Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[K+].O[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].O>CN(C)C=O.CCCCCC>[CH2:13]([O:1][C:10]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:11]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: O=Cc1ccccc1O
Reactant: [OH-]
Reactant: CCCCCCCCCCCCCCCBr
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCOc1ccc(C=O)cc1
Reaction time: 1 h

Procedure:
A 100-ml four-necked flask was used, 2.79 g (42.3 mM) of 85-percent by weight caustic potash was suspended in 30 ml of dimethylformamide, and 10 ml of dimethylformamide solution containing 5.28 g (43.2 mM) of hydroxybenzaldehyde was dropped thereto while being kept at 20° C. or lower. Thereafter, aging was performed at 30° C. for 1 hour. Subsequently, 9.58 g (32.9 mM) of 1-bromopentadecane was added and aging was performed at 70° C. for 21 hours. The reaction solution was dispersed into water, and extracted with toluene. After washing with water, concentration is performed so as to produce 11.03 g of slightly colored viscous liquid. Subsequently, a recrystallization treatment was performed with hexane so as to produce 8.91 g (purity 98.3%) of p-pentadecanoxybenzaldehyde.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10](Cl)(=[O:12])[CH3:11].[OH:14][CH:15]1[C:24]2[N:23]=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH2:18][CH:17]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH2:16]1>CN(C)C1C=CN=CC=1.ClCCl>[C:10]([O:14][C@@H:15]1[C:24]2[N:23]=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH2:18][C@H:17]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[CH2:16]1)(=[O:12])[CH3:11]
Reactant: COc1ccc(CC2Cc3cc(C)cnc3C(O)C2)cc1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C[C@H]2Cc3cc(C)cnc3[C@@H](OC(C)=O)C2)cc1
Reaction time: 8 h
Yield: 115 %

Procedure:
Diisopropylethylamine (0.51 g, 3.9 mmol), a catalytic amount of 4-dimethylaminopyridine and a solution of acetyl chloride (0.31 g, 3.9 mmol) in dichloromethane (5 ml) were added slowly to a solution of 5,6,7, 8-tetrahydro-8-hydroxy-6-((4-methoxyphenyl)methyl)-3-methylquinoline (1.12 g, 3.9 mmol) in dichloromethane (7 ml) at room temperature. The mixture was stirred overnight before further additions of acetyl chloride (0.32 g, 4 mmol) and diisopropylethylamine (0.51 g, 4 mnmol) were made. The mixture was again stirred overnight then diluted with dichloromethane (15 ml) and washed with water (1×15 ml), sodium hydrogen carbonate (1×15 ml), brine (1×15 ml) and water (1×15 ml). After drying (MgSO4) the reaction mixture was concentrated under reduced pressure to give an oil (1.46 g). This product was chromatographed on silica gel eluting with ethyl acetate/hexane (1:1) to give a fraction which on evaporation gave a solid (0.8 g). The solid was recrystallised from hexane to afford the title compound, (0.45 g), mp 113°-115° C., [α]D27 =+46° (1%CHCl3).
Reaction SMILES: Cl[C:2]1[N:10]([CH2:11][C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[C:14]#[N:15])[C:9]2[C:8](=[O:20])[N:7]([CH3:21])[C:6](=[O:22])[N:5]([CH3:23])[C:4]=2[N:3]=1.[C:24]([O:28][C:29]([NH:31][C@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29](=[O:30])[NH:31][CH:32]1[CH2:36][CH2:35][N:34]([C:2]2[N:10]([CH2:11][C:12]3[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=3[C:14]#[N:15])[C:9]3[C:8](=[O:20])[N:7]([CH3:21])[C:6](=[O:22])[N:5]([CH3:23])[C:4]=3[N:3]=2)[CH2:33]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2C#N)n(C)c1=O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Product: Cn1c(=O)c2c(nc(N3CCC(NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2C#N)n(C)c1=O

Procedure:
2-(8-Chloro-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl)benzonitrile (1A) (100 mg, 0.30 mmol) was reacted with (3S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (282 mg, 1.52 mmol), and purified as described in example 7, step A, to afford compound (8A) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)[CH:15]=3)[N:10]=[CH:9]2)[CH:7]=1.[CH:27]1[C:35]2[C:34]3[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=3[O:32][C:31]=2[C:30]([C:40](O)=[O:41])=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH:27]1[C:35]2[C:34]3[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=3[O:32][C:31]=2[C:30]([C:40]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([N:8]3[C:17](=[O:18])[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([N:19]5[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]5)[CH:15]=4)[N:10]=[CH:9]3)[CH:7]=2)=[O:41])=[CH:29][CH:28]=1
Reactant: O=C(O)c1cccc2c1oc1ccccc12
Reactant: Cc1ccc(N)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc3c2oc2ccccc23)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
A solution of 3-(5-amino-2-methylphenyl)-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one (0.165 g) in DMF (0.5 ml) was added to a stirred mixture of dibenzofuran-4-carboxylic acid (0.1 g), diisopropyethylamine (0.164 ml), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V) (0.214 g) and DMF (0.5 ml) and the reaction mixture was stirred at ambient temperature for 16 hours. The mixture was diluted with water and the resultant solid was isolated, washed in turn with water and diethyl ether and dried under vacuum at 55° C. There was thus obtained the title compound (0.228 g); NMR Spectrum: (DMSOd6) 2.07 (s, 3H), 2.25 (s, 3H), 2.5-3.3 (m, 8H), 7.55 (m, 7H), 7.83 (m, 4H), 8.12 (s, 1H), 8.21 (d, 1H), 8.34 (d, 1H), 10.59 (s, 1H); Mass Spectrum: M+H+ 544.
Reaction SMILES: IC1C=CC(C2NC([C@@H](N3C(=O)[C@@H](CCC(O)=O)NC3=O)C(C)C)=NC=2)=CC=1.C1(C[C@H]2NC(=O)[N:35]([C@H:39]([C:48]3[NH:49][C:50]([C:54]4[CH:59]=[CH:58][C:57]([I:60])=[CH:56][C:55]=4F)=[C:51](C)[N:52]=3)[C@H:40]([C:42]3C=CC=C[CH:43]=3)C)C2=O)CC1.C(O[C:68]([NH:70][C@H:71]([C:75]1[CH:80]=[CH:79][C:78]([O:81][CH2:82][C:83](=[O:87])N(C)C)=[CH:77][CH:76]=1)[C:72]([OH:74])=O)=[O:69])(C)(C)C.[Cl:88]N1C(=O)CCC1=O>>[Cl:88][C:55]1[CH:56]=[C:57]([I:60])[CH:58]=[CH:59][C:54]=1[C:50]1[NH:49][C:48]([C@@H:39]([N:35]2[C:72](=[O:74])[C@@H:71]([C:75]3[CH:76]=[CH:77][C:78]([O:81][CH2:82][CH2:83][OH:87])=[CH:79][CH:80]=3)[NH:70][C:68]2=[O:69])[CH2:40][CH2:42][CH3:43])=[N:52][CH:51]=1
Reactant: CN(C)C(=O)COc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1nc([C@H]([C@@H](C)c2ccccc2)N2C(=O)N[C@H](CC3CC3)C2=O)[nH]c1-c1ccc(I)cc1F
Agent: CC(C)[C@@H](c1ncc(-c2ccc(I)cc2)[nH]1)N1C(=O)N[C@H](CCC(=O)O)C1=O
Product: CCC[C@@H](c1ncc(-c2ccc(I)cc2Cl)[nH]1)N1C(=O)N[C@H](c2ccc(OCCO)cc2)C1=O

Procedure:
Prepared by the same method as described in example 1 except that (i) 2-chloro-1,4-diiodo-benzene was used in place of 2-fluoro-1,4-diiodo-benzene in step 80-A; (ii) (S)-2-tert-butoxycarbonylamino-pentanoic acid was used in place of (2S,3S)-2-tert-butoxycarbonylamino-3-phenyl-butyric acid in step 80-E; (iii) chlorination of the 5-position of the imidazole ring with N-chlorosuccinimide in step 80-F was omitted and (iv) removal of protecting groups and cyclization to form the hydantoin in step 80-H was performed as described in step 34-H. HR-MS: calcd for C24H24ClIN4O4 [M+H+] 595.0604. Found 595.0603.
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=1.C([Li])(C)(C)C.[Cl:13][C:14]1[CH:45]=[CH:44][C:17]([C:18]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]([CH3:30])[C:25](=[O:31])[CH:24]=[C:23]3[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Si:38]([CH3:41])([CH3:40])[CH3:39])[C:33]=2[C:42]#[CH:43])=[O:19])=[CH:16][CH:15]=1>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([OH:19])([C:4]2[N:3]([CH3:7])[C:2]([SH:1])=[N:6][CH:5]=2)[C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]([CH3:30])[C:25](=[O:31])[CH:24]=[C:23]3[C:32]2[CH:33]=[CH:42][CH:43]=[C:36]([C:35]#[C:34][Si:38]([CH3:41])([CH3:39])[CH3:40])[CH:37]=2)=[CH:44][CH:45]=1
Reactant: Cn1ccnc1S
Reactant: C#Cc1c(-c2cc(=O)n(C)c3ccc(C(=O)c4ccc(Cl)cc4)cc23)cccc1[Si](C)(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cn1c(C(O)(c2ccc(Cl)cc2)c2ccc3c(c2)c(-c2cccc(C#C[Si](C)(C)C)c2)cc(=O)n3C)cnc1S
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
2-Mercapto-1-methylimidazole (2.08 g, 18.2 mMol) was dissolved in anhydrous THF (200 mL) under an atmosphere of dry N2. The solution was cooled to −78° C. and a solution of tert-butyl lithium (1.7 M in pentane, 22 mL, 37 mMol) was added. The solution was then warmed to 0° C. After a yellow precipitate formed, the solution was cooled to −78° C. and a solution of 6-(4-chloro-benzoyl)-1-methyl-4-(3-trimethylsilanyl ethynyl-phenyl)-1H-quinolin-2-one (8.55 g, 18.2 mMol) in anhydrous THF (25 mL) was added. After 30 minutes, the solution was warmed to 0° C. and stirred at this temperature for 1 hour. The reaction mixture was then warmed to ambient temperature and stirred overnight. The reaction was quenched with 20 mL of saturated aqueous ammonium chloride (NH4Cl) and then partitioned between DCM and water. The DCM layer was dried over sodium sulfate (Na2SO4), filtered and concentrated under vacuum. The residue was chromatographed on flash silica gel eluting with a gradient from DCM to MeOH/DCM (3:97) to give 5.0 g of the titled compound as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[C:13]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:14]=1.C(O)C.O1CCCC1>ClCCl>[CH2:13]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2)[CH3:14]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CN1CCc2c(O)cccc2C1
Solvent: CCO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOc1cccc2c1CCN(C)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of 5-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (0.5 g, 3.07 mmol), triphenylphosphine (1.0 g, 3.83 mmol) and ethanol (0.27 mL, 4.61 mmol) in dry tetrahydrofurane 0.597 mL (3.83 mmol) diethyldiazodicarboxylate was added dropwise. After the reaction mixture was stirred at r.t. overnight, it was diluted with dichloromethane, washed with water, and the product was extracted into dilute aqueous hydrochloric acid solution, which was washed with dichloromethane. The aqueous phase was made alkaline with aqueous sodium hydroxide, and extracted with dichloromethane. The dichloromethane solution was dried over Na2SO4 and evaporated. The product was purified by silicagel chromathography (System E) and recrystallised from absolute ethanol. Yield 0.586 g, 48%. 1H NMR (CDCl3): 7.07 (1H, t, 8.1 Hz), 6.64 (2H, m), 4.01 (2H, q, 7.1 Hz), 3.55 (2H, s), 2.81 (2H, t, 6.1 Hz), 2.67 (2H, t, 6.1 Hz), 2.44 (3H, s), 1.40 (3H, t, 6.8 Hz). 13C NMR (CDCl3): 156.5, 135.9, 126.1, 123.0, 118.4, 108.3, 63.3, 57.9, 52.7, 46.0, 23.8, 14.9; MS (EI+): 191 (83%), 190 (100%), 162 (15%), 160 (16%), 148 (61%), 120 (28%), 104 (48%); Rt (HPLC)=8.1 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:13](Br)[CH:14]=[CH2:15]>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]([CH2:15][CH:14]=[CH2:13])([OH:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: C=CCBr
Product: C=CCC1(O)CCC(C(=O)OCC)CC1

Procedure:
The title compound is prepared from 4-oxo-cyclohexanecarboxylic acid ethyl ester and allyl bromide following a procedure analogous to that described in Step 1 of Intermediate 2. Yield: quantitative; Mass spectrum (ESI+): m/z=213 [M+H]+.
Reaction SMILES: C(O[C:4](=[O:31])[CH:5]([N:7]1[CH:11]=[C:10]([C:12]2[C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([OH:29])([C:25]([F:28])([F:27])[F:26])[C:16]=3[CH:15]=[C:14]([F:30])[CH:13]=2)[CH:9]=[N:8]1)[CH3:6])C.C=[O:33].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)[CH:54]=[O:55]>O1CCCC1>[F:30][C:14]1[CH:13]=[C:12]([C:10]2[CH:9]=[N:8][N:7]([C:5]([CH3:6])([CH2:54][OH:55])[C:4]([OH:31])=[O:33])[CH:11]=2)[C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([OH:29])([C:25]([F:27])([F:28])[F:26])[C:16]=2[CH:15]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)C(C)n1cc(-c2cc(F)cc3c2-c2ccccc2C3(O)C(F)(F)F)cn1
Reactant: C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(CO)(C(=O)O)n1cc(-c2cc(F)cc3c2-c2ccccc2C3(O)C(F)(F)F)cn1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a solution of an optically active form (27.9 g) of 2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propionic acid ethyl ester and paraformaldehyde (17.0 g) in dimethylformamide (100 ml) was added at room temperature a 1M solution (170 ml) of tetrabutylammonium fluoride in tetrahydrofuran, and the mixture was stirred at 100° C. for 6 hr. The reaction mixture was filtered through celite, and the solid was washed with ethyl acetate (100 ml). To the filtrate was added 1N hydrochloric acid (400 ml), and the mixture was extracted with ethyl acetate (100 ml). The separated aqueous layer was extracted twice with ethyl acetate (100 ml). The combined organic layer was successively washed once with 1N hydrochloric acid (100 ml), twice with brine (water/saturated brine=100 ml/10 ml) and once with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was azeotroped twice with toluene to give the title compound (26.6 g).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].Br[CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C([O-])([O-])=O.[K+].[K+]>CC#N.CCOC(C)=O>[C:7]([O:6][C:4](=[O:5])[C@H:3]([NH:2][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)(C)OC(=O)[C@H](N)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)CCCN[C@@H](C(=O)OC(C)(C)C)c1ccccc1
Temperature: 50 °C
Yield: 73.7 %

Procedure:
A mixture of (R)-tert-butyl 2-amino-2-phenylacetate hydrochloride (0.5 g, 2.051 mmol), ethyl 4-bromobutanoate (0.44 g, 2.26 mmol), and K2CO3 (1.13 g, 8.21 mmol) in CH3CN (10 mL) was heated to 50° C. for 40 hours. The mixture was diluted with EtOAc and then washed with H2O and brine. The organic was then dried (MgSO4), filtered and concentrated. Purification by chromatography (silica gel, 40% EtOAc in Hexanes) afforded 486 mg (74%) of the title compound. MS (ESI) m/z 322 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br>CC(C)=O>[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: BrCCCCCCBr
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(-c2ccc(OCCCCCCBr)cc2)cc1
Yield: 67 %

Procedure:
A mixture of 4'-hydroxy-4-cyanobiphenyl (7.8 g, 40 mmol), potassium carbonate (8.3 g, 60 mmol), 1,6-dibromohexane (29.8 g, 120 mmol), and acetone (80 milliliters ("mL")) was heated to reflux for 6 hours ("h") under a nitrogen atmosphere. The acetone was concentrated and the residue dissolved in ether-dichloromethane (4:1, 400 mL). The solution was filtered through glass fiber. The filtrate was washed with water and brine, dried over magnesium sulfate, and concentrated. Excess 1,6-dibromohexane was removed by Kugelrohr distillation up to 75° C. at 0.1 mm Hg. The material remaining in the pot was recrystallized from ethanol (100 mL), filtered while hot, and cooled in the freezer to give crystals of the 4'-(6-bromohexyloxy)-4-cyanobiphenyl (9.6 g, 67%): melting point ("mp") 65.5-66° C., nematic mesophase at 63° C. in cooling; NMR (CDCl3) 7.55(s, 4H), 7.49(d, 2H), 6.82(d, 2H), 3.91(t, 2H), 2.0-1.3(m, 8H); IR (CH2Cl2) 2222, 1602 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.O=[C:11]([CH2:17][C:18](=O)[CH3:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:17][C:18]([CH3:19])=[N:9]2)=[CH:4][CH:3]=1.[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:18]([CH3:19])=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: NNc1ccc(F)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(-c2ccc(F)cc2)n1
Product: CCOC(=O)c1cc(C)nn1-c1ccc(F)cc1

Procedure:
To ethanol (30 ml) were added 4-fluorophenylhydrazine (5 g) and ethyl 2,4-dioxovalerate (10.6 g) and the mixture was refluxed for 3 h. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (mobile phase: chloroform) to give ethyl 1-(4-fluorophenyl)-3-methylpyrazole-5-carboxylate (2 g) and ethyl 1-(4-fluorophenyl)-5-methylpyrazole-3-carboxylate (3 g).
Reaction SMILES: [CH3:1][C:2]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2=[C:17]3[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]3[C:8](=[O:19])[C:9]2=[O:18].[O:20]1CCOCC1.OO.S(=O)(=O)(O)O.[OH-:33].[Na+]>O>[CH3:1][C:2]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:9]([OH:18])=[O:33])=[C:17]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:8]([OH:19])=[O:20]
Reactant: C1COCCO1
Reactant: Cc1c2ccccc2c2c3c(cccc13)C(=O)C2=O
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: OO
Agent: [Na+]
Solvent: O
Product: Cc1c2ccccc2c(C(=O)O)c2c(C(=O)O)cccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1b (2.411 g, 9.79 mmol) was suspended in 34 mL of 2M NaOH(aq) and dioxane (169.5 mL) at 15° C. This suspension was then treated with 28.85 mL of 30% aqueous hydrogen peroxide solution at 15° C. (dropwise addition over 15 minutes) causing the orange suspension to immediately lighten to an off-white colour and some material dissolved to form a pale orange-yellow solution. This mixture was then stirred at room temperature for a period of 60 minutes at room temperature during which time most of the off-white solid dissolved to form a turbid orange-yellow solution. The reaction mixture was then diluted with 319 mL of de-ionised water and acidified with 10% aqueous sulfuric acid (to pH 1). This caused the solution to deepen to a red-orange colour and after about 5-10 minutes a red-orange precipitate started to very slowly deposit from the solution. The mixture was then stirred vigorously at room temperature overnight during which time additional precipitate deposited from solution. The solid in the suspension was then collected by filtration (porosity 3 sinter) and washed with 2×150 mL portions of de-ionised water and air-dried on the sinter for 30 minutes. The deep red-orange solid was then further dried in vacuo in a vacuum oven at a vacuum pressure of 0.1 torr for a period of 24 hours at 40 deg C. Yield: 2.202 g (80.25%, red-orange powder).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].Cl[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:25][C:26]3[CH:31]=[N:30][C:29]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:28][CH:27]=3)=[CH:21][CH:22]=2)[N:5]=1)[CH3:2]
Reactant: ClCc1ccc(-c2ccccc2)nc1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1nn(Cc2ccc(OCc3ccc(-c4ccccc4)nc3)cc2)cc1CCC(=O)O
Temperature: 80 °C
Reaction time: 5 h
Yield: 90.8 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]propionate (690 mg), 5-chloromethyl-2-phenylpyridine (470 mg), potassium carbonate (450 mg) and N,N-dimethylformamide (10 ml) was stirred at 80° C. for 5 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel chromatography to obtain a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). After a mixture of the resulting colorless oily substance, 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (5 ml) was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[4-(6-phenyl-3-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (900 mg, yield: 91%). This was recrystallized from acetone-hexane. Melting point: 140–141° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:33])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28]C=C(C(C)C)[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][OH:43])[CH2:37][CH2:36]1.C[C@H]1[N:50](C)[C@@H:49]([CH3:52])[CH2:48]N(CCO)C1.[ClH:56].CCOCC>CO>[ClH:1].[ClH:56].[CH:49]([N:50]1[CH:28]=[CH:29][C:24]([CH2:23][N:18]2[C:19]3[C:15](=[C:14]([NH:13][C:11]([C:8]4[N:5]5[CH:6]=[CH:7][C:2]([O:43][CH2:42][CH2:41][N:38]6[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]6)=[CH:3][C:4]5=[N:10][CH:9]=4)=[O:12])[CH:22]=[CH:21][CH:20]=3)[C:16]([CH3:33])=[N:17]2)=[N:25]1)([CH3:52])[CH3:48].[ClH:1]
Reactant: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(Cl)ccn34)c12
Reactant: CN1CCN(CCO)CC1
Reactant: C[C@@H]1CN(CCO)C[C@H](C)N1C
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Cc1nn(Cc2ccn(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(OCCN5CCN(C)CC5)ccn34)c12

Procedure:
Prepared according to Example 7, Step F, substituting 7-chloro-N-(1-((1-isopropyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide for 7-chloro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide and 2-(4-methylpiperazin-1-yl)ethanol for 2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)ethanol. The HCl salt was prepared by subjecting the compound to 4M HCl/ether (20 equivalents) in methanol and concentrating under reduced pressure to give the bis-HCl salt (45%). MS (APCI), positive scan, m/z=556.3 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:6][NH:5][C:4](=[O:7])[CH:3]1[O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:32]([O:34][C:35](=[O:38])[CH2:36]Br)[CH3:33].O>C1COCC1>[CH2:32]([O:34][C:35](=[O:38])[CH2:36][N:5]1[CH2:6][C:2]([CH3:21])([CH3:1])[CH:3]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:18])([F:20])[F:19])[CH:10]=2)[C:4]1=[O:7])[CH3:33]
Reactant: CCOC(=O)CBr
Reactant: CC1(C)CNC(=O)C1Oc1ccc(C#N)c(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CN1CC(C)(C)C(Oc2ccc(C#N)c(C(F)(F)F)c2)C1=O
Temperature: 25 °C

Procedure:
To a −78° C. stirring solution of 4-(4,4-Dimethyl-2-oxo-pyrrolidin-3-yloxy)-2-trifluoromethyl-benzonitrile (Compound (1), product of Example 3, Step E, 5.00 g, 16.8 mmoles) in 100 mL THF under a nitrogen atmosphere was added lithium bis(trimethylsilyl)amide (1 M in THF, 18.4 mL, 18.4 mmoles) and bromoacetic acid ethyl ester (2) (2.0 mL, 18.4 mmoles). The cooling bath was allowed to warm up to ambient temperature overnight. Water (25 mL) was added and the reaction mixture was concentrated in vacuo. Methylene chloride (100 mL) and water (50 mL) was added, the mixture is agitated and the layers are separated. The organic layer was concentrated in vacuo. The product (3) is used as is for the next reaction.