) and pyridine (10 cm3) was stirred at the ambient temperature (ca. 20° C.) for 24 hours. The mixture was poured into dilute aqueous hydrochloric acid solution and hhe aqueous mixture extracted with ethyl acetate (3×250 cm3). The combined organic layers were washed with brine, then dried over anhydrous magnesium sulphate. Evaporation of the solvent under reduced pressure gave a dark oil (4 g) which was purified by column chromatography on a silica gel support, eluting with petroleum ether (boiling range (60°-80° C.) containing 20% by volume ethyl acetate, to give the title compound (3.9 g) as a yellow oil.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]1[CH:10]=[C:9]([S:11](=[O:20])(=[O:19])[NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:7]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:6]=1)C>[OH-].[Na+]>[NH:21]([C:8]1[C:9]([S:11](=[O:20])(=[O:19])[NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][C:5]([C:4]([OH:36])=[O:3])=[CH:6][C:7]=1[NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cc(NCc2ccccc2)c(Nc2ccccc2)c(S(=O)(=O)Nc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(NCc2ccccc2)c(Nc2ccccc2)c(S(=O)(=O)Nc2ccccc2)c1

Procedure:
A solution of ethyl-4-anilino-3-benzylamino-5-phenylsulphamyl-benzoate (3 g) in 1N sodium hydroxide (30 ml) was heated on a steam bath for 1 hour. The 4-anilino-3-benzylamino-5-phenylsulphamyl-benzoic acid was precipitated by addition of 4N hydrochloric acid until pH 2, and recrystallized from acetone-water and 80% ethanol in water; the melting point was 243°C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([OH:11])=[CH:4][CH:3]=1.[C:12]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:12][O:11][C:5]1[C:6]([N+:8]([O-:10])=[O:9])=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(O)c([N+](=O)[O-])n1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(C)nc1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
Commercially available 6-Methyl-2-nitro-pyridin-3-ol (Aldrich) (5.09 g, 33 mmol) in acetone (50 mL) was treated with K2CO3 (5.47 g, 39.6 mmol) and MeI (3.09 mL, 49.5 mmol). The orange suspension was heated to 50° C. for 90 hours. After evaporation of the solvent in vacuo the crude mixture was treated with 1N NaOH (50 mL) and extracted with EtOAc (2×50 mL) the combined organic phases was washed with brine (2×50 mL), dried over Na2SO4, filtered and concentrated in vacuo. 3-Methoxy-6-methyl-2-nitro-pyridine was obtained as a yellow solid.
Reaction SMILES: [NH:1]1[C:5](=O)[CH2:4][CH2:3][C:2]1=[O:7].Br[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1>>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][CH:5]1[NH:1][C:2](=[O:7])[CH2:3][CH2:4]1
Reactant: BrCc1ccccn1
Reactant: O=C1CCC(=O)N1
Product: O=C1CCC(Cc2ccccn2)N1

Procedure:
5-(Pyridin-2-ylmethyl)pyrrolidin-2-one is synthesized from pyrrolidine-2,5-dione and 2-(bromomethyl)pyridine according to S. Lebrun et al. (Tetrahedron Asymmetry 2003, 14, 2625-2632).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([NH:5][CH2:6][CH2:7][O:8][CH2:9][C:10]#[C:11][CH2:12][C:13]1[C:14](=[O:27])[NH:15][C:16](=[O:26])[N:17]([CH:25]=1)[C@@H:18]1[O:24][C@H:21]([CH2:22][OH:23])[CH2:20][CH2:19]1)=[O:4].O=P(Cl)(Cl)Cl.[P:35](OC)([O:39]C)([O:37]C)=[O:36]>>[P:35]([O:23][CH2:22][C@H:21]1[O:24][C@@H:18]([N:17]2[CH:25]=[C:13]([CH2:12][C:11]#[C:10][CH2:9][O:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[C:2]([F:28])([F:1])[F:29])[C:14](=[O:27])[NH:15][C:16]2=[O:26])[CH2:19][CH2:20]1)([OH:39])([OH:37])=[O:36]
Reactant: O=C(NCCOCC#CCc1cn([C@H]2CC[C@@H](CO)O2)c(=O)[nH]c1=O)C(F)(F)F
Reactant: COP(=O)(OC)OC
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(NCCOCC#CCc1cn([C@H]2CC[C@@H](COP(=O)(O)O)O2)c(=O)[nH]c1=O)C(F)(F)F
Reaction time: 2.5 h

Procedure:
To a solution of 5 (30 mg, 0.0738 mmol) in P(O)(OCH3)3 (0.5 mL) was treated with POCl3 (70 μL, 0.73 mmol) at 0° C., followed by stirring at r.t for 2-3 h and then evaporating solvent under reduced pressure and purification by preparative reverse phase HPLC to afford the corresponding mono phosphate 6. 31P NMR (CD3OD, 121.4 MHz) δ 0.79 (s); 19F NMR (CDCl3, 282.2 MHz) δ −77.37 (s, CF3). To a dried solution of 6 in DMF (1 mL) were added 1,1′-carbonyldiimidazole (CDI, 33 mg, 0.21 mmol), followed by stirring at r.t. for 5 h and then quenching with MeOH (8 μL, 0.21 mmol). A solution of tetrabutylammonium pyrophosphate (TBAPP, 143.0 mg, 0.33 mmol) and tributyl amine (0.15 mL, 0.66 mmol) in DMF (1.5 mL) was added to the above solution at r.t under Ar, followed by stirring overnight and then quenched with 2.0 M TEAB. After evaporating solvent, the organic residue was purified by preparative reverse phase HPLC with 100 mM TEAA/AcCN (0 to 50% gradient) to give the corresponding triphosphate 7. 1H NMR (D2O, 300 MHz) δ 7.74 (s, 1H, H6), 5.95 (dd, 1H, H1′, J=3.3 and 6.3 Hz), 4.29-4.20 (m, 1H, H4′), 4.18-4.07 (m, 3H, CH2 and H5′), 4.02-3.92 (m, 1H, H5′), 3.58 (t, 2H, CH2, J=5.1 Hz), 3.38 (t, 2H, CH2, J=5.1 Hz), 3.20 (s, 2H, CH2), 2.35-2.22 (m, 1H, H2′), 2.10-1.92 (m, 3H, H2′ and 2H3′). 31P NMR (D2O, 121.4 MHz) δ −10.52 (d, J=19.2 Hz), −10.95 (d, J=20.3 Hz), −22.96 (t, J=20.3 Hz); 19F NMR (D2O, 282.2 MHz) δ −76.37 (s, CF3). Removal of trifluro acetate (TFA) protecting group was accomplished by treatment with NH4OH (33%, 500 μL) at 60° C. for 20 min and then at r.t for 1 h to give the corresponding triphosphate 8 (17 mM, 500 μL).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH2:25]([C:27]1[CH:31]=[C:30]([C:32](O)=[O:33])[N:29]([CH3:35])[N:28]=1)[CH3:26].S(Cl)(Cl)=O>CN(C)C=O.CN(C)C(=O)C>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([F:24])=[C:2]([NH:1][C:32]([C:30]5[N:29]([CH3:35])[N:28]=[C:27]([CH2:25][CH3:26])[CH:31]=5)=[O:33])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: CCc1cc(C(=O)O)n(C)n1
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)n(C)n1
Yield: 55.2 %

Procedure:
Using N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (327 mg, 1.0 mmol), 3-ethyl-1-methyl-1H-pyrazole-5-carboxylic acid (170 mg, 1.1 mmol) tetrahydrofuran (2.0 mL), N,N-dimethylformamide (1 drop), thionyl chloride (0.08 mL, 1.1 mmol) and N,N-dimethylacetamide (6.0 mL), and by a reaction in the same manner as in Example 203, the title compound (256 mg, 55%) was obtained as colorless crystals. melting point 236° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)[C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)O1.[Br:37][C:38]1[CH:43]=[CH:42][C:41](I)=[CH:40][CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:37][C:38]1[CH:43]=[CH:42][C:41]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]([C:29]4[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=4)[C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)=[CH:40][CH:39]=1
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)cc1
Reactant: Brc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(-c3ccc(-c4ccc(Br)cc4)cc3)cc2)cc1
Temperature: 95 °C
Yield: 69.9 %

Procedure:
A mixture of compound 8 (3.0 g, 6.3 mmol), 1-bromo-4-iodobenzene (3.57 g, 12.6 mmol), Pd(PPh3)4 and potassium carbonate (1.74 g, 12.6 mmol) in dioxane/water (40 ml/8 ml) was degassed and heated at 95° C. for 24 hours. After being cooled to RT, yellow solid precipitated and collected by filtration. The solid was recrystallized in dichloromethane/methanol to give a pale yellow solid (2.22 g). The filtrate was loaded on silica gel and purified by flash column to give additional amount of yellow solid 9 (0.42 g). Total amount is 2.64 g, in 83% yield.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][CH2:4][C:5]1[N:6]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)[CH:7]=[CH:8][N:9]=1.[CH2:20]([C:22]1[NH:26][C:25](=[O:27])[NH:24][C:23]=1C(O)=O)[CH3:21]>>[CH2:20]([C:22]1[NH:26][C:25](=[O:27])[NH:24][C:23]=1[C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([N:6]2[CH:7]=[CH:8][N:9]=[C:5]2[CH2:4][CH2:3][CH:2]([CH3:1])[CH3:19])=[CH:18][CH:17]=1)[CH3:21]
Reactant: CCc1[nH]c(=O)[nH]c1C(=O)O
Reactant: CC(C)CCc1nccn1-c1ccc(C(=O)O)cc1
Product: CCc1[nH]c(=O)[nH]c1C(=O)c1ccc(-n2ccnc2CCC(C)C)cc1

Procedure:
In a manner similar to that described in Example I react 4-[2-(3-methylbutyl)-1H-imidazol-1-yl]benzoic acid and 5-ethyl-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylic acid to produce the title compound which can be purified by chromatography of the crude base on silica gel.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[C:12]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][CH:15]=[C:14](B(O)O)[CH:13]=1.C([O-])([O-])=O.[K+].[K+].COCCOC>O>[C:12]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:17]=[CH:16][CH:15]=[C:14]([C:2]2[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=2)[CH:13]=1
Reactant: CC(C)(C)c1ccnc(Br)c1
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)c1ccnc(-c2cccc(-c3ccccc3)c2)c1
Yield: 8.9 %

Procedure:
15.0 g (0.7 mol) of 2-bromo-4-tert-butyl-pyridine was added to 13.8 g (0.7 mol) of 3-biphenylboronic acid, 2.4 g (0.002 mol) of Pd(Ph3)4, 26 g (0.188 mol) of K2CO3, 100 mL of DME and 100 mL of water. The reaction mixture was refluxed for 20 hours and separated on silica gel column with 10% ethyl acetate in hexane. ˜18.0 g (˜90% yield) 2-(biphenyl-3-yl)-4-tert-butylpyridine was obtained. MS confirmed the desired product.
Reaction SMILES: [Si]([O:8][CH:9]1[C:17]2[C:12](=[CH:13][C:14]([F:18])=[CH:15][CH:16]=2)/[C:11](=[CH:19]/[C:20]([NH2:22])=[O:21])/[CH2:10]1)(C(C)(C)C)(C)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[F:18][C:14]1[CH:13]=[C:12]2[C:17]([CH:9]([OH:8])[CH2:10]/[C:11]/2=[CH:19]\[C:20]([NH2:22])=[O:21])=[CH:16][CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)OC1C/C(=C\C(N)=O)c2cc(F)ccc21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: NC(=O)/C=C1\CC(O)c2ccc(F)cc21
Yield: 62.1 %

Procedure:
A solution of (E)-2-(3-((tert-butyldimethylsilyl)oxy)-6-fluoro-1-indanylidene) acetamide (1.80 g, 5.6 mmoles) and pyridinium p-toluenesulfonate (0.85 g, 3.4 mmoles, Aldrich) in ethanol (65 mL) was heated at 55°-68° C. for 3.5 hours under a nitrogen atmosphere and evaporated in vacuo. The residue was dissolved in ethyl acetate (150 mL) and washed successively with water (2×150 mL) and brine (150 mL), dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate, gradually increasing the polarity to ethyl acetate: ethanol (95:5). The fractions containing the major spot were combined and evaporated in vacuo, and the residue was dried in a vacuum at 80° C. for 18 hours to give 0.72 g (62%) of (E)-2-(6-fluoro-3-hydroxy-1-indanylidene)acetamide as a white solid, mp 166°-168° C.;
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]([NH:12][C:13](=[O:16])[CH2:14]Cl)([CH3:11])[CH2:9][OH:10])[CH:7]=1.[K].CCSC([N:24]([CH2:29][CH:30]([CH3:32])[CH3:31])CC(C)C)=O>[Pd]>[C:29](=[N:24][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2([CH3:11])[NH:12][C:13](=[O:16])[CH2:14][O:10][CH2:9]2)[CH:7]=1)([C:30]1[CH:31]=[CH:11][CH:8]=[CH:9][CH:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(CO)(NC(=O)CCl)c1cc(Br)ccc1F
Reactant: CCSC(=O)N(CC(C)C)CC(C)C
Agent: [Pd]
Agent: [K]
Product: CC1(c2cc(N=C(c3ccccc3)c3ccccc3)ccc2F)COCC(=O)N1

Procedure:
In a reaction sequence analogous to that described for the preparation of the optically active Building block H, the cyclization of the (RS)-N-[1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide with potassium tent-butylate, followed by the palladium-catalyzed amination yielded the (RS)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-methyl-morpholin-3-one. Its reaction with Lawesson's reagent and the following treatment with hydrochloric acid yielded the title compound as a light yellow solid. Mass (calculated) C11H13FN2OS.ClH [276.762]; (found) [M+H]+=241.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14](O)=[O:15])[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[Cl-].[NH4+].C([N:33](C(C)C)C(C)C)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[C:14]([NH2:33])=[O:15])[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a turbid solution of 1 g (2.47 mMol) (−)-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid in 15 ml N,N-dimethyl formamide were added 0.264 g (4.94 mmol) ammonium chloride, 0.42 ml (2.47 mmol) ethyl diisopropylamine, 0.378 g (2.47 mmol) N-hydroxybenzotriazole monohydrate and 0.947 g (4.94 mmol) N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride. The reaction mixture is stirred for 14 h at room temperature and then poured onto water. The phases were separated and the aqueous phase extracted three times with ethyl acetate. The combined organic layers were twice washed with water, once with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with ethyl acetate. Colorless solid (93%). MS (Turbo Spray): m/z=404.3 [M+H].