Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][CH:25]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]2)=[N:22][CH:23]=1.[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([F:53])[C:39]=1[OH:54]>>[Cl:37][C:38]1[CH:43]=[C:42]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C:18]2[CH:23]=[N:22][C:21]([NH:24][CH:25]3[CH2:29][CH2:28][NH:27][CH2:26]3)=[CH:20][CH:19]=2)[CH:41]=[C:40]([F:53])[C:39]=1[OH:54]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Product: O=C(c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1ccc(NC2CCNC2)nc1)C1CC1
Yield: 45 %

Procedure:
Following general procedure D, tert-butyl 3-(5-(6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino)pyridin-2-ylamino)pyrrolidine-1-carboxylate (100 mg, 0.18 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (73 mg, 0.27 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (42 mg, 45% over 2 steps) as a yellow solid: 1H NMR (500 MHz, MeOD+TFA-d) δ 9.40 (br s, 1H), 8.22 (dd, J=8.8, 2.0 Hz, 1H), 8.17-8.06 (m, 2H), 8.00 (d, J=8.8 Hz, 1H), 7.55 (dd, J=8.9, 2.7 Hz, 1H), 7.19-7.13 (m, 2H), 6.83-6.76 (m, 1H), 4.65-4.56 (m, 1H), 3.66-3.49 (m, 2H), 3.45-3.30 (m, 2H), 2.87 (br s, 1H), 2.48-2.37 (m, 1H), 2.19-2.08 (m, 1H), 1.28-1.16 (m, 4H). ESI MS m/z 518 [C28H25ClFN5O2+H]+; HPLC>99.0% (AUC), tR=10.43 min.
Reaction SMILES: [F:1][C@:2]12[CH2:12][CH2:11][O:10][C:9]3[CH:13]=[CH:14][C:15]([N+:17]([O-])=O)=[CH:16][C:8]=3[C@@:7]1([CH3:20])[N:6]=[C:5]([N:21]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:4]([CH3:37])([CH3:36])[S:3]2(=[O:39])=[O:38]>C(O)C.[Pd]>[NH2:17][C:15]1[CH:14]=[CH:13][C:9]2[O:10][CH2:11][CH2:12][C@:2]3([F:1])[S:3](=[O:39])(=[O:38])[C:4]([CH3:37])([CH3:36])[C:5]([N:21]([C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[N:6][C@:7]3([CH3:20])[C:8]=2[CH:16]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc([N+](=O)[O-])ccc3OCC[C@]2(F)S(=O)(=O)C1(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc(N)ccc3OCC[C@]2(F)S(=O)(=O)C1(C)C
Reaction time: 2 h
Yield: 100 %

Procedure:
A mixture of tert-butyl N-[(4aS,11bR)-4a-fluoro-3,3,11b-trimethyl-10-nitro-4,4-dioxo-5,6-dihydro-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (20 mg, 0.035 mmol) and 10% Pd on carbon (18.62 mg, 0.017 mmol) in Ethanol (0.2 mL) was stirred under hydrogen atmosphere for 2 hours. The mixture was passed through a celite cake and rinsed with ethyl acetate and ethanol. The filtrate was concentrated in vacuo to afford the title compound (19 mg, 0.035 mmol, 100% yield) as a yellow oil. MS m/z=564.2 (M+Na).
Reaction SMILES: CN1CCOCC1.Cl[C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10].[NH2:15][CH:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[CH2:21][C:22]([NH:24][CH:25]([CH3:36])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1)=[O:23].O>C(Cl)Cl>[C:34]([C:31]1[CH:30]=[CH:29][C:28]([O:27][CH2:26][CH:25]([NH:24][C:22](=[O:23])[CH2:21][CH:17]2[CH2:18][CH2:19][CH2:20][CH:16]2[NH:15][C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH3:36])=[CH:33][CH:32]=1)#[N:35]
Reactant: CC(COc1ccc(C#N)cc1)NC(=O)CC1CCCC1N
Reactant: CC(C)OC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: CC(COc1ccc(C#N)cc1)NC(=O)CC1CCCC1NC(=O)OC(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.7 %

Procedure:
0.4 g of N-methyhnorpholine, and subsequently 0.5 g of isopropyl chloroformate were added to a suspension containing 1.2 g of 2-amino-N-[2-(4-cyanophenoxy)-1-methylethyl]cyclopentylacetic acid amide suspended in 40 ml of methylene chloride at -15° C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 1.4 g of the desired product in the form of a colorless plated crystal (yield: 90%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][CH2:6][C:7](=O)[CH3:8])[CH3:2].S(=O)(=O)(O)O.[F:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23]N)=[CH:19][CH:18]=1>C(O)C>[CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6]1[C:21]2[C:20](=[CH:19][CH:18]=[C:17]([F:16])[CH:22]=2)[NH:23][C:7]=1[CH3:8])[CH3:2]
Reactant: NNc1ccc(F)cc1
Reactant: CCOC(=O)CCC(C)=O
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)Cc1c(C)[nH]c2ccc(F)cc12

Procedure:
4-Oxo-pentanoic acid ethyl ester (17.6 ml, 0.124 mol.) and conc. sulfuric acid (10 ml) were added to a solution of 4-fluorophenylhydrazine (20.2 g, 0.124 mol.) in abs. ethanol (90 ml), and the mixture was heated at reflux for 4 h. For working up, the mixture was filtered over silica gel and washed with ethanol (3×20 ml). The solution was poured into 500 ml of ice-water and extracted with ether (3×100 ml). The combined extracts were washed with 2M sodium hydrogen carbonate solution (50 ml), dried, filtered and concentrated. By recrystallisation from EE/cyclohexane (1:1) it was possible to obtain (5-fluoro-2-methyl-1H-indol-3-yl)acetic acid ethyl ester in a yield of 4.5 g (yellow solid, m.p. 61–62° C.).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:9]([O-])=O)=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH:12](=O)[CH2:13][CH3:14]>>[CH2:13]([CH:12]1[NH:9][C:3]2[C:4](=[CH:6][CH:7]=[CH:8][C:2]=2[CH3:1])[N:5]2[CH:1]=[CH:2][CH:8]=[C:7]12)[CH3:14]
Reactant: Cc1cccc(N)c1[N+](=O)[O-]
Reactant: CCC=O
Product: CCC1Nc2c(C)cccc2-n2cccc21

Procedure:
The title compound was prepared 3-methyl-2-nitro aniline according to the sequence of Examples 1 and 2, and the resulting oil treated with proprionaldehyde according to the procedure of Example 3 to yield a brown solid, mp 65-68° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]3[CH:18]=[C:19]([Cl:26])[C:20]([C:22]([F:25])([F:24])[F:23])=[CH:21][C:16]=3[N:15]=[C:14]2[C:27]([NH2:30])([CH3:29])[CH3:28])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[C:31](Cl)(=[O:33])[CH3:32].O>ClCCl>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:17]3[CH:18]=[C:19]([Cl:26])[C:20]([C:22]([F:24])([F:25])[F:23])=[CH:21][C:16]=3[N:15]=[C:14]2[C:27]([NH:30][C:31](=[O:33])[CH3:32])([CH3:29])[CH3:28])=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(=O)OCCc1ccc(-n2c(C(C)(C)N)nc3cc(C(F)(F)F)c(Cl)cc32)cc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)NC(C)(C)c1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(C)=O)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 58.4 %

Procedure:
To a solution of 2-{4-[2-(1-amino-1-methylethyl)-6-chloro-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl acetate (step 3, 121 mg, 0.27 mmol) in dichloromethane (5 ml) was added acetyl chloride (0.02 ml, 0.3 mmol). The reaction mixture was stirred at room temperature for 7 h. To the reaction mixture was added water (5 ml) and the aqueous mixture was extracted with dichloromethane (30 ml). The organic layer was washed with water (5 ml) and brine (10 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with CH2Cl2/methanol (10/1) to afford 76 mg (57%) of the title compound as white amorphous.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:15]/[CH:16]=[C:17](/[C:28]1[N:33]=[C:32]([O:34][CH3:35])[C:31]([Cl:36])=[CH:30][CH:29]=1)\[C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=1.O>C(#N)C>[C:24]([C:21]1[CH:22]=[CH:23][C:18](/[C:17](/[C:28]2[CH:29]=[CH:30][C:31]([Cl:36])=[C:32]([O:34][CH3:35])[N:33]=2)=[CH:16]\[CH2:15][N:4]2[CH2:5][CH2:6][N:2]([CH3:1])[C:3]2=[O:7])=[CH:19][CH:20]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CN1CCNC1=O
Reactant: COc1nc(/C(=C/CBr)c2ccc(C(C)(C)C)cc2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1nc(/C(=C/CN2CCN(C)C2=O)c2ccc(C(C)(C)C)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 84 h
Yield: 10.1 %

Procedure:
1-Methyl-2-imidazolidinone (80 mg) and potassium carbonate (135 mg) were added to a solution of 6-[(1E)-3-bromo-1-(4-tert-butylphenyl)prop-1-en-1-yl]-3-chloro-2-methoxypyridine (123 mg) in acetonitrile (2 mL), and the mixture was stirred at room temperature for 3.5 days. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→0:10) to give 1-[(2E)-3-(4-tert-butylphenyl)-3-(5-chloro-6-methoxypyridin-2-yl)prop-2-en-1-yl]-3-methylimidazolidin-2-one as a yellow oil (13 mg, 10%).
Reaction SMILES: [H][H].[CH2:3]([NH2:5])[CH3:4].[CH2:6]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[C@@H:23]2[O:35][C@H:34]([CH2:36][O:37]C(=O)C)[C@@H:29]([O:30]C(=O)C)[C@H:24]2[O:25]C(=O)C)=[C:16](Cl)[N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([O:13][C:14]1[N:15]=[C:16]([NH:5][CH2:3][CH3:4])[C:17]2[N:18]=[CH:19][N:20]([C:21]=2[N:22]=1)[C@@H:23]1[O:35][C@H:34]([CH2:36][OH:37])[C@@H:29]([OH:30])[C@H:24]1[OH:25])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(OCc4ccccc4)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCN
Reactant: [H][H]
Product: CCNc1nc(OCc2ccccc2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 40 %

Procedure:
A compound having a structure of the above formula was prepared where the substituent R1 is —CH2CH3, R2 is hydrogen, and R3 is benzyl (—CH2C6H5). The compound (C19H23N5O5) was prepared by reaction of ethylamine with 2-benzyloxy-6-chloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine (Example 3) as described in Example 2, Step E. The final product was isolated in 40% yield as a solid with melting point of 170-171° C. 1H-NMR (DMSO-d6): δ 1.13 (t, 3H, J=8); 3.6 (m, 4H); 3.9 (m, 1H); 4.1 (m, 1H); 4.5 (m, 1H); 5.18 (m, 2H); 5.32 (s, 2H); 5.42 (d, 1H, J×6); 5.78 (d, 1H, J=6); 7.41 (m, 5H); 7.93 (bm, 1H); 8.15 (s, 1H).
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][C@@H:8]([OH:10])[CH2:9][C@H:2]12.[F:11][C:12]([F:24])([F:23])[C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[F:24][C:12]([F:11])([F:23])[C:13]1[CH:14]=[CH:15][C:16]([S:19]([N:6]2[CH2:5][CH2:4][N:3]3[CH2:7][C@@H:8]([OH:10])[CH2:9][C@@H:2]3[CH2:1]2)(=[O:21])=[O:20])=[CH:17][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: O[C@H]1C[C@@H]2CNCCN2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCN2C[C@@H](O)C[C@@H]2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To (7S,8aR)-octahydropyrrolo[1,2-a]pyrazin-7-ol (0.208 g, 1.463 mmol) and 4-(trifluoromethyl)benzene-1-sulfonyl chloride (0.358 g, 1.463 mmol) in dichloromethane (3 mL) was added triethylamine (303 mg, 3 mmol). The mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by chromatography on silica gel (CH2Cl2/CH3OH=10:1) to give the title compound (0.4 g, 78% yield). MS (ESI) m/z 421 (M+H)+.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH:9]([C:13]([OH:15])=[O:14])[CH2:8]1.[CH3:16]O>>[CH3:5][O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][C@H:9]([C:13]([O:15][CH3:16])=[O:14])[CH2:8]1.[CH3:5][O:6][C@H:7]1[CH2:12][CH2:11][CH2:10][C@H:9]([C:13]([O:15][CH3:16])=[O:14])[CH2:8]1
Reactant: COC1CCCC(C(=O)O)C1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1CCC[C@@H](OC)C1
Product: COC(=O)[C@H]1CCC[C@H](OC)C1
Reaction time: 0.25 h
Yield: 29 %
Yield: 56 %

Procedure:
Under a nitrogen atmosphere, thionyl chloride (11.3 g, 0.0948 mol) was slowly dropped into methanol (30 ml) at −5° C. over a period of 20 minutes. After 15 minutes, a solution of 3-methoxycyclohexylcarboxylic acid (5.0 g, 0.0316 mol, cis:trans=4:3) in methanol (30 ml) was added dropwise thereto over a period of 15 minutes. After 2.5 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogencarbonate solution. The aqueous layer was re-extracted with ethyl acetate and then the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain methyl cis-3-methoxycyclohexane-carboxylate (3.0673 g, 56%) and methyl trans-3-methoxycyclohexanecarboxylate (1.5859 g, 29%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([OH:24])=O)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:28]([NH2:30])[CH3:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[C:21]([C:22]([NH:30][CH2:28][CH3:29])=[O:24])[CH:20]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1c(C(=O)Nc2cccc(C(=O)O)c2)nnn1Cc1ccc(Cl)c(Cl)c1
Reactant: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCNC(=O)c1cccc(NC(=O)c2nnn(Cc3ccc(Cl)c(Cl)c3)c2C)c1
Temperature: 40 °C

Procedure:
A mixture of 3-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]benzoic acid (Example 63) (0.143 g, 0.35 mmol), ethylamine in THF, 2M solution (1.75 mL, 0.35 mmol), HATU (0.199 g, 0.52 mmol) and DIPEA (0.09 mL, 0.52 mmol) in DMF was stirred at 40° C. for 1 week. The solvent was evaporated and the residue was washed with water and extracted with DCM. The organic phase was dried over sodium sulphate, filtered and concentrated. The title compound was obtained after recrystallisation from acetonitrile as white solid (49 mg, 32%). HRMS calculated for C20H19Cl2N5O2 (M+H)+432.0994, found: 432.0957, Rt: 2.82 min. MP: 192.2° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[S:8][CH2:7][CH2:6][C:5]2([C:15]([OH:17])=[O:16])[OH:14].CCCCCCC>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[S:8][CH2:7][CH2:6][C@@:5]2([C:15]([OH:17])=[O:16])[OH:14]
Reactant: COc1cc(Cl)cc2c1SCCC2(O)C(=O)O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(Cl)cc2c1SCC[C@]2(O)C(=O)O

Procedure:
The enantiomers of 6-chloro-4-hydroxy-8-methoxythiochromane-4-yl-carboxylic acid (3.00 g, 10.9 mmol; see step (v) above) were separated using chiral chromatography (Kromasil TBB; heptane:ethyl acetate:formnic acid) affording 1.13 g of the faster moving, not wanted S-enantiomer, and 1.19 g (79%) of the slower moving sub-title compound. ee=94.6%
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18](I)[CH:19]=2)[N:14]=[CH:13][N:12]=1.[CH3:22][C:23]1[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:26]2=[N:27][CH:28]=[C:29](B3OC(C)(C)C(C)(C)O3)[CH:30]=[C:25]2[N:24]=1.C(=O)([O-])O.[Na+]>O1CCOCC1.O.CC(=O)OCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:29]3[CH:30]=[C:25]4[N:24]=[C:23]([CH3:22])[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:46])([CH3:48])[CH3:47])[C:26]4=[N:27][CH:28]=3)[CH:19]=2)[N:14]=[CH:13][N:12]=1
Reactant: Ic1ccc2ncnc(N3CCc4ccccc4C3)c2c1
Reactant: Cc1nc2cc(B3OC(C)(C)C(C)(C)O3)cnc2n1COCC[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1nc2cc(-c3ccc4ncnc(N5CCc6ccccc6C5)c4c3)cnc2n1COCC[Si](C)(C)C
Yield: 72.4 %

Procedure:
0.87 g of 4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-iodoquinazoline, 0.96 g of 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyridine, 0.52 g of sodium hydrogencarbonate and 0.29 g of Pd(PPh3)2Cl2 in 17 ml of dioxane and 2 ml of water are heated at 90° C. under nitrogen in a flask until the reaction is complete (HPLC check, about 3 hours). The cooled reaction solution is diluted with EA and washed 3 times with water. The organic phase is dried over sodium sulfate and purified by means of column chromatography (gradient EA: methanol 0-30% in 20 min), giving 0.85 g of 4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]quinazoline as white powder (yield 60%, content 86%); MS-FAB (M+H+)=523.2; Rf (polar method): 2.12 min.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:8])[CH2:5][CH2:6][CH3:7].[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](F)=[C:14]([F:19])[CH:13]=1)=[O:11]>CN(C=O)C.C(OCC)(=O)C>[F:19][C:14]1[CH:13]=[C:12]([C:10](=[O:11])[CH3:9])[CH:17]=[CH:16][C:15]=1[O:8][CH:4]([CH3:3])[CH2:5][CH2:6][CH3:7]
Reactant: CC(=O)c1ccc(F)c(F)c1
Reactant: CCCC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC(C)Oc1ccc(C(C)=O)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.058 g of NaH was added to a solution of 0.176 g of 2-pentanol in 2 ml of DMF, and the solution was stirred at room temperature for 1 hour. Then 0.312 g of 3,4-difluoroacetophenone was added, and the mixture was stirred at room temperature overnight. The reaction solution was taken up in ethyl acetate and washed twice with water. The organic phase was dried over sodium sulfate and concentrated in vacuo. The resulting compound was reacted further without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14](=[O:18])[NH:15]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.Br[CH2:20][CH2:21][O:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27]([CH3:33])=[N:28]2.C(N(CC)C(C)C)(C)C>CC(O)C>[CH3:33][C:27]1[CH:26]=[CH:25][C:24]2[C:29](=[CH:30][CH:31]=[CH:32][C:23]=2[O:22][CH2:21][CH2:20][N:1]2[CH2:2][CH2:3][CH:4]([O:7][C:8]3[CH:17]=[C:16]4[C:11]([CH2:12][CH2:13][C:14](=[O:18])[NH:15]4)=[CH:10][CH:9]=3)[CH2:5][CH2:6]2)[N:28]=1
Reactant: Cc1ccc2c(OCCBr)cccc2n1
Reactant: O=C1CCc2ccc(OC3CCNCC3)cc2N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1ccc2c(OCCN3CCC(Oc4ccc5c(c4)NC(=O)CC5)CC3)cccc2n1
Yield: 46.3 %

Procedure:
7-(Piperidin-4-yloxy)-3,4-dihydro-1H-quinolin-2-one (0.064 g, 0.25 mmol) and 5-(2-bromoethoxy)-2-methylquinoline (0.069 g, 0.25 mmol) were mixed together in propan-2-ol (20 mL), N,N-diisopropylethylamine (0.336 g, 2.6 mmol) added and the mixture heated at reflux for 48 h. The volatiles were removed by evaporation to dryness under reduced pressure and the residue partitioned between ethyl acetate and saturated NaHCO3 aq. The phases were separated, the organic phase washed with water, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography on SiO2, eluting with a gradient of ethyl acetate in 60–80° C. petroleum ether, gave the title compound (0.05 g, 45%) as a white solid, after trituration under 60–80° C. petroleum ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH3:14].CN([CH:18]=[O:19])C.O=P(Cl)(Cl)Cl>C1C(Cl)=CC=C(Cl)C=1>[CH3:14][O:13][C:4]1[CH:5]=[C:6]([CH:18]=[O:19])[C:7]2[C:12]([C:3]=1[O:2][CH3:1])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: COc1ccc2ccccc2c1OC
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: Clc1ccc(Cl)cc1
Product: COc1cc(C=O)c2ccccc2c1OC
Temperature: 0 °C
Yield: 68.9 %

Procedure:
A mixture of 1,2-dimethoxynaphthalene (0.74 g, 4 mmol) and DMF (0.8 mL, 10 mmol) in dichlorobenzene (0.8 mL) was stirred with POCl3 at 100° C. for 2 h. The reaction mixture was cooled to 0° C., quenched with a cold aqueous solution of NaOAc, diluted with H2O and extracted with benzene. The extracts were dried (MgSO4), concentrated and in vacuo and dichlorobenzene was removed by kugelrohr distillation at 110° C./0.5 mm Hg. Column chromatography (20% EtOAc in hexane) gave the product 518 (596 mg, 68%), which was used in the following step without further purification. 1H NMR (CDCl3) 10.42 (s, 1H), 9.00-9.15 (m, 1H), 8.15-8.30 (m, 1H), 7.61 (s, 1H), 7.50-7.65 (m, 2H), 4.12 (s, 3H), 4.07 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[C:22]2[CH:23]=[C:24]3[CH:28]=[CH:27][CH:26]=[C:25]3[O:29][CH:30]=2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:32].C(OCC)C>ClCCl>[ClH:32].[ClH:32].[O:29]1[C:25]2=[CH:26][CH:27]=[CH:28][C:24]2=[CH:23][C:22]([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][N:16]2[CH2:15][CH2:14][C@H:11]2[CH2:10][CH2:9][C@H:8]([NH2:7])[CH2:13][CH2:12]2)=[CH:30]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reaction time: 2 h

Procedure:
To a mixture of trans-{4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester (2.3 g, 5.39 mmol) in dichloromethane (40 ml) was added at room temperature hydrochloric acid solution (4M in dioxane, 20.2 ml, 80.9 mmol) and the mixture was allowed to stir for 2 h, diethyl ether (50 ml) was added and the mixture was allowed to stir for 30 min at room temperature. The precipitate was collected by filtration, washed with diethyl ether and dried to yield the title compound as a white solid (1.89 g, 88%), MS (ISP) m/z=327.4 [(M+H)−], mp 339° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([CH2:28][CH2:29][CH3:30])([C:23]([O:25]CC)=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH2:28][CH2:29][CH3:30])[C:23]([OH:25])=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC(CCc1ccccc1OCc1ccccc1)(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCC(CCc1ccccc1OCc1ccccc1)(C(=O)O)C(=O)OCC
Temperature: 25 °C
Reaction time: 96 h
Yield: 61.2 %

Procedure:
To a solution of diethyl 2-(2-(2-benzyloxyphenyl)ethyl)-2-propylmalonate (10 g) in ethanol (50 ml), a solution of potassium hydroxide (1.9 g) in ethanol (180 ml) was added and the mixture was refluxed under heating for 6.5 hours. Ethanol (45 ml) was added thereto and the mixture was stirred at room temperature for 4 days. The reaction mixture was poured into a dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with a saturated brine and dried over sodium sulfate. The solvent was distilled away under reduced pressure and the residue was subjected to silica gel chromatography (eluent; chloroform-methanol=12:1) to give the subject compound (5.7 g).
Reaction SMILES: N[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:4].C=O.[C:16]([BH3-])#[N:17].[Na+].[C:20](O)(=O)C>CO>[CH3:20][N:17]([CH3:16])[CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)[OH:4]
Reactant: NCC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: [BH3-]C#N
Reactant: CC(=O)O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN(C)CC(O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34 %

Procedure:
To a solution of 2-amino-1-(4-nitrophenyl)ethanone (500 mg, 2.30 mmol), paraformaldehyde (207 mg, 6.90 mmol), and sodium cyanoborohydride (433 mg, 6.90 mmol) in methanol (30 mL) was added acetic acid (catalytic) and the reaction stirred at room temperature for 18 h. The reaction mixture was quenched with water and the layers were separated. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated, and chromatographed (CH2Cl2/MeOH) to afford the desired product (164 mg, 34%) as an orange oil: ESI MS m/z 211 [C10H14N2O3+H]+.