Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([C@@H:10]2[CH2:12][C@H:11]2[C:13]2[N:17]([CH3:18])[C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[N:14]=2)[CH:4]=1)[NH2:2].[Si:23]([O:30][C@@H:31]([CH3:40])[C:32]([N:34]=[C:35](N(C)C)[CH3:36])=O)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].C(=O)(O)[O-].[Na+]>C(O)(=O)C.COCCOC>[Si:23]([O:30][C@H:31]([C:32]1[N:1]([C:3]2[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([C@@H:10]3[CH2:12][C@H:11]3[C:13]3[N:17]([CH3:18])[C:16]4[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=4[N:14]=3)[CH:4]=2)[N:2]=[C:35]([CH3:36])[N:34]=1)[CH3:40])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: Cc1nc(NN)cc([C@@H]2C[C@H]2c2nc3ccccc3n2C)n1
Reactant: CC(=NC(=O)[C@H](C)O[Si](C)(C)C(C)(C)C)N(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COCCOC
Product: Cc1nc([C@@H]2C[C@H]2c2nc3ccccc3n2C)cc(-n2nc(C)nc2[C@H](C)O[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of Intermediate 6 (1.8 g, 6.1 mmol) in acetic acid (40 ml) was added Intermediate 13 (4.0 g, 14.7 mmol) as a crude reaction mixture in 1,2-dimethoxyethane (40 mL). The reaction mixture was allowed to stir for 5 minutes at room temperature and then heated at 80° C. for 1 h. The reaction was cooled to room temperature, poured carefully over saturated aqueous sodium bicarbonate solution (200 mL), and the aqueous layer was made basic to pH˜8 by the addition of solid sodium bicarbonate. The solution was extracted with ethyl acetate (200 mL) and the organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-60% EtOAc/hexanes) to afford 13-1 as an oil. MS: m/z=504.4 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([NH2:15])=O)[C:7](=[CH:11][CH:12]=1)[C:8]([NH2:10])=O)([O-:3])=[O:2].P(Cl)(Cl)(Cl)=O.Cl>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([C:13]#[N:15])[C:7](=[CH:11][CH:12]=1)[C:8]#[N:10])([O-:3])=[O:2]
Reactant: NC(=O)c1ccc([N+](=O)[O-])cc1C(N)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc([N+](=O)[O-])cc1C#N

Procedure:
4-nitrophthalamide (220g; 1.05 moles) is suspended in pyridine (840ml). Into this vigrously stirred suspension, phosphorus oxychloride (220 ml; 2.40 moles) is added at such a rate that the reaction maintains a temperature range of 65°-70° C during the 30 minute addition time. The same temperature is maintained an additional hour by external heating. The resulting mixture is neutralized with 12 N hydrochloric acid (150 ml). The purple solid is collected by filtration and dried. The residue is extracted with ethyl acetate (3 × 700 ml) and the purple extract is decolorized with activated charcoal, washed first with 0.4 N sodium hydroxide saturated with sodium chloride (3 × 70 ml) and then with water (4 × 70 ml). Drying and evaporation of the extract leaves 91g of II as pale yellow crystals; yield, 50%, mp142°-144° C; lit. (7) mp 138°-139° C; lit. (4) 142° C.
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:26])=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25]2([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[O:26][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]2)=[CH:21][CH:22]=1
Reactant: O=C(CCc1ccc(F)cc1)c1ccccc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(CCc2ccc(F)cc2)(c2ccccc2)O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared as described in General Method 1 using 3.1 mL of methyl acetoacetate, 1.2 g of NaH 60% dispersion in oil, 18 mL of 1.6M n-butyl lithium in hexane, 6.0 g of 3-(4-fluorophenyl)propiophenone and 200 mL of tetrahydrofuran. After addition of the ketone, the reaction was stirred for 15 minutes at 0° C. then allowed to warm to room temperature and stirred for 4 hours. The crude product was triturated from diethyl ether to afford a solid (m.p. 155°-157° C. ). 1H NMR (CDCl3) δ 2.23-2.29 (m, 2 H), 2.42-2.52 (m, 1 H), 2.67-2.78 (m, 1 H), 2.97 (dd, 2 H), 3.35 (dd, 2 H), 7.34-7.47 (m, 5 H), 6.91-7.07 (m, 4 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][NH:22][CH2:23][CH3:24])[CH:6]=1.Cl[C:27]([O:29][CH3:30])=[O:28]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][N:22]([CH2:23][CH3:24])[C:27]([O:29][CH3:30])=[O:28])[CH:6]=1
Reactant: CCNCc1cc(Br)ccc1Oc1cc(CC(=O)OC)ccc1OC
Reactant: COC(=O)Cl
Product: CCN(Cc1cc(Br)ccc1Oc1cc(CC(=O)OC)ccc1OC)C(=O)OC

Procedure:
Prepared according to the procedure described in Example 3 Step 3, using the following starting materials: [3-(4-bromo-2-ethylaminomethyl-phenoxy)-4-methoxy-phenyl]-acetic acid methyl ester and methyl chloroformate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:19]=1)/[CH:7]=[CH:8]/[C:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=2[S:11][CH:10]=1.[CH3:21][C:22]1[N:23]=[CH:24][N:25]([C:27]2[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=2)[C:30](O)=[O:31])[CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[NH2:18][C:17]1[C:12]2[S:11][CH:10]=[C:9](/[CH:8]=[CH:7]/[C:6]3[CH:19]=[C:2]([NH:1][C:30](=[O:31])[C:29]4[CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=[C:27]([N:25]5[CH:26]=[C:22]([CH3:21])[N:23]=[CH:24]5)[CH:28]=4)[CH:3]=[CH:4][C:5]=3[CH3:20])[C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: Cc1cn(-c2cc(C(=O)O)cc(C(F)(F)F)c2)cn1
Reactant: Cc1ccc(N)cc1/C=C/c1csc2c(N)ncnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cn(-c2cc(C(=O)Nc3ccc(C)c(/C=C/c4csc5c(N)ncnc45)c3)cc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
(E)-7-(5-amino-2-methylstyryl)thieno[3,2-d]pyrimidine-4-amine (100 mg, 0.354 mmol) and 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)benzoic acid (96 mg, 0.354 mmol) were dissolved in DMF (1.5 mL), HATU (404 mg, 1.063 mmol) and TEA (0.248 mL, 1.7728 mmol) were added thereto and stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried with MgSO4, filtered and concentrated. The resulting mixture was purified by silica gel chromatography to obtain the title compound (142 mg, 75% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][S:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:23])=[O:22])[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(Cl)n1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc(Cl)n1)c1ccccc1
Yield: 93 %

Procedure:
6-Chloropyridin-2-amine (0.3 g, 2 mmol) was dissolved in DCM (20 mL) and then pyridine (0.57 mL, 7.0 mmol) was added to the mixture with stirring. Then, benzenesulfonyl chloride (0.36 mL, 2.8 mmol) was added into the mixture. The mixture was allowed to stir under inert atmosphere for 2 hours. The mixture was diluted with DCM and saturated NaHCO3, and then the aqueous layer was extracted with DCM three times. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (10-100% EtOAc/hexanes) to provide N-(6-chloropyridin-2-yl)benzenesulfonamide (0.5 g, 80% yield) as a colorless oil. MS (ESI pos. ion) m/z: 254 (MH+). Calculated exact mass for C11H8ClNO2S: 253.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[NH:11][CH2:12][CH2:13][N:7]3[C:6]=2[C:5]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([C:29](C)=[O:30])=[C:24]([CH3:32])[CH:23]=1>CN(C)C=O.O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:29]([C:25]4[C:24]([CH3:32])=[CH:23][C:22]([CH3:21])=[CH:27][C:26]=4[CH3:28])=[O:30])[CH2:12][CH2:13][N:7]3[C:6]=2[C:5]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: CC(=O)c1c(C)cc(C)cc1C
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3C(=O)c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46.8 %

Procedure:
To a solution of 8-chloro-5-(1-ethylpropyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole (32.9 mg, 0.125 mmol) in N,N-dimethylformamide (0.5 mL) was added sodium hydride (19.8 μL, 0.142 mmol) at 0° C. After 15 min, to the mixture was added 2,4,6-trimethylacetophenone (27.2 mg, 0.149 mmol). The reaction mixture was stirred at room temperature for 18 hrs. The mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic layer was washed and brine (×1), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-30% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from n-hexane to give the title compound as a pale pink powder (24.0 mg, 0.0585 mmol, 47%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]([NH:19][CH:20]3[CH2:22][CH2:21]3)=[O:18])[N:14]=[N:13]2)=[C:8]([OH:23])[CH:7]=1)=[O:5])[CH3:2].Br[CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]([NH:19][CH:20]3[CH2:22][CH2:21]3)=[O:18])[N:14]=[N:13]2)=[C:8]([O:23][CH:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:26])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(Br)c1ccccc1
Reactant: CCNC(=O)c1ccc(-n2cc(C(=O)NC3CC3)nn2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)c1ccc(-n2cc(C(=O)NC3CC3)nn2)c(OC(C)c2ccccc2)c1
Reaction time: 16 h
Yield: 33.4 %

Procedure:
A solution (500 μl; 70 μmol) of 1-{4-[(ethylamino)carbonyl]-2-hydroxyphenyl}-N-cyclopropyl-1H-1,2,3-triazole-4-carboxamide (0.14M) in DMF, and a solution (500 μl; 105 μmol) of (1-bromoethyl)benzene (0.21M) in DMF, and a powder of potassium carbonate (30 mg) were mixed at room temperature, and the mixture was stirred for 16 hr. Water (2 ml) was added to the reaction mixture, and the mixture was extracted with dichloromethane (3 ml). The solvent was evaporated under reduced pressure, and the residue was dissolved in DMSO (1 ml) and purified by preparative HPLC (Gilson, Inc., high-throughput purification system, column: YMC CombiPrep ODS-A S-5 μm, 50×20 mm, solvent: solution A; 0.1% formic acid aqueous solution, solution B; 0.1% formic acid acetonitrile solution, gradient cycle: 0 min (solution A/solution B=95/5), 1.00 min (solution A/solution B=95/5), 5.20 min (solution A/solution B=5/95), 6.40 min (solution A/solution B=5/95), 6.50 min (solution A/solution B=95/5), 6.60 min (solution A/solution B=95/5), flow rate: 25 ml/min, detection method: UV 220 nm) to give the title compound (9.8 mg) (LC/MS purity 100%, ESI+:420 [M+H]+).
Reaction SMILES: [C:1]1([C:7]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10](=[S:18])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][C:21]#[N:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]1([C:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:10]([S:18][CH2:20][C:21]#[N:22])[NH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: S=C1NN=C(c2ccccc2)C1c1ccccc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCSc1[nH]nc(-c2ccccc2)c1-c1ccccc1
Reaction time: 1 h
Yield: 65.8 %

Procedure:
To a solution of 3,4-diphenyl-1H-pyrazole-5(4H)-thione (0.5 g, 1.981 mmol) in DMF (5 mL), were added 2-bromoacetonitrile (0.238 g, 1.981 mmol) and K2CO3 (0.274 g, 1.981 mmol) at room temperature. After stirring at the same temperature for 1 h, the reaction was extracted with ethyl acetate, which was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (0.38 g). LCMS m/z=292.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.20 (s, 2H), 7.35-7.45 (m, 10H), 13.7 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=1.[Cl:15]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:15][C:9]1[C:10]([CH:13]=[O:14])=[CH:11][NH:12][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: O=Cc1c[nH]c(-c2ccccc2F)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1c[nH]c(-c2ccccc2F)c1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
To a solution (15 mL) of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (1.0 g) in N,N-dimethylformamide was added N-chlorosuccinimide (0.71 g) at 0° C., and the mixture was stirred at 60° C. for 2 hr. The mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=8:1→3:1) to give the title compound as a yellow powder (yield 0.55 g, 46%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH2:9]1.[NH2:25][C:26]1[C:27]([C:34](O)=[O:35])=[N:28][C:29]([Br:33])=[C:30]([F:32])[CH:31]=1>CCOC(C)=O>[NH2:25][C:26]1[C:27]([C:34]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C@@H:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([N:14]3[C:15](=[O:24])[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:22]3=[O:23])[CH2:9]2)=[O:35])=[N:28][C:29]([Br:33])=[C:30]([F:32])[CH:31]=1
Reactant: Nc1cc(F)c(Br)nc1C(=O)O
Reactant: Nc1cnccc1C1CCCC(N2C(=O)c3ccccc3C2=O)C1
Solvent: CCOC(C)=O
Product: Nc1cc(F)c(Br)nc1C(=O)Nc1cnccc1[C@@H]1CCC[C@H](N2C(=O)c3ccccc3C2=O)C1

Procedure:
Following Method 9, 2-(3-(3-aminopyridin-4-yl)cyclohexyl)-isoindoline-1,3-dione and 3-amino-6-bromo-5-fluoropicolinic acid were coupled and following addition of EtOAc and washing with H2O, NaCl(sat.) and drying over MgSO4, 3-amino-6-bromo-N-(4-((1R,3S)-3-(1,3-dioxoisoindolin-2-yl)cyclohexyl)pyridin-3-yl)-5-fluoropicolinamide was obtained. LCMS (m/z): 538.1/540.1 (MH); LC Rt=3.46 min.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:9]([OH:15])[C:10](=[NH:14])[O:11]CC)[CH:6]=[CH:7][CH:8]=1.[O:16]1CCC[CH2:17]1>C1(C)C=CC=CC=1>[Cl:2][C:3]1[CH:4]=[C:5]([CH:9]2[O:15][C:17](=[O:16])[NH:11][C:10]2=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=N)C(O)c1cccc(Cl)c1
Reactant: C1CCOC1
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(c2cccc(Cl)c2)O1

Procedure:
By the procedure of Example 3, ethyl 1-(3-chlorophenyl)-1-hydroxymethanecarboximidate hydrochloride (9 g., 38 moles) in 250 ml. of tetrahydrofuran was converted to toluene recrystallized 5-(3-chlorophenyl)oxazolidine-2,4-dione (4.5 g., 56%, m.p. 142°-144° C.).
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[N:9][CH:8]=1)=[O:5].CC1(C)C(C)(C)OB([C:26]2[CH:27]=[C:28]([N:32]3[CH:36]=[CH:35][CH:34]=[N:33]3)[CH:29]=[CH:30][CH:31]=2)O1>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N:32]3[CH:36]=[CH:35][CH:34]=[N:33]3)[CH:27]=2)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[N:9][CH:8]=1)=[O:5]
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccnnc1
Reactant: CC1(C)OB(c2cccc(-n3cccn3)c2)OC1(C)C
Product: Nc1ncc(-c2cccc(-n3cccn3)c2)cc1C(=O)Nc1ccnnc1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridazin-4-yl-nicotinamide (see step 1 in the synthesis of “A16”) and 1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole gives the compound “A18”;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[Cl:18])C(OC)=O.[Cl-].[Li+].O>CS(C)=O>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[Cl:18]
Reactant: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)Cc1ccc([N+](=O)[O-])cc1Cl
Temperature: 100 °C

Procedure:
2-(4-nitro-2chlorophenyl)-malonic acid dimethyl ester was dissolved in DMSO, then lithium chloride (0.759 g), and water (0.15 mL) were added. The mixture was heated to 100° C. for 3h. The reaction was cooled and the product purified by chromatography on silica gel eluting with hexane/ethyl acetate (9:1) to give the title compound as a yellow oil (1.77 g).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCOCC1.O.[Cl-].[Na+].O>[C:16]([N:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2)CC1
Yield: 89.8 %

Procedure:
To a solution of N-Boc-piperazine (14) (1.00 g, 5.37 mmol) in dioxane (5 mL), a solution of NaOH (0.50 g, 12.9 mmol) in water (5 mL) followed by a solution of benzoyl chloride (0.75 mL, 6.44 mmol) in dioxane (2 mL) under vigorous stirring were added. The reaction mixture was stirred at ambient temperature for 4 hours, diluted with brine (20 mL), and extracted with ethyl acetate (2×25 mL). The organic extract was washed successively with brine (20 mL), saturated NaHCO3 (20 mL), saturated KH2PO4 (20 mL), and dried (Na2SO4). The solvents were evaporated to give the title compound (1.400 g, 90%) which was used in the next step of the synthesis without further purification. 1H NMR (CDCl3, HMDS), δ: 1.41 (s, 9H), 2.86 (t, J=5.0 Hz, 4H); 3.62 (t, J=5.0 Hz, 4H); 7.34 (s, 5H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:23]([F:25])[F:24])[N:3]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=1>>[F:24][CH:23]([F:25])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[CH:7]=[C:2]([C:28]3[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)cc(N2CCOCC2)n1
Reactant: OB(O)c1cccnc1
Product: FC(F)c1nc2ccccc2n1-c1nc(-c2cccnc2)cc(N2CCOCC2)n1
Yield: 77 %

Procedure:
Using a similar procedure to Example 47, reaction of 1-[4-chloro-6-(4-morpholinyl)-2-pyrimidinyl]-2-(difluoromethyl)-1H-benzimidazole (International Publ. No. WO 2008/032028, the disclosure of which is incorporated herein by reference in its entirety) and 3-pyridinylboronic acid gave 2-(difluoromethyl)-1-[4-(4-morpholinyl)-6-(3-pyridinyl)-2-pyrimidinyl]-1H-benzimidazole in 77% yield: mp (CH2Cl2/hexanes) 172-179° C.; 1H NMR (DMSO-d6) δ 9.44 (d, J=2.2 Hz, 1H), 8.75 (dd, J=4.8, 1.5 Hz, 1H), 8.61 and 8.59 (2m, 1H), 8.39 (d, J=8.20 Hz, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.82 (t, JHF=52.8 Hz, 1H), 7.62 (dd, J=8.0, 4.8 Hz, 1H), 7.55-7.51 (m, 2H), 7.46-7.42 (m, 1H), 3.88-3.84 (m, 4H), 3.79-3.77 (m, 4H); Anal. Calcd. for C21H18F2N6O1.9H2O: C, 49.1; H, 4.8; N, 15.6. Found: C, 49.0; H, 4.4; N, 15.0%
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=2[NH:15][N:14]=1>>[F:23][C:12]([F:11])([F:22])[C:13]1[C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=2[N:15]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=2)[N:14]=1
Reactant: N#CCc1ccc(Br)cc1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Product: N#CCc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
The title compound was prepared from (4-bromophenyl)acetonitrile and 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole using a similar procedure to that described for Example 7.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:13](=[O:14])[N:12]([CH2:15][CH2:16][CH2:17][F:18])[N:11]=[N:10]2)=[C:4]([N+:19]([O-])=O)[C:3]=1[OH:22]>C(O)(=O)C.[Fe]>[NH2:19][C:4]1[C:3]([OH:22])=[C:2]([Cl:1])[CH:7]=[C:6]([F:8])[C:5]=1[N:9]1[C:13](=[O:14])[N:12]([CH2:15][CH2:16][CH2:17][F:18])[N:11]=[N:10]1
Reactant: O=c1n(CCCF)nnn1-c1c(F)cc(Cl)c(O)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1c(O)c(Cl)cc(F)c1-n1nnn(CCCF)c1=O
Temperature: 25 °C
Yield: 88.8 %

Procedure:
Iron powder (2.3 g) was added to a solution of 1-(4-chloro-6-fluoro-3-hydroxy-2-nitrophenyl)-4-(3-fluoropropyl)-1,4-dihydro-5-oxo-5H-tetrazole (3.4 g) in acetic acid (50 ml) and stirred at room temperature over night. The reaction mixture was filtered through a celite bed. The filtrate was concentrated under reduced pressure and purified by a silica gel column, eluted with hexane-ethyl acetate (2:1) to give yellow crystals (2.75 g).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[CH:9]=[N:10][NH:11][CH:12]=1.[CH3:13][C:14]1([CH3:29])[CH2:19][CH:18](OS(C)(=O)=O)[CH2:17][CH2:16][CH:15]1[C:25]([O:27][CH3:28])=[O:26]>CN(C=O)C.O>[Br:7][C:8]1[CH:9]=[N:10][N:11]([CH:18]2[CH2:17][CH2:16][CH:15]([C:25]([O:27][CH3:28])=[O:26])[C:14]([CH3:29])([CH3:13])[CH2:19]2)[CH:12]=1
Reactant: COC(=O)C1CCC(OS(C)(=O)=O)CC1(C)C
Reactant: Brc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1CCC(n2cc(Br)cn2)CC1(C)C
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Cesium carbonate (2.93 g, 9 mmol) and 4-bromopyrazole (482 mg, 3.3 mmol) were added to a solution of methyl 2,2-dimethyl-4-[(methylsulfonyl)oxy]cyclohexanecarboxylate (0.79 g, 3 mmol) in DMF (10 mL). The mixture was stirred at 80° C. for 16 hours. Then the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/petroleum ether) to give methyl 4-(4-bromo-1H-pyrazol-1-yl)-2,2-dimethylcyclohexanecarboxylate. MS ESI calc'd. for C13H20BrN2O2 [M+H]+ 315 and 317. found 315 and 317. 1H NMR (400 MHz, CDCl3): δ 7.35 (s, 1H), 7.22 (s, 1H), 4.53-4.50 (m, 1H), 3.69 (s, 3H), 2.26-2.18 (m, 1H), 2.06-1.78 (m, 4H), 1.36-1.28 (m, 2H), 1.06 (s, 3H), 0.97 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:19]([CH2:34][CH3:35])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=O)[NH:27][C:26]=1[CH3:33])=[O:24])[CH3:18].N1CCCCC1>C(O)C>[CH2:34]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:11][C:10]2=[O:16])[NH:27][C:26]=1[CH3:33])=[O:24])[CH3:35]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2c(cccc2-c2ccccc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4ccccc4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 55.9 %

Procedure:
To a solution of 4-phenyl-1,3-dihydro-indol-2-one (41.9 mg, 0.20 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (53.1 mg, 0.20 mmol) in ethanol (1 mL) was added piperidine (0.1 mL). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 2,4-dimethyl-5-(2-oxo-4-phenyl-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (51 mg, 56%)