Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[O:7][CH2:8][CH:9]1[CH2:13][CH2:12][CH2:11][NH:10]1)([O-:3])=[O:2].C=O.[BH3-][C:24]#N.[Na+].CC(O)=O>CC#N>[CH3:24][N:10]1[CH2:11][CH2:12][CH2:13][CH:9]1[CH2:8][O:7][C:6]1[CH:14]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:16]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(OCC2CCCN2)cc(C(F)(F)F)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN1CCCC1COc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reaction time: 0.75 h

Procedure:
2-(3-Nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine (6 mmol) was dissolved in CH3CN (20 mL) and formaldehyde (2.4 mL, 37% aqueous) was added. NaBH3CN (607 mg) was added, an exotherm was observed. The pH is monitored every 15 min and adjusted to ˜7 with AcOH. After 45 min, the mixture was concentrated in vacuo and the residue is dissolved in EtOAc, washed with 6N NaOH, 1N NaOH, and 2N HCl (3×). The acid washings were combined, adjusted to ˜pH 10 with solid Na2CO3 and extracted with EtOAc (2×) The EtOAc fractions were combined, dried with Na2SO4, and purified with flash chromatography (SiO2, 95:5:0.5 CH2Cl2:MeOH:NH4OH) to afford 1-methyl-2-(3-nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:19]=[CH:18][N:17]([C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)[N:21]=3)[N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:29][C:26]([F:27])([F:28])[C:24]1[CH:23]=[C:22]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=2)[N:21]=[C:20]([N:17]2[CH:18]=[N:19][C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=3)=[N:16]2)[CH:25]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ncn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-c2ncn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)n2)c1
Yield: 26.8 %

Procedure:
To a cooled and stirred solution of the above prepared N-tert-butyl-3-{1-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-1H-[1,2,4]triazol-3-yl}-benzenesulfonamide (0.090 g, 0.16 mmol) in dichloromethane (3 mL) was added TFA (3 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane/diethyl ether and dried to yield the title compound as a white solid (0.022 g, 27%). MS (ISP) 514.3 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:10].[CH3:17][C:18]([C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)([C:20]1[O:21][CH:22]=[CH:23][N:24]=1)[CH3:19]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:31]([C:28]2[CH:27]=[CH:26][C:25]([C:18]([CH3:19])([C:20]3[O:21][CH:22]=[CH:23][N:24]=3)[CH3:17])=[CH:30][CH:29]=2)(=[O:32])=[O:33])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:10])[CH:4]=1
Reactant: CC(C)(c1ccc(S(=O)(=O)Cl)cc1)c1ncco1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccn1
Product: CC(C)(c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccn2)cc1)c1ncco1

Procedure:
The title compound was prepared from (2-amino-5-chloro-phenyl)-pyridin-2-yl-methanone and 4-(1-methyl-1-oxazol-2-yl-ethyl)-benzenesulfonyl chloride following the general procedure described for the preparation of N-aryl-benzenesulfonamides. MS: m/z 482 (M++1).
Reaction SMILES: [O:1]=[C:2]1[C:11](=[O:12])[NH:10][C:9]2[C:4](=[CH:5][C:6]([N:16]3[CH:20]=[CH:19][N:18]=[CH:17]3)=[C:7]([N+:13]([O-])=O)[CH:8]=2)[N:3]1[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C1COCC1.[H][H]>[C].[Pd].CO>[NH2:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)[N:3]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:2](=[O:1])[C:11](=[O:12])[NH:10]2
Reactant: [H][H]
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(-n3ccnc3)cc21
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(N)c(-n3ccnc3)cc21
Yield: 85.6 %

Procedure:
A mixture of 1.30 g of ethyl 2-[2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl]acetate, 80 ml of THF, 20 ml of methanol and 600 mg of 10% palladium-carbon was stirred in a hydrogen gas atmosphere for 36 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 1.02 g (86%) of ethyl 2-[6-amino-2,3-dioxo-7-(1H-imidazol-1-yl)-l,2,3,4-tetrahydroquinoxalin-1-yl]acetate.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]2[O:19][CH2:20][C:21]([CH3:24])([CH3:23])[N:22]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C([OH:28])(C)C.Cl.[OH-].[Na+]>O>[C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([O:19][CH2:20][C:21]([NH2:22])([CH3:24])[CH3:23])=[O:28])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(C)COC(CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)=N1
Reactant: CC(C)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(N)COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 45 °C

Procedure:
In a 1-liter, three-neck, round-bottom flask equipped with a thermometer, stirrer and condenser were placed 66.2 g (0.2 mole) 2-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethyl]-4,4-dimethyl-2-oxazoline, prepared as disclosed in inventors' application Ser. No. 043,787, filed on May 30, 1979, now abandoned and application Ser. No. 181,325, filed on Aug. 25, 1980 which is a continuation of said application Ser. No. 043,787, entitled "Derivatives of 2-Oxazolines as antioxidants," assigned to Uniroyal, Inc. and filed concurrently herewith, the disclosure of which is hereby incorporated herein by reference, 400 ml isopropanol and 33 ml 6 N hydrochloric acid. The mixture was heated to 45° C. for 2 hours and then cooled. To this stirred solution were added 250 ml of water and 33 ml of 6 N sodium hydroxide. The product was removed by filtration and dried. The title compound, (52 g), thus obtained, melted at 97°-99° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:15]=O)[CH:11]=2)[CH2:6]1)=[O:4].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl.C(=O)([O-])O.[Na+]>[F:1][C:2]([F:18])([F:17])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:15][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH2:6]1)=[O:4]
Reactant: C1CCNCC1
Reactant: O=Cc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(N1CCc2cc(CN3CCCCC3)ccc2C1)C(F)(F)F
Reaction time: 15 h

Procedure:
2-(2,2,2-Trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-6-carbaldehyde (2 g, 7.78 mmol) and piperidine (660 mg, 7.78 mmol) were dissolved in 1,2-dichloroethane (24 ml), and sodium triacetoxyborohydride (2.29 g, 10.89 mmol) was added. The reaction mixture was stirred for 15 h, then diluted with dichloromethane, and sat. sodium hydrogen carbonate solution (100 ml) was added. After phase separation, the aqueous phase was extracted with dichloromethane (3×100 ml). The combined organic phases were washed with sat. sodium chloride solution (50 ml), dried over magnesium sulfate and concentrated under vacuum. The crude product was purified by column chromatography (silica gel, ethyl acetate/dichloromethane/methanol 10:1:1+ammonia solution (25% aq.)). Yield: 1.88 g (74%)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:19]1[CH:28]=[CH:27][C:26]2[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:32])([CH3:31])[C:21]=2[CH:20]=1.[Br:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]Br>>[Br:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:19]1[CH:28]=[CH:27][C:26]2[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:31])([CH3:32])[C:21]=2[CH:20]=1
Reactant: BrCCCCCBr
Reactant: CCOC(=O)c1ccc(-c2ccc(O)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Product: CCOC(=O)c1ccc(-c2ccc(OCCCCCBr)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Yield: 70.1 %

Procedure:
In a manner similar to that of Example 1a, by reaction of 5 g (11.6 mmol) of ethyl 4′-hydroxy-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate with 5.2 ml (38.5 mmol) of 1,5-dibromopentane. 4.7 g of ethyl 4′-(5-bromopentyloxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a white solid (yield=70%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH2:23]([N:25]([CH2:36][CH3:37])[CH2:26][CH2:27][O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)[CH3:24].COCCOCCOC>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14]([NH:33][C:32]3[CH:31]=[CH:30][C:29]([O:28][CH2:27][CH2:26][N:25]([CH2:36][CH3:37])[CH2:23][CH3:24])=[CH:35][CH:34]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CCN(CC)CCOc1ccc(N)cc1
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Solvent: O
Solvent: COCCOCCOC
Product: CCN(CC)CCOc1ccc(Nc2ncc3cc(-c4c(Cl)cccc4Cl)c(=O)n(C)c3n2)cc1
Temperature: 150 °C

Procedure:
A mixture of 0.155 g (0.40 mmol) of 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 37, 0.167 g (0.80 mmol) of 4-(2-diethylaminoethoxy)aniline and 1 mL of (2-methoxyethyl)ether (bp 162° C.) was heated with stirring in a 150° C. oil bath. All solid gradually dissolved over a period of 10 minutes. The solution was heated another 10 minutes and cooled to 100° C. Water was added dropwise until slight turbidity. The crystals that separated on inducement were filtered, washed with 0.5 mL of ether and 2 mL of water, and dried; wt 0.105 g. Purification was effected by chromatography eluting with chloroform, then ethyl acetate and finally 10% methanol/chloroform to obtain fraction with pure product. The eluent was evaporated to dryness. The remaining amorphous solid was dissolved in 1 mL of warm ethyl acetate. The crystals that separated on inducement were filtered and washed sparingly with ethyl acetate and ether; wt 0.042 g; mp 141°-143° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([C:25]([NH2:27])=[O:26])=[CH:24][C:18]=3[N:17]=2)=[CH:12][CH:11]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>CN(C)C1C=CN=CC=1.CN(C=O)C>[C:28]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([C:25]([NH2:27])=[O:26])=[CH:24][C:18]=3[N:17]=2)=[CH:14][CH:15]=1)(=[O:30])[CH3:29]
Reactant: NC(=O)c1ccc2[nH]c(-c3ccc(OCCC4CCCCN4)cc3)nc2c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)N1CCCCC1CCOc1ccc(-c2nc3cc(C(N)=O)ccc3[nH]2)cc1
Reaction time: 24 h
Yield: 45.7 %

Procedure:
To a solution of 2-[4-(2-piperidin-2-yl-ethoxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide (75 mg, 0.21 mmol) and 4-(dimethylamino)pyridine (13 mg, 0.10 mmol) in DMF (0.5 mL) was added acetic anhydride (20 μL, 0.23 mmol). The reaction mixture was stirred for 18 h before additional acetic anhydride (1 equiv.) and DMAP (3 equiv.) were added. After an additional 24 h, HPLC monitoring indicated reaction completion. The crude material was purified by reverse phase HPLC (C18; H2O/CH3CN/0.01% TFA), providing 39 mg (47%) of product. HPLC (Method C): Rt=4.70. MS (ESI+): mass calcd. for C23H26N4O3, 406.20; m/z found, 407.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 8.18 (s, 1H), 8.03-7.96 (m, 3H), 7.71 (d, J=8.6 Hz, 1H), 7.18 (d, J=9.0 Hz, 1H), 7.13 (d, J=9.0 Hz, 1H), 4.41-4.26 (m, 1H), 4.15-3.94 (m, 1H), 4.04-3.98 (m, 1H), 3.69-3.64 (m, 1H), 2.67-2.60 (m, 1H), 2.41-2.21 (m, 1H), 1.97 (s, 3H), 1.98-1.85 (m, 1H), 1.72-1.52 (m, 5H), 1.48-1.23 (m, 1H).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][CH:13]1[CH2:19][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[N:15]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:41][N:40]=[N:39][N:38]=3)=[CH:27][CH:26]=2)[C:14]1=[O:42])=[O:11])=O)(C)(C)C.[ClH:43]>CO>[ClH:43].[NH2:8][CH2:9][C:10]([NH:12][CH:13]1[CH2:19][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[N:15]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:41][N:40]=[N:39][N:38]=3)=[CH:27][CH:26]=2)[C:14]1=[O:42])=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)NC1CCc2ccccc2N(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)C1=O
Agent: Cl
Solvent: CO
Product: NCC(=O)NC1CCc2ccccc2N(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
The intermediate obtained in Step C (109 mg, 0.196 mmol) was dissolved in 2 mL of methanol and treated with 0.1 mL of concentrated hydrochloric acid. The reaction mixture was stirred at room temperature for 16 hours then solvents were removed under vacuum and the residue redissolved in water and washed with ethyl acetate. The aqueous layer was separated and the solvent removed under vacuum to yield 87 mg (0.17 mmol, 88%) of the title compound. 1H NMR (200 MHz, CD3OD): 2.10 (m, 1 H), 2.48 (m, 3 H), 3.68 (s,2 H), 4.37 (m,1 H), 4.84 (d,14 Hz,1 H), 5.22 (d,14 Hz,1 H), 6.9-7.7 (m,12 H). FAB-MS: calculated for C26H25N7O2 467; found 468 (M+H,100%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[O:4][Si:5]([CH2:10][CH3:11])([CH2:8][CH3:9])[CH2:6][CH3:7].ClC1C=CC=C(C(OO)=[O:28])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[F:19][C:2]([F:18])([F:1])[CH:3]([C:12]1[CH:17]=[CH:16][N+:15]([O-:28])=[CH:14][CH:13]=1)[O:4][Si:5]([CH2:8][CH3:9])([CH2:6][CH3:7])[CH2:10][CH3:11]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC[Si](CC)(CC)OC(c1ccncc1)C(F)(F)F
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC[Si](CC)(CC)OC(c1cc[n+]([O-])cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.2 %

Procedure:
To 40 ml of chloroform were added 5.5 g of 4-[2,2,2-trifluoro-1-(triethylsilyloxy)ethyl]pyridine, and 7.5 g of meta-chloroperbenzoic acid, and the mixture was stirred at 0° C. for 2 hours, and at room temperature for 3 hours. Thereafter, the reaction solution was poured into an aqueous saturated sodium sulfite solution, followed by extraction with chloroform three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 5 g of 4-[2,2,2-trifluoro-1-(triethylsilyloxy)ethyl]pyridine N-oxide.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:33])[NH:14][C:15]=23)[CH2:31][CH2:32]1
Reactant: COCC(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-methylphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f19) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22](O)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[CH2:25]([NH:29][CH3:30])[CH:26]([CH3:28])[CH3:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:29]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH3:30])=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: CNCC(C)C
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)CN(C)C(=O)c1ccc(C(=O)NCc2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, N-isobutylmethylamine, TBTU, and triethylamine in DMSO at ambient temperature.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11](O)[CH2:10][CH2:9]1)=[O:7].I[Si](C)(C)C.[NH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[Ba+2]>C(Cl)(Cl)Cl>[N:29]1([CH:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([C:6](=[O:7])[C:5]3[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:9][CH2:10]2)[C:38]2[CH:33]([CH2:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: COc1ccc(C(=O)N2CCC(O)c3ccccc32)cc1OC
Agent: C[Si](C)(C)I
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)N2CCC(N3CCCC4CC=CC=C43)c3ccccc32)cc1OC
Reaction time: 2 h
Yield: 36.7 %

Procedure:
1-(3,4-Dimethoxybenzoyl)-1,2,3,4-tetrahydro-4-quinolinol (400 mg, 1.28 mmol) prepared in Reference Example 2 was dissolved in chloroform (10 ml), to which iodotrimethylsilane (638 mg, 3.19 mmol) was then added on ice and stirred for 2 hours. After the reaction mixture was concentrated, the residue was dissolved in THF (10 ml) and mixed with 1,2,3,4-tetrahydroquinoline (511 mg, 3.84 mmol) and barium carbonate (505 mg, 2.56 mmol), followed by stirring at room temperature for 48 hours. After the reaction mixture was filtered to remove insoluble products and concentrated, the residue was applied to silica gel column chromatography (developing solvent: ethyl acetate/hexane=1/3) and the resulting eluate was recrystallized from diethyl ether-hexane to give the product of interest, i.e., 4-(tetrahydroquinolin-1-yl)-1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-quinoline (202 mg, yield: 37%) as a white crystal.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([CH2:20][C:21]([O-:23])=[O:22])=[CH:15][CH:14]=2)(C(C)(C)C)(C)C.[F-].[CH2:25]([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[OH:8][CH2:9][CH2:10][C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([CH2:20][C:21]([O:23][CH3:25])=[O:22])=[CH:15][CH:14]=2
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)[Si](C)(C)OCCc1cc2cc(CC(=O)[O-])ccc2[nH]1
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc2[nH]c(CCO)cc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 2-(2-(t-butyldimethylsilyl-oxyethyl)-indole-5-acetate (400 mg; 1.15 mmol) in ca. 4 ml of THF was added a 1 M tetrabutylammonium fluoride in THF (1.2 mL; 1.05 eq) at 0° C. After 15 minutes, the reaction was allowed to warm to room temperature and stirred for an additional 3 hours. It was con-centrated, diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried (Na2SO4), concentrated and chromatographed (silica gel, hexane:ethyl acetate 4:1) to yield 241 mg of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:32]3[CH2:37][CH2:36][C@@H:35]([N:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)[CH2:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[S:19][C:20]([CH2:30][CH3:31])=[C:21](C5C=CC(C)=CC=5)[N:22]=4)=[CH:13][CH:12]=3)[C:3]=12.[C:45]1([CH3:54])[CH:50]=[CH:49][CH:48]=[C:47](B(O)O)[CH:46]=1>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:32]3[CH2:33][CH2:34][C@@H:35]([N:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)[CH2:36][CH2:37]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[S:19][C:20]([CH2:30][CH3:31])=[C:21]([C:47]5[CH:48]=[CH:49][CH:50]=[C:45]([CH3:54])[CH:46]=5)[N:22]=4)=[CH:13][CH:12]=3)[C:3]=12
Reactant: Cc1cccc(B(O)O)c1
Reactant: CCc1sc(Nc2ccc(-c3nn([C@H]4CC[C@@H](N5CCN(C)CC5)CC4)c4ncnc(N)c34)cc2)nc1-c1ccc(C)cc1
Product: CCc1sc(Nc2ccc(-c3nn([C@H]4CC[C@@H](N5CCN(C)CC5)CC4)c4ncnc(N)c34)cc2)nc1-c1cccc(C)c1

Procedure:
The procedure described for cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5-ethyl-4-(4-methylphenyl)-1,3-thiazol-2-amine was used to convert m-tolylboronic acid (0.175 g, 1.29 mmol) to the title compound. Purification of the product by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 10.0-12.0 min) afforded cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5-ethyl-4-(3-methylphenyl)-1,3-thiazol-2-amine as an off-white solid (0.051 g, 0.084 mmol); RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 10.13 min; MS (MH)+ 608.
Reaction SMILES: CC(=CC)C.P([O-])(O)(O)=O.[Na+].[CH3:12][C:13]1[N:18]=[C:17]([CH3:19])[C:16]([O:20][CH2:21][C@@:22]2([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][O:35][CH3:36])=[C:29]([F:37])[CH:28]=3)[CH2:24][C@H:23]2[CH:25]=[O:26])=[CH:15][N:14]=1.Cl([O-])=[O:39].[Na+]>O.CC(C)=O.O>[CH3:12][C:13]1[N:18]=[C:17]([CH3:19])[C:16]([O:20][CH2:21][C@@:22]2([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][O:35][CH3:36])=[C:29]([F:37])[CH:28]=3)[CH2:24][C@H:23]2[C:25]([OH:39])=[O:26])=[CH:15][N:14]=1
Reactant: COCOc1ccc([C@]2(COc3cnc(C)nc3C)C[C@H]2C=O)cc1F
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COCOc1ccc([C@]2(COc3cnc(C)nc3C)C[C@H]2C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 56.1 %

Procedure:
2-methyl-2-butene (11.5 ml) and sodium dihydrogen phosphate (3.89 g) were added to an acetone-water (100 ml-25 ml) solution of the compound 321-7 (7.8 g). The reaction solution was cooled on ice. Sodium chlorite (3.91 g) was added to the reaction solution, and the obtained mixture was stirred at room temperature for 15 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=9:1 to 0:1), so as to obtain the title compound (4.57 g).