Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=[CH:9][O:10]C)=[CH:6][CH:5]=[CH:4][N:3]=1>C(O)=O>[Br:1][C:2]1[C:7]([CH2:8][CH:9]=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COC=Cc1cccnc1Br
Solvent: O=CO
Product: O=CCc1cccnc1Br
Temperature: 80 °C
Reaction time: 3 h
Yield: 49.1 %

Procedure:
A solution of E and Z mixture of 2-bromo-3-(2-methoxyvinyl)pyridine (1.88 g, 8.79 mmol) in formic acid (96%, 10 mL) was stirred at 60° C. for 16 hours and at 80° C. for 3 hours before cooled to room temperature. Most of formic acid was removed. The mixture was diluted with ethyl acetate, washed with sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. Purification by chromatography on silica gel gave 2-(2-bromopyridin-3-yl)acetaldehyde (864 mg, 53% yield) as yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[OH:16].[C:17](O)(=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)C#N>C(#N)C>[CH3:15][CH:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:1]=[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[O:16][C:3]=3[CH:4]=2)=[N:13][NH:12][C:11](=[O:14])[CH2:10]1
Reactant: O=C(O)c1ccccc1
Reactant: CC1CC(=O)NN=C1c1ccc(N)c(O)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: N#CC(Cl)(Cl)Cl
Product: CC1CC(=O)NN=C1c1ccc2nc(-c3ccccc3)oc2c1
Temperature: 120 °C

Procedure:
219 mg (1 mmol) 6-(4-amino-3-hydroxy-phenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one, 122 mg (1 mmol) benzoic acid, 1.7 g (3 mmol) polymer-bound triphenylphosphine, 289 mg (2 mmol) trichloroacetonitrile and 7.5 ml acetonitrile are placed in a microwave vial and heated to 120° C. for 15 min at 200 W. The resin is filtered off and washed with methanol as well as acetonitrile. The solv. is eliminated by rotary evaporation i.V. and the residue is purified by RP-HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.C([Li])CCC.[O:20]1[CH2:24][CH2:23]OS1(=O)=O.Cl>C1COCC1>[Cl:8][C:6]1[C:7]([CH2:23][CH2:24][OH:20])=[C:2]([Cl:1])[N:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:5]=1
Reactant: O=S1(=O)OCCO1
Reactant: Clc1cc(Cl)nc(N2CCOCC2)n1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OCCc1c(Cl)nc(N2CCOCC2)nc1Cl
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
To a solution of 4-(4,6-dichloropyrimidin-2-yl)morpholine (468 mg, 2.0 mmol) in THF (20 mL) was added n-butyllithium (1.56 mL, 1.6 M) dropwise at −78° C. After stirring for 30 min, 1,3,2-dioxathiolane 2,2-dioxide (336 mg, 2.71 mmol) was added, and after stirring for an additional 40 min, 6 N HCl (6.67 mL) was added. The reaction was stirred at room temperature for 18 h and then at 40° C. for 4 h. The reaction mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried with MgSO4, filtered and concentrated by rotary evaporation. The resulting residue was purified by silica gel chromatography using a gradient of EtOAc/heptane (25-75%) to give the title compound (231 mg, 42%). 1H NMR (400 MHz, CDCl3) δ 3.84 (t, J=7.0 Hz, 2 H), 3.80-3.76 (m, 4 H), 3.76-3.72 (m, 4 H), 3.04 (t, J=7.0 Hz, 2 H). m/z (APCI+) for C10H13Cl2N3O2 277.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14](B3OC(C)(C)C(C)(C)O3)=[CH:13][C:12]=2[O:26][CH3:27])=[O:9])[N:5]([CH3:7])[CH:6]=1.Br[C:29]1[N:30]=[C:31]([C@H:39]2[CH2:44][CH2:43][C@H:42]([N:45]3[CH2:50][CH2:49][N:48]([CH3:51])[CH2:47][CH2:46]3)[CH2:41][CH2:40]2)[N:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[C:33]=12>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:29]3[N:30]=[C:31]([C@H:39]4[CH2:40][CH2:41][C@H:42]([N:45]5[CH2:46][CH2:47][N:48]([CH3:51])[CH2:49][CH2:50]5)[CH2:43][CH2:44]4)[N:32]4[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[C:33]=34)=[CH:13][C:12]=2[O:26][CH3:27])=[O:9])[N:5]([CH3:7])[CH:6]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc(Cl)cn1C
Reactant: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](N2CCN(C)CC2)CC1
Product: COc1cc(-c2nc([C@H]3CC[C@H](N4CCN(C)CC4)CC3)n3ccnc(C)c23)ccc1NC(=O)c1cc(Cl)cn1C

Procedure:
Reaction of 4-chloro-N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1H-pyrrole-2-carboxamide (30 mg) and 1-bromo-8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazine (30 mg) according to the procedure described in example 4 step 4c and purification by column chromatography (silica gel; dichloromethane with gradient 0 to 20% of methanol) gave 4-chloro-N-(2-methoxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-pyrrole-2-carboxamide (21 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:7]=2[CH:14]=1.[CH3:15][C@H:16]1[O:21][C@@H:20]([CH3:22])[CH2:19][NH:18][CH2:17]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[CH3:22][C@H:20]1[O:21][C@@H:16]([CH3:15])[CH2:17][N:18]([C:11]([C:9]2[O:10][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][C:7]=3[CH:8]=2)=[O:13])[CH2:19]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: COc1ccc2oc(C(=O)O)cc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc2oc(C(=O)N3C[C@@H](C)O[C@@H](C)C3)cc2c1

Procedure:
In a flask were mixed together the above prepared 5-methoxy-benzofuran-2-carboxylic acid (0.428 g, 2.23 mmol), cis-2,6-dimethylmorpholine (0.308 g, 1.2 eq.), (benzotriazol-1-yloxy)-tris-(dimethylamino)phosphonium hexafluorophosphate (1.18 g, 1.2 eq.) and 2.4 eq. of N-ethyldiisopropylamine (0.915 mL) in 9 mL of abs. THF and allowed to react during one night at ambient temperature. Pouring onto crashed ice/AcOEt/NH4Cl-solution, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=7/3 generated 0.614 g of the title compound as colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][B:5]([C:7]2[CH:8]=[N:9][NH:10][CH:11]=2)[O:4][C:3]1([CH3:13])[CH3:12].Br[CH2:16][CH:17]([CH3:19])[CH3:18].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH2:16]([N:9]1[CH:8]=[C:7]([B:5]2[O:6][C:2]([CH3:14])([CH3:1])[C:3]([CH3:13])([CH3:12])[O:4]2)[CH:11]=[N:10]1)[CH:17]([CH3:19])[CH3:18]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 80 °C
Reaction time: 4 h
Yield: 88.5 %

Procedure:
A mixture of 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1 g, 5.15 mmol, 1.00 equiv), 1-bromo-2-methylpropane (1.05 g, 7.66 mmol, 1.49 equiv) and Cs2CO3 (3.36 g, 10.31 mmol, 2.00 equiv) in acetonitrile (60 mL) was stirred at 80° C. for 4 h. The reaction was cooled to room temperature and the solid material was removed by filtration. The filtrate was diluted with ethyl acetate (30 mL) and then washed with brine (40 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give 1.14 g (88%) of 1-iso-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a colorless oil. 1H-NMR (300 MHz, CDCl3): δ 7.78 (s, 1H), 7.65 (s, 1H), 3.91 (d, J=7.2 Hz, 2H), 2.24-2.19 (m, 1H), 1.32 (s, 12H), 0.90 (d, J=7.2 Hz, 6H) ppm. LCMS (method D, ESI): RT=1.51 min, m/z=251.0 [M+H]+.
Reaction SMILES: CC1(C)CCC(C)(C)C2C=C(O)C(C(O)=O)=CC1=2.[CH3:19][C:20]1([CH3:37])[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[C:26]2[C:25]([Br:32])=[C:24]([OH:33])[C:23]([C:34]([OH:36])=[O:35])=[CH:22][C:21]1=2.CC(CC(C1C(O)=CC(O)=C(CC=C(C)C)C=1[O-])=O)C.[CH3:58][O:59][CH2:60]Cl>>[CH3:19][C:20]1([CH3:37])[CH2:29][CH2:28][C:27]([CH3:30])([CH3:31])[C:26]2[C:25]([Br:32])=[C:24]([O:33][CH2:58][O:59][CH3:60])[C:23]([C:34]([OH:36])=[O:35])=[CH:22][C:21]1=2
Reactant: COCCl
Reactant: CC1(C)CCC(C)(C)c2c1cc(C(=O)O)c(O)c2Br
Agent: CC(C)=CCc1c(O)cc(O)c(C(=O)CC(C)C)c1[O-]
Agent: CC1(C)CCC(C)(C)c2cc(C(=O)O)c(O)cc21
Product: COCOc1c(C(=O)O)cc2c(c1Br)C(C)(C)CCC2(C)C

Procedure:
5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-hydroxynaphthalene (Compound H, available in accordance with the publication Krause Synthesis 1972 140), is the starting material in the example shown in Reaction Scheme 2. Compound H is brominated to provide the corresponding 3-bromo compound (Compound I) which is thereafter protected in the hydroxyl function by treatment with methoxymethyl chloride (MOMCl) to yield 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-methoxymethoxy-2-bromonaphthalene (Compound J). Compound J is reacted with t-butyllithium and carbon dioxide to provide the corresponding carboxylic acid (Compound K) from which the methoxymethyl protecting group is removed by acid to give 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-hydroxynaphthalene-3-carboxylic acid (Compound L). Compound L is brominated to yield 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-1-bromo-2-hydroxynaphthalene-3-carboxylic acid (Compound M). Compound L and Compound M serve as reagents in accordance with Formula 6. The hydroxy group of Compound X is protected for further transformations with methoxymethyl chloride (MOMCl) in the presence of base, yielding 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-1-bromo-2-methoxymethoxynaphthalene-3-carboxylic acid (Compound N). ##STR5##
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([NH2:13])(=[O:12])=[O:11].O.O.[C:16]([O-:19])(=[O:18])[CH3:17].[Li+].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].O>C(O)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:16]([O:19][C:7]1[CH:8]=[CH:9][C:4]2[N:3]=[C:2]([S:10](=[O:12])(=[O:11])[NH2:13])[S:1][C:5]=2[CH:6]=1)(=[O:18])[CH3:17]
Reactant: NS(=O)(=O)c1nc2ccccc2s1
Reactant: CC(=O)[O-]
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Pd+2]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Oc1ccc2nc(S(N)(=O)=O)sc2c1

Procedure:
A stirred solution of benzothiazole-2-sulfonamide (2.14 g, 0.01 mole), palladium acetate (2.25 g, 0.01 mole), lithium acetate dihydrate (1.65, 0.025 mole) and potassium dichromate (5.9 g, 0.02 mole) in acetic acid (25 ml) is heated on a steam bath for 24 hours then poured into H2O (100 ml) to give 2-sulfamoyl-6-benzothiazolyl acetate which melts at 193°-4° C. after recrystallization from 2-propanol.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[C:4](=[O:23])[C:3]=1[C:24](=O)[CH2:25][C:26]1[CH:30]=[CH:29][S:28][CH:27]=1.O.[NH2:33][NH2:34].C(=O)([O-])O.[Na+]>CN(C=O)C>[S:28]1[CH:29]=[CH:30][C:26]([CH2:25][C:24]2[C:3]3[C:4](=[O:23])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:20])([F:21])[F:22])[CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:34][N:33]=2)=[CH:27]1
Reactant: NN
Reactant: O=C(Cc1ccsc1)c1c(O)c2cccnc2n(-c2cccc(OC(F)(F)F)c2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3ccsc3)n[nH]c2c2cccnc2n1-c1cccc(OC(F)(F)F)c1
Temperature: 115 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-hydroxy-3-(3-thienylacetyl)-1-(3-trifluoromethoxyphenyl)-1,8-naphthyridin-2(1H)-one (80 mg, 0.18 mmol) produced in Synthesis Example 42 in DMF (3 mL) was added hydrazine monohydrate (purity of 80%, 44 μL), and the mixture was stirred at 110 to 120° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, washed with water, recrystallized from methanol, and dried to give 3-(3-thienylmethyl)-5-(3-trifluoromethoxyphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (47 mg, yield 60%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([NH:15][C:16]#[N:17])=[O:14])=[N:4][C:5]([Cl:12])=[C:6]([NH:8][CH:9]([CH3:11])[CH3:10])[N:7]=1.C(N(CC)CC)C.[SH2:25]>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]([C:13]([NH:15][C:16]([NH2:17])=[S:25])=[O:14])=[N:4][C:5]([Cl:12])=[C:6]([NH:8][CH:9]([CH3:11])[CH3:10])[N:7]=1
Reactant: CC(C)Nc1nc(N)c(C(=O)NC#N)nc1Cl
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(C)Nc1nc(N)c(C(=O)NC(N)=S)nc1Cl

Procedure:
To a stirred solution of (3-amino-5-isopropylamino-6-chloropyrazinoyl)cyanamide (6.0 g., 0.0235 mole) in pyridine (40 ml) is added triethylamine (4 ml.). The reaction mixture is heated on a steam bath for 11/2 hours while a slow stream of hydrogen sulfide gas is bubbled into the solution. The reaction mixture is cooled and added to ice-water to give 6 g. of (3-amino-5-isopropylamino-6-chloropyrazinoyl)thiourea which melts at 195° C. after recrystallization from ethanol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:13])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=O)([O-:3])=[O:2].O=S(Cl)Cl.[Cl:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21].C(Cl)(Cl)Cl>C1C=CC=CC=1>[NH2:13][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][C:7]=1[C:8]([NH:21][C:20]1[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=1[Cl:18])=[O:10]
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: Nc1ccccc1Cl
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: Nc1cc([N+](=O)[O-])ccc1C(=O)Nc1ccccc1Cl
Yield: 27.4 %

Procedure:
Prepared according to Procedure A using 4-nitroanthranilic acid (5.0 g, 27.5 mmol) and SOCl2 (5.0 mL, 68.6 mmol) in benzene (150 mL), followed by 2-chloroaniline (5.8 mL, 55.0 mmol) and CHCl3 (150 mL). The product was purified by chromatography in CH2Cl2 followed by recrystallization from MeOH to provide 2.20 g of an orange-brown solid (31%). 1H NMR (CDCl3) δ: 8.41 (dd, J=1.3, 8.3 Hz, 1H); 8.31 (br s, 1H); 7.67 (d, J=8.6 Hz, 1H); 7.57 (d, J=2.1 Hz, 1H); 7.52 (dd, J=2.2, 8.5 Hz, 1H); 7.44 (dd, J=1.3, 8.1 Hz, 1H); 7.35 (dt, J=1.3, 7.9 Hz, 1H); 7.13 (dt, J=1.4, 7.8 Hz, 1H); 5.88 (br s, 2H). MS (ES): m/z 292.0 (M+)
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH3:10][O:9][C:7]([C:5]1[O:6][C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:3][CH:4]=1)=[O:8]
Reactant: COC(=O)c1ccc(Br)o1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccccc2)o1
Yield: 38 %

Procedure:
A mixture of methyl 5-bromofuroate (1 g, 5 mmoles), phenylboronic acid (1 g, 8.2 mmoles), tetrakis(triphenylphosphine)palladium(0) (0.2 g, 0.17 mmoles), sodium carbonate (1.5 g, 17.4 mmoles) in toluene (100 ml) was refluxed for 16 hours. After cooling, the solvent was evaporated and the yellow residue was partioned between water (50 ml) and ethyl acetate (50 ml). The aqueous layer was extracted with ethyl acetate (3×30 ml) and the combined organic layers washed with water (1×30 ml) and dried (MgSO4). The residue was purified by flash chromatography (20% ethyl acetate/70% cyclohexane and 10% diethyl ether/90% cyclohexane) to afford (7) (384 mg). This ester was used directly in the next step.
Reaction SMILES: Cl[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1)[CH3:3].[C:11]1([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([NH:25][C:26]3[NH:30][C:29]4[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=4[N:27]=3)[CH2:21][CH2:20]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[F:10][C:7]1[CH:8]=[CH:9][C:4]([CH:2]([N:27]2[C:28]3[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=3[N:30]=[C:26]2[NH:25][CH:22]2[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:20][CH2:21]2)[CH3:3])=[CH:5][CH:6]=1
Reactant: CC(Cl)c1ccc(F)cc1
Reactant: c1ccc(CCN2CCC(Nc3nc4ccccc4[nH]3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CC(c1ccc(F)cc1)n1c(NC2CCN(CCc3ccccc3)CC2)nc2ccccc21
Yield: 40.7 %

Procedure:
A mixture of 1.6 parts of 1-(1-chloroethyl)-4-fluorobenzene, 3.2 parts of N-[1-(2-phenylethyl)-4-piperidinyl]-1H-benzimidazol-2-amine, 1 part of sodium carbonate, 0.1 parts of potassium iodide and 120 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is cooled, poured onto water and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, yielding 1.8 parts (40.7%) of 1-[1-(4-fluorophenyl)ethyl]-N-[1-(2-phenylethyl)-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 161.7° C.
Reaction SMILES: C[C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:10][C:11]([C@H:13]2[CH2:15][C@@H:14]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:12])[CH3:9])=[N:6][CH:7]=1.Cl.[NH2:23][C@H:24](C1C=CC(C#N)=NC=1)C>>[C:7]([C:2]1[N:23]=[CH:24][C:5]([C@@H:8]([NH:10][C:11]([C@H:13]2[CH2:15][C@@H:14]2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:12])[CH3:9])=[CH:4][CH:3]=1)#[N:6]
Reactant: Cc1ccc([C@H](C)NC(=O)[C@H]2C[C@@H]2c2ccccc2)nc1
Reactant: C[C@H](N)c1ccc(C#N)nc1
Agent: Cl
Product: C[C@H](NC(=O)[C@H]1C[C@@H]1c1ccccc1)c1ccc(C#N)nc1

Procedure:
Prepared analogously to Compound 2 using IM46 and commercially available 5-((S)-1-amino-ethyl)-pyridine-2-carbonitrile hydrochloride (Supplier Netchem Inc., Catalog No 549493). Yield=0.104 g (20%). %). 1H NMR (600 MHz, DMSO) δ 8.76 (d, 1H), 8.71 (s, 1H), 8.02 (d, 1H), 7.94 (d, 1H), 7.29 (m, 2H), 7.19 (m, 1H), 7.12 (d, 2H), 5.03 (m, 1H), 2.21 (m, 1H), 1.92 (m, 1H), 1.40 (d, 3H), 1.37 (m, 1H), 1.23 (m, 1H). LC-MS (m/z) 292.0 (MH+), tR=1.31 min (method A).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH3:12][C:13]1[CH:18]=[C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:16]=[C:15]([CH3:25])[C:14]=1[NH2:26].C(N(CC)C(C)C)(C)C>ClCCCl>[CH2:5]([O:4][C:2](=[O:3])[NH:26][C:14]1[C:15]([CH3:25])=[CH:16][C:17]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)=[CH:18][C:13]=1[CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1cc(N2CCOCC2)cc(C)c1N
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1cc(N2CCOCC2)cc(C)c1NC(=O)OCc1ccccc1
Reaction time: 16 h
Yield: 47 %

Procedure:
Benzyl chloroformate (32 mg) was added to a solution of 0.15 M 2,6-dimethyl-4-morpholin-4-yl-phenylamine and 0.30 M N,N-diisopropyl-ethylamine in 1,2-dichloroethane (1 mL). The vial was shaken for 16 hours and concentrated in vacuo. Aqueous sodium hydroxide (1 M, 2 mL) was added and the crude mixture was extracted with isopropyl acetate/tetrahydrofuran (4:1, 2.5 mL). The organic phase was concentrated in vacuo and redissolved in dimethyl sulfoxide (0.5 mL) of which 0.2 mL was subjected to preparative LC-MS purification to furnish 9.5 mg (47% yield) of the title compound as an oil. LC-MS (m/z) 341 (MH+); tR=2.28, (UV, ELSD) 100%, 100%.
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.Br[C:32]1[N:33]=[C:34]2[CH:40]=[C:39]([CH3:41])[N:38]([S:42]([C:45]3[CH:51]=[CH:50][C:48]([CH3:49])=[CH:47][CH:46]=3)(=[O:44])=[O:43])[C:35]2=[N:36][CH:37]=1.[NH:52]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[NH2:53].CC([O-])(C)C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:41][C:39]1[N:38]([S:42]([C:45]2[CH:51]=[CH:50][C:48]([CH3:49])=[CH:47][CH:46]=2)(=[O:44])=[O:43])[C:35]2=[N:36][CH:37]=[C:32]([NH:53][NH:52][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[N:33]=[C:34]2[CH:40]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: Cc1ccc(S(=O)(=O)n2c(C)cc3nc(Br)cnc32)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2c(C)cc3nc(NNC(=O)OC(C)(C)C)cnc32)cc1
Temperature: 80 °C
Yield: 14 %

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) (0.250 g, 0.273 mmol) and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.232 g, 0.546 mmol) were combined in 1,4-dioxane (15 mL). The flask was evacuated with some bubbling of solvent and then carefully refilled with nitrogen (3 times). Nitrogen was then bubbled directly into the reaction mixture. The mixture was then heated at about 80° C. for about 10 min and then removed from the heating source. 2-Bromo-6-methyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (1.0 g, 2.73 mmol), tert-butyl hydrazinecarboxylate (0.541 g, 4.10 mmol) and NaOt-Bu (0.501 mL, 4.10 mmol) were added and the reaction was heated at about 80° C. for about 1 h. The reaction was cooled to ambient temperature and the solvents removed under reduced pressure. The black residue was then taken up in EtOAc (50 mL) and filtered. The filtrate was washed with saturated aqueous NH4Cl (50 mL), EDTA (1.0 M aqueous, 50 mL) and saturated aqueous NaHCO3 (50 mL). The solution was dried over anhydrous Na2SO4, filtered, and concd under reduced pressure. The material was purified by chromatography on silica gel (80 g) eluting with 25-100% EtOAc in heptane to provide tert-butyl 2-(6-methyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate (0.160 g, 14%) as a brown oil: LCMS (Table 1, Method a) Rt=2.51 min; MS m/z: 418 (M+H)+.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(C2NC=CN=2)=CN=C(CCN)N=1.Cl[C:24]1[N:29]=[C:28]([O:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[C:27]([N+:36]([O-:38])=[O:37])=[CH:26][CH:25]=1.[Cl:39][C:40]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:41]=1[C:47]1[C:52]([C:53]2[NH:54][CH:55]=[CH:56][N:57]=2)=[CH:51][N:50]=[C:49]([NH:58][CH2:59][CH2:60][NH:61]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:48]=1>>[Cl:39][C:40]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:41]=1[C:47]1[C:52]([C:53]2[NH:57][CH:56]=[CH:55][N:54]=2)=[CH:51][N:50]=[C:49]([NH:58][CH2:59][CH2:60][NH:61][C:24]2[N:29]=[C:28]([O:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[C:27]([N+:36]([O-:38])=[O:37])=[CH:26][CH:25]=2)[N:48]=1
Reactant: CN(C)CCOc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Agent: NCCc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1
Product: CN(C)CCOc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]

Procedure:
(2-{6-[(2-{[4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]amino}ethyl)amino]-3-nitro(2-pyridyloxy)}ethyl)dimethylamine was prepared from [4-(2,4-dichloro-phenyl)-5-imidazol-2-ylpyrimidin-2-ylethylamine and [2-(6-chloro-3-nitro(2-pyridyloxy))-ethyl]dimethylamine in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]ethyl}amine.