Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20](B5OC(C)(C)C(C)(C)O5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:31]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Br[C:33]1[N:34]=[C:35]([CH2:39][C:40]([CH3:43])([OH:42])[CH3:41])[N:36]([CH3:38])[CH:37]=1.[F-].[Cs+].O>CN(C=O)C.[Cu]I.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>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:33]5[N:34]=[C:35]([CH2:39][C:40]([CH3:43])([OH:42])[CH3:41])[N:36]([CH3:38])[CH:37]=5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:31]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: Cn1cc(Br)nc1CC(C)(C)O
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(B3OC(C)(C)C(C)(C)O3)cc1OCC2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3cn(C)c(CC(C)(C)O)n3)cc1OCC2
Temperature: 130 °C
Yield: 16.2 %

Procedure:
To a mixture of 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (200 mg, 0.48 mmol) and 1-(4-bromo-1-methyl-1H-imidazol-2-yl)-2-methyl-propan-2-ol (166 mg, 0.71 mmol) in dry DMF (2 mL) under nitrogen was added CsF (180 mg, 1.19 mmol), CuI (9 mg, 0.048 mmol) and Pd(PPh3)4 (27 mg, 0.024 mmol). The reaction mixture was heated at 130° C. for 40 min under microwave. Cooled to room temperature, the resulting mixture was poured into water and extracted with EtOAc. Dried organics over sodium sulfate and purified by pre-HPLC to give 272 as a white solid (34.9 mg, yield: 16%). 1H NMR (DMSO-d6, 400 MHz): δ8.51 (s, 1H), 7.90 (s, 1H), 7.86 (s, 1H), 7.23-7.11 (m, 3H), 5.93-5.89 (m, 1H), 4.54-4.52 (m, 4H), 3.74-3.66 (m, 5H), 1.46 (dd, J=6.4 Hz, 6H), 1.24(brs, 6H). MS: (ESI, m/z)=448 [M+H]+
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[CH2:11]([NH2:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(O)CC>O>[CH2:11]([NH:23][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: Clc1ncnc2nc[nH]c12
Reactant: CCCCCCCCCCCCN
Solvent: CCCO
Solvent: O
Product: CCCCCCCCCCCCNc1ncnc2nc[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
A mixture of 6-chloropurine (2.5 g, 0.016 mole) and n-dodecylamine (7.4 g, 0.04 mole) in 40 ml. of n-propanol was refluxed for 5 hours. The reaction mixture was stirred at room temperature for 1 hour and cooled with water (15° C.) for another hour. The product was collected by filtration, washed by two 5 ml. portions of n-propanol and dried in a vacuum oven overnight to give 4.5 g (92% yield) of 6-n-dodecylaminopurine, a colorless solid, m.p. 159°-160° C., λ max (H2O)=268 nm, ε=17.3×103.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:22])[CH2:6][C@@H:7]([C:20]#[CH:21])[N:8](N1[C@H](C)C[C@H](N)C1=O)[C:9](=[O:11])[CH3:10])[CH3:3].N1C2NCCCC=2C=CC=1C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[CH2:2]([O:4][C:5](=[O:22])[CH2:6][C@@H:7]([C:20]#[CH:21])[NH:8][C:9](=[O:11])[CH3:10])[CH3:3]
Reactant: C#C[C@H](CC(=O)OCC)N(C(C)=O)N1C(=O)[C@@H](N)C[C@H]1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=Cc1ccc2c(n1)NCCC2
Solvent: CC(Cl)Cl
Product: C#C[C@H](CC(=O)OCC)NC(C)=O

Procedure:
To a solution of 13-11 (450 mg, 1.39 mmol) and 5,6,7,8-tetrahydro-[1,8]naphthyridine-2-carbaldehyde (225 mg, 1.39 mmol) in dichloroethane at 0° C. was added Na(OAc)3BH. After 1.5 h the reaction was quenched with sat. NaHCO3, diluted with EtOAc, washed with sat. NaHCO3, brine and dried over MgSO4. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:20:10 chloroform/ethyl acetate/MeOH to give 13-12 as a colorless foam.
Reaction SMILES: [C:1]([O:10]C1C=CC=CC=1)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:1](=[O:10])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[OH:4])=[CH:20][CH:19]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(Oc1ccccc1)c1ccccc1O
Product: O=C(Nc1ccc(Cl)cc1)c1ccccc1O

Procedure:
The 4′-chloro-salicylanilide was prepared by condensing phenyl salicylate with 4-chloroaniline then purified as described in Example 2a.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-])=O)(=[O:4])=[O:3]>C(O)C.[Pd]>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CS(=O)(=O)c1ccccc1N
Reaction time: 16 h
Yield: 96.2 %

Procedure:
2-Methylsulfonyinitrobenzene (6.0g, 0.03 mol) was suspended in absolute ethanol (60 mL). 6% Pd/C catalyst (50% wet; 1.01 g) was added and the suspension was hydrogenated in a Parr shaker at 40 psi for 16 hours. The catalyst was then filtered over a pad of infusorial earth and washed with ethanol (2×10 ml). The filtrate was concentrated to dryness on a rotary evaporator. 4.94 g (96% yield) of the product was obtained as white crystals. mp 82-84° C. 1H NMR (CDCl3) δ 7.7 (dd, 1H), 7.2-7.3 (m, 1H), 6.5-6.8 (m, 2H), 5.04 (bs, 2H), 3.07 (s, 3H); CIMS (m/e) 172 (M+H+, 100%).
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[CH:7][C:6]([C:9](OC)=[O:10])=[N:5]1)([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH:1]([N:4]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[N:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccn(C(C)C)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)n1ccc(CO)n1
Reaction time: 3 h
Yield: 82.9 %

Procedure:
To methyl 1-isopropyl-1H-pyrazole-3-carboxylate (5.0 g, 29.7 mmol) in anhydrous ether (0.5M, 60 mL) at 0° C. was added lithium aluminum hydride (32.7 mL, 32.7 mmol). The cold bath was removed and the mixture stirred for 3 hours. The mixture was poured slowly into an Erlenmeyer flask containing cold (0° C.) Rochelle's salt solution (1 L). After stirring for 1 hour, the mixture was diluted with Et2O (200 mL). The organic phase was separated, and the aqueous phase was further extracted with Et2O. The combined extracts were concentrated and dried under high vacuum to afford (1-isopropyl-1H-pyrazol-3-yl)methanol (3.45 g, 83% yield) as a clear oil.
Reaction SMILES: [F-].[Cs+].Br[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[CH2:5].[O:12]1[CH2:17][CH2:16][CH2:15][O:14][CH:13]1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[S:25][C:26]3[C:31]([N:32]=2)=[CH:30][CH:29]=[C:28]([Sn](C)(C)C)[N:27]=3)=[C:20]([F:37])[CH:19]=1>CN(C=O)C.CC(=O)OCC.[Cu]I.[Pd].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>[O:12]1[CH2:17][CH2:16][CH2:15][O:14][CH:13]1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[S:25][C:26]3[C:31]([N:32]=2)=[CH:30][CH:29]=[C:28]([C:4]([CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)=[CH2:5])[N:27]=3)=[C:20]([F:37])[CH:19]=1
Reactant: C=C(Br)C1CCCCC1
Reactant: C[Sn](C)(C)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1
Agent: [Cu]I
Agent: [Pd]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1)C1CCCCC1
Temperature: 55 °C

Procedure:
A mixture of copper(I) iodide (0.0159 g, 0.0835 mmol), cesium fluoride (0.380 g, 2.50 mmol), (1-bromovinyl)cyclohexane (0.947 g, 5.01 mmol), tetrakis(triphenylphosphine) palladium (0) (0.0965 g, 0.0835 mmol), and 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(trimethylstannyl)-thiazolo[5,4-b]pyridine (0.800 g, 1.67 mmol) in 7.5 mL DMF was heated at 55° C. for several hours. The reaction mixture was cooled, diluted with EA, and filtered through celite. The organic layer was washed with water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give a solid, which was adsorbed onto silica gel and purified by silica gel chromatography, 0-40-100% EA/hexanes to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-cyclohexylvinyl)thiazolo[5,4-b]pyridine as an off white solid. MS (ESI) m/z: calculated: 424.2; Observed: 425.1 (M++1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[NH:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:8]([CH3:14])=[N:7]1.[OH-].[Na+]>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:11][C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]([CH3:14])[N:7]=1
Reactant: CC1=NC(c2ccco2)NC(C)(C)C1
Agent: [Na+]
Agent: [OH-]
Product: CC1CC(C)(C)NC(c2ccco2)=N1

Procedure:
A sample of 150 g. of 2-furyl-4,4,6-trimethyl-2,3,4,5-tetrahydropyrimidine and 10 g. of solid sodium hydroxide were heated to 180° C. over a 2 hr. period. The resulting product was distilled under diminished pressure to yield 52 grams of 2-furyl-4,4,6-trimethyl-3,4,5,6-tetrahydropyrimidine b2.0 120°-122° C., solidified during distillation; infrared spectrum, 3.06μ, NH, 6.20μ, C=N. Nuclear magnetic resonance spectrum, solvent CDCl3 ; δ in ppm. 7.38 m, 1H; 6.90 m, 1H; 6.40 m, 1H; 3.55 m, 1H; 1.72 d of d's, 2H; 1.25 d, 3H; 1.20 s, 6H.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[CH3:18][C:19]([O:22][C:23]([NH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:24])([CH3:21])[CH3:20]>C(O)C>[C:19]([O:22][C:23](=[O:24])[NH:25][CH:26]1[CH2:31][CH2:30][N:29]([C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:28][CH2:27]1)([CH3:21])([CH3:18])[CH3:20]
Reactant: Clc1ncnc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 80 °C
Yield: 37.4 %

Procedure:
To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (74 mg, 0.48 mmol) in ethanol (1 ml) was added triethylamine (200 μl, 1.43 mmol) and 4-N-Boc-aminopiperidine (106 mg, 0.53 mmol). The solution was heated at 80° C. for 4 hours, and then cooled to room temperature. The precipitate was collected by filtration and washed with ethanol (2 ml), then dried under vacuum to yield the product (57 mg, 36%). LC/MS (LCT) Rt 4.57 [M+H]+318
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[Na+].[Na+].O.[C:20](Cl)(Cl)=[O:21]>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:20](=[O:21])[O:9][C:7](=[O:8])[C:6]=2[CH:10]=1
Reactant: O=C(Cl)Cl
Reactant: CNc1ccc(I)cc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1c(=O)oc(=O)c2cc(I)ccc21
Reaction time: 2 h

Procedure:
To a stirred solution of 5-iodo-2-(methylamino)benzoic acid (10 g, 36 mmol), sodium carbonate (4 g, 36 mmol) and water (130 ml, 7218 mmol), cooled to 0° C., was slowly added, via addition funnel, a 2M phosgene (18 ml, 36 mmol) solution in toluene. After 2 hrs, the precipitated product was isolated by filtration. The solids were washed with 100 ml of water, 150 ml of a 1:1 mixture ethanol and ether, 100 ml of ether, and dried under vacuum to give the desired product. Yield=7.15 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[C:12]1([CH:18]2[O:20][CH:19]2[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+]>C(O)C.C(Cl)(Cl)Cl>[OH:20][CH:19]([CH:18]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Reactant: CCOC(=O)C1OC1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCOC(=O)C(O)C(Oc1ccc(Cl)cc1[N+](=O)[O-])c1ccccc1
Yield: 32.6 %

Procedure:
To a stirred mixture of 4-chloro-2-nitrophenol (11.68 g, 67.32 mmol), ethyl 3-phenyloxirane-2-carboxylate (9.61 g, 50.00 mmol) in ethanol (200 mL) was added portionwise 60% sodium hydride (738 mg, 20.00 mmol) and the red mixture stirred at reflux for 3 days. The solvent was removed in vacuo. The residue was dissolved in chloroform and extracted three times with 10% aqueous potassium carbonate. The organic layer was washed with water and brine, dried, filtered and evaporated to afford a brown residue. The residue was dissolved in a minimal volume of chloroform and precipitated by adding diethyl ether to afford the title compound (5.970 g, 33%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ1.16 (t, 3H, J=7.0 Hz), 4.09 (q, 2H, J=7.0 Hz), 4.29 (t, 1H, J=7.0 Hz), 5.63 (d, 1H, J=7.0 Hz), 6.09 (d, 1H, J=7.0 Hz), 7.19-7.60 (m, 7H), 7.97 (d, 1H, J=2.6 Hz). MS APCI, m/z=388 (M+Na). LC/MS: 2.78 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[C:15]([O:22][CH2:23][CH3:24])[CH:14]=3)[O:10][N:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C1C=CC=CC=1Br.B1([C:45]2[CH2:50][CH2:49][N:48](C(OC(C)(C)C)=O)[CH2:47][CH:46]=2)OC(C)(C)C(C)(C)O1.B(O)O>>[CH2:23]([O:22][C:15]1[CH:14]=[C:13]([C:11]2[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:45]4[CH2:50][CH2:49][NH:48][CH2:47][CH:46]=4)=[CH:3][CH:4]=3)[N:12]=2)[CH:18]=[CH:17][C:16]=1[O:19][CH2:20][CH3:21])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CCOc1ccc(-c2nc(-c3ccc(Br)cc3)no2)cc1OCC
Agent: FC(F)(F)c1ccccc1Br
Agent: OBO
Product: CCOc1ccc(-c2nc(-c3ccc(C4=CCNCC4)cc3)no2)cc1OCC
Yield: 57 %

Procedure:
When the product of Step B was substituted for 2-trifluoromethyl-bromobenzene and 3,6-dihydro-2H-pyridine-1-tert-butoxycarbonyl-4-boronic acid was substituted for 4-carbaldehyde boronic acid in Example 36 Step A, the similar process gave the title compound in 57% yield. This (0.085 g) was dissolved in anhydrous CH2Cl2 (2 ml) and CF3CO2H (0.5 ml) was added to it. The mixture was stirred for 3 h, then the solvent was evaporated to dryness. The residue was purified by FCC (SiO2) to give the title compound (0.063 g, 93%), as a colourless solid. 1H-NMR (CDCl3) 1.47-1.52 (m, 6H); 2.72 (m, 2H); 3.33-3.29 (m, 2H); 3.75 (m, 2H); 4.14-4.24 (m, 4H); 6.2 (s, 1H); 6.97 (d, 1H, J=8.4 Hz); 7.64-7.68 (m, 3H); 7.78 (d, 1H, J=8.42); 8.24 (d, 2H, J=8.19 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[CH:21]=[CH:20][C:12]3[NH:13][C:14](=[O:19])[O:15][C:16]([CH3:18])([CH3:17])[C:11]=3[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[S:22]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23]1>>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:21]=[CH:20][C:12]3[NH:13][C:14](=[O:19])[O:15][C:16]([CH3:18])([CH3:17])[C:11]=3[CH:10]=2)[CH:3]=[C:2]([C:24]2[CH:25]=[CH:26][S:22][CH:23]=2)[CH:7]=1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(Br)c3)cc21
Reactant: OB(O)c1ccsc1
Product: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(-c4ccsc4)c3)cc21

Procedure:
Prepared from 6-(3-bromo-5-fluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one and 3-thiophene boronic acid according to procedure B. A brownish-orange solid: mp 200-203° C.; 1H-NMR (CDCl3) δ8.62 (s, 1H), 7.53 (q, 1H, J=1.4 Hz), 7.50 (d, 1H, J=1.5 Hz), 7.49 (d, 1H, J=2.0 Hz), 7.45-7.40 (m, 1H), 7.35 (d, 1H, J=1.8 Hz), 7.27-7.24 (m, 2H), 7.15 (dt, 1H, J=5.8, 2.0 Hz), 694 (d, 1H, J=8.2 Hz), 1.80 (s, 6H); MS ((−)APCI) [M−H]− @ m/z 352. Anal. Calc. For C20H16FNO2S 0.50 H2O: C, 66.28; H, 4.73; N, 3.87. Found: C, 66.54; H, 5.03; N, 3.52.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28](Cl)[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:20][C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5].ClC1C=CC=C([F:51])C=1C(NC1C(C(O)=O)=NNC=1)=O>>[Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([F:51])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:20][C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5]
Reactant: O=C(O)c1n[nH]cc1NC(=O)c1c(F)cccc1Cl
Reactant: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)c1c(Cl)cccc1Cl
Product: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)c1c(F)cccc1Cl

Procedure:
The compound was prepared in a manner analogous to 2,6-dichloro-N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (Example 94E), but using 4-(2-chloro-6-fluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid, to give 2-chloro-6-fluoro-N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (37 mg) as a pink solid. (LC/MS: Rt 2.04, [M+H]+ 455.18).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([NH2:14])[NH:10][C:9]=2[CH:8]=[C:7]([N+:15]([O-:17])=[O:16])[CH:6]=1)=[O:4].[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([C:28](O)=[O:29])[N:19]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([NH:14][C:28]([C:20]3[N:19]=[CH:18][C:27]4[C:22]([CH:21]=3)=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:29])[NH:10][C:9]=2[CH:8]=[C:7]([N+:15]([O-:17])=[O:16])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc2[nH]c(N)nc12
Reactant: O=C(O)c1cc2ccccc2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COC(=O)c1cc([N+](=O)[O-])cc2[nH]c(NC(=O)c3cc4ccccc4cn3)nc12
Yield: 80.8 %

Procedure:
0.5 g (2.12 mmol) of 2-amino-6-nitro-1H-benzoimidazole-4-carboxylic acid methyl ester was reacted with 0.37 g (2.12 mmol) of isoquinoline 3-carboxylic acid and 0.89 g (2.33 mmol) of HBTU as described in general procedure A to provide 0.67 g (80%) of 2-[(Isoquinoline-3-carbonyl)-amino]-6-nitro-1H-benzoimidazole-4-carboxylic acid methyl ester. LCMS: 392 (M+1)+. The ester was dissolved in dry DMF (5 mL) and 0.22 g (5.1 mmol) of LiCl in one portion was added. The resulting mixture was stirred at 120° C. for 12 h, diluted with water, and the solid was collected by filtration. The solid was washed with water (20 mL), ether (10 mL) and dried under vacuum to provide 0.6 g (93%) of 2-[(isoquinoline-3-carbonyl)-amino]-6-nitro-1H-benzoimidazole-4-carboxylic acid. LCMS: 378 (M+1)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.C(N(CC)CC)C.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:27][C@@H:26]1[CH2:38][CH2:39][OH:40])=[O:24])([CH3:21])([CH3:20])[CH3:19]>ClCCl>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:27][C@@H:26]1[CH2:38][CH:39]=[O:40])=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C[C@@H]1CCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C[C@@H]1CC=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 50249.6 %

Procedure:
Add dichloromethane (3 mL) to a 50 mL dry schlenk flask, followed by oxalyl chloride (0.178 g, 1.4 mmol) and cool the solution to −78° C. and treat with dimethyl sulfoxide (0.171 g, 2.2 mmol) and triethylamine (0.505 g, 5.0 mmol). After 10 min, add a solution of (S)-4-benzyl-2-(2-hydroxy-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (0.320 g, 1.0 mmol) in dichloromethane (5 mL) and stir the resulting mixture at −78° C. for 1 hour. Quench the reaction mixture by adding sat. NaHCO3, extract the aqueous solution with CH2Cl2, wash the organic solvent with brine, and dry over Na2SO4. Purification by silica gel chromatography of the crude product using MeOH/CH2Cl2 (5% to 10%) as eluent to give the title compound (160 g, 50%) as a light yellow oil: mass spectrum (Electrospray): m/z=319.2 (M+1); 1H NMR (400 MHz, CDCl3): δ9.74 (t, 1H, J=2.0 Hz), 7.33–7.21 (m, 5H), 4.57 (br, 1H), 3.88 (m, 2H), 33.52–3.40 (m, 21H), 3.15–3.05 (m, 1H), 2.83–2.66 (m, 4H), 2.22–2.18 (m, 1H), 2.03 (dt, 1H, J=3.4, 11.8 Hz), 1.44 (s, 9H).
Reaction SMILES: NCC(N)C.[C:6]1([CH:12]([NH2:15])[CH2:13][NH2:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:16]([NH:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][N:33]=1)[C:28](O)=O)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:6]1([CH:12]2[CH2:13][NH:14][C:28]([C:27]3[CH:31]=[CH:32][N:33]=[C:25]([NH:24][C:16](=[O:23])[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:26]=3)=[N:15]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCC(N)c1ccccc1
Reactant: O=C(O)c1ccnc(NC(=O)c2ccccc2)c1
Agent: CC(N)CN
Product: O=C(Nc1cc(C2=NC(c3ccccc3)CN2)ccn1)c1ccccc1
Yield: 17 %

Procedure:
Following the procedure as described in Example 9, making variations as required to replace 1,2-diaminopropane with 1-phenylethane-1,2-diamine to react with 2-benzamidoisonicotinic acid, N-(4-(4-phenyl-4,5-dihydro-1H-imidazol-2-yl)pyridin-2-yl)benzamide was obtained in 17% yield: MS (ES+) m/z 343.3 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:7](SC)=[N:6][C:5](=[O:10])[N:4]([CH:11]([CH3:13])[CH3:12])[C:3]1=[O:14].[CH3:15][NH:16][CH3:17]>O1CCCC1>[CH3:1][N:2]1[C:7]([N:16]([CH3:17])[CH3:15])=[N:6][C:5](=[O:10])[N:4]([CH:11]([CH3:13])[CH3:12])[C:3]1=[O:14]
Reactant: CSc1nc(=O)n(C(C)C)c(=O)n1C
Reactant: CNC
Solvent: C1CCOC1
Product: CC(C)n1c(=O)nc(N(C)C)n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 10 parts of 1-methyl-3-isopropyl-6-methylthio-s-triazine-2,4(1H,3H)-dione in 100 parts of tetrahydrofuran at 0° is saturated with dimethylamine. The reaction is allowed to warm to room temperature and stand overnight. The solvent is evaporated and the residue triturated with ether to afford 9 parts of 1-methyl-3-isopropyl-6-dimethylamino-s-triazine-2,4(1H,3H)-dione, m.p. 104°-106°.
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C:7]1[CH:8]=[C:9]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1)[C:10](N(OC)C)=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH3:25][Mg]Cl>C1COCC1.CCOCC>[C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C:7]1[CH:8]=[C:9]([C:10](=[O:11])[CH3:25])[CH:16]=[C:17]([C:19]([F:21])([F:20])[F:22])[CH:18]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CON(C)C(=O)c1cc(O[Si](C)(C)C(C)(C)C)cc(C(F)(F)F)c1
Reactant: C[Mg]Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1cc(O[Si](C)(C)C(C)(C)C)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99950.2 %

Procedure:
To an ice-cold suspension of 3-(tert-butyl-dimethyl-silanyloxy)-N-methoxy-N-methyl-5-trifluoromethyl-benzamide (500 mg, 1.37 mmol) in THF (5 mL) was added dropwise 3.0M CH3MgCl (687 mL, 2.06 mmol) at 0° C. The mixture was stirred for 3 hours at room temperature, and then diluted with Et2O. The reaction mixture was washed with saturated ammonium chloride, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography to give 1-[3-(tert-butyl-dimethyl-silanyloxy)-5-trifluoromethyl-phenyl]-ethanone (436 g, 99%).
Reaction SMILES: [C:1]([NH:4][C@@H:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)[CH3:6])(=[O:3])[CH3:2].[N+:17]([O-])([OH:19])=[O:18].S(=O)(=O)(O)O>>[C:1]([NH:4][C@@H:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])[CH3:6])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc([C@@H](C)NC(C)=O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc([C@@H](C)NC(C)=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Methyl (R)-4-(1-acetamidoethyl)benzoate (2 g) was added portionwise to a mixed solution of conc. nitric acid (1.2 ml) and conc. sulfuric acid (1.2 ml) under ice-cooling, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into ice-water, and extracted with chloroform. The extract was washed with water, dried, and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-hexane to give 1.4 g of methyl (R)-4-(1-acetamidoethyl)-3-nitrobenzoate.