Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C:8]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[F:22])=[CH:12][C:11]([NH2:24])(Cl)[NH:10][N:9]=1)=[O:7])(C)(C)C.Cl[CH2:26][CH:27]=O>C(O)C>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:13]2[C:8]([C:6]([OH:5])=[O:7])=[N:9][N:10]3[CH:26]=[CH:27][N:24]=[C:11]3[CH:12]=2)=[C:16]([F:22])[CH:17]=1
Reactant: O=CCCl
Reactant: CC(C)(C)OC(=O)C1=NNC(N)(Cl)C=C1Nc1ccc(Br)cc1F
Solvent: CCO
Product: O=C(O)c1nn2ccnc2cc1Nc1ccc(Br)cc1F
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a suspended solution of 6-amino-4-(4-bromo-2-fluoro-phenylamino)-6-chloro-pyridazine-3-carboxylic acid tert-butyl ester (61 mg, 0.16 mmol) in ethanol (5 ml) in a bomb reactor is added at room temperature chloroacetaldehyde (0.12 ml of 50% aqueous solution, 5.0 equivalents). The reaction mixture is sealed and stirred at 80° C. for two days, and then cooled to room temperature. The solvent is removed, and the residue is diluted with ethyl acetate (20 ml). The organic layer is washed with saturated NaCl (20 ml×3), dried over Na2SO4, and concentrated. The residue is purified by flash column chromatography to provide the desired product.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg].CO[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[O:26][CH2:27][C:28]([CH3:31])([CH3:30])[N:29]=1>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[O:26][CH2:27][C:28]([CH3:31])([CH3:30])[N:29]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccccc1C1=NC(C)(C)CO1
Reactant: BrCCCCCCCCc1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccccc2CCCCCCCCc2ccccc2)=N1
Reaction time: 24 h

Procedure:
8-Phenyloctyl bromide was prepared from 8-phenyloctanol, carbon tetrabromide and triphenylphosphine in methylene chloride. A solution of 8-phenyloctanoic acid (19.8 mmol) in sieve dried tetrahydrofuran (5 ml) was reduced with diborane in tetrahydrofuran (30 ml, 29.1 mmol) at 20° C. for 4 hours to give 8-phenyloctanol. To an ice cold solution of the octanol (ca. 19.8 mmol) and carbon tetrabromide (21.98 mmol) in methylene chloride (50 ml) was added triphenylphosphine (22.30 mmol) in methylene chloride (50 ml) and the resulting solution was stirred for 2.5 hours. The volatiles were evaporated and the residue was taken up in ether (100 ml), cooled in ice, and filtered. The filtrate was evaporated and distilled to afford 8-phenyloctyl bromide as an oil. To 8-phenyloctyl bromide and 21.27 mmol of magnesium) in distilled tetrahydrofuran (40 ml) was added 2-(2-methoxyphenyl)-4,4-dimethyloxazoline (17.10 mmol) in tetrahydrofuran (20 ml). After stirring for 24 hours, the reaction mixture was similarly worked up to yield 2-[2-(8-phenyloctyl)phenyl]-4,4-dimethyloxazoline as an oil. A solution of the oxazoline (11.58 mmol) in methyl iodide (20 ml) as refluxed under argon for 18 hours. Removal of the volatiles afforded the corresponding 3,4,4-trimethyloxazolinium iodide as a white solid (mp 76.5°-78° D.). To an ice cold solution of the iodide (9.46 mmol) in methanol (35 ml) was added in portions sodium borohydride (9.20 mmol). Treatment of the reaction mixture as in Example 1(c) results in the isolation of the desired product as an oil.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:21][C:22]#[CH:23])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].I[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:21][C:22]#[C:23][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Ic1ccccc1
Reactant: C#CCOCCn1c(CCCC)nc2cnc3ccccc3c21
Product: CCCCc1nc2cnc3ccccc3c2n1CCOCC#Cc1ccccc1
Reaction time: 0.25 h
Yield: 61.8 %

Procedure:
Using the general method of Example 12 Part A, 2-butyl-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline (4.0 g, 13.08 mmol) was reacted with iodobenzene (1.6 mL, 14.38 mmol) at 90° C. After 15 minutes the reaction was judged complete. The volatiles were removed under reduced pressure and the resulting oil was purified by chromatography over silica gel (98/2 dichloromethane/methanol) and recrystallization from mixture of ethyl acetate/hexane to provide 3.1 g of 2-butyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline as a tan solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[CH:9]=[C:8]1[C:16]([O:18]CC)=O.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]2[S:29][C:28]([CH3:30])=[N:27][C:26]=2[CH:31]=1>>[CH3:30][C:28]1[S:29][C:25]2[CH:24]=[CH:23][C:22]([NH:21][C:16]([C:8]3[N:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[C:11]4=[N:12][CH:13]=[CH:14][CH:15]=[C:10]4[CH:9]=3)=[O:18])=[CH:31][C:26]=2[N:27]=1
Reactant: Cc1nc2cc(N)ccc2s1
Reactant: CCOC(=O)c1cc2cccnc2n1-c1ccccn1
Product: Cc1nc2cc(NC(=O)c3cc4cccnc4n3-c3ccccn3)ccc2s1

Procedure:
This compound was prepared according to the experimental protocol described in Example 6.2, starting with ethyl 1-(2-pyridyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate obtained according to the protocol described in step 8.1 and 5-amino-2-methylbenzothiazole. A white solid is obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:19])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.Cl[CH2:21][CH:22]=O>>[Br:1][C:2]1[C:3]([CH3:19])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=2)[C:5]2[N:6]([CH:21]=[CH:22][N:8]=2)[CH:7]=1
Reactant: O=CCCl
Reactant: Cc1c(Br)cnc(N)c1-c1cccc(C(F)(F)F)c1
Product: Cc1c(Br)cn2ccnc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 5-bromo-4-methyl-3-(3-trifluoromethyl-phenyl)-pyridin-2-ylamine (Int. 1, 237 mg, 0.716 mmol), using a similar method to that used in Example 5 (Step 1) and replacing 1-chloropropan-2-one with 2-chloroacetaldehyde (185 μL, 1.43 mmol) (233 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[O:9])=[CH:4][C:3]=1[N+:20]([O-])=O>[Pd]>[NH2:20][C:3]1[CH:4]=[C:5]([C:8]([C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[O:9])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: COC(=O)c1ccccc1C(=O)c1ccc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Product: COC(=O)c1ccccc1C(=O)c1ccc(N)c(N)c1
Yield: 98.5 %

Procedure:
A solution of methyl 2-[(4-amino-3-nitrophenyl)carbonyl]benzoate (420 mg, 1.39 mmol) in a mixture of terahydrofuran-ethyl acetate (1:1, 20 mL) was hydrogenated over 10% Pd—C (10 mg) for 18 h. The catalyst removed by filtration and the filtrate concentrated to give methyl 2-[(3,4-diaminophenyl)carbonyl]benzoate (370 mg, 98%) as a brown powder. MS (EI) for C15H14N2O3: 293 (MNa+).
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[CH2:16][S:17][C:5]=2[CH:4]=[CH:3][CH:2]=1)=[CH:13][C:12]([OH:18])=[CH:11][CH:10]=4.N1C=CN=C1.[CH3:24][C:25]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])[CH3:26]>CN(C=O)C>[C:25]([Si:28]([CH3:30])([CH3:29])[O:18][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]1[C:6]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[S:17][CH2:16][C:15]2=1)([CH3:27])([CH3:26])[CH3:24]
Reactant: Oc1ccc2[nH]c3c(c2c1)CSc1ccccc1-3
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]c3c(c2c1)CSc1ccccc1-3
Reaction time: 2 h

Procedure:
6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-ol (820 mg, 3.24 mmoL) in DMF (10 mL) was treated with imidazole (331 mg, 4.862 mmoL) followed by TBSCl (733 mg, 4.862 mmoL) at room temperature. The reaction was stirred for 2 hours. The reaction mixture was then partitioned between CH2Cl2 and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The crude material (the oil) was then purified by column chromatography (silica gel; hexanes:EtOAc 4:1 as eluent) to yield the title compound as a brown solid.
Reaction SMILES: [C:1]1(O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([N:19]3[C:27]4[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=4)[C:21]([CH2:30][C:31]([OH:33])=[O:32])=[C:20]3[CH3:34])=[N:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1.C1(N=C=NC2CCCCC2)CCCCC1>COCCOC>[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([N:19]3[C:27]4[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=4)[C:21]([CH2:30][C:31]([O:33][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:32])=[C:20]3[CH3:34])=[N:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2-c1ncnc2cc(Cl)ccc12
Reactant: Oc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: COCCOC
Product: COc1ccc2c(c1)c(CC(=O)Oc1ccccc1)c(C)n2-c1ncnc2cc(Cl)ccc12
Temperature: 25 °C

Procedure:
A mixture of phenol (0.27g.) and anhydrous 1-(7-chloroquinazolin-4-yl)-5-methoxy-2-methylindol-3-ylacetic acid (1.0g.) in dry 1,2-dimethoxyethane (20ml.; dried over sodium aluminosilicate powder) was stirred at room temperature and treated with dicyclohexylcarbodiimide (0.75g.). The mixture became opaque, and was stirred overnight at room temperature and then filtered. Evaporation of the filtrate gave a dark yellow syrup, which was purified by chromatography on silica gel (175g.), using an increasing gradient of ether in petroleum ether (b.p. 40°-60° C.) (polarity increased by incremental addition of 10% v/v ether). The major product, phenyl 1-(7-chloroquinazolin-4-yl)-5-methoxy-2-methylindol-3-ylacetate, was obtained as a yellow glass (NMR: OCH3 at 6.20τ; pure by TLC: systems A and D), from the petrol rich fractions. A second product, 1-[1-(7-chloroquinazolin-4-yl)-5-methoxy-2-methylindol-3-ylacetyl]-1,3-dicyclohexylurea, was obtained as a pale yellow solid of m.p. 105°-107° C. NMR: OCH3 at 6.23τ; pure by TLC: system C).
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[C:4]1[C:9]2[N:10]([CH2:24][CH2:25][CH2:26]O)[C:11]([NH:13][C:14]3[C:15]([O:22][CH3:23])=[N:16][C:17]([O:20][CH3:21])=[N:18][CH:19]=3)=[N:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2].CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH3:21][O:20][C:17]1[N:16]=[C:15]([O:22][CH3:23])[C:14]([N:13]2[C:11]3=[N:12][C:8]4[C:9](=[C:4]([N:3]([CH2:1][CH3:2])[CH2:28][CH3:29])[CH:5]=[CH:6][CH:7]=4)[N:10]3[CH2:24][CH2:25][CH2:26]2)=[CH:19][N:18]=1
Reactant: CCN(CC)c1cccc2nc(Nc3cnc(OC)nc3OC)n(CCCO)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCN(CC)c1cccc2nc3n(c12)CCCN3c1cnc(OC)nc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.5 %

Procedure:
To a solution of 3-{7-(diethylamino)-2-[(2,4-dimethoxypyrimidin-5-yl)amino]-1H-benzimidazol-1-yl}propan-1-ol (Reference Example 97; 90 mg, 0.224 mmol) in pyridine (2.0 mL) was added methanesulfonyl chloride (0.035 mL, 0.449 mmol) at 0° C. The mixture was warmed to room temperature and stirred for 3 hr. Aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a solid, which was recrystallized from n-hexane/ethyl acetate to give the title compound (50 mg, 0.131 mmol, 58%) as a pale brown solid.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[C:4]([O:14][CH2:15][C:16]#[CH:17])=[N:5][C:6](F)=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>>[NH2:1][C:6]1[C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:3]([Cl:2])=[C:4]([O:14][CH2:15][C:16]#[CH:17])[N:5]=1
Reactant: C#CCOc1nc(F)c(C(F)(F)F)cc1Cl
Reactant: N
Product: C#CCOc1nc(N)c(C(F)(F)F)cc1Cl

Procedure:
Starting from 3.1 g (0.182 mol) of ammonia and 10 g (0.039 mol) of 3-chloro-6-fluoro-2-propargyloxy-5-trifluoromethylpyridine, 4.1 g (42.3% of theory) of the title compound of m.p. 56°-58° C. (Table II, No. 2.035) and 2.7 g (27% of theory) of reisolated starting material were obtained after stirring for 3 hours at 110° C. under the same conditions as described in Example III.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][NH:12]3)=[CH:4][CH:3]=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=[O:40])C>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:40])[NH:12]3)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2cccc3[nH]ccc23)cc1
Reactant: CC(=O)O
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Temperature: 27 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
To the suspension of 4-(4-chloro-phenyl)-1H-indole (1.52 g, 6.68 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (81 mL) was added pyridinium tribromide (90% purity from Aldrich, 7.12 g, 20.0 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (30 mL). Zinc dust was added to the reaction mixture portionwise until the color changed from deep red to light yellow, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated, and the syrupy residue was suspended in water (500 mL) for 0.5 hour. The solid product was precipitated out, filtered, and washed repeatedly with water to remove the zinc salt and pyridine salt. After high vacuum dry, a pure product (1.54 g, 94%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=3)[CH:14]=[CH:13][C:5]=1[C:6](Cl)=[N:7]2.Cl.[NH2:24][CH2:25][C:26]1[S:27][CH:28]=[CH:29][N:30]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CC(N(C)C)=O>[Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=3)[CH:14]=[CH:13][C:5]=1[C:6]([NH:24][CH2:25][C:26]1[S:27][CH:28]=[CH:29][N:30]=1)=[N:7]2
Reactant: Cn1cc(-c2ccc3c(Cl)nc4ccnc(Cl)c4c3c2)cn1
Reactant: NCc1nccs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: Cn1cc(-c2ccc3c(NCc4nccs4)nc4ccnc(Cl)c4c3c2)cn1
Temperature: 130 °C

Procedure:
To a solution of 1,6-dichloro-9-(1-methyl-1H-pyrazol-4-yl)benzo[c]-1,6-naphthyridine (50 mg, 0.152 mmol) and 2-aminomethylthiazole hydrochloride (92 mg, 0.608 mmol) in DMA (1.5 mL), triethylamine (85 μl, 0.608 mmol) was added. The reaction mixture was heated to 130° C. for 1 h via microwave irradiation. After cooling to room temperature, aqueous sodium hydrogen carbonate (saturated) was added. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to afford 1-chloro-9-(1-methyl-1H-pyrazol-4-yl)-N-(1,3-thiazol-2-ylmethyl)benzo[c]-1,6-naphthyridin-6-amine as a yellow solid. LRMS (APCI) calc'd for (C20H16ClN6S) [M+H]+, 407.1; found 407.0.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:11]=[C:10]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:9]=[CH:8][C:7]=1[NH:21][C:22](=[O:30])[C:23]([OH:29])([CH3:28])[C:24]([F:27])([F:26])[F:25].O>N1C=CC=CC=1>[C:1]([NH:5][C:6]1[CH:11]=[C:10]([S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:13])=[O:14])[CH:9]=[CH:8][C:7]=1[NH:21][C:22](=[O:30])[C:23]([OH:29])([CH3:28])[C:24]([F:27])([F:25])[F:26])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2)cc1N)C(F)(F)F
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1cc(S(=O)(=O)c2ccccc2)ccc1NC(=O)C(C)(O)C(F)(F)F
Temperature: 25 °C

Procedure:
Acetyl chloride (0.018 ml) was added to an ice-cooled solution of N-[2-amino-4-(phenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 184) (0.097 g) in pyridine (1 ml) and the solution was allowed to warm up to ambient temperature over 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic extracts were combined, washed with brine and dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 10-40% ethyl acetate/hexane to give the title compound (0.89 g) as a solid. Mp 205-207° C., NMR: 1.5 (s, 3H), 2.1 (s, 3H), 7.57-7.75 (m, 4H), 7.8-7.9 (m, 2H) 7.9-8.05 (m, 3H), 9.8 (brs, 1H), 10.1 (brs, 1H); MS (ESP−): 429.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[CH2:19]([NH:23][C:24]1[C:25]([NH2:38])=[CH:26][CH:27]=[C:28]([O:30][CH2:31][CH2:32][N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[CH:29]=1)[CH2:20][CH2:21][CH3:22]>C(O)C>[CH2:19]([N:23]1[C:24]2[CH:29]=[C:28]([O:30][CH2:31][CH2:32][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[CH:27]=[CH:26][C:25]=2[N:38]=[C:15]1[C:14]1[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:12][CH:13]=1)[CH2:20][CH2:21][CH3:22]
Reactant: O=Cc1ccc(OCCc2ccc(Cl)cc2)cc1
Reactant: CCCCNc1cc(OCCN2CCCC2)ccc1N
Solvent: CCO
Product: CCCCn1c(-c2ccc(OCCc3ccc(Cl)cc3)cc2)nc2ccc(OCCN3CCCC3)cc21
Yield: 39.6 %

Procedure:
This compound was prepared according to the General Procedure K by refluxing a mixture of 4-[2-(4-chloro-phenyl)-ethoxy]-bezaldehyde (synthesized via General Procedure A) (100 mg) and N2-Butyl-4-(2-pyrrolidin-1-ylethoxy)-benzene-1,2-diamine (synthesized via General Procedures G1 and G2 and H) (50 mg) in ethanol overnight. Ethanol was removed in vacuo and the residue was purified by silica gel chromatography using 5% MeOH in DCM to give pure 1-butyl-2-{4-[2-(4-chlorophenyl)ethoxy]-phenyl}-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzimidazole (37.0 mg, 40%).
Reaction SMILES: [F:1][C:2]([F:13])([C:9]([F:12])([F:11])[F:10])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].I[CH2:15][CH2:16][C:17]([F:26])([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[F:25][C:17]([F:26])([C:18]([F:23])([F:24])[C:19]([F:20])([F:21])[F:22])[CH2:16][CH2:15][C:4]([CH2:3][C:2]([F:13])([F:1])[C:9]([F:10])([F:11])[F:12])([C:7]#[N:8])[C:5]#[N:6]
Reactant: FC(F)(F)C(F)(F)C(F)(F)CCI
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CC(C#N)(CCC(F)(F)C(F)(F)C(F)(F)F)CC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 10 h
Yield: 0.8 %

Procedure:
In 50 ml of acetone, 3.2 g of 2-(2,2,3,3,3-pentafluoropropyl)malononitrile and 7.2 g of 5-iodo-1,1,1,2,2,3,3-heptafluoropentane were dissolved, 3.2 g of potassium carbonate was added and the mixture was stirred at room temperature for 10 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture and the mixture was extracted with t-butyl methyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.05 g of 2-(3,3,4,4,5,5,5-heptafluoropentyl)-2-(2,2,3,3,3-pentafluoropropyl)malononitrile (hereinafter, referred to as the present compound (96)):
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:15]=[C:16]([NH:21][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:17]=[CH:18][C:19]=3[CH3:20])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][N:3]=1.[CH3:30][NH:31][CH3:32]>CN1C(=O)CCC1.CO>[CH3:30][N:31]([CH3:32])[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:15]=[C:16]([NH:21][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:17]=[CH:18][C:19]=3[CH3:20])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][N:3]=1
Reactant: CNC
Reactant: Cc1ccc(NC(=O)c2ccccc2)cc1-c1cc2cnc(Cl)cc2n(C)c1=O
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cc1ccc(NC(=O)c2ccccc2)cc1-c1cc2cnc(N(C)C)cc2n(C)c1=O
Temperature: 100 °C

Procedure:
N-(3-(7-chloro-1,2-dihydro-1-methyl-2-oxo-1,6-naphthyridin-3-yl)-4-methylphenyl)benzamide A6 (45 mg, 0.11 mmol) is dissolved in NMP (1 mL) and treated with dimethyl amine (0.56 mL of a 2.0 M solution in methanol). The reaction mixture is heated to 100° C. for 12 h. Upon cooling to rt, the reaction is purified by preparative LCMS.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[CH:3]=1.CC(OC)(C)C.[Br:16]Br>O>[Br:16][C:6]1[CH:5]=[C:4]([CH3:9])[CH:3]=[C:2]([F:1])[C:7]=1[NH2:8]
Reactant: Cc1ccc(N)c(F)c1
Reactant: BrBr
Solvent: O
Solvent: COC(C)(C)C
Product: Cc1cc(F)c(N)c(Br)c1
Temperature: 18 °C
Reaction time: 0.5 h

Procedure:
6-fluoro-4-methylaniline 6 (15 kg) was added to a mixture of MTBE (92 L, 66.6 kg) calcium carbonate (12 kg) and water (135 kg), inerted and cooled to <5° C. Bromine (18.22 kg) was charged, keeping T<10° C. Age for 30 minutes at T<10° C. The batch was warmed to ˜18° C. and allowed to settle.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[F:11].Br[C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:4][C:3]=1[F:11]
Reactant: Brc1ncccn1
Reactant: OB(O)c1ccc(Br)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Fc1cc(-c2ncccn2)ccc1Br
Reaction time: 8 h

Procedure:
4-Bromo-3-fluorophenyl boronic acid (28AB) (1.0 g, 4.57 mmol, 1 equiv), 2-bromopyrimidine (1AB) (2.18 g, 13.7 mmol, 3 equiv), and 2M sodium carbonate (12 mL) were added in a pressure vessel (150 mL) and a (1v:1v) mixture of toluene and ethanol (25 mL: 25 mL) was added. The mixture was then bubbled with nitrogen gas for about 10 minutes. Tetrakistriphenylphosphine palladium (0) (266 mg, 0.23 mmol, 0.05 equiv) was added to the mixture. The reaction vessel was tightly capped, placed in an oil bath at 90° C., and stirred overnight.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[CH:11]=[N:12][OH:13].Cl.Cl[CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[CH:11]=[N:12][O:13][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: ON=Cc1c(Br)ccc2c1OCO2
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1C=NOCCN1CCCC1)OCO2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 5-bromo-1,3-benzodioxole-4-carbaldehyde oxime (0.244 g, 1 mmol) in dry DMF (15 ml), 1-(2-chloroethyl)pyrrolidine hydrochloride (0.207 g, 1.22 mmol) and NaH (0.138 g, 3.45 mmol, 60% dispersion in oil) were added. The reaction mixture was stirred at ambient temperature for 5 minutes and then heated at 80° C. overnight. Then the reaction mixture was cooled to ambient temperature and quenched with methanol (4 ml). After evaporation of the solvent in vacuo, water (25 ml) was added to the residue, and the mixture was extracted with dichloromethane (2×25 ml). The combined organic phases were dried over anhydrous MgSO4. The solvent was evaporated in vacuo, and the residue was purified by column chromatography with a mixture of chloroform:ethyl acetate (10:1) as the eluent. After the isolation of the unreacted starting material, the eluent was changed to ethyl acetate:isopropanol:cc. NH3 (9:1:0.5). The crude product was digerated with water.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:21])([CH3:20])[C:9]([NH:11][NH:12]C(OC(C)(C)C)=O)=[O:10])=[CH:4][C:3]=1[O:22][CH3:23].Cl>CCOC(C)=O.CCOCC>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:21])([CH3:20])[C:9]([NH:11][NH2:12])=[O:10])=[CH:4][C:3]=1[O:22][CH3:23]
Reactant: COc1cc(C(C)(C)C(=O)NNC(=O)OC(C)(C)C)ccc1Cl
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COc1cc(C(C)(C)C(=O)NN)ccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 123.2 %

Procedure:
To a solution of tert-butyl 2-(2-(4-chloro-3-methoxyphenyl)-2-methylpropanoyl)hydrazine carboxylate (12.63 g, 0.04 mol) in EtOAc (100 mL) at 0° C. was added 2M HCl in Et2O (92 mL). The resulting solution was stirred at room temperature 18 h and concentrated in vacuo. The residue was triturated with Et2O, collected by filtration and dried to give 2-(4-chloro-3-methoxyphenyl)-2-methylpropanehydrazide hydrochloride (6.88 g, 67%) as a white solid. 1H NMR (400 MHz, DMSO) δ 11.64 (s, 1H), 7.41-7.39 (d, 1H), 7.01 (s, 1H), 6.92-6.89 (d, 1H), 3.91 (s, 3H), 1.53 (s, 6H).