Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3](=[O:17])[CH2:4][C:5]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])([CH3:7])[CH3:6].[CH2:20]([Mg]Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH2:20]([C:3]([OH:17])([CH2:4][C:5]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])([CH3:7])[CH3:6])[C:2]([F:1])([F:18])[F:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)C(F)(F)F
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1ccccc1)C(F)(F)F
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a chilled (−70° C.) solution of 70 mg (0.25 mmol) of 1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (Example 1) in 2.5 mL of anhydrous THF was added a 2.0 M solution of benzyl magnesium chloride in THF. The mixture was stirred for 30 minutes and then was quenched with 15 mL of saturated aqueous ammonium chloride and extracted with five 5 mL portions of EtOAc. The combined organic layers were washed with three 5 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was chromatographed on silica gel using hexanes to load the sample, and then eluted with hexanes and then EtOAc-hexanes (0.5:99.5, then 1:99) to afford 58 mg (62%) of the title compound as an oil.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:6])[CH2:4][CH3:5].CC(C)([O-])C.[K+].Cl[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:1][CH2:2][C@@H:3]([OH:6])[CH2:4][CH3:5]
Reactant: Clc1ccccn1
Reactant: CC[C@H](O)CN
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CC[C@H](O)CNc1ccccn1

Procedure:
(S)-1-Aminobutan-2-ol (35 millimoles), potassium tertiary butoxide (77 millimoles) and 2-chloropyridine (38.5 millimoles) were used in a similar manner to Example 1(a) to obtain the title compound, [α]D26 =+10°(1.12% concentration in trichloromethane).
Reaction SMILES: CO[C:3](=[C:14]([C:17]#[N:18])[C:15]#[N:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1.Cl.[C:20]([NH:24][NH2:25])([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C>CCO>[N+:11]([C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[CH2:4][C:3]1[C:14]([C:15]#[N:16])=[C:17]([NH2:18])[N:24]([C:20]([CH3:23])([CH3:22])[CH3:21])[N:25]=1)([O-:13])=[O:12]
Reactant: COC(Cc1cccc([N+](=O)[O-])c1)=C(C#N)C#N
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)n1nc(Cc2cccc([N+](=O)[O-])c2)c(C#N)c1N

Procedure:
Reagent 2-(1-methoxy-2-(3-nitrophenyl)ethylidene)malononitrile (1.2 g; 4.7 mmol) was combined with tert-butylhydrazine-HCl (0.57 g; 5.2 mmol; Sigma-Aldrich), 1.4 mL triethylamine in 50 mL EtOH for at 2 hours at 80° C. The reaction was concentrated in vacuo, resuspended in brine and extracted with chloroform. The organic layer was dried over MgSO4. Following, the organic suspension was filtered, concentrated in vacuo, and purified on silica gel in 1% MeOH:CHCl3 to yield 3-(3-nitrobenzyl)-1-tert-butyl-5-amino-1H-pyrazole-4-carbonitrile (ESI-MS m/z [M−CH3]+ found 285.5, calculated 285.14; 1H NMR (400 MHz, DMSO): δ8.11 (s, 1H), 8.08-8.12 (m, 1H), 7.69 (d, J=8 Hz, 1H), 7.59-7.64 (m, 1H), 3.96 (s, 2H), 3.34 (br, 2H), 1.52 (s, 9H)). This product was combined with formamide as per Cmpd 1 to yield 3-(3-nitrobenzyl)-1-tert-butyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (ESI-MS m/z [M+H]+ found 327.4, calculated 327.15; 1H NMR (400 MHz, DMSO): δ 8.22 (s, 1H), 8.14 (s, 1H), 8.07 (d, J=8 Hz, 1H), 7.67 (d, J=8 Hz, 1H), 7.59 (d, J=8 Hz, 1H), 7.22 (br, 2H), 4.52 (s, 2H), 1.70 (s, 9H)). Reduction of this material was completed as per Cmpd 1 to yield 3-(3-aminobenzyl)-1-tert-butyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (ESI-MS m/z [M+H]+ found 297.13, calculated 297.17). The reduced precursor was coupled to 3-(trifluoromethyl)phenyl isocyanate and purified as described for Cmpd 1 to yield Cmpd 4 1-(3-((1-tert-butyl-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)methyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea (ESI-MS m/z [M+H]+ found 484.5, calculated 484.2; 1H NMR (400 MHz, DMSO): δ 9.25 (s, 1H), 8.96 (s, 1H), 8.32 (s, 1H), 8.06 (s, 1H), 7.46-7.55 (m, 2H), 7.40 (s, 1H), 7.29 (d, J=8 Hz, 2H), 7.20 (t, J=8 Hz, 1H), 6.89 (d, J=8 Hz, 1H), 4.39 (s, 2H), 1.73 (s, 9H). 13C NMR (400 MHz, DMSO): δ 29.25, 33.40, 60.74, 99.58, 116.43 (d), 116.95, 118.86, 122.13, 122.64, 124.69 (q), 129.29, 129.98 (q), 130.32, 139.60, 140.06, 141.16, 143.31, 149.70, 152.69, 152.92, 154.81, 159.12 (q)).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=[C:4]([Cl:20])[N:3]=1.Cl.[CH2:22]([NH2:24])[CH3:23].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:20][C:4]1[N:3]=[C:2]([NH:24][CH2:22][CH3:23])[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=1
Reactant: CCN
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)NCc1cccc(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCNc1nc(Cl)cc(C)c1C(=O)NCc1cccc(F)c1
Temperature: 100 °C
Yield: 13 %

Procedure:
A suspension of 626 mg (2.0 mmol) 2,6-dichloro-N-(3-fluorobenzyl)-4-methyl-pyridine-3-carboxylic acid amide (synthesis is described in section a) of example 2), 244 mg (2.4 mmol) ethylamine hydrochloride and 689 mg (5.0 mmol) K2CO3 in DMF (6 ml) was heated to 100° C. for 3 d. Then the RM was poured into ice water (10 ml), followed by extraction with EtOAc (3×15 ml). The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 1:1) provided 84 mg (0.26 mmol, 13%) 6-chloro-2-ethylamino-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide.
Reaction SMILES: FC1C(C(O)=O)=C([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)C(C)=CC=1.[F:17][C:18]1[C:19]([CH3:28])=[C:20]([C:24](I)=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22]>>[F:17][C:18]1[C:19]([CH3:28])=[C:20]([C:24]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22]
Reactant: Cc1ccc(F)c(C(=O)O)c1-n1nccn1
Reactant: Cc1c(F)ccc(I)c1C(=O)O
Product: Cc1c(F)ccc(-n2nccn2)c1C(=O)O

Procedure:
The title compound was prepared following the same general protocol as described for 6-fluoro-3-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid in Example A352 using 3-fluoro-6-iodo-2-methylbenzoic acid. MS (ESI) 222 (M+H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:9](=[O:11])[NH:10][C:5]2=[N:4][CH:3]=1.B(O)(O)[C:21]1[CH:26]=[CH:25][C:24]([C:27]([NH2:29])=[O:28])=[CH:23][CH:22]=1.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O>[O:11]=[C:9]1[NH:10][C:5]2=[N:4][CH:3]=[C:2]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([NH2:29])=[O:28])=[CH:23][CH:22]=3)[N:7]=[C:6]2[N:8]1[CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: NC(=O)c1ccc(B(O)O)cc1
Reactant: O=c1[nH]c2ncc(Br)nc2n1CCC1CCOCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1ccc(-c2cnc3[nH]c(=O)n(CCC4CCOCC4)c3n2)cc1
Yield: 89 %

Procedure:
4-(2-oxo-3-(2-(Tetrahydro-2H-pyran-4-yl)ethyl)-2,3-dihydro-1H-imidazol-[4,5-b]pyrazin-5-yl)benzamide. 6-Bromo-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (0.400 g, 1.22 mmol), 4-carboxamide-phenylboronic acid (0.241 g, 1.46 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (0.098 g, 0.12 mmol), potassium phosphate (1.03 g, 4.88 mmol), water (2 ml) and dimethylformamide (7 mL) were reacted according to General Procedure B. The solution was condensed under reduced pressure and the product was crystallized from dichloromethane to give (0.400 g, 89% yield). 1H NMR (400 MHz, CD3OD) δ 8.54 (s, 1H) 8.40 (s, 1H), 8.09 (d, J=8.4, 2H), 7.94 (d, J=8.4, 1H), 4.08 (t, J=6.8, 2H), 3.92 (dd, J=11.2, 3.2, 2H), 3.64 (m, 2H), 1.83 (m, 4H), 1.59 (m, 1H), 1.38 (qd, J=12.8, 4.4, 2H); MS (ESI) m/z 368.4 [M+1]+; mp 233-236° C.
Reaction SMILES: [C:1]1([C:7]2[C:13]3=[CH:14][NH:15][C:16]4[CH:17]=[CH:18][CH:19]=[C:11]([C:12]=43)[C:10](=[O:20])[NH:9][N:8]=2)C=CC=CC=1.N1C2C=CC=C(C(OC)=O)C=2C=C1.C(Cl)(=O)C.[Cl-].[Al+3].[Cl-].[Cl-].O.NN>ClC(Cl)C.CO.Cl>[CH3:1][C:7]1[C:13]2=[CH:14][NH:15][C:16]3[CH:17]=[CH:18][CH:19]=[C:11]([C:12]=32)[C:10](=[O:20])[NH:9][N:8]=1
Reactant: O=C1NN=C(c2ccccc2)c2c[nH]c3cccc1c23
Agent: COC(=O)c1cccc2[nH]ccc12
Agent: Cl
Agent: NN
Solvent: CC(=O)Cl
Solvent: O
Solvent: CC(Cl)Cl
Product: CC1=NNC(=O)c2cccc3[nH]cc1c23

Procedure:
In a manner similar to that described for compound 28, a solution of methyl indole-4-carboxylate (427 mg, 2.44 mmol) in dichloroethane (7 mL) was treated with acetyl chloride (0.5 mL) and aluminum chloride (130 mg). The intermediate ketone (198 mg, 0.92 mmol) in MeOH (5 mL) and conc. HCl (0.05 mL) was treated, as described, with hydrazine hydrate (0.1 mL). The product precipitated, was collected by filtration and rinsed with ice-cold MeOH to give 1,5-dihydro-3-methyl-[1,2]diazepino[4,5,6-cd]-indol-6-one, 168 mg (92%) as a bright yellow solid: m.p. 335-336° C.; 1H NMR (300 MHz, d6-DMSO) δ 2.17 (s, 3H), 7.19 (t, J=7.8 Hz, 1H), 7.54 (m, 2H), 7.67 (d, J=2.8 Hz, 1H), 10.12 (s, 1H), 11.90 (br s, 1H). HRMS (FAB, MH+) Calcd for C11H10N3O: 200.0824. Found: 200.0827. Anal. (C11H9N3O) C, H, N.
Reaction SMILES: [OH:1][C@:2]1([C:30]([O:32]C)=[O:31])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]([CH3:29])[CH:20]=2)=[CH:13][CH:12]=1)(=[O:10])=[O:9].[OH-].[Na+].CO>C1COCC1>[OH:1][C@:2]1([C:30]([OH:32])=[O:31])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][S:8]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]([CH3:29])[CH:20]=2)=[CH:15][CH:16]=1)(=[O:9])=[O:10]
Reactant: COC(=O)[C@@]1(O)CCC[C@H]1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCC[C@]3(O)C(=O)O)cc2)c2ccccc2n1
Reaction time: 5 h
Yield: 438.1 %

Procedure:
To a solution of methyl (1R,2R)-1-hydroxy-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylate (0.19 g, 0.4 mmol ) in THF (2 mL) was added sodium hydroxide solution (5 M, 2 mL) and methanol (2 mL) to make the reaction mixture homogenous. The reaction was stirred for 5 h, and then the MeOH/THF was removed in vacuo. The reaction was quenched with a pH 3 sodium phoshphate buffer. Ethyl acetate was added to this mixture, resulting in the formation of a white precipitate which was isolated by filtration to afford (1R,2R)-1-hydroxy-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylic acid (0.8 g, 42%) as a white solid. MS: 457.0 (M+H)+
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:27])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:26])[C@H:17]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH2:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:35]1([S:41](Cl)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[CH2:2]([O:9][C:10](=[O:27])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:26])[C@H:17]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:18][S:41]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:43])=[O:42])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 86.9 %

Procedure:
L-phenylalanyl-L-proline benzylester hydrochloride (1.94 g, 5 mmole) was dissolved in methylene chloride (30 ml), and triethylamine (1.11 g, 11 mmole) was added thereto at -30° C. Methylene chloride (10 ml) solution of benzene sulfonyl chloride (0.86 g, 5 mmole) was added dropwise to the solution. The mixture was stirred for 1 hour at less than 0° C., and then for 5 hours at room temperature, and methylene chloride (60 ml) was added thereto. The solution was washed with 5% aqueous sodium bicarbonate (100 ml, twice), 1N aqueous hydrochloric acid (100 ml, twice) and water (100 ml) in the order given, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give N-benzenesulfonyl-L-phenylalanyl-L-proline benzylester (yield: 2.14 g, 86.9%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:15][C:16]([OH:18])=O)[N:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:45][C:46]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)=[CH:48][C:47]=1[C:58]([F:61])([F:60])[F:59].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:45][C:46]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:57][CH2:56][N:55]([C:16](=[O:18])[CH2:15][N:8]3[C:9]4=[N:10][CH:11]=[CH:12][CH:13]=[C:14]4[C:6]([C:2]4[NH:1][CH:5]=[CH:4][N:3]=4)=[N:7]3)[CH2:54][CH2:53]2)=[CH:48][C:47]=1[C:58]([F:60])([F:59])[F:61]
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Reactant: FC(F)(F)c1cc(N2CCNCC2)ccc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cn1nc(-c2ncc[nH]2)c2cccnc21)N1CCN(c2ccc(Cl)c(C(F)(F)F)c2)CC1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
This compound was prepared by Protocol A. A vial was charged with 2-(3-(1H-imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)acetic acid (55 mg, 0.226 mmol), HBTU (125 mg, 0.33 mmol), 1-(4-Chloro-3-trifluoromethyl-phenyl)-piperazine dihydrochloride (170 mg, 0.50 mmol), anhydrous DMF (2.0 mL), and DIPEA (0.5 mL). The vial was capped, heated to 45° C., and stirred overnight. The following day, the volatiles were removed in vacuo and separation by preparative hplc (reverse phase, acetonitrile-water gradient) gave 1-[4-(4-Chloro-3-trifluoromethyl-phenyl)-piperazin-1-yl]-2-[3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]-ethanone: MS (ES) [M+H]+ found: 490.4
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]([N:37]([CH3:38])[CH3:39])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N(Cc3ccccc3)C(=O)N(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(N(Cc3ccccc3)C(=O)N(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-(dimethylaminocarbonyl)-benzylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[F:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1I.[Cl-].[Li+].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Cu]I>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:17]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[F:11])[CH:6]=[CH:5]2
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: Fc1cnccc1I
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Fc1cnccc1-n1ccc2cc(Br)ccc21
Temperature: 120 °C

Procedure:
5-Bromo-1H-indole [CA.S. 10075-50-0] (2 g, 10.202 mmol) was dissolved in DMF (16 ml). A nitrogen stream was bubbled through the mixture and then were added 3-Fluoro-4-iodopyridine [CA.S. 22282-75-3] (2.502 g, 11.222 mmol), lithium chloride (0.432 g, 10.202 mmol), copper(I) iodide (0.0195 g, 0.102 mmol) and K2CO3 (4.23 g, 30.605 mmol). The reaction mixture was heated at 120° C. for 2 days. After cooling to room temperature, the reaction mixture was refilled with lithium chloride (0.100 g) and (copper(I) iodide (0.010) stirred at 120° C. for 16 h. After cooling to room temperature, the reaction mixture was washed with NH3 (aqueous sat. solution) and extracted with DCM. The organic layer was separated, washed with water, dried (Na2SO4), and the solvent was evaporated in vacuo. The residue was purified by column chromatography (silica gel; eluent:Heptane/EtOAc up to 15% as eluent). The desired fractions were collected and the solvent was evaporated in vacuo to yield intermediate compound D20 (1.37 g, 46%).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[NH:22][C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[N:19]=3)[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:34][CH2:35][O:36][CH2:37][CH3:38].O>C(#N)C>[CH3:4][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:14][CH:15]([C:18]3[N:22]([CH2:34][CH2:35][O:36][CH2:37][CH3:38])[C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[N:19]=3)[CH2:16][CH2:17][N:12]2[CH3:13])=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: CCOCCCl
Reactant: CC(C)(C)c1ccc(CN2CCC(c3nc4ccccc4[nH]3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOCCn1c(C2CCN(C)C(c3ccc(C(C)(C)C)cc3)C2)nc2ccccc21

Procedure:
To a solution of 3.47 g of 2-[1-((4-(1,1-dimethylethyl)phenyl) methyl)piperidine-4-yl]-1H-benzimidazole in 80 ml of acetonitrile, 1.38 g of potassium carbonate and 1.08 ml of 2-chloroethyl-ethyl ether are added and the mixture is refluxed for 8 hours; then is left to cool and poured onto 200 ml of water; it is extracted with ether (3×30 ml) and the ethereal layer is washed with water (3×20 ml) and dried over anhydrous sodium sulfate. The oil obtained by elimination of the ether is purified by column chromatography by using chloroform/methanol (98/2) as eluent, thus obtaining 2 g of 2-[1-((4-(1.1-dimethylethyl)phenyl(methyl) piperidine-4-yl]-1-(2-ethoxyethyl)-1H-benzimidazole. Mp: 51°-53° C.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8](B(O)O)=[CH:9][CH:10]=2)[CH:5]=[N:4]1)[CH3:2].Cl[C:16]1[C:25]([N:26]([CH:28]([CH3:30])[CH3:29])[CH3:27])=[N:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:31]([O:33][CH3:34])=[O:32])[CH:22]=2)[N:17]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:16]3[C:25]([N:26]([CH:28]([CH3:30])[CH3:29])[CH3:27])=[N:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:31]([O:33][CH3:34])=[O:32])[CH:22]=4)[N:17]=3)=[CH:9][CH:10]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: CCn1ncc2cc(B(O)O)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCn1ncc2cc(-c3nc4ccc(C(=O)OC)cc4nc3N(C)C(C)C)ccc21
Temperature: 90 °C
Reaction time: 4 h
Yield: 48.4 %

Procedure:
To a solution of 1-ethyl-1H-indazol-5-ylboronic acid (196 mg, 1.03 mmol) in dioxane (6 mL) was added methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (Scheme I, 120 mg, 0.41 mmol), K3PO4 (259 mg, 1.23 mmol), Pd(PPh3)4 (20 mg, 0.02 mmol) and water (5 drops) with stirring for 4 h at 90° C. in an oil bath under an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum and then purified by a silica gel column with 1% to 5% ethyl acetate in petroleum ether to afford methyl 2-(1-ethyl-1H-indazol-5-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a light yellow solid (80 mg, 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](/[CH:10]=[CH:11]/[C:12](O)=[O:13])=[CH:7][C:6]=2[CH:15]=1.CCN(CC)CC.ClC(OCC(C)C)=O.[N-:31]=[N+:32]=[N-:33].[Na+]>CC(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](/[CH:10]=[CH:11]/[C:12]([N:31]=[N+:32]=[N-:33])=[O:13])=[CH:7][C:6]=2[CH:15]=1
Reactant: O=C(O)/C=C/c1cc2cc(Cl)ccc2s1
Reactant: [N-]=[N+]=[N-]
Agent: CC(C)COC(=O)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)/C=C/c1cc2cc(Cl)ccc2s1
Reaction time: 1 h

Procedure:
To a suspension of (2E)-3-(5-chloro-1-benzothien-2-yl)acrylic acid in acetone (0.2 M) at 0° C. were added Et3N (1.3 equiv) followed by isobutyl chloroformate (1.3 equiv). After stirring for 1 h, H2O solution (2 M) of NaN3 (1.3 equiv) was then added. The resulting mixture was stirred for a period of 0.5 h at 0° C. and 30 min at room temperature. H2O was then added followed by filtration and wash with H2O to provide the title compound.
Reaction SMILES: [C:1]1([C:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:8]2[C:12]([C:13]3[C:18]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)=[CH:17][CH:16]=[C:15]([F:26])[CH:14]=3)=[N:11][N:10]=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:39]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[C:33]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:8]2[C:12]([C:13]3[C:18]([C:19]4[CH:24]=[CH:23][C:22]([CH2:25][Br:39])=[CH:21][CH:20]=4)=[CH:17][CH:16]=[C:15]([F:26])[CH:14]=3)=[N:11][N:10]=[N:9]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccc(F)cc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(-c2ccc(CBr)cc2)c(-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reaction time: 3 h

Procedure:
To a solution of N-Triphenylmethyl-5-(4-fluoro-4'-methyl-biphen-2-yl)tetrazole (454.4 mg; 0.9161 mmol) in dry CCl4 (8 mL) was added N-bromosuccinimide (179.2 mg; 1.1 eq) and a catalytic amount of AIBN. The reaction was heated to reflux (105°-115°) under N2. After 3 hrs. the reaction was cooled and filtered through a cotton plugged pipet to remove the succinimide formed. The solvent was removed and replaced by EtOAc/Et2O. The reaction was washed with 1N NaOH and brine. The organic solution was dried over anhydrous MgSO4, filtered, and concentrated in vacuo to afford the product. The crude product was used in the next reaction.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:29])[CH2:4][CH2:5][N:6]1[C:26](=[O:27])[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:15]4[C:16]5[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[C:17]=5[CH:18]=[CH:19][C:20]=4[N:8]([C:9]=23)[C:7]1=[O:28]>O.CO.Cl.[C].[Pd]>[CH3:2][N:3]([CH3:29])[CH2:4][CH2:5][N:6]1[C:26](=[O:27])[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:15]4[C:16]5[CH2:24][CH2:23][CH2:22][CH:21]([OH:25])[C:17]=5[CH:18]=[CH:19][C:20]=4[N:8]([C:9]=23)[C:7]1=[O:28]
Reactant: CN(C)CCn1c(=O)c2cccc3c4c5c(ccc4n(c1=O)c23)C(=O)CCC5
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: CN(C)CCn1c(=O)c2cccc3c4c5c(ccc4n(c1=O)c23)C(O)CCC5
Yield: 77.3 %

Procedure:
0.5 g (1.2 mmol) of the compound of Example 4 was dissolved in a mixture of water (50 ml) with methanol (25 ml) and 1.2 ml of 1 N hydrochloric acid was added thereto. Next, hydrogenation was effected in the presence of palladium-carbon under a hydrogen pressure of about 4.5 kg/cm2. After confirming the completion of the reaction by thin layer chromatography, the catalyst was filtered off and the residue was concentrated to about 2/3. After adding 50 ml of water and 5 ml of conc. aqueous ammonia thereto, the obtained mixture was extracted with ethyl acetate. The organic layer was taken up, washed with an aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to thereby give 0.35 g of the title compound.