Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Mg+].[Br-].CCO[CH2:7][CH3:8].ClC1[C:11]2[N:12]([CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:18]=2)[CH:13]=[CH:14][N:15]=1.C1COCC1>CN1C(=O)CCC1>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:17]2[N:18]=[C:11]3[C:7]([CH3:8])=[N:15][CH:14]=[CH:13][N:12]3[CH:16]=2)=[CH:24][CH:23]=1
Reactant: Fc1ccc(-c2cn3ccnc(Cl)c3n2)cc1
Reactant: CCOCC
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: Cc1nccn2cc(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.1 %

Procedure:
A solution of 3M MeMgBr in Et2O (16.1 mL, 48.3 mmol) was added drop-wise to a mixture of 8-chloro-2-(4-fluorophenyl)-imidazo[1,2-a]pyrazine (10.0 g, 40.6 mmol), ferric acetylacetonate (0.71 g, 2.0 mmol), THF (240 mL), and NMP (23 mL) at about 0° C. The mixture was warmed to ambient temperature over about 1 hour. After about 1 hour, the reaction was cooled to about 0° C. and treated with additional 3M MeMgBr in Et2O (4 mL, 12 mmol). The mixture was allowed to warm to ambient temperature over about 1 h. After about an additional 1 h, the mixture was quenched with water and extracted with EtOAc. The organic layers were combined and dried with Na2SO4. After concentration, the crude material was purified by FCC on silica gel using EtOAc as an eluent to afford the expected product as an off-white solid (9.6 g, 100%): LC/MS (Table 1, Method b) Rt=1.8 min; MS m/z: 228.2 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].Cl[C:11]([C@:13]12[CH2:48][CH2:47][C@@H:46]([C:49]([CH3:51])=[CH2:50])[C@@H:14]1[C@@H:15]1[C@@:28]([CH3:31])([CH2:29][CH2:30]2)[C@@:27]2([CH3:32])[C@@H:18]([C@:19]3([CH3:45])[C@@H:24]([CH2:25][CH2:26]2)[C:23]([CH3:34])([CH3:33])[C:22]([C:35]2[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=2)=[CH:21][CH2:20]3)[CH2:17][CH2:16]1)=[O:12]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:9][O:8][C:6](=[O:7])[CH2:5][NH:4][CH2:3][CH2:2][NH:1][C:11]([C@:13]12[CH2:48][CH2:47][C@@H:46]([C:49]([CH3:51])=[CH2:50])[C@@H:14]1[C@@H:15]1[C@@:28]([CH3:31])([CH2:29][CH2:30]2)[C@@:27]2([CH3:32])[C@@H:18]([C@:19]3([CH3:45])[C@@H:24]([CH2:25][CH2:26]2)[C:23]([CH3:34])([CH3:33])[C:22]([C:35]2[CH:36]=[CH:37][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:43][CH:44]=2)=[CH:21][CH2:20]3)[CH2:17][CH2:16]1)=[O:12]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)Cl)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: COC(=O)CNCCN
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCNCC(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 20 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 2-(2-aminoethylamino)acetate (33.5 mg, 0.254 mmol), Hunig'sBase (0.089 mL, 0.507 mmol) and DMAP (20.66 mg, 0.169 mmol) in DCM (1.5 mL) was added methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(chlorocarbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (100 mg, 0.169 mmol) in DCM (1.5 mL). The reaction mixture was stirred at 20° C. for three hours. LCMS indicated the formation of desired product. The reaction mixture was quenched with distilled water, extracted with DCM (3×4 mL). All the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound as a white solid (90 mg, 76%). LCMS: m/e 713.45 (M−H)−, 2.75 min (method 1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:19][C:20]3[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=3)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:7][N:8]2[C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH2:17][CH3:18])[CH:15]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:38])C(=O)C1>C(Cl)(Cl)(Cl)Cl.O>[Br:38][C:7]1[N:8]([C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH2:17][CH3:18])[CH:15]=2)[C:9]2[C:5]([C:6]=1[S:19][C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2
Reactant: CCCn1cc(-n2cc(Sc3cccc(C(=O)OCC)c3)c3ccc(Cl)cc32)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCCn1cc(-n2c(Br)c(Sc3cccc(C(=O)OCC)c3)c3ccc(Cl)cc32)cn1
Reaction time: 12 h
Yield: 48.2 %

Procedure:
To a stirred solution of compound 3 (100 mg, 0.22 mmol) in CCl4 (10 mL) was added NBS (44.85 mg, 0.25 mmol) at RT under inert atmosphere and stirred for 12 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated under reduced pressure to obtain the crude. This was purified by silica gel column chromatography using 10-15% EtOAc/Hexanes to afford compound 4 (55 mg, 47%) as an off-white solid. 1H NMR (500 MHz, CDCl3): δ 7.90 (s, 1H), 7.78-7.77 (m, 1H), 7.68 (s, 1H), 7.66 (s, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.25-7.24 (m, 2H), 7.20 (s, 1H), 7.14 (d, J=8.5 Hz, 1H), 4.35 (q, J=7.0 Hz, 2H), 4.20 (t, J=7.5 Hz, 2H), 2.03-1.98 (m, 2H), 1.35 (t, J=7.0 Hz, 3H), 1.01 (t, J=7.5 Hz, 3H); LC-MS (ESI): 93.3%; m/z 520.8 (M++2); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 5.02 min; 5 mM NH4OAc: ACN; 0.8 mL/min).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][C:10]#[CH:11].[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:40])[C:18]=1[CH2:19][C:20]1[C:29]2[C:24](=[C:25](OS(C(F)(F)F)(=O)=O)[C:26]([O:30][CH3:31])=[CH:27][CH:28]=2)[CH:23]=[N:22][N:21]=1.C(NCC)C>C(OCC)C.[Cu]I>[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:40])[C:18]=1[CH2:19][C:20]1[C:29]2[C:24](=[C:25]([C:11]#[C:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=2)[CH:23]=[N:22][N:21]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1OS(=O)(=O)C(F)(F)F
Reactant: C#CCOCCOCCOC
Agent: [Cu]I
Solvent: CCNCC
Solvent: CCOCC
Product: COCCOCCOCC#Cc1c(OC)ccc2c(Cc3c(Cl)cncc3Cl)nncc12
Yield: 46.2 %

Procedure:
A suspension under N2 of 3-[2-(2-methoxy-ethoxy)-ethoxy]-propyne (810 mg, 5.12 mmoles), prepared as described in example 133, trifluoro-methanesulfonic acid 1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazin-5-yl ester (2 g, 4.27 mmoles), prepared as described in example 73, and diethylamine (40 ml) was added under stirring with bis(triphenylphosphine)PdCl2 (60 mg, 0.085 mmole) and CuI (16.18 mg, 0.085 mmole). The mixture was refluxed for 6 hours, then dried. The residue was flash chromatographed (eluent: ethyl acetate) to give a solid which was taken up in ethyl ether, filtered and dried under vacuum, at 40° C. to give 940 mg of the title compound (yield: 46%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([N:7](CC2C=CC(OC)=CC=2OC)[S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3I)=[C:13]([C:26]#[N:27])[CH:12]=2)(=[O:10])=[O:9])=[N:4][CH:3]=1.[NH2:39][C:40]1[CH:45]=[CH:44][C:43](B2OC(C)(C)C(C)(C)O2)=[CH:42][N:41]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[NH2:39][C:40]1[N:41]=[CH:42][C:43]([C:19]2[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=2[O:17][C:14]2[CH:15]=[CH:16][C:11]([S:8]([NH:7][C:5]3[S:6][C:2]([Cl:1])=[CH:3][N:4]=3)(=[O:9])=[O:10])=[CH:12][C:13]=2[C:26]#[N:27])=[CH:44][CH:45]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: COc1ccc(CN(c2ncc(Cl)s2)S(=O)(=O)c2ccc(Oc3ccc(F)cc3I)c(C#N)c2)c(OC)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: N#Cc1cc(S(=O)(=O)Nc2ncc(Cl)s2)ccc1Oc1ccc(F)cc1-c1ccc(N)nc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
Example 587 from above can be prepared as follows. N-(5-Chloro-1,3-thiazol-2-yl)-3-cyano-N-(2,4-dimethoxybenzyl)-4-(4-fluoro-2-iodophenoxy)benzenesulfonamide (Preparation 217, 100 mg, 0.146 mmol), 2-aminopyridine-5-boronic acid pinacol ester (35.4 mg, 0.161 mmol), palladium (0) tetrakis(triphenylphoshine) (17.3 mg, 0.015 mmol) and caesium carbonate (143 mg, 0.438 mmol) were charged to a 25 ml round-bottomed flask and purged with nitrogen (×3). To this was added fresh degassed 1,4-dioxane (4 ml) and fresh degassed water (1 ml) and the vessel was heated to 60° C. and stirred for 16 hours. The solvent was removed in vacuo and the residue was dissolved in methanol (2 ml) before loading on to a ISOLUTE™ SCX-2 cartridge (2 g). The cartridge was washed with methanol (50 ml) followed by ammonia (2 M in methanol, 50 ml). The basic washes were concentrated in vacuo and the residue was dissolved in dichloromethane (10 ml). To this solution was added trifluoroacetic acid (1 ml) and the solution stirred at room temperature for 18 hours before concentrating in vacuo. The residue was dissolved in methanol (2 ml) and loaded on to a ISOLUTE™ PE-AX cartridge (5 g). The cartridge was washed with methanol (3 column volumes) followed by formic acid (2% solution in methanol, 3 column volumes). The acidic washes were concentrated in vacuo to afford a sticky yellow solid which was triturated in dichloromethane to afford the title compound as a white solid.
Reaction SMILES: [C:1]([CH:5]1[CH2:9][N:8]([CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[CH2:6]1)(OC)=[O:2].C(Cl)(Cl)Cl.C(O)C>C(O)C.[Ni]>[OH:2][CH2:1][CH:5]1[CH2:9][N:8]([CH:10]([CH3:11])[CH3:12])[C:7](=[O:13])[CH2:6]1
Reactant: COC(=O)C1CC(=O)N(C(C)C)C1
Agent: [Ni]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CC(C)N1CC(CO)CC1=O
Reaction time: 24 h

Procedure:
92.5 g (0.5 mol) of 4-carbomethoxy-1-isopropyl-pyrrolidone in 1.2 l of ethanol were hydrogenated in the presence of about 50 g of Raney-Nickel for 48 hours at 160° - 180° C under a hydrogen pressure of 200 atmospheres. Then it was determined with the aid of thin layer chromatography (CHCl3 /C2H5OH= 95:5) if the reduction was finished. Otherwise 20 g of Raney-Nickel were added again and hydrogenated for another 24 hours. In most of the tests hydrogenation had finished after this time.
Reaction SMILES: [CH2:1]([C:3]1([CH2:25][CH3:26])[CH2:12][CH:11]([CH2:13][CH2:14][S:15]([NH:18][CH2:19][C:20]([O:22]C)=[O:21])(=[O:17])=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:24])[CH:9]=2)[O:4]1)[CH3:2].[OH-].[K+]>>[CH2:25]([C:3]1([CH2:1][CH3:2])[CH2:12][CH:11]([CH2:13][CH2:14][S:15]([NH:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:17])=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:24])[CH:9]=2)[O:4]1)[CH3:26]
Reactant: CCC1(CC)CC(CCS(=O)(=O)NCC(=O)OC)c2cc(C)ccc2O1
Agent: [K+]
Agent: [OH-]
Product: CCC1(CC)CC(CCS(=O)(=O)NCC(=O)O)c2cc(C)ccc2O1
Yield: 92.6 %

Procedure:
By hydrolysis of 1.0 g (2.6 mmol) of methyl [(2,2-diethyl-6-methylchroman-4-yl)ethylsulfonylamino]acetate with 0.44 g (7.8 mmol) of KOH analogously to Example 2a, 0.89 g of [(2,2-diethyl-6-methylchroman-4-yl)ethylsulfonylamino]acetic acid is obtained.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:9]([NH2:10])=[CH:8][C:7]2[O:11][CH2:12][CH2:13][O:14][C:6]=2[CH:5]=1.[CH:16]([NH2:18])=O>>[CH2:13]1[CH2:12][O:11][C:7]2[CH:8]=[C:9]3[C:4]([C:3](=[O:2])[NH:18][CH:16]=[N:10]3)=[CH:5][C:6]=2[O:14]1
Reactant: NC=O
Reactant: COC(=O)c1cc2c(cc1N)OCCO2
Product: O=c1[nH]cnc2cc3c(cc12)OCCO3

Procedure:
A mixture of 2.0 g. of 6-amino-3,4-ethylenedioxybenzoic acid methyl ester and 6 ml. of 99% formamide is refluxed for 1.5 hours, then cooled, diluted with 5 ml. of water and the resulting precipitate filtered off, water washed and dried to obtain 6,7-ethylenedioxyquinazolin-4(3H)-one, m.p. 275° C.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH2:4][C:5](=[CH2:9])[C:6]([OH:8])=[O:7].[C:14]([OH:17])(=[S:16])[CH3:15]>>[C:14]([S:16][CH2:9][CH:5]([CH2:4][C:3]1[CH:10]=[CH:11][CH:12]=[CH:13][C:2]=1[CH3:1])[C:6]([OH:8])=[O:7])(=[O:17])[CH3:15]
Reactant: C=C(Cc1ccccc1C)C(=O)O
Reactant: CC(O)=S
Product: CC(=O)SCC(Cc1ccccc1C)C(=O)O
Reaction time: 72 h

Procedure:
To the acid from Step 3 (11.4 g, 65 mmol) add thioacetic acid (9.8 g, 129 mmol). After 3 days, concentrate, treat with toluene, and concentrate again to obtain a solid. Recrystallize from CH2Cl2 :hexane to obtain the title compound, m.p. 63°-70°.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:3]=1[CH:21]([CH2:26][CH2:27][CH3:28])[C:22]([O:24]C)=[O:23].[OH-].[Li+].Cl>O1CCOCC1.O>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:3]=1[CH:21]([CH2:26][CH2:27][CH3:28])[C:22]([OH:24])=[O:23]
Reactant: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Temperature: 60 °C
Yield: 40.5 %

Procedure:
To a solution of methyl [2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate (0.100 g; 0.254 mmol) in a mixture of dioxane (5 mL) and water (1.3 mL) was added a 1N lithium hydroxide solution (2.55 mL; 2.55 mmol). The reaction mixture was heated at 60° C. for 8 h. After cooling to room temperature, the reaction mixture was acidified with 1N HCl (pH˜2) and partially concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulphatesulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.039 g (40%) of the title compound as a white solid.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[F:13][C:14]([F:35])([F:34])[C:15]1[CH:16]=[C:17]([S:21][CH2:22][CH2:23][CH2:24][C:25]2[N:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([OH:29])=O)[CH:18]=[CH:19][CH:20]=1.[NH2:36][CH2:37][C:38]1[S:39][CH:40]=[CH:41][CH:42]=1>C(Cl)Cl>[S:39]1[CH:40]=[CH:41][CH:42]=[C:38]1[CH2:37][NH:36][C:27]([C:26]1[C:25]([CH2:24][CH2:23][CH2:22][S:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:13])([F:35])[F:34])[CH:16]=2)=[N:33][CH:32]=[CH:31][CH:30]=1)=[O:29]
Reactant: O=C(O)c1cccnc1CCCSc1cccc(C(F)(F)F)c1
Reactant: NCc1cccs1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(NCc1cccs1)c1cccnc1CCCSc1cccc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
91 mg (0.6 mmol) of CDI were added to a solution of 240 mg (0.7 mmol) of 2-(3-(3-(trifluoromethyl)phenylthio)propyl)nicotinic acid (VB004) in DCM (7 ml), and stirring was carried out for 30 min at RT. 79 mg (0.7 mmol) of 2-(aminomethyl)thiophene were then added and stirring was carried out for a further 5 d at RT. The mixture was then washed with a 4M aq. NH4Cl sol. (2×10 ml) and a 1M NaHCO3 sol. (2×10 ml). The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by means of CC (EA), yielding 134 mg (0.3 mmol, 44%). MS: m/z 437.1 [m+H]+.
Reaction SMILES: N1C=CC=N1.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([CH3:18])[CH:17]=1)[C:11]([O:13]C)=O.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:11]([C:10]2[CH:15]=[C:16]([CH3:18])[CH:17]=[C:8]([O:7][CH3:6])[CH:9]=2)=[O:13])=[CH:22][N:21]=1
Reactant: COC(=O)c1cc(C)cc(OC)c1
Reactant: Cc1ccc(Cl)nc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Agent: c1cn[nH]c1
Product: COc1cc(C)cc(C(=O)Cc2ccc(Cl)nc2)c1

Procedure:
For the synthesis of the pyrazole derivative, first, as illustrated in Reaction Scheme 10, methyl 3-methoxy-5-methylbenzoate of Formula 2a is allowed to undergo a nucleophilic attack at its carboxylic carbon by the activated methylene group of 2-chloro-5-methylpyridine in the presence of lithium hexamethyldisilazide to afford 2-(2-chloropyridin-5-yl)-1-(3-methoxy-5-methylphenyl)ethanone, represented by Formula 28. The compound of Formula 28 is converted into a pyrazole derivative through two successive steps. In this regard, the ethanone compound of Formula 28 is heated with N,N-dimethylformamide dimethylacetal, successively followed by cyclization with hydrazine hydrate into 4-(2-chloropyridin-5-yl)-3-(3-methoxy-5-methylphenyl)-1H-pyrazol, represented by Formula 29. The reaction of the pyrazole compound of Formula 29 with iodoacetonitrile in the presence of potassium carbonate produces two regioisomers 4-(2-chloropyridin-5-yl)-3-(3-methoxy-5-methylphenyl)-1H-pyrazol-1-yl)acetonitrile, represented by Formula 30, and 4-(2-chloropyridin-5-yl)-5-(3-methoxy-5-methylphenyl)-1H-pyrazol-1-yl)acetonitrile, represented by Formula 31. In the presence of a palladium catalyst, the regioisomers of Formulas 31 and 32 are subjected to nucleophilic substitution with various arylboronic acids to synthesize various compounds represented by Formulas 32a-c and 33a-c. Finally, these compounds are demethylated with boron trifluoride dimethyl sulfide to synthesize target pyrazole derivatives of Formulas 34a-c and 35a-c.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:56])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH2:52][OH:53])[CH:46]([O:54][CH3:55])[CH2:45]2)[CH:7]([CH3:57])[CH:6]([O:58][Si:59]([C:62]([CH3:65])([CH3:64])[CH3:63])([CH3:61])[CH3:60])[CH2:5][C:4]1=[O:66])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1.FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:56])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH2:52][O:53][CH2:71][C:72]3[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=3)[CH:46]([O:54][CH3:55])[CH2:45]2)[CH:7]([CH3:57])[CH:6]([O:58][Si:59]([C:62]([CH3:63])([CH3:64])[CH3:65])([CH3:61])[CH3:60])[CH2:5][C:4]1=[O:66])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCCO)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCCOCc4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2-hydroxyethoxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (41.7 mg in 0.6 ml 33% methylene chloride in cyclohexane), benzyl trichloroacetimidate (15.8 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 7 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×5 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate: hexane (1:3)+1% methanol) gave the title compound (24 mg). (1H NMR was consistent with the desired structure).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[CH:7]=1.[CH:22]([N:25]([C:33]1[S:34][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:36][N:37]=1)[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:24])[CH3:23].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C(O)C.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>[C:28]([O:27][C:26]([N:25]([CH:22]([CH3:24])[CH3:23])[C:33]1[S:34][C:35]([C:2]2[CH:3]=[C:4]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]3[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=3)[CH:7]=2)=[CH:36][N:37]=1)=[O:32])([CH3:31])([CH3:30])[CH3:29]
Reactant: CCOC(=O)c1cn2cc(Br)cc(-c3ccccc3)c2n1
Reactant: CC(C)N(C(=O)OC(C)(C)C)c1ncc(B2OC(C)(C)C(C)(C)O2)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cn2cc(-c3cnc(N(C(=O)OC(C)(C)C)C(C)C)s3)cc(-c3ccccc3)c2n1
Temperature: 80 °C
Yield: 51 %

Procedure:
A solution of ethyl 6-bromo-8-phenylimidazo[1,2-a]pyridine-2-carboxylate (0.10 g, 0.29 mmol) and tert-butyl isopropyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)carbamate (0.128 g, 0.34 mmol) in toluene (3 mL) and ethanol (1 mL) was bubbled nitrogen for 20 mins. The mixture was then treated with Pd(PPh3)4 (30 mg, 0.026 mmol) and K3PO4 (2 M, 1 mL, 2 mmol) and heated at 80° C. overnight. The reaction was cooled, poured into ethyl acetate (200 mL), washed with brine, separated, and concentrated. The residue was purified by column chromatography on silica gel using ethyl acetate in hexanes (10-50%) as eluent. The product containing fractions were concentrated to give 75 mg (53% yield) of ethyl 6-(2-(tert-butoxycarbonyl-(isopropyl)amino)thiazol-5-yl)-8-phenylimidazo[1,2-a]pyridine-2-carboxylate as a white solid. LCMS (Conditions C): 4.30 min (RT); (M+H)+=507.38 (100%).
Reaction SMILES: [NH2:1][C:2]([CH:4]1[C:13](=[O:14])[NH:12][C:11]2[N:10]=[C:9]([C:15]3[C:20]([O:21]CC4C=CC(OC)=CC=4)=[CH:19][CH:18]=[CH:17][C:16]=3[O:31][CH2:32][CH:33]3[CH2:35][CH2:34]3)[CH:8]=[C:7]([CH:36]3[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]3)[C:6]=2[CH2:5]1)=[O:3].[ClH:49]>O1CCOCC1>[ClH:49].[CH:33]1([CH2:32][O:31][C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([OH:21])[C:15]=2[C:9]2[N:10]=[C:11]3[C:6]([CH2:5][CH:4]([C:2]([NH2:1])=[O:3])[C:13](=[O:14])[NH:12]3)=[C:7]([CH:36]3[CH2:37][CH2:38][NH:39][CH2:40][CH2:41]3)[CH:8]=2)[CH2:34][CH2:35]1
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCN(C(=O)OC(C)(C)C)CC3)c3c(n2)NC(=O)C(C(N)=O)C3)cc1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)C1Cc2c(C3CCNCC3)cc(-c3c(O)cccc3OCC3CC3)nc2NC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a stirred solution of tert-butyl 4-(6-(aminocarbonyl)-2-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)-1-piperidinecarboxylate (0.120 g, 0.187 mmol) in 1,4-dioxane (3 mL) was added 4N HCl in dioxane (1 mL). The mixture was stirred at room temperature for 2 hrs. The resulted precipitate was collected by filtration, washed with acetonitrile, and dried under reduced pressure to give 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(4-piperidinyl)-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxamide hydrochloride. (0.080 g, yield 90%)
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[N:8]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]#[N:20])=[CH:11][CH:10]=2)[C:7]([S:21][CH2:22][C:23]([NH:25][CH2:26][C:27]([O:29]CC)=[O:28])=[O:24])=[N:6][CH:5]=1.C1COCC1.O.Cl>O>[Br:3][C:4]1[N:8]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]#[N:20])=[CH:11][CH:10]=2)[C:7]([S:21][CH2:22][C:23]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:24])=[N:6][CH:5]=1
Reactant: CCOC(=O)CNC(=O)CSc1ncc(Br)n1-c1ccc(C#N)c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(-n2c(Br)cnc2SCC(=O)NCC(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.8 %

Procedure:
Aqueous lithium hydroxide solution (1M, 0.47 ml, 0.473 mmol) was added to a solution of ethyl 2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)acetate (112 mg, 0.237 mmol) in 3:1, THF/water (0.95 mL) and stirred for 18 h at room temperature. After concentrating, the crude reaction mixture was acidified with aqueous HCl solution (1M 1.2 mL), diluted with water (10 mL), stirred to break up solids, and filtered to afford 2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)acetic acid as an off-white solid (99 mg, 94%).