Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23](O)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:26]1[C:35]2[CH2:34][CH2:33][NH:32][CH2:31][C:30]=2[CH:29]=[CH:28][C:27]1=[O:36]>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([N:32]3[CH2:33][CH2:34][C:35]4[NH:26][C:27](=[O:36])[CH:28]=[CH:29][C:30]=4[CH2:31]3)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=c1ccc2c([nH]1)CCNC2
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)N3CCc4[nH]c(=O)ccc4C3)cs2)c1-c1ccc(F)cc1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and 5,6,7,8-tetrahydro-1,6-naphthyridin-2(1H)-one and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]([CH:12]([CH3:14])[CH3:13])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=[C:4]([N+:15]([O-])=O)[CH:3]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:15][C:4]1[CH:3]=[C:2]([F:1])[C:7]2[N:8]([CH:12]([CH3:14])[CH3:13])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=1
Reactant: CC(C)n1c(=O)oc2cc([N+](=O)[O-])cc(F)c21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)n1c(=O)oc2cc(N)cc(F)c21

Procedure:
Prepared from 4-fluoro-3-isopropyl-6-nitro-1,3-benzoxazol-2(3H)-one (Step 1, 0.87 g, 3.64 mmol), ammonium chloride (1.95 g, 36.4 mmol) and iron powder (0.81 g, 14.6 mmol) in ethanol (30 ml) and water (15 ml) according to the method of EXAMPLE 86, Step 7 (0.77 g, 99%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[CH3:8].Br[CH2:11][C:12](=O)[CH3:13]>C(#N)C>[Cl:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]2[N:3]([CH:11]=[C:12]([CH3:13])[N:1]=2)[N:4]=1
Reactant: CC(=O)CBr
Reactant: Cc1cc(Cl)nnc1N
Solvent: CC#N
Product: Cc1cn2nc(Cl)cc(C)c2n1

Procedure:
3-Amino-6-chloro-4-methylpyridazine (5.50 g, 38.3 mmol) and bromoacetone (6.90 g, 40.0 mmol) were heated in acetonitrile (50.0 ml) for 8 hours under reflux. The reaction solution was concentrated under reduced pressure, and water (100 ml) was added to the residues which were then adjusted to pH 9 with 20% aqueous sodium hydroxide and extracted twice with ethyl acetate. The extracts were combined, dried over anhydrous magnesium sulfate and concentrated, and the residues were purified by silica gel column chromatography (ethyl acetate:chloroform=1:2), to give the title compound as white crystals. The yield was 3.80 g (54.6%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([CH:9]=O)[CH:5]=[CH:4][N:3]=1.[CH:11]1([NH2:14])[CH2:13][CH2:12]1.[BH4-].[Na+].[OH-].[Na+]>CO>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][NH:14][CH:11]2[CH2:13][CH2:12]2)[CH:5]=[CH:4][N:3]=1
Reactant: NC1CC1
Reactant: Cc1c(C=O)ccnc1Cl
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(CNC2CC2)ccnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A mixture of 2-chloro-3-methylpyridine-4-carbaldehyde (58.35 g, 375 mmol) and cyclopropylamine (52.6 mL, 750 mmol) in MeOH (800 mL) was stirred overnight at rt. The mixture was cooled to 0° C. and NaBH4 (18.4 g, 488 mmol) was added portionwise. The mixture was stirred overnight at rt. Aq. 1M NaOH (250 mL) was added and the solvents were partially removed under reduced pressure. The aq. phase was extracted with EtOAc (3×). The combined org. phases were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification fy FC yielded the compound (54.56 g, 74%) as a pale yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][OH:10])=[CH:7][CH:8]=1.[H-].[Na+].[Br:13][C:14]1[CH:19]=[C:18](F)[CH:17]=[C:16]([Cl:21])[CH:15]=1>CN1CCCC1=O>[Br:13][C:14]1[CH:19]=[C:18]([O:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:17]=[C:16]([Cl:21])[CH:15]=1
Reactant: COc1ccc(CO)cc1
Reactant: Fc1cc(Cl)cc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COc1ccc(COc2cc(Cl)cc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a mixture of 5.8 ml of p-methoxybenzyl alcohol and 90 ml of N-methylpyrrolidone was added 2.13 g of sodium hydride (60% oil dispersion), and the resulting mixture was stirred at room temperature for 45 minutes in a nitrogen atmosphere. To the reaction mixture was added 9.3 g of 1-bromo-3-chloro-5-fluorobenzene, followed by stirring at 50° C. for 3 hours. The reaction mixture was poured into 50 ml of ice-diluted hydrochloric acid and extracted three times with diethyl ether-hexane (1:1 by volume). The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography using a hexane-ethyl acetate (19:1 by volume) mixed solvent. The fraction containing the desired compound was concentrated to furnish 13.2 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[C@H:10]([CH2:12][CH:13]([CH3:15])[CH3:14])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].CN1CCOCC1>CC#N>[CH2:1]([O:8][C:9](=[O:16])[C@H:10]([CH2:12][CH:13]([CH3:14])[CH3:15])[NH:11][C@@H:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Reactant: CCOC(=O)C(C)Br
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CCOC(=O)[C@@H](C)N[C@@H](CC(C)C)C(=O)OCc1ccccc1
Yield: 25.8 %

Procedure:
L-Leucine benzyl ester (186.65 g, 0.843M), ethyl 2-bromopropionate (153.1 g, 0.846M) and N-methylmorpholine (165 ml, 1.5M) were dissolved in dry CH3CN (800 ml) and refluxed for 12 h. The solvent was removed in vacuo and the residue partitioned between H2O (21) and EtOAc (3×11). The organic phase was washed with brine, dried and evaporated in vacuo. The resulting oil was chromatographed on SiO2 in 7.5% EtOAc in hexane to give the title compound (70 g) as the faster running fraction; (Found: C,67.02; H,8.42; N,4.25; C18H27NO4 requires C,67.26; H,8.47; N,4.36); νmax film 1730 cm-1 ; δ (CDCl3) 0.88 and 0.9 (each 3H, each d, each J=6.5 Hz, CH(CH3)2) 1.23 (3H,t,J=7 Hz,CH3CH2O), 1.27 (3H,d,J=7 Hz,CH3CH), 1.5 (2H,m,CHCH2), 1.7 (1H, heptet, J=7 Hz, CH(CH3)2), 2.2 (1H, br s,NH), 3.32 (2H,m, CHNHCH), 4.10 and 4.12 (each 1H, each q, each J=7 Hz, OCH2CH3), 5.12 (2H,s, OCH2C6H5) and 7.34 (5H,s, C6H5); m/e 322 (100%; [m+1])+, 260 (15), 186 (26) and 112 (28).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:13]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)=[CH:18][N:17]=1)[CH2:14][CH3:15]>CN(C=O)C.O>[N:1]1([CH:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[CH:18][N:17]=2)[CH2:14][CH3:15])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCC(Br)c1ccc(-c2cccc(OC)c2)cn1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(c1ccc(-c2cccc(OC)c2)cn1)n1ccnc1
Temperature: 50 °C
Yield: 12 %

Procedure:
To a solution of imidazole (0.2 g, 2.9 mmol) in DMF (5 mL) was added potassium carbonate (0.4 g, 2.9 mmol) and 2-(1-bromopropyl)-5-(3-methoxyphenyl)pyridine under nitrogen and the reaction was heated to 50° C. for 3 h. The contents were cooled to rt, diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The layers were separated, the organic layer was washed with brine solution (2×30 mL), dried over sodium sulphate and distilled off to get the crude product. The product was purified by preparative TLC (2000μ; pure ethyl acetate) to provide 2-(1-(1H-imidazol-1-yl)propyl)-5-(3-methoxyphenyl)pyridine (50 mg, 12% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.86 (s, 1H), 8.09 (d, 1H), 7.81 (s, 1H), 7.40 (m, 2H), 7.36 (s, 1H), 7.25 (d, 2H), 6.97 (d, 1H), 6.89 (s, 1H), 5.37 (q, 1H), 3.80 (s, 3H), 2.25 (m, 2H), 0.82 (t, 3H); LC-MS m/z calcd for [M+H]+ 294.15. found 294.2.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[N:7][NH:6][N:5]=1)([O-:3])=[O:2].[CH2:9]1COCC1.[H-].[Na+].IC>CC(C)=O>[CH3:9][N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[N:6]1
Reactant: O=[N+]([O-])c1cn[nH]n1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CI
Product: Cn1cc([N+](=O)[O-])nn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
To a 100-mL single-neck round-bottomed containing 4-nitro-2H-1,2,3-triazole (2.0 g, 17.5 mmol) and THF (10 mL) at 0° C. was added NaH (1.7 g, 35.0 mmol, 2.0 eq.). The mixture was stirred at 0° C. for 15 min. A solution of iodomethane (3.68 g, 26.3 mmol, 1.5 eq.) in acetone (40 mL) was added and the resulting reaction mixture was stirred at room temperature for 2 h. After this time, the reaction was quenched by water (20 mL) at 0° C. and concentrated under reduced pressure. The residue was diluted with dichloromethane (100 mL). It was then washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 6:1 petroleum ether/ethyl acetate to afford 293a (800 mg, 35%) as a light yellow solid and the regioisomer 1-methyl-5-nitro-1H-1,2,3-triazole (1.34 g, 60%) as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.34 (s, 1H), 4.26 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][C:14]([OH:17])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CS(O[CH:23]([CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)[CH3:24])(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:12]=[CH:13][C:14]([O:17][CH:23]([CH:25]3[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:29][CH2:30]3)[CH3:24])=[N:15][CH:16]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CC(OS(C)(=O)=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cnc(O)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(Oc1cnc(-c2ccc(S(C)(=O)=O)cc2)cn1)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound (0.463 g, 58%) was prepared as a white foam from 5-[4-(methylsulfonyl)phenyl]-2-pyrazinol (and tautomers thereof) (prepared as in Example 145, Step 2, 0.43 g, 1.72 mmol), (±)-1,1-dimethylethyl 4-{1-[(methylsulfonyl)oxy]ethyl}-1-piperidinecarboxylate (0.74 g, 2.41 mmol) and K2CO3 (0.48 g, 3.44 mmol) in DMF (15 mL) in a manner similar to Example 150, Step 3. The crude product was purified by chromatography on a silica gel column eluted with 1:2 EtOAc/hexanes then 40% EtOAc/hexanes to give the title compound as a white foam. 1H NMR (400 MHz, CDCl3): δ 8.53 (s, 1H), 8.24 (s, 1H), 8.10 (d, 2H, J=8.3 Hz), 8.02 (d, 2H, J=8.3 Hz), 5.15-5.05 (m, 1H), 4.20-4.10 (m, 2H), 3.07 (s, 3H), 2.75-2.60 (m, 2H), 1.85-1.55 (m, 3H), 1.44 (s, 9H), 1.40-1.20 (m, 5H); LRMS (ESI), m/z 462 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH3:11])=[CH:4][CH:3]=1.O[C@H:26]1[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[C:12]1([C:9]([CH2:10][CH3:11])=[C:8]([C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=2)[C:5]2[CH:6]=[CH:7][C:2]([O:1][C@@H:26]3[CH2:30][CH2:29][NH:28][CH2:27]3)=[CH:3][CH:4]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(O)cc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=C(c1ccc(O)cc1)c1ccc(O[C@@H]2CCNC2)cc1)c1ccccc1
Yield: 19.7 %

Procedure:
Following the same procedure as described in example 16, step D & E, 4-(1-(4-hydroxylphenyl)-2-phenylbut-1-enyl)phenol (150 mg, 0.474 mmol) was reacted with (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (107 mg, 0.571 mmol), followed by de-Boc in condition of TFA/CH2Cl2, to give the desired product (36 mg, 20% yield, Z/E=1/1). m/z=386[M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[CH:5][C:4]=1[S:16](Cl)(=[O:18])=[O:17].[C:20]1([NH2:27])[C:21]([NH2:26])=[CH:22][CH:23]=[CH:24][CH:25]=1.N1C=CC=CC=1>ClCCl>[NH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:27][S:16]([C:4]1[CH:5]=[C:6]([S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])(=[O:18])=[O:17]
Reactant: COc1ccc(S(=O)(=O)C(F)(F)F)cc1S(=O)(=O)Cl
Reactant: Nc1ccccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)C(F)(F)F)cc1S(=O)(=O)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To a solution of 2-methoxy-5-trifluoromethanesulfonyl-1-benzenesulfonyl chloride (5 g) in dry dichloromethane (10 mL), benzene-1,2-diamine (5 g) was added followed by addition of dry pyridine (10 mL) at 0° C. The resulting deep red reaction mixture was then stirred at room temperature for 4 h. The reaction mixture was diluted with dichloromethane (250 mL). The contents were washed with saturated aqueous sodium chloride solution (50 mL) and saturated aqueous sodium carbonate solution (50 mL). The organic phase was dried over sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc (7:1 to 4:1) to give N-(2-aminophenyl)-2-methoxy-5-trifluoromethanesulfonylbenzenesulfonamide (6 g). LC: Tr 0.95 min, MS: 411 (M+1)+. 1H NMR (CDCl3, 400 MHz): δ 4.18 (bs, 2H), 4.21 (s, 3H), 6.43 (m, 2H), 6.57 (bs, 1H), 6.75 (dd, 1H), 7.02 (t, 1H), 7.35 (d, 1H), 8.22 (dd, 1H), 8.40 (d, 1H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2=[CH:9][CH:10]=[C:11]3[C:20]([N:19]=[C:18]4[C:13]([CH:14]=[CH:15][CH:16]=[C:17]4[C:21](O)=[O:22])=[N:12]3)=[C:7]2[N:6]=[CH:5][CH:4]=1.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH2:28]>>[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH:28][C:21]([C:17]1[C:18]2[C:13](=[N:12][C:11]3[C:20]([N:19]=2)=[C:7]2[N:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]2=[CH:9][CH:10]=3)[CH:14]=[CH:15][CH:16]=1)=[O:22]
Reactant: COc1ccnc2c1ccc1nc3cccc(C(=O)O)c3nc12
Reactant: CN(C)CCN
Product: COc1ccnc2c1ccc1nc3cccc(C(=O)NCCN(C)C)c3nc12

Procedure:
4-Methoxypyrido [2,3-α]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide was prepared from 4-Methoxypyrido[2,3-α]phenazine-11-carboxylic acid (II.1) and N,N-dimethylethylenediamine
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=12.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:33][CH3:34])=[C:25]([O:28][CH2:29][CH2:30][CH2:31]Cl)[CH:26]=3)[N:21]=[CH:20][N:19]=2)=[C:13]([F:35])[CH:12]=1.C(Cl)Cl>CN(C=O)C>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:33][CH3:34])=[C:25]([O:28][CH2:29][CH2:30][CH2:31][N:7]4[CH2:8][CH2:9][N:4]5[CH:3]=[N:2][N:1]=[C:5]5[CH2:6]4)[CH:26]=3)[N:21]=[CH:20][N:19]=2)=[C:13]([F:35])[CH:12]=1
Reactant: c1nnc2n1CCNC2
Reactant: COc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1OCCCCl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1OCCCN1CCn2cnnc2C1
Temperature: 80 °C
Reaction time: 36 h
Yield: 18.6 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (0.15 g) in DMF (8 mL) was added Ag2CO3 (1.00 g) and a solution of N-(4-bromo-2-fluorophenyl)-6-(3-chloropropoxy)-7-methoxy quinazolin-4-amine (0.40 g) in DMF (2 mL) at room temperature under stirring. The mixture was stirred at 80° C. for 36 h under N2 and cooled to room temperature. To this, CH2Cl2 (100 mL) was added. The mixture was washed with brine (100 mL×3), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to give the product (89 mg, 18.50%), HPLC: 91.13%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 528.1 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.03-2.10 (m, 2H), 2.68 (t, J=13.20 Hz, 2H), 3.03 (t, J=10.80 Hz, 2H), 3.75 (s, 2H), 3.89 (s, 3H), 4.03 (t, J=10.80 Hz, 2H), 4.08 (t, J=12.40 Hz, 2H), 7.03 (m, 1H), 7.24 (s, 1H), 7.32 (m, 1H), 7.38 (s, 1H), 7.81-7.84 (m, 2H), 8.46 (s, 1H), 8.70 (s, 1H) ppm.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:37]=[CH:36][C:17]2[NH:18][C:19]([S:21][CH2:22][C:23]3[C:28]([CH3:29])=[C:27]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[N:26]=[CH:25][N:24]=3)=[N:20][C:16]=2[CH:15]=1.N>ClCCl>[CH3:12][O:13][C:14]1[CH:37]=[CH:36][C:17]2[NH:18][C:19]([S:21]([CH2:22][C:23]3[C:28]([CH3:29])=[C:27]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[N:26]=[CH:25][N:24]=3)=[O:9])=[N:20][C:16]=2[CH:15]=1
Reactant: COc1ccc2[nH]c(SCc3ncnc(N4CCCCC4)c3C)nc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: N
Solvent: ClCCl
Product: COc1ccc2[nH]c(S(=O)Cc3ncnc(N4CCCCC4)c3C)nc2c1
Yield: 63.7 %

Procedure:
A solution of m-chloroperbenzoic acid (2.16 g) in dichloromethane (40 ml) was added to a stirred solution of 5-methoxy-2-(5-methyl-6-piperidino-4-pyrimidinylmethylthio)-(1H)-benzimidazole (4.0 g) in dichloromethane (110 ml) cooled to between -40° and -50°. After a further hour at -40°, ammonia was passed through the reaction mixture and the precipitated solid filtered off. The filtrate was stripped, and the residual glass triturated with acetonitrile to give 5-methoxy-2-(5-methyl-6-piperidino-4-pyrimidinylmethylsulphinyl)-(1H)-benzimidazole 2.66 g, m.p. 87°-89°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].[CH3:18][C:19]1[C:24]([CH2:25][CH2:26]O)=[CH:23][CH:22]=[C:21]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[N:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:6])([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:26][CH2:25][C:24]2[C:19]([CH3:18])=[N:20][C:21]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:30][CH:29]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:10]=1[CH3:16])[CH3:7])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCO
Reactant: CCOC(=O)C(C)(C)Oc1cc(O)ccc1C
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1cc(OCCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1C
Temperature: 0 °C
Reaction time: 20 h

Procedure:
0.24 g (1.0 mmol) of the above prepared 2-(5-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester, 0.31 g (1.10 mmol) of 2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethanol (see below example 70E]) and 0.32 g (1.20 mmol) of triphenylphosphine were dissolved in 10 ml of THF. The stirred reaction mixture was cooled down to 0° C. and a solution of 0.27 g (1.15 mmol) of di-tert.-butyl azodicarboxylate in 5 ml of THF was added drop by drop. Then, the reaction warmed up to ambient temperature. After 20 hours, the solvent was evaporated and the residue purified by chromatography (SiO2, heptane/EtOAc=95:5 to 9:1) to give 0.23 g of the title compound as colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][C:9]2[CH:17]=[CH:16][C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29]Br.C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([CH2:29][C:21]2[S:20][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:22]=2)[C:9]2[CH:17]=[CH:16][C:12]3[NH:13][CH:14]=[N:15][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: BrCc1nc2ccccc2s1
Reactant: CCc1ccc(CNc2ccc3nc[nH]c3c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1ccc(CN(Cc2nc3ccccc3s2)c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from N-(4-ethylbenzyl)benzimidazol-5-amine (251 mg; 1 mmol; 1 eq.), (benzo[d]-thiazol-2-yl)methylbromide (251 mg; 1.1 mmol; 1.1 eq.) and K2CO3 (152 mg; 1.1 mmol; 1.1 eq.) according to method 6; Yield: 0.118 g (29.6%);; MS m/z: 399.4 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 1.14 (t, 3H, 3J=7.6 Hz); 2.56 (q, 2H, 3J=7.6 Hz); 4.74 (s, 2H); 5.02 (s, 2H); 6.85-6.86 (m, 2H); 7.15-7.17 (m, 2H); 7.26-7.27 (m, 2H); 7.36-7.39 (m, 2H); 7.46-7.49 (m, 1H); 7.94-7.95 (m, 2H), 7.98-8.00 (m, 1H); 11.98 (br s, 1H); HPLC (METHOD [A]): rt 17.02 min (97.8%)
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][OH:19])=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:20]([C:24]1[CH:48]=[CH:47][C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33](B3OC(C)(C)C(C)(C)O3)[C:32]=2[CH3:46])=[O:29])=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[C:20]([C:24]1[CH:48]=[CH:47][C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:2]3[N:3]=[C:4]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][OH:19])=[CH:13][CH:12]=4)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=3)[C:32]=2[CH3:46])=[O:29])=[CH:26][CH:25]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: Cn1cc(Br)nc(Nc2ccc(CCO)cc2)c1=O
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1B1OC(C)(C)C(C)(C)O1
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: COCCOC
Solvent: O
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(CCO)cc2)n1
Temperature: 95 °C
Yield: 75.6 %

Procedure:
A mixture of 5-bromo-3-[4-(2-hydroxy-ethyl)-phenylamino]-1-methyl-1H-pyrazin-2-one (1) (1.0 g; 3.11 mmol), 4-tert-butyl-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide (1.5 g; 3.57 mmol), tetrakis(triphenylphosphine)palladium (560 mg; 0.5 mmol), 1N sodium carbonate (8 mL), and 1,2-dimethoxyethane (40 mL) was heated at 95° C. in a sealed pressure vessel for 16 hr. The mixture was cooled to room temperature, treated with water (70 mL) and extracted with ethyl acetate (3×60 mL). The combined organic extracts were washed with water (2×40 mL) and brine (1×40 mL), dried over solid sodium sulfate, and evaporated under reduced pressure. The resulting residue was chromatographed on silica using methanol/CH2Cl2 (1:9) as eluent to provide 1.2 g of 5-bromo-3-[4-(2-hydroxy-ethyl)-phenylamino]-1-methyl-1H-pyrazin-2-one (2) as a light tan solid. MS 511.23 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].[NH:29]([CH2:33][CH2:34][OH:35])[CH2:30][CH2:31][OH:32].[I-].[Na+]>COCCOC>[OH:32][CH2:31][CH2:30][N:29]([CH2:33][CH2:34][OH:35])[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28]
Reactant: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCCl
Reactant: OCCNCCO
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCN(CCO)CCO
Temperature: 135 °C

Procedure:
Using an analogous procedure to that described in Example 157, 196.5 mg (0.5 mmol) of the 7-(2-chloro-ethoxy)-4-(1H-indazol-6-ylamino)-6-methoxy-quinoline-3-carbonitrile, 525.7 mg (5.0 mmol) of diethanolamine and 75.0 mg (0.5 mmol) of sodium iodide in 6 mL of DME was heated at 135° C. for 15 hr. The work up gave 109.1 mg (47.2%) of the product as a yellow solid, m.p. 150° C. (dec.), mass (electrospray, m/e): M+H 463.0.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[CH:9]=[N:10][NH:11][C:3]=12.[NH2:12][CH2:13][CH2:14][CH2:15][OH:16]>C1(C)C(C)=CC=CC=1>[OH:16][CH2:15][CH2:14][CH2:13][NH:12][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[CH:9]=[N:10][NH:11][C:3]=12
Reactant: NCCCO
Reactant: Cc1cc(Cl)c2[nH]ncc2n1
Solvent: Cc1ccccc1C
Product: Cc1cc(NCCCO)c2[nH]ncc2n1
Yield: 64.3 %

Procedure:
7-Chloro-5-methyl-H-pyrazolo[4,3-b]pyridine (D4) (0.5 g, 0.003 mole) and 3-aminopropanol (0.75 g, 0.01 mole) in dry xylene (5 ml) were heated under reflux for 4 h. The solvent was removed under reduced pressure and the resulting oil recrystallised from methanol/ethyl acetate to give the hydrochloride salt of the title compound as a white crystalline solid (398 mg, 55%), m.p. 194°-196° C.