Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH3:25])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[N:19][C:20](F)=[CH:21][C:22]=3[CH3:23])=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1>O>[CH2:1]([C:3]1[CH:4]=[C:5]([CH3:25])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[N:19][C:20]([NH:33][CH2:32][C:31]4[CH:34]=[CH:35][C:28]([O:27][CH3:26])=[CH:29][CH:30]=4)=[CH:21][C:22]=3[CH3:23])=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(N2CCN(C(=O)c3cnc(F)cc3C)CC2)c(C)c1
Reactant: COc1ccc(CN)cc1
Solvent: O
Product: CCc1cnc(N2CCN(C(=O)c3cnc(NCc4ccc(OC)cc4)cc3C)CC2)c(C)c1
Temperature: 160 °C
Reaction time: 6 h

Procedure:
To [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (320 mg) described in Preparation Example 176 was added 4-methoxybenzylamine (1 mL), and the mixture was stirred at 160° C. for 6 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl][6-(4-methoxybenzylamino)-4-methylpyridin-3-yl)methanone (330 mg). The obtained [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl][6-(4-methoxybenzylamino)-4-methylpyridin-3-yl)methanone (330 mg) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (10 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated from the reaction mixture, 1N aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography to give (6-amino-4-methylpyridin-3-yl) [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone. The obtained (6-amino-4-methylpyridin-3-yl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone and triethylamine (0.30 mL) were dissolved in dichloromethane (10 mL), 3-chloropropane-1-sulfonyl chloride (0.18 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 3.5 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was dissolved in N,N-dimethylformamide (10 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.16 mL) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography to give the title compound (220 mg).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Cl:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:31][CH2:30][N:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([Cl:22])[CH:24]=3)[CH2:34][CH2:33]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: Clc1cccc(N2CCNCC2)c1
Product: CCc1cc(NC(=O)N2CCN(c3cccc(Cl)c3)CC2)c(OC)nc1C
Yield: 84 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: Br[C:2]1[N:18]=[C:5]2[CH:6]=[C:7]([NH:10]C(=O)OC(C)(C)C)[CH:8]=[CH:9][N:4]2[N:3]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.C(OCC)(=O)C.O.[ClH:31].C(OCC)(=O)C>>[ClH:31].[N:19]1([C:2]2[N:18]=[C:5]3[CH:6]=[C:7]([NH2:10])[CH:8]=[CH:9][N:4]3[N:3]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)Nc1ccn2nc(Br)nc2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccn2nc(N3CCCC3)nc2c1
Temperature: 150 °C

Procedure:
The tert-butyl (2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)carbamate (75 mg) obtained in (Example 3.15) <Step 4> and pyrrolidine (1 ml) were stirred under microwave heating at 150° C. for 1 hour. Thereafter, ethyl acetate (10 ml) and water (3 ml) were added to the reaction solution. An organic layer was separated, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. Thereafter, potassium hydroxide (134 mg) was added to an ethanol (2 ml) solution of the obtained residue, and the obtained mixture was then heated to reflux for 16 hours. Thereafter, the solvent was distilled away under reduced pressure, and potassium hydroxide (134 mg) was added to an ethylene glycol (2 ml) solution of the obtained residue, followed by heating the obtained mixture at 155° C. for 2 hours. The solvent was distilled away under reduced pressure, and ethyl acetate (10 ml) and water (3 ml) were then added to the obtained residue. An organic layer was separated, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (silica gel:eluent; heptane:ethyl acetate=50:50-0:100) to obtain a crude product. The obtained crude product was dissolved in 4 N hydrochloric acid-ethyl acetate (1 ml), and the precipitated solid was then collected by filtration, so as to obtain the title compound (16 mg) in the form of a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][C:5]=1[CH3:13])([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.[NH2:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1.N1C=CC=CC=1>ClCCCl.CN(C)C=O>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:20][C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[O:10])=[CH:6][C:5]=1[CH3:13])([O-:3])=[O:2]
Reactant: Nc1nccs1
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1cc(C(=O)Nc2nccs2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
4-Nitro-3-methyl-benzoic acid (83 mmol) was suspended in 1,2-dichloroethane (500 mL) and dimethylformamide (DMF) (5 mL) under an argon atmosphere. Oxalylchloride (2M in dichloromethane, 62.3 mL) was added slowly to the stirred suspension. After stirring at room temperature for 1 h, the solvent was removed by evaporation under reduced pressure, and the reaction mixture was re-dissolved in 1,2-dichloroethane (400 mL). A suspension of 2-aminothiazole (83 mmol) and pyridine (83 mmol) in 1,2-dichloroethane (100 mL) was added portion wise. The reaction mixture was stirred at 50° C. over night. The solvent was removed under reduced pressure and the solids were re-suspended in ethyl acetate (500 mL) and NaHCO3 (sat.) (500 mL). The solids were removed by filtration and the liquid phases were separated. The organic phase was washed with NaHCO3 (sat.), dried over MgSO4, filtered and evaporated. The crude product was re-crystallized from ethyl acetate and the product fractions were combined to give 4-nitro-3-methyl-N-thiazol-2-yl-benzamide.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:25][C:26](=[O:30])[CH2:27][O:28][NH2:29])([CH3:24])([CH3:23])[CH3:22].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[C:21]([O:25][C:26](=[O:30])[CH2:27][O:28][NH:29][C:18]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:20])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)CON
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.20 g, 0.72 mmol) in dry DCM (20 mL) were added tert-butyl(aminooxy)acetate 88 (0.13 g, 0.86 mmol, Organic Letters, 2002, 4(6) 869-872), 1-hydroxybenzotriazole (0.15 g, 1.11 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.21 g, 1.10 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by column chromatography to give tert-butyl[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]acetate 89 (0.23 g, 79%) as a white solid.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=[O:4].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(CBr)c1ccc(O)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(CBr)c1ccc(OC2CCCCO2)cc1

Procedure:
2-Bromo-4'-hydroxyacetophenone (860 mg) was dissolved in dichloromethane (20 ml), and 3,4-dihydro-2H-pyran (550 μl) and pyridinium p-toluenesulfonate (100 mg) were added to the solution at room temperature with stirring. After reaction for 17 hours, the reaction mixture was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: hexane/ethyl acetate=10/1) gave 2-bromo-4'-((2RS)-2-tetrahydropyranyloxy)acetophenone (1.01 g) having a melting point of 102-104° C.
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([OH:14])=O)[CH2:3][C:4]1[C:5]([F:11])=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1.[NH:22]([CH3:47])[C@H:23]([C:27]([N:29]([CH3:46])[C@H:30]([C:43]([NH2:45])=[O:44])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:33]=1)=[O:28])[CH:24]([CH3:26])[CH3:25].O>C1COCC1>[NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([N:22]([CH3:47])[C@H:23]([C:27]([N:29]([CH3:46])[C@H:30]([C:43]([NH2:45])=[O:44])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([C:39]([CH3:42])([CH3:40])[CH3:41])[CH:33]=1)=[O:28])[CH:24]([CH3:26])[CH3:25])=[O:14])[CH2:3][C:4]1[C:5]([F:11])=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1F)C(=O)O
Reactant: CN[C@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1ccc(O)cc1F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 23 h
Yield: 15.4 %

Procedure:
To a solution of the above crude Boc-Tyr(2-F)-OH (0.82 g), N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (0.77 g, 2.11 mmol) and CMPI (0.81 g, 3.17 mmol) in THF (5 ml), TEA (1.18 ml, 8.44 mmol) was added under cooling with ice and stirred at room temperature for 23 hours. The reaction mixture was mixed with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: chloroform:methanol:concentrated aqueous ammonia=30:1:0.05), giving the titled compound (0.21 g, 15%).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][C@@H:8]([CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[O:9][C@H:10]2[CH2:16][NH:17][CH:18]=[O:19])([CH3:3])[CH3:2].[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:23]2[CH2:22][CH2:21][CH:20]([CH:8]3[CH2:7][C:6]4[C:11](=[CH:12][CH:13]=[C:14]([CH3:15])[C:5]=4[O:4][CH:1]([CH3:3])[CH3:2])[CH:10]([CH2:16][NH:17][CH:18]=[O:19])[O:9]3)[CH2:25][CH2:24]2)=[CH:29][CH:28]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Cc1ccc2c(c1OC(C)C)C[C@@H](C1CCNCC1)O[C@H]2CNC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc2c(c1OC(C)C)CC(C1CCN(Cc3ccc(F)cc3)CC1)OC2CNC=O

Procedure:
Stir a suspension of N-((1R,3S)-5-Isopropoxy-6-methyl-3-(4-piperidinyl)-1-isochromanylmethyl)formamide (1.0 mmol) with 4-fluorobenzaldehyde (3.0 mmol) and sodium triacetoxyborohydride (3.0 mmol) in dichloromethane (5 mL) at room temperature overnight. Apply the reaction mixture directly to a 5 g SCX column and elute and concentrate the appropriate fractions to obtain N-[3-[1-(4-fluoro-benzyl)-piperidin-4-yl]-5-isopropoxy-6-methyl-isochroman-1-ylmethyl]-formamide. Use the compound directly for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:15](Cl)=[O:16]>>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:15]([O:16]/[C:15](/[C:14]1[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:12]([O:11][CH3:10])[CH:13]=1)=[CH:8]\[C:7]1[C:6]([Cl:9])=[CH:5][N:4]=[CH:3][C:2]=1[Cl:1])=[O:16]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: Cc1c(Cl)cncc1Cl
Product: COc1ccc(C(=O)O/C(=C\c2c(Cl)cncc2Cl)c2ccc(OC)c(OC)c2)cc1OC

Procedure:
The compound was obtained starting from 3,5-dichloro-4-methyl-pyridine and 3,4-dimethoxy-benzoyl chloride, following the procedure of Example 31.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]3[CH:17]=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH:8]=[CH:7][N:6]=1)[CH3:2].Br[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([F:30])[CH:24]=1.C([O-])(=O)C.[K+]>CS(C)=O>[CH2:20]([N:3]([CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:23]4[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([F:30])[CH:24]=4)=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH:8]=[CH:7][N:6]=1)[CH2:1][CH3:2])[CH3:21]
Reactant: CCN(CC)Cc1cc(-c2ccn3ccnc3c2)ccn1
Reactant: Nc1ccc(Br)cc1F
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCN(CC)Cc1cc(-c2ccn3c(-c4ccc(N)c(F)c4)cnc3c2)ccn1
Temperature: 100 °C
Reaction time: 14 h
Yield: 20.6 %

Procedure:
Combine diethyl-(4-imidazo[1,2-a]pyridin-7-yl-pyridin-2-ylmethyl)-amine (1.00 g, 3.57 mmol), 4-bromo-2-fluoro-phenylamine (1.36 g, 7.13 mmol) and potassium acetate (0.700 g, 7.13 mmol) in DMSO (4 mL). De-gas the mixture for 10 minutes with N2. Add dichlorobis(triphenylphosphine) palladium (II) (0.250 g, 0.357 mmol); stir the reaction mixture for 14 hours under N2 at 100° C. Purify using an SCX cartridge (10 g VARIAN bond elut), eluting with 1:1 methanol:dichloromethane, then 1:1 2 M NH3 in methanol:dichloromethane. Purify via reverse phase chromatography using a 25 cm by 50.8 mm (i.d.) column w/10 micron particles (MeCN/0.03% HCl H2O (5:95) to 100% MeCN; 30 min). Compound obtained is partitioned between ethyl acetate and 1 N NaOH. Wash the organic layer with aqueous saturated sodium chloride, dry over magnesium sulfate, filter, and concentrate to afford the title compound (0.286 g, 21%). MS(ES), m/z 390 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[O:4].CON(C)[C:20](=[O:24])[CH:21]([CH3:23])[CH3:22]>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[CH:8][C:9]=1[NH:10][C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[O:4]
Reactant: COC(=O)c1sccc1NC(=O)C(F)(F)F
Reactant: CON(C)C(=O)C(C)C
Product: COC(=O)c1sc(C(=O)C(C)C)cc1NC(=O)C(F)(F)F

Procedure:
3-(2,2,2-Trifluoroacetylamino)thiophene-2-carboxylic acid methyl ester and N-methoxy-N-methylisobutyramide were reacted by method M. The product with the molecular weight of 323.29 (C12H12F3NO4S) was obtained in this way; MS (ESI): 324 (M+H+).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][N:8]=1)=[O:6].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C1COCC1>[CH3:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[N:8]=1)=[O:6]
Reactant: COC(=O)c1n[nH]c2ccccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1nn(S(=O)(=O)c2ccc(C)cc2)c2ccccc12
Temperature: 30 °C
Reaction time: 4 h

Procedure:
To a suspension of sodium hydride (4.6 g, 150 mmol, 80% in paraffin oil) indry THF (100 mL), a solution of 3-indazolecarboxylic acid methyl ester [(J.Am. Chem. soc, 74, 2009 (1952)] (22.0 g, 125 mmol) in dry THF (100 mL) was added dropwise with stirring while the inner temperature was maintained under 30° C. The reaction mixture was stirred for 30 minutes and then a solution of p-toluenesulphonyl chloride (28.0 g, 150 mmol) in dry THE (100 mL) was added dropwise to the stirring reactant. After 4 hours, the solvent was evaporated in vacuo and the residue partitioned between water and CH2Cl2. The organic phase was separated, dried over Na2SO4 and the solvent evaporated to leave a solid which was recrystallized from ethyl acetate (31.0 g, 75%), m.p. 163°-165° C.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[N:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1>C(#N)C>[N:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:35][CH2:36][N:37]([CH2:2][C:3]([NH:5][C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([C:12]4[CH:21]=[N:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[N:13]=4)[CH:7]=3)=[O:4])[CH2:38][CH2:39]2)=[CH:30][CH:29]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: O=C(CBr)Nc1cccc(-c2cnc3ccccc3n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(CN1CCN(c2ccncc2)CC1)Nc1cccc(-c2cnc3ccccc3n2)c1
Yield: 24.2 %

Procedure:
A mixture of 2-bromo-N-(3-(quinoxalin-2-yl)phenyl)acetamide (100 mg, 0.292 mmol), potassium carbonate (51 mg, 0.365 mmol) and 1-(4-pyridyl)-piperazine (50 mg, 0.307 mmol) in acetonitrile (5 mL) was heated at reflux for 15 min. The solvent was evaporated in vacuo and the crude reaction mixture was purified by preparative LCMS to afford 2-(4-(pyridin-4-yl)piperazin-1-yl)-N-(3-(quinoxalin-2-yl)phenyl)acetamide (30 mg, 24% yield). LCMS calculated for C25H24N6O (M+H): 425.50. found 425.44. 1H-NMR (DMSO-d6, 400 Mhz) δH: 10.04 (1H, br.), 9.52 (1H, s), 8.58 (1H, m), 8.15-8.10 (4H, m), 8.05-8.08 (1H, m), 7.82-7.95 (3H, m), 7.55-7.60 (1H, m), 6.85 (2H, m), 3.45 (4H, m), 3.25 (2H, s), 2.72 (4H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](C=O)[S:5][C:6]=1[N+:7]([O-:9])=[O:8].[Cl-].[NH4+].[CH:14]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])OCC>CCO>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]([O:18][CH2:19][CH3:20])[O:21][CH2:22][CH3:23])[S:5][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: O=Cc1cc(Br)c([N+](=O)[O-])s1
Reactant: CCOC(OCC)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(OCC)c1cc(Br)c([N+](=O)[O-])s1
Temperature: 60 °C
Reaction time: 14 h
Yield: 81.2 %

Procedure:
To a solution of 4-bromo-5-nitrothiophene-2-carbaldehyde (Int. 65) (6.981 g, 29.6 mmol) in EtOH (50 ml), ammonium chloride (0.475 g, 8.87 mmol) and triethyl orthoformate (7.39 ml, 44.4 mmol) were added, and the resulting solution was stirred at 60° C. for 14 hours. Additional triethyl orthoformate (7.39 ml, 44.4 mmol) was added, and the mixture was vigorously refluxed for further 2 days. The solvent was evaporated under vacuum and the crude was partitioned between water and EtOAc. The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated. The crude was purified by chromatography on silica gel cartridge (petroleum ether/EtOAc=9/1) to afford 3-bromo-5-(diethoxymethyl)-2-nitrothiophene (Int. 66) (7.456 g, 24.04 mmol).
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[CH:9][NH:8][N:7]=1.[F:24][C:25]([F:35])([F:34])[C:26](=O)[CH2:27][C:28](OCC)=[O:29]>CCOCC>[OH:29][C:28]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[CH:13][C:14]([S:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[C:6]2[N:5]=[C:26]([C:25]([F:35])([F:34])[F:24])[CH:27]=1
Reactant: Nc1n[nH]cc1-c1ccc(Sc2ccccc2)cc1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Solvent: CCOCC
Solvent: CC(=O)O
Product: Oc1cc(C(F)(F)F)nc2c(-c3ccc(Sc4ccccc4)cc3)cnn12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
In an 8 ml acetic acid solution of 1.07 g of 3-amino-4-(4phenylthiophenyl)pyrazole, 0.6 ml of ethyl 4,4,4-trifluoroacetoacetate was added and stirred for 2 hours at 100° C. After allowing to cool, ether was added, and the precipitate was filtered and dried, and the title compound was obtained (200 mg, 13%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([F:19])=[CH:21][CH:22]=1)[CH:6]=[C:5]2[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1
Reactant: CN1CC=C(c2c[nH]c3c(F)cc(F)cc23)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CC=C(c2cn(C(=O)c3ccc(F)cc3)c3c(F)cc(F)cc23)CC1

Procedure:
(6.3 mg, 42%); from 5,7-difluoro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4g, 10 mg, 0.04 mmol) and 4-fluorobenzoyl chloride (9.5 mg, 0.06 mmol) with 1M NaN(TMS)2 (60 μL, 0.06 mmol) in THF (0.5 mL) at RT.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:13][CH:14]=1)(C(C)(C)C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:27][CH2:28][O:29][CH3:30]>CC#N>[CH3:30][O:29][CH2:28][CH2:27][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:13][CH:14]=1
Reactant: COC(=O)Cc1ccc(O[Si](C)(C)C(C)(C)C)cn1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COCCOc1ccc(CC(=O)OC)nc1

Procedure:
To a stirred solution of methyl 2-(5-((tert-butyldimethylsilyl)oxy)pyridin-2-yl)acetate (500 mg, 3 mmol) in MeCN was added Cs2CO3 (1.4 g, 4.5 mmol) followed by 1-bromo-2-methoxyethane (621 mg, 4.5 mmol) at room temperature. The whole mixture was heated to 80° overnight. LC-MS showed desired product. It was filtered, evaporated and purified by a standard method.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:17])([C:13]([O:15][CH3:16])=[O:14])[CH2:11][C:10]([C:18]([O:20]C)=O)=[N:9]2)=[CH:4][CH:3]=1.C[Al](C)C.[I:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:17])([C:13]([O:15][CH3:16])=[O:14])[CH2:11][C:10]([C:18]([NH:31][C:30]3[CH:32]=[CH:33][C:27]([I:26])=[CH:28][CH:29]=3)=[O:20])=[N:9]2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(I)cc1
Reactant: COC(=O)C1=NN(c2ccc(F)cc2)C(C)(C(=O)OC)C1
Agent: C[Al](C)C
Solvent: ClCCl
Product: COC(=O)C1(C)CC(C(=O)Nc2ccc(I)cc2)=NN1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
The compound of Example 11 (0.5 g) was dissolved in dichloromethane (5 ml) and added to a mixture of trimethylaluminum (2M in toluene, 1.68 ml) and 4-iodoaniline (0.7 g) in dichloromethane (10 ml). The mixture was stirred at room temperature for 16 hours and partitioned between 1N HCl (100 ml) and dichloromethane (100 ml). The organic layer was dried and evaporated to leave a solid. Recrystallization from ether/hexanes gave the title compound (0.73 g): m.p.: 84°-85° C. NMR (CDCl3) 8.4 (br, NH), 7.7-6.9 (m, ArH, 12H), 3.8 (s, OMe, 3H), 3.8 (d, CH, 1H), 3.3 (d, CH, 1H), 1.7 (s, Me, 3H).