Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]([C:10]([NH:12][CH:13]3[CH:22](O)[CH2:21][CH2:20][C:15]4([O:19][CH2:18][CH2:17][O:16]4)[CH2:14]3)=[O:11])=[CH:8][C:7]=2[F:26])[CH2:3][CH2:2]1.C(N(CC)CC)C.O>CS(C)=O>[CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]([C:10]3[O:11][C:22]4[CH2:21][CH2:20][C:15]5([O:16][CH2:17][CH2:18][O:19]5)[CH2:14][C:13]=4[N:12]=3)=[CH:8][C:7]=2[F:26])[CH2:3][CH2:2]1
Reactant: O=C(NC1CC2(CCC1O)OCCO2)c1ccc(OCC2CC2)c(F)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: Fc1cc(-c2nc3c(o2)CCC2(C3)OCCO2)ccc1OCC1CC1
Reaction time: 1 h
Yield: 44.7 %

Procedure:
To a solution of 4-(cyclopropylmethoxy)-3-fluoro-N-(8-hydroxy-1,4-dioxaspiro[4.5]dec-7-yl)benzamide (14.2 g) in dimethyl sulfoxide (100 mL) were added triethylamine (16.3 mL) and sulfur trioxide-pyridine complex (18.6 g), and the mixture was stirred for 1 hr under a nitrogen stream. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the obtained residue in THF (100 mL) was added (methoxycarbonylsulfamoyl)triethylammonium hydroxide inner salt (14.0 g), and the mixture was stirred at 60° C. for 1 hr. To the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and subjected to silica gel column chromatography (NH, ethyl acetate). The solvent was evaporated, and the obtained solid was washed with diethyl ether to give the title compound (6.00 g).
Reaction SMILES: [C:1]([O:20][CH2:21][CH:22]([O:25][CH2:26][C:27](OC(C)(C)C)=[O:28])[CH:23]=[CH2:24])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C.Cl>C(Cl)Cl>[C:1]([O:20][CH2:21][CH:22]([O:25][CH2:26][CH:27]=[O:28])[CH:23]=[CH2:24])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCC(=O)OC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: ClCCl
Product: C=CC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCC=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Crude mixture from Step 4-(3) (tert-butyl 2-((1-(trityloxy)but-3-en-2-yl)oxy)acetate 3.01 kg, 6.771 mol, 1.00 equiv.) was dissolved in CH2Cl2 (5.81 L). The reaction mixture was cooled down to −78° C. DIBAL (1.5 M in toluene, 4.14 L, 6.19 mol, 1.00 equiv.) was added in portions while maintaining temperature below −65° C. The reaction was stirred at −78° C. for additional 30 min. Aq. HCl (4.00 L, 2.0 M) was added slowly to the reaction mixture while maintaining temperature below −60° C. The reaction was then warmed up to 16.8° C. Aq. HCl (2.0 M, 3.50 L) was added slowly to the reaction mixture. The organic phase was extracted then successively washed with aq. HCl (1M, 7.50 L) and 10% aq.NaHCO3 (3.75 L). The organic phase was was taken to the next step as a crude solution (11.48 kg). 1H NMR (500 MHz, DMSO) δ ppm 9.62 (s, 1H), 7.43 (dd, J=8.3, 0.9 Hz, 6H), 7.32 (dd, J=13.5, 5.6 Hz, 6H), 7.25 (t, J=7.3 Hz, 3H), 5.81-5.70 (m, 1H), 5.30 (dd, J=17.3, 1.0 Hz, 1H), 5.24 (dd, J=10.4, 0.8 Hz, 1H), 4.19 (q, J=18.2 Hz, 2H), 4.05 (dd, J=11.4, 6.2 Hz, 1H), 3.16 (dd, J=9.7, 6.3 Hz, 1H), 3.05 (dd, J=9.7, 4.4 Hz, 1H); 13C NMR (125 MHz, DMSO) δ ppm 201.70, 144.14, 135.92, 128.75, 128.32, 127.48, 119.01, 86.55, 80.79, 74.60, 66.57.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:13]N(C)C=O.C(=O)([O-])[O-].[K+].[K+].CI>C(Cl)Cl.C(OCC)(=O)C>[CH3:13][O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CN(C)C=O
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CI
Solvent: CCOC(C)=O
Product: COc1ccc([N+](=O)[O-])c(C=O)c1
Temperature: 23 °C
Reaction time: 10 h

Procedure:
5-Hydroxy-2-nitrobenzaldehyde (25.0 g, 150 mmol) was dissolved in N,N-dimethylformamide (200 mL, 2000 mmol), followed by potassium carbonate (20.7 g, 150 mmol) and methyl iodide (10.2 mL, 164 mmol). The reaction mixture was stirred for 10 hours at 23° C. Ethyl acetate (1000 mL) was added, and the mixture was washed with water and brine. Organic layer was dried over sodium sulfate. Removal of solvent gave a crude solid product, which was treated with DCM and hexanes. The solid was collected and washed with hexanes (27.0 g, 100%). 1H NMR (CHLOROFORM-d) δ: 10.50 (s, 1H), 8.18 (d, J=9.0 Hz, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.16 (dd, J=9.2, 2.9 Hz, 1H), 3.97 (s, 3H). MS (M+1): 182.10.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:5][CH:4]=1)=O.[CH3:19][CH:20]1[CH2:24][CH2:23][CH2:22][NH:21]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C1COCC1>[CH3:19][CH:20]1[CH2:24][CH2:23][CH2:22][N:21]1[CH2:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:5][CH:4]=1
Reactant: CC1CCCN1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC1CCCN1Cc1ccc(CCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.1 %

Procedure:
To a solution of tert-butyl 2-(4-formylphenyl)ethylcarbamate (3.0 g, 12.0 mmol), 2-methylpyrrolidine (1.44 ml, 14.4 mmol) and acetic acid (1.4 ml, 24.0 mmol) in THF (100 ml) was added sodium triacetoxyborohydride (5.1 g, 24.0 mmol), and the mixture was stirred at room temperature for 16 hrs. 10% Sodium hydrogencarbonate solution (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 ml). The extract was washed with saturated brine, and dried over magnesium sulfate, and solvent was evaporated under reduced pressure. The residue was purified by alumina column chromatography (developing solvent; hexane:ethyl acetate=4:1) to give the title compound (3.10 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:19])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[C:8]([C:13]([O:15]CC)=[O:14])=[C:7]2[OH:18].C1COCC1.[Li+].[OH-]>CO.C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH3:19])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:13]([OH:15])=[O:14])=[C:7]2[OH:18]
Reactant: CCOC(=O)c1c(O)c2cc(C)cc(F)c2[nH]c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(F)c2ncc(C(=O)O)c(O)c2c1
Temperature: 40 °C
Yield: 91.6 %

Procedure:
To a solution of ethyl 8-fluoro-4-hydroxy-6-methylquinolone-3-carboxylate (0.50 g) in 30 mL of 1:1 MeOH:THF is added 8 mL of 1M LiOH. The reaction is maintained at 40° C. overnight. The reaction mixture is cooled to room temperature, then diluted with 20 mL glacial acetic acid. The resulting precipitate is collected, washed with H2O, and dried to yield 0.382 g of 8-fluoro-4-hydroxy-6-methyl-3-quinolinecarboxylic acid as a white solid. To a solution of this acid (0.23 g) and 4-chlorophenylhydrazine (0.21 g) in 10 mL DMF is added triethylamine (0.16 m), EDC (0.24 g), and HOBt (0.16 g). The mixture is stirred at room temperature for 3 days. Upon diluting the reaction mixture with 100 mL H2O, an orange solid precipitates. The crude product is adsorbed onto silica and chromatographed eluting with 4% MeOH in CHCl2. Fractions homogenous by TLC are condensed and recrystallized from EtOAc/hexanes to yield 0.0181 g of the desired product as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:12]4[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][C:13]=4[N:14]=[CH:15][N:16]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[C:29]([C:33]1[O:37][N:36]=[C:35]([NH:38][C:39](=O)[O:40]C2C=CC=CC=2)[CH:34]=1)([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[C:29]([C:33]1[O:37][N:36]=[C:35]([NH:38][C:39]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([O:10][C:11]4[C:12]5[CH2:19][NH:18][CH2:17][C:13]=5[N:14]=[CH:15][N:16]=4)=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[O:40])[CH:34]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)no1
Reactant: CC(C)(C)OC(=O)N1Cc2ncnc(Oc3ccc4[nH]ccc4c3)c2C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)n2ccc3cc(Oc4ncnc5c4CNC5)ccc32)no1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Tert-butyl 4-(1H-indol-5-yloxy)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (127 mg, 0.360 mmol) is dissolved in THF (8 mL), flushed with nitrogen and cooled to 0° C. Sodium hydride (23 mg, 0.575 mmol, 60% in mineral oil) is added and the mixture is stirred for 10 minutes. Phenyl 5-tert-butylisoxazol-3-ylcarbamate (140 mg, 0.538 mmol) is added neat and the reaction is allowed to stir at room temperature overnight. The reaction is cooled in an ice bath and quenched with a saturated solution of ammonium chloride (100 mL). The mixture is then diluted with ethyl acetate and the product is extracted (2×100 mL EtOAc). The organic layers are combined, dried and concentrated to a brown oil that is dissolved in 10 mL of DCM and cooled in an ice bath and 10 mL of TFA is added. Following completion of the reaction the DCM and TFA are removed and ethyl acetate is added to the residue along with ammonium hydroxide to quench the remaining TFA. The mixture is diluted with water and extracted with ethyl acetate (2×50 mL). The organic layers are removed, dried, and concentrated. The residue is absorbed onto silica and separated via FCC (0-6% Methanol/DCM) to obtain N-(5-tert-butylisoxazol-3-yl)-5-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-1H-indole-1-carboxamide. MS (ESI) m/z 419.2 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.56 (s, 1H) 8.29 (d, J=8.84 Hz, 1H) 8.17 (d, J=3.79 Hz, 1H) 7.47 (d, J=2.27 Hz, 1H) 7.15 (dd, J=8.97, 2.40 Hz, 1H) 6.76 (d, J=3.28 Hz, 1H) 6.68 (s, 1H) 4.07-4.14 (m, 4H) 1.34 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([NH:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:9]=[CH:10][CH:11]=1.[F:24][C:25]([F:32])([F:31])[CH2:26][S:27](Cl)(=[O:29])=[O:28].C(=O)([O-])[O-].[K+].[K+]>ClCCCl.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([N:12]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[S:27]([CH2:26][C:25]([F:32])([F:31])[F:24])(=[O:29])=[O:28])[CH:9]=[CH:10][CH:11]=1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: COc1ccccc1Oc1cccc(NCc2cccnc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: c1ccncc1
Product: COc1ccccc1Oc1cccc(N(Cc2cccnc2)S(=O)(=O)CC(F)(F)F)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
The resultant N-(3-(2-methoxyphenoxy)phenyl)pyrid-3-ylmethylamine was dissolved in 2:1 1,2-dichloroethane/pyridine (6 mL) under nitrogen, cooled (5° C.), and treated with 2,2,2-trifluoroethylsulfonyl chloride (300 mg, 1.64 mmol). After one hour at 5° C., the mixture was allowed to warm to room temperature and stirred for 18 h. The product mixture was treated with anhydrous potassium carbonate (500 mg), stirred 30 min, filtered, and the filtrate concentrated in vacuo. The residue was chromatographed on silica gel (eluted with 2:1 dichloromethane/ethyl acetate) to afford the title compound (226 mg, 50%) as a viscous pale amber oil. The hydrochloride salt was obtained by treatment of this material in methanol with ethereal HCl. 1H NMR: 8.49 (d,1H,J=4 Hz), 8.29 (s,1H), 7.60-7.65 (m,1H), 7.20-7.25 (m,2H), 7.10-7.20 (m,1H), 6.97 (d,1H,J=8 Hz), 6.90 (m,2H), 6.80-6.85 (m,2H), 6.76 (m,1H), 4.82 (s,2H), 3.70-3.85 (m,2H), 3.75 (s,3H). MS calcd. 452.4; MS (M+1) 453.3
Reaction SMILES: CN([CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]([CH3:13])[CH:6]=1)C.CI.[CH2:16]=[CH:17][CH:18]=[CH2:19]>C(OCC)(=O)C>[CH3:13][C:7]1[C:8](=[O:12])[C:9]([CH3:11])=[CH:10][C:5]2([CH2:19][CH2:18][CH:17]=[CH:16][CH2:4]2)[CH:6]=1
Reactant: Cc1cc(CN(C)C)cc(C)c1O
Reactant: C=CC=C
Solvent: CCOC(C)=O
Solvent: CI
Product: CC1=CC2(C=C(C)C1=O)CC=CCC2
Temperature: 120 °C
Yield: 87.6 %

Procedure:
To a 250 mL glass reaction vessel containing an ethyl acetate (120 mLs) solution of N,N-dimethyl,2,6-dimethyl-4-aminomethylphenol (3.58 g; 20 mmols), there was added methyl iodide (20 mmols) to give a colorless slurry. The reaction vessel was sealed and 1,3-butadiene (100 mmols) was introduced into the system. The reaction mixture was heated to 120° C. and the pressure was increased from atmospheric up to 70 psig. The reaction mixture was maintained at these conditions for approximately 16 hours. The reaction vessel was then cooled to room temperature. After cooling, the reaction mixture was filtered to remove ammonium iodide salt by-product. The filtrate was concentrated to afford a viscous oil which was crystallized from ethanol to give 3.3 g of 2,4-dimethylspiro[5.5]undeca-1,4,8-trien-3-one (84% yield by vapor phase chromatography).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:35][CH2:36][CH3:37])=[C:8]([N:10]=[C:11]2[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14](=[O:23])[C:13](=[C:24]3[N:28]([CH2:29]C)[C:27]4[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=4[S:25]3)[S:12]2)[CH:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO.C1COCC1>[CH2:16]([N:15]1[C:14](=[O:23])[C:13](=[C:24]2[N:28]([CH3:29])[C:27]3[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=3[S:25]2)[S:12][C:11]1=[N:10][C:8]1[CH:9]=[C:4]([CH:1]([OH:3])[CH3:2])[CH:5]=[CH:6][C:7]=1[NH:35][CH2:36][CH3:37])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCNc1ccc(C(C)=O)cc1N=C1SC(=C2Sc3ccccc3N2CC)C(=O)N1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCNc1ccc(C(C)O)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
The product of Example 38 was reduced with sodium borohydride in 1:1 MeOH/THF and chromatographed (TEA-washed silica gel, 0-10% MeOH/DCM) to afford the title compound. 1H-NMR (CDCl3): δ 7.47-7.54 (3H, m), 7.28-7.37 (4H, m), 7.17 (1H, m), 6.99-7.06 (3H, m), 6.57 (1H, d), 5.19 (2H, s), 4.80 (1H, q), 3.76 (3H, s), 3.01 (2H, q), 1.48 (3H, d), 1.04 (3H, s); MS(ESI): 517 (MH+).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]5[CH:24]=[N:23][CH:22]=[C:21]([CH:25]6[CH2:27][CH2:26]6)[N:20]=5)[CH:17]=4)[N:12](S(C4C=CC(C)=CC=4)(=O)=O)[CH:11]=3)[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[OH-].[Na+].[Na+].[Cl-]>O1CCOCC1.CCOC(C)=O>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]5[CH:24]=[N:23][CH:22]=[C:21]([CH:25]6[CH2:27][CH2:26]6)[N:20]=5)[CH:17]=4)[NH:12][CH:11]=3)[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(C4CC4)n3)c3cc(-c4cncc(C5CC5)n4)ccc32)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: c1cc2[nH]cc(-c3cncc(C4CC4)n3)c2cc1-c1cncc(C2CC2)n1
Temperature: 120 °C
Yield: 50 %

Procedure:
A glass microwave reaction vessel was charged with 3,5-bis(6-cyclopropylpyrazin-2-yl)-1-tosyl-1H-indole (72 mg, 0.14 mmol) and 1 M NaOH (aq., 0.71 mL, 0.71 mmol) in dioxane (1.5 mL). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 120° C. for 20 min. Saturated NaCl (aq.) was added and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography, eluting with a gradient of 0-70% EtOAc in hexanes, to the title compound (25 mg, 0.07 mmol, 50% yield) as a light-yellow solid. MS (ESI, pos. ion) m/z: 354.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.90 (s, 1H), 9.07-9.14 (m, 1H), 8.95 (d, J=6.46 Hz, 2H), 8.53 (s, 1H), 8.37 (d, J=3.91 Hz, 2H), 7.89-7.97 (m, 1H), 7.60 (s, 1H), 2.22-2.33 (m, 2H), 1.06-1.26 (m, 8H).
Reaction SMILES: [CH3:1][Li].Br[C:4]1[N:8]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:7]=[C:6]([C:21]#[N:22])[C:5]=1[S:23][CH3:24].CI>C(OCC)C.O1CCCC1>[Cl:20][C:10]1[CH:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:14]([Cl:15])[C:9]=1[N:8]1[C:4]([CH3:1])=[C:5]([S:23][CH3:24])[C:6]([C:21]#[N:22])=[N:7]1
Reactant: [Li]C
Reactant: CSc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1Br
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CI
Product: CSc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C
Temperature: 0 °C

Procedure:
A 1.4 M solution of methyllithium (31 ml) in ethyl ether was added to a stirred solution of 5-bromo-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylthio-1H-pyrazole-3-carbonitrile (17.67 g) in dry tetrahydrofuran (THF) at −65° C. over 15-minutes and allowed to warm to 0° C. over 3-hours. After recooling to −65° C., methyl iodide (3.06 ml) in THF was added over 3 minutes, the mixture warmed to −20° C. over 1.5 hours, and then partitioned between aqueous ammonium chloride and dichloromethane. The organic phase was dried (magnesium sulfate), evaporated and purified by flash chromatography on silica gel eluting with hexane/methyl tert-butylether to give 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-methyl-4-methylthio-1H-pyrazole-3-carbonitrile (6.2 g) having a purity of 90.7 area percent by HPLC.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([N:7]([CH2:36][CH:37]([CH3:39])[CH3:38])[NH:8][C:9](=[O:35])[C@@H:10]([C@@H:15]([C:25](=[O:34])[NH:26][O:27]C1CCCCO1)[CH2:16]/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:11][CH:12]([CH3:14])[CH3:13])(=[O:6])=[O:5].O.[C:41]1([CH3:51])[CH:46]=[CH:45][C:44]([S:47]([OH:50])(=[O:49])=[O:48])=[CH:43][CH:42]=1>CO>[C:41]1([CH3:51])[CH:42]=[CH:43][C:44]([S:47]([OH:50])(=[O:48])=[O:49])=[CH:45][CH:46]=1.[NH2:1][CH2:2][CH2:3][S:4]([N:7]([CH2:36][CH:37]([CH3:39])[CH3:38])[NH:8][C:9](=[O:35])[C@@H:10]([C@@H:15]([C:25](=[O:34])[NH:26][OH:27])[CH2:16]/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:11][CH:12]([CH3:14])[CH3:13])(=[O:5])=[O:6]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)S(=O)(=O)CCN)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)S(=O)(=O)CCN)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88.3 %

Procedure:
A solution of 0.25 g of (E)-2′-(2-aminoethanesulphonyl)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in 5 ml of methanol was treated with 0.1 g of p-toluene-sulphonic acid monohydrate. The mixture was stirred for 2.5 hours at room temperature and evaporated. The residue was triturated with diethyl ether, filtered off and dried to give 0.255 g of (E)-2′-(2-aminoethanesulphonyl)-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide p-toluene-sulphonate in the form of a white solid.
Reaction SMILES: C(Cl)Cl.[N+:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1B(O)O)([O-:6])=[O:5].[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27](Br)=[N:28][CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu]I.O>[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N+:4]([O-:6])=[O:5])=[N:28][CH:29]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=[N+]([O-])c1ccccc1B(O)O
Reactant: Brc1ccc(OCc2ccccc2)cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1ccccc1-c1ccc(OCc2ccccc2)cn1
Temperature: 25 °C
Yield: 51.7 %

Procedure:
[1,1′-Bis(diphenylphosphino)ferrocnee]dichloropalladium(II), w/DCM (0.077 g, 0.095 mmol) was added to a solution containing (2-nitrophenyl)boronic acid (0.316 g, 1.893 mmol), 5-(benzyloxy)-2-bromopyridine (0.5 g, 1.893 mmol), Copper(I) iodide (0.036 g, 0.189 mmol) and Potassium carbonate (1.420 ml, 2.84 mmol) in DMF (Volume: 6.31 ml). Let the reaction cool to room temperature. Diluted reaction with water, extracted with ethyl acetate, combined organics, dried, filtered and concentrated. Purified with Combiflash using 15% ethyl acetate in hexanes to afford 5-(benzyloxy)-2-(2-nitrophenyl)pyridine (0.3 g, 0.979 mmol, 51.7% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([CH3:18])[CH:12]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:8][C:6]2[C:5]([CH3:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)=[CH:12][C:13]=1[CH3:18]
Reactant: Cc1cnc(Cl)nc1N
Reactant: Cc1cc(Br)ccc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2nc(Cl)ncc2C)ccc1Cl
Temperature: 25 °C
Yield: 38.2 %

Procedure:
A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.34 g, 2.34 mmol), 4-bromo-1-chloro-2-methyl-benzene (0.58 g, 2.8 mmol), Pd2(dba)3 (0.21 g, 0.23 mmol), Xantphos (0.47 g, 0.47 mmol) and cesium carbonate (2.3 g, 7 mmol) were suspended in dioxane (9 mL) microwaved at 160° C. for 20 min. The reaction mixture was cooled to room temperature and centrifuged down. Solvents were then decanted and evaporated. Resulting residue was purified by flash chromatography on silica gel to afford title compound as yellow solids (0.24 g, 38%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.Cl.[CH3:35][N:36]([CH3:47])[CH2:37][CH2:38][O:39][C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43]>CC(O)C.Cl>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:43][C:42]3[CH:44]=[CH:45][CH:46]=[C:40]([O:39][CH2:38][CH2:37][N:36]([CH3:47])[CH3:35])[CH:41]=3)[N:7]=2)[CH:18]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: CN(C)CCOc1cccc(N)c1
Agent: Cl
Solvent: CC(C)O
Product: CN(C)CCOc1cccc(Nc2nccc(-c3c(-c4cccc(C(=O)Nc5c(F)cccc5F)c4)nc4ccccn34)n2)c1
Temperature: 180 °C
Yield: 26.8 %

Procedure:
In a 5 mL microwave vial with septum cap, 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (0.150 g, 0.325 mmol) and 3-{[2-(dimethylamino)ethyl]oxy}aniline hydrochloride (PCT Publication No. WO2004/087652) (0.63 g, 0.29 mmol) were taken up in iPrOH (3 mL) and concentrated HCl (5 drops) was added. The vial was sealed and heated in the microwave at 180° C. for 15 min. The crude product was adsorbed onto silica gel and flash chromatographed to give the title compound (0.047 g, 26%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.22 (s, 1H), 9.75 (s, 1H), 9.51 (d, J=6.6 Hz, 1H), 8.26-8.47 (m, 2H), 8.03 (d, J=7.7 Hz, 1H), 7.84 (d, J=7.7 Hz, 1H), 7.76 (d, J=9.0 Hz, 1H), 7.59 (t, J=7.8 Hz, 1H), 7.44-7.54 (m, 2H), 7.31-7.44 (m, 1H), 7.11-7.29 (m, 4H), 7.08 (t, J=6.6 Hz, 1H), 6.62 (d, J=5.3 Hz, 1H), 6.53 (dd, J=8.2, 1.6 Hz, 1H), 3.94 (t, J=5.8 Hz, 2H), 2.55 (t, J=5.7 Hz, 2H), 2.14 (s, 6H). MS (M+H, ES+) 606.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:31]2[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[F:21])[CH2:33][CH2:32]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Product: COc1ccc2nc(OC)c(NC(=O)N3CCN(c4ccccc4F)CC3)nc2c1
Yield: 72 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(2-fluorophenyl)piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 72%). 1H NMR (300 MHz, CDCl3): δ 3.18 (s, 4H), 3.73-3.88 (m, 6H), 4.11-4.15 (m, 4H), 6.88-7.15 (m, 5H), 7.33 (s, 1H), 7.51 (d, J=8.7 Hz, 1H), 7.64 (d, J=9.0 Hz, 1H).