Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1.[F:31][C:32]([F:42])([F:41])[C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:36][C:35]2[CH:38]=[CH:39][CH:40]=[C:33]([C:32]([F:31])([F:41])[F:42])[CH:34]=2)[CH:6]=1
Reactant: COC(=O)Cc1cccc(OCCCNCC(c2ccccc2)c2ccccc2)c1
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2)CC(c2ccccc2)c2ccccc2)c1
Temperature: 45 °C
Reaction time: 18 h
Yield: 76.6 %

Procedure:
To a solution of {3-[3-(2,2-diphenyl-ethylamino)-propoxy]-phenyl}-acetic acid methyl ester (3) (0.40 g, 0.001 mol) in DMF (10 mL), was added 3-trifluoromethylbenzyl bromide (0.24 g, 0.001 mol) and powdered potassium carbonate (0.96 g, 0.007 mol), the reaction mixture was heated and stirred at 45° C. for 18 hours. After cooling, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, concentrated to an oil, which was purified by flash chromatography (8:2 Hexanes/EtOAc) to give the desired product as oil 0.43 g in 77% yield. 1H NMR (CDCl3) δ 7.40 (d, 1H), 7.37 (s, 1H), 7.24 (m, 7H), 7.19 (m, 6H), 6.83 (d, 1H), 6.62 (s, 1H), 6.59 (dd, 1H), 4.16 (t, 1H), 3.67 (s, 3H), 3.63 (s, 2H), 3.58 (t, 2H), 3.55 (s, 2H), 3.08 (d, 2H), 2.61 (t, 2H), 1.79 (t, 2H); 13C NMR (CDCl3) δ 173.4, 160.4, 144.7, 143.7, 142.2, 136.6, 133.8, 133.5, 131.9, 130.8, 130.2, 129.9, 129.8, 127.8, 126.8, 125.1, 125.0, 122.7, 116.8, 115.7, 114.5, 66.8, 61.1, 60.2, 53.5, 51.8, 42.6, 28.2.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[CH2:10]([NH:14][CH:15]1[CH2:20][C:19]([CH3:22])([CH3:21])[N:18]([O:23][CH2:24][CH2:25][CH3:26])[C:17]([CH3:28])([CH3:27])[CH2:16]1)[CH2:11][CH2:12][CH3:13]>C1(C)C(C)=CC=CC=1.O>[CH2:10]([N:14]([CH:15]1[CH2:16][C:17]([CH3:28])([CH3:27])[N:18]([O:23][CH2:24][CH2:25][CH3:26])[C:19]([CH3:21])([CH3:22])[CH2:20]1)[C:8]1[N:1]=[C:2]([N:14]([CH2:10][CH2:11][CH2:12][CH3:13])[CH:15]2[CH2:16][C:17]([CH3:27])([CH3:28])[N:18]([O:23][CH2:24][CH2:25][CH3:26])[C:19]([CH3:22])([CH3:21])[CH2:20]2)[N:4]=[C:5]([Cl:6])[N:7]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCNC1CC(C)(C)N(OCCC)C(C)(C)C1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: Cc1ccccc1C
Solvent: O
Product: CCCCN(c1nc(Cl)nc(N(CCCC)C2CC(C)(C)N(OCCC)C(C)(C)C2)n1)C1CC(C)(C)N(OCCC)C(C)(C)C1
Reaction time: 1.5 h

Procedure:
A four-necked round-bottom flask equipped with a mechanical stirrer, thermocouple, dropping funnel and condenser is charged with 27.3 g (0.148 mol) of cyanuric chloride and 200 mL of xylene at 0-5° C. 40 g (0.148 mol) of compound I-102 in 25 mL of xylene are slowly added over 20 minutes to this solution. After 90 minutes, further 40 g (0.148 mol) of compound I-102 in 25 mL of xylene and 25 mL of water are slowly added over 20 minutes to the system allowing the temperature to reach 45° C.
Reaction SMILES: [CH3:1][N:2]([CH3:38])[C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([C@@H:10]2[CH2:14][C@H:13]([S:15]CC3C=CC(OC)=CC=3)[CH2:12][N:11]2[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)=[O:26])=[O:9])[CH2:4]1.FC(F)(F)C(O)=O.[F:46][C:47]([F:53])([F:52])[S:48]([OH:51])(=[O:50])=[O:49]>C1(OC)C=CC=CC=1>[F:46][C:47]([F:53])([F:52])[S:48]([OH:51])(=[O:50])=[O:49].[CH3:1][N:2]([CH3:38])[C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([C@@H:10]2[CH2:14][C@H:13]([SH:15])[CH2:12][N:11]2[C:25]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=2)=[O:26])=[O:9])[CH2:4]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC[C@H](N(C)C)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CN(C)[C@H]1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
845 mg of (2S,4S)-2-[(3S)-3-dimethylamino-1-pyrrolidinylcarbonyl]-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (1) above] were suspended in 1.7 ml of anisole, and 8.5 ml of trifluoroacetic acid and 0.28 ml of trifluoromethanesulfonic acid were added to the resulting suspension, whilst ice-cooling, after which the mixture was stirred at room temperature for 1 hour. The cycle comprising removing the solvent by evaporation under reduced pressure, washing the residue with hexane to remove anisole, adding diethyl ether to the mixture, cooling the mixture to -78° C. to solidify the product and milling the product, followed by decantation, was repeated several times to obtain 1.14 g of the title compound as a powder.
Reaction SMILES: [N+:1]([C:4]1[C:9](Cl)=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([O:14]CC)=[O:13])([O-:3])=[O:2].[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[OH:25].C(=O)([O-])[O-].[K+].[K+]>>[N+:1]([C:4]1[C:9]([O:25][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([Cl:24])[C:18]=2[Cl:17])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([OH:14])=[O:13])([O-:3])=[O:2]
Reactant: Oc1cccc(Cl)c1Cl
Reactant: CCOC(=O)Cc1cccc(Cl)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(O)Cc1cccc(Oc2cccc(Cl)c2Cl)c1[N+](=O)[O-]
Yield: 29.2 %

Procedure:
A mixture of ethyl 2-(2-nitro-3-chlorophenyl)acetate (10 g.), 2,3-dichlorophenol (7.4 g.), anhydrous potassium carbonate (8.5 g.) and cupric oxide (1 g.) was treated in a similar manner to the above to give 2-[2-nitro-3-(2,3-dichlorophenoxy)phenyl]acetic acid (4.1 g.). mp 178° to 183° C.
Reaction SMILES: [NH2:1][C@H:2]([CH2:9]O)[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.[BrH:11]>C(O)(=O)C.C(O)C>[Br:11][CH2:9][C@@H:2]([NH2:1])[CH2:3][C:4]1[NH:8][CH:7]=[N:6][CH:5]=1
Reactant: N[C@H](CO)Cc1c[nH]cn1
Reactant: Br
Solvent: CCO
Solvent: CC(=O)O
Product: N[C@H](CBr)Cc1cnc[nH]1
Temperature: 110 °C

Procedure:
900 mg (S)-histidinol (×2HCl) are dissolved in 20 mL HBr in acetic acid (32%) and heated to 110° C. in the microwave for 6 h. The solvent is eliminated in vacuo, the residue is dissolved in ethanol and again freed from the solvent in vacuo. This crude product is used in the next reaction step without further purification.
Reaction SMILES: [C:1]1([C:7]2[N:22]=[C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([NH2:15])[N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>>[C:27]1([O:26][C:24](=[O:25])[NH:15][C:14]2[N:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:22]=[C:10]3[CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:13]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Reactant: O=C(Cl)Oc1ccccc1
Product: O=C(Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12)Oc1ccccc1

Procedure:
The title compound, MS m/e (%): 408 (M+H+, 100), was prepared in accordance with the general method of example 31 from 2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine and phenyl chloroformate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][NH:6][C:7]([C:9]1[N:10]([CH2:27][CH:28]([O:31][CH3:32])[O:29][CH3:30])[CH:11]=[C:12]([C:24]([CH3:26])=[CH2:25])[C:13](=[O:23])[C:14]=1[O:15]CC1C=CC=CC=1)=[O:8].[H][H]>CO.[C].[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][NH:6][C:7]([C:9]1[N:10]([CH2:27][CH:28]([O:31][CH3:32])[O:29][CH3:30])[CH:11]=[C:12]([CH:24]([CH3:25])[CH3:26])[C:13](=[O:23])[C:14]=1[OH:15])=[O:8]
Reactant: [H][H]
Reactant: C=C(C)c1cn(CC(OC)OC)c(C(=O)NCc2cccc(Cl)c2)c(OCc2ccccc2)c1=O
Agent: [Pd]
Solvent: CO
Product: COC(Cn1cc(C(C)C)c(=O)c(O)c1C(=O)NCc1cccc(Cl)c1)OC
Yield: 87.1 %

Procedure:
To a solution of 3-benzyloxy-1-(2,2-dimethoxyethyl)-5-isopropenyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (60 mg) in methanol (1 ml) was added 5% palladium-carbon (20 mg) and the mixture was stirred under an atmospheric pressure of hydrogen for 16 hr. A solid was filtered off and the filtrate was concentrated to give 1-(2,2-dimethoxyethyl)-3-hydroxy-5-isopropyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (43 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:12]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19](CC2SC=C(C(OC)=O)N=2)[CH2:18][CH2:17]1)=[O:13].Cl[CH2:33][C:34]1[N:35]=[C:36]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[S:37][CH:38]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:12]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:33][C:34]2[N:35]=[C:36]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[S:37][CH:38]=2)[CH2:18][CH2:17]1)=[O:13]
Reactant: CCOC(=O)c1nc(CCl)cs1
Reactant: COC(=O)c1csc(CN2CCC(CNC(=O)c3n[nH]c4ccc(OC)cc34)CC2)n1
Product: CCOC(=O)c1nc(CN2CCC(CNC(=O)c3n[nH]c4ccc(OC)cc34)CC2)cs1

Procedure:
Ethyl 4-{[4-({[(5-methoxy-1H-indazol-3-yl)carbonyl]amino}methyl) piperidin-1-yl]methyl}-1,3-thiazole-2-carboxylate 13 was prepared, according to the procedure described for compound 7, using ethyl 4-(chloromethyl)-1,3-thiazole-2-carboxylate. Yield: 45 mg, 11%.
Reaction SMILES: C([Li:5])CCC.[CH3:6][C:7]1([CH3:15])[CH2:12][CH2:11][CH2:10][C:9]([CH3:14])([CH3:13])[NH:8]1>C1CCCCC1.O1CCCC1>[Li:5][N:8]1[C:9]([CH3:14])([CH3:13])[CH2:10][CH2:11][CH2:12][C:7]1([CH3:15])[CH3:6]
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: [Li]N1C(C)(C)CCCC1(C)C
Yield: 100 %

Procedure:
A solution of 0.17 mole of lithium 2,2,6,6-tetramethyl piperidide is prepared by the addition of 0.17 mole of n-butyllithium (2.3 moles) in 74 ml of cyclohexane to 0.17 mole (28.7 ml) of 2,2,6,6-tetramethylpiperidine in 120 ml of tetrahydrofuran at a temperature below -20° C.
Reaction SMILES: C([O-])=O.[K+].C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:15](=[O:17])[CH3:16])[CH:12]=[CH:13][CH:14]=1>[Ru].CO>[Cl:8][C:9]1[CH:10]=[C:11]([C@H:15]([OH:17])[CH3:16])[CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)c1cccc(Cl)c1
Agent: [Ru]
Agent: O=C[O-]
Agent: [K+]
Solvent: CO
Solvent: O=CO
Product: C[C@@H](O)c1cccc(Cl)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
A ruthenium complex RuCl[(R,R)-Tsdpen] (mesitylene) (2.1 mg, 0.0033 mmol), potassium formate (1.0 g, 12 mmol), formic acid (138 mg, 3 mmol) and 3′-chloroacetophenone (1.55 g, 10 mmol, substrate/catalyst ratio=3000) were set in a 20 mL glass Schlenk-type reaction tube under an argon atmosphere. Methanol (6 mL) was added thereto and stirred at 50° C. for 24 hours to give (R)-1-(3′-chlorophenyl)ethanol at 100% yield and 96.5% ee optical purity.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([O:12][CH3:13])=[O:11])[CH:3]=[CH:2]1.Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1.[H-].[Na+]>CN(C=O)C>[F:23][C:22]([F:24])([F:25])[C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([O:12][CH3:13])=[O:11])[CH:3]=[CH:2]1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: COC(=O)c1cccc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2ccn(Cc3cccc(C(F)(F)F)c3)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl 1H-indole-7-carboxylate (1 g, 5.71 mmol) and 1-(bromomethyl)-3-(trifluoromethyl)benzene (956 ul, 6.28 mmol) were dissolved in DMF (16 ml), in an ice bath. 60% w/w NaH (251 mg, 6.28 mmol) was added portionwise. The ice bath was removed and the mixture stirred at RT for 30 min. The reaction mixture was quenched with NH4Cl(sat.) and extracted 3 times with ether. The organic layers were combined, washed with water and brine. The compound was purified by flash chromatography on silica gel. 1H NMR (500 MHz, DMSO-d6): δ 7.40 (d, 1H), 7.25 (s, 1H), 7.10 (m, 1H), 7.00 (m, 2H), 6.75 (s, 1H), 6.65 (t, 1H), 6.50 (d, 1H), 6.25 (s, 1H), 5.25 (s, 2H), 2.05 (d, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:20](=O)[CH3:21].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH3:21])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCOCC1
Reaction time: 6 h
Yield: 96.6 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-[(oxan-4-yl)amino]benzoate (2.0 g, 6.1 mmol) in DCE (10 ml) under a nitrogen atmosphere was added acetaldehyde (1.0 ml, 18 mmol) followed by acetic acid (2.1 ml, 37 mmol) and the reaction was left to stir for 5 min before the addition of sodium triacetoxyborohydride (6.6 g, 31 mmol). The reaction was stirred for 16 h at room temperature after which time additional acetaldehyde (1.0 ml, 22 mmol) and sodium triacetoxyborohydride (3.0 g, 14 mmol) were added and the reaction was stirred for a further 6 h whereupon distilled water (100 ml) was added and the phases were separated. The aqueous phase was washed with EtOAc (3×100 ml), the combined organics were then dried using Na2SO4, filtered and evaporated to afford the title compound as a colourless oil (2.10 g, 93%) which was suitable for use without any further purification. LC-MS 96%, 2.38 min (3.5 minute LC-MS method), m/z=356.1/357.9, 1H NMR (500 MHz, Chloroform-d) δ 7.70 (d, J=2.0 Hz, 1H), 7.36 (d, J=2.0 Hz, 1H), 3.95 (d, J=11.3 Hz, 2H), 3.88 (d, J=9.1 Hz, 3H), 3.32 (td, J=11.5, 2.5 Hz, 2H), 3.04 (q, J=7.1 Hz, 2H), 2.98-2.87 (m, 1H), 2.44 (s, 3H), 1.77-1.55 (m, 4H), 0.86 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16](C)[C:17](OC(C)(C)C)=O)[N:9]=[CH:8][N:7]=[C:6]2[O:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30]([CH3:35])=[CH:29]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][NH:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30]([CH3:35])=[CH:29]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCN(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCOc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
A solution of 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methyl-N-tert-butoxycarbonylamino)ethoxy)quinazoline (550 mg, 1.15 mmol), (prepared as described in Example 149), in methylene chloride (10 ml) containing TFA (12 ml) was stirred for 3 hours at ambient temperature. After removal of the volatiles under vacuum, the residue was partitioned between methylene chloride and sodium hydrogen carbonate. The pH of the aqueous layer was adjusted to 11 with 2N sodium hydroxide. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was triturated with ether, filtered and dried under vacuum to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methylamino)ethoxy)quinazoline (356 mg, 82%).
Reaction SMILES: [ClH:1].Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:33][C:34]([O:36]CC)=[O:35])[C:10]([C:12]1[CH:32]=[CH:31][C:15]2[N:16]([CH3:30])[C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=3)=[N:18][C:14]=2[CH:13]=1)=[O:11].[OH-].[Na+]>>[ClH:1].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:33][C:34]([OH:36])=[O:35])[C:10]([C:12]1[CH:32]=[CH:31][C:15]2[N:16]([CH3:30])[C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][CH:22]=3)=[N:18][C:14]=2[CH:13]=1)=[O:11]
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CCc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CC(=O)O)c3ccccn3)ccc21

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide-dihydrochloride and sodium hydroxide solution.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:3]=1.[CH3:22]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:22][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc(Br)c2c([N+](=O)[O-])ccnc21
Reactant: CB1OB(C)OB(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cn(COCC[Si](C)(C)C)c2nccc([N+](=O)[O-])c12

Procedure:
A solution of 80 mg (210 μmol) of 3-bromo-4-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine, 27 mg (210 μmol) of trimethylboroxine, 25 mg (20 μmol) of tetrakis(tri-phenylphosphine)palladium and 103 mg (640 μmol) of potassium carbonate in 2.00 ml of degassed DMF is stirred in a sealed pressure vessel at 110° C. for 6 h and then at RT overnight. The suspension is then filtered through an Extrelut silica gel cartridge, the cartridge is washed with a mixture of dichloromethane/methanol 1:1 and the filtrate is concentrated under reduced pressure. The residue is purified by preparative RP-HPLC.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([O:11]C)=O)[CH:4]=1.[CH3:13][NH2:14]>CO.C1COCC1>[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([NH:14][CH3:13])=[O:11])[CH:4]=1
Reactant: CN
Reactant: COC(=O)c1cc(Cl)ccn1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Cl)ccn1
Reaction time: 5 h
Yield: 97 %

Procedure:
A suspension of methyl 4-chloropyridine-2-carboxylate HCl salt (89.0 g, 428 mmol) in MeOH (75 mL) at 0°0 C. was treated with a 2.0 M methylamine solution in THF (1 L) at a rate which kept the internal temp. below 5° C. The resulting mixture was stored at 3° C. for 5 h, then concentrated under reduced pressure. The resulting solids were suspended in EtOAc (1 L) and filtered. The filtrate was washed with a saturated NaCl solution (500 mL), dried (Na2SO4) and concentrated under reduced pressure to afford 4-chloro-N-methyl-2-pyridinecarboxamide as pale-yellow crystals (71.2 g, 97%): mp 41-43° C.; 1H-NMR (DMSO-d6) δ 2.81 (s, 3H), 7.74 (dd, J=5.1, 2.2 Hz, 1H), 8.00 (d, J=2.2, 1H), 8.61 (d, J=5.1 Hz, 1H), 8.85 (brd, 1H); CI-MS m/z 171 ((M+H)+).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].C([NH:8][C:9](=[O:36])[N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:11]1[S:12][C:13]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)=[CH:14]C=1C(OCC)=O)(=O)C.Cl>C(O)C>[CH3:34][CH:33]([CH3:35])[CH2:32][N:10]1[C:11]2[S:12][C:13]([CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)=[CH:14][C:3]=2[C:2](=[O:1])[NH:8][C:9]1=[O:36]
Reactant: CC[O-]
Reactant: CCOC(=O)c1cc(Cc2cccc3ccccc23)sc1N(CC(C)C)C(=O)NC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)Cn1c(=O)[nH]c(=O)c2cc(Cc3cccc4ccccc34)sc21
Reaction time: 3 h
Yield: 65.2 %

Procedure:
Sodium ethoxide (0.036 g) was added to a solution of N′-acetyl-N-(2-methylpropyl)-N-[3-ethoxycarbonyl-5-(1-naphthalenylmethyl)-2-thienyl]urea (0.20 g) in ethanol (4 ml). The mixture was stirred for 3 hours then further sodium ethoxide (0.036 g) was added. After a further 3 hours, the mixture was poured into hydrochloric acid (2M, 20 ml) and extracted with ethyl acetate (2×20 ml). The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residual solid was recrystallised from ethyl acetate/hexane to give the title compound (0.105 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](OCC)=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Li].[H-].O>O1CCCC1>[NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][OH:17])=[CH:14][CH:15]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1ccc(COc2cccnc2N)cc1
Agent: [H-]
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ncccc1OCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.8 %

Procedure:
A solution of 2-amino-3-(4-ethoxycarbonylbenzyloxy)pyridine (1.04 g) in tetrahydrofuran (15 ml) was added dropwise to a suspension of lithium alminum hydride (0.24 g) in tetrahydrofran (24 ml) with ice cooling over a period of 10 minutes. After being stirred for 1.5 hours at room temperature, the excess reagent was decomposed with a small amount of water and the resulting precipitates were filtered off by suction. The filtrate was evaporated in vacuo and the crystalline residue was washed with diethyl ether to give 2-amino-3-(4-hydroxymethylbenzyloxy)pyridine (0.79 g).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:23][O:24][C:25]1[C:26](=[O:53])[C:27]([CH3:52])=[C:28]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([O:44][CH2:45][C:46]3[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=3)=[C:39]([CH:43]=2)[C:40](O)=[O:41])[C:29](=[O:33])[C:30]=1[O:31][CH3:32]>C(Cl)Cl>[CH3:23][O:24][C:25]1[C:26](=[O:53])[C:27]([CH3:52])=[C:28]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([O:44][CH2:45][C:46]3[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=3)=[C:39]([CH:43]=2)[C:40]([N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:41])[C:29](=[O:33])[C:30]=1[O:31][CH3:32]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)O)c2)=C(C)C1=O
Reactant: c1ccc2c(c1)CCCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)N3CCCc4ccccc43)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 39.3 %

Procedure:
1,2,3,4-Tetrahydroquinoline (0.126 g, 0.946 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.272 g, 1.42 mmol) were added to a methylene chloride solution (20 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-pyridylmethyloxy)benzoic acid (0.200 g, 0.473 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=9:1) to obtain the titled compound (0.100 g, 0.186 mmol, 39%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)[C:8]=1[C:9]([NH2:11])=[O:10])([OH:3])=[O:2].[CH2:20](O)[CH3:21]>Cl>[Cl:19][C:14]1[CH:13]=[C:12]([N:7]2[C:8]([C:9]([NH2:11])=[O:10])=[C:4]([C:1]([O:3][CH2:20][CH3:21])=[O:2])[CH:5]=[N:6]2)[CH:17]=[C:16]([Cl:18])[CH:15]=1
Reactant: NC(=O)c1c(C(=O)O)cnn1-c1cc(Cl)cc(Cl)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1cnn(-c2cc(Cl)cc(Cl)c2)c1C(N)=O

Procedure:
Two g of the compound of Example 2 was suspended in 80 ml of absolute ethanol and hydrogen chloride 9as was bubbled through for 5 minutes. The mixture was then heated under reflux for 2 hours and cooled, and was then filtered. The solids were collected and dried to obtain 1.25 g of the desired product, m.p. 164°-166°.