Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:21]1[CH:25]=[C:24]([C:26](O)=[O:27])[CH:23]=[N:22]1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:26]([C:24]3[CH:25]=[N:21][NH:22][CH:23]=3)=[O:27])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCCCOc1cc(CN2CCCCC2)ccn1
Reactant: O=C(O)c1cn[nH]c1
Product: O=C(NCCCCCOc1cc(CN2CCCCC2)ccn1)c1cn[nH]c1

Procedure:
Following a procedure similar to that described in Example 64, but using 5-(4-piperidinomethyl-2-pyridyloxy)pentylamine and 4-pyrazolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 105°-106° C., in a yield.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9](C(=O)C)[CH2:10][CH2:11][N:12]=2)=[C:6](Cl)[N:5]([NH2:17])[CH:4]([CH3:18])[N:3]=1.[CH3:19][O-:20].[Na+].O>CO>[Cl:1][C:2]1[C:7]([C:8]2[NH:9][CH2:10][CH2:11][N:12]=2)=[C:6]([O:20][CH3:19])[N:5]([NH2:17])[CH:4]([CH3:18])[N:3]=1
Reactant: CC(=O)N1CCN=C1C1=C(Cl)N(N)C(C)N=C1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(C2=NCCN2)C(Cl)=NC(C)N1N
Reaction time: 2 h
Yield: 85.7 %

Procedure:
10 g 4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine are mixed with a solution of 3.78 g sodium methylate in 35 ml methanol and boiled for 2 hours. Then 100 ml water are added, cooled, and vacuum dried. 7.2 g of 4-chloro-6-methoxy-2-methyl-5-(2-imidazolin-2-yl)-aminopyrimidine is obtained. (Melting point 217°-219° C., decomposition) from nitromethane.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:32])([CH3:31])[CH2:10][C:11]([CH:17]=[N:18][C:19]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]3[C:20]=2[CH:21]=[N:22][C:23]([CH3:30])=[N:24]3)([OH:16])[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[F:29][C:26]1[CH:27]=[CH:28][C:19]([NH:18][CH:17]2[C:6]3[C:5](=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=3)[C:9]([CH3:31])([CH3:32])[CH2:10][C:11]2([C:12]([F:14])([F:15])[F:13])[OH:16])=[C:20]2[C:25]=1[N:24]=[C:23]([CH3:30])[N:22]=[CH:21]2
Reactant: COc1cccc(C(C)(C)CC(O)(C=Nc2ccc(F)c3nc(C)ncc23)C(F)(F)F)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ncc2c(NC3c4ccc(O)cc4C(C)(C)CC3(O)C(F)(F)F)ccc(F)c2n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 33.7 %

Procedure:
60 mg (0.133 mmol) of 4-(3-methoxyphenyl)-1,1,1-trifluoro-2-{[8-fluoro-2-methylquinazolin-5-ylimino]-methyl}-4-methylpentan-2-ol is mixed with 1.3 ml of a 1 M solution of boron tribromide in dichloromethane while being cooled in an ice bath. After 45 minutes of stirring at room temperature, the reaction mixture is mixed with ice, and saturated sodium bicarbonate solution is added drop by drop until a pH of 8 is reached. The cold bath is removed, and the mixture is stirred vigorously for 15 minutes. After extraction with ethyl acetate, the combined organic extracts are washed with water and then with brine. After drying, the solvent is spun off, and the residue is chromatographed on silica gel (mobile solvent ethyl acetate/hexane). Finally, 19.5 mg (33.5%) of the desired compound is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:25])=[C:5]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:6]([CH3:11])=[CH:7][C:8]=1[O:9][CH3:10].CN(C)C=[O:29]>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:6]([CH3:11])[C:7](=[O:29])[C:8]=1[O:9][CH3:10]
Reactant: COC(=O)CCCCCCCCCc1c(C)cc(OC)c(OC)c1O
Reactant: CN(C)C=O
Product: COC(=O)CCCCCCCCCC1=C(C)C(=O)C(OC)=C(OC)C1=O

Procedure:
A dimethylformamide solution of methyl 10-(3,4-dimethoxy-2-hydroxy-6-methylphenyl)decanoate (129 mg) is oxidized in the same manner as Example 20. This procedure yields 2,3-dimethoxy-5-methyl-6-(9-methoxycarbonylnonyl)-1,4-benzoquinone (91 mg) as orange-yellow needles melting at 37° C.-38° C.
Reaction SMILES: [Cl:1]C(OC(Cl)C)=O.C([N:15]1[CH2:20][CH2:19][CH2:18][C:17](=[CH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)[CH2:16]1)C1C=CC=CC=1>C(Cl)Cl>[ClH:1].[C:28]([C:25]1[CH:24]=[CH:23][C:22]([CH:21]=[C:17]2[CH2:18][CH2:19][CH2:20][NH:15][CH2:16]2)=[CH:27][CH:26]=1)#[N:29]
Reactant: CC(Cl)OC(=O)Cl
Reactant: N#Cc1ccc(C=C2CCCN(Cc3ccccc3)C2)cc1
Solvent: ClCCl
Product: Cl
Product: N#Cc1ccc(C=C2CCCNC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
1.8 g of 1-chloroethyl chloroformate in 5 ml of methylene chloride are added dropwise to 2.9 g of 1-benzyl-3-(4-cyanobenzylidene)piperidine in 20 ml of methylene chloride at 0° C. and the mixture is stirred at 0° C. for 30 minutes. After 20 minutes at ambient temperature, it is evaporated down, the residue is taken up in 20 ml of methanol and the mixture is reflux-heated for 30 minutes. The reaction solution is evaporated down, and the residue is triturated with 100 ml of ethyl acetate and suction-filtered. 1.9 g of 3-(4-cyanobenzylidene)piperidine hydrochloride are obtained as a colourless powder.
Reaction SMILES: O[C:2]1[C:3]2[C:8]([C:9]([O:27][CH3:28])=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][C@@H:11]3[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)=[CH:7][C:6]([CH3:29])=[C:5](/[CH:30]=C/C)[C:4]=2[O:33][CH2:34][O:35][CH3:36].N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=[O:46].[Na+].[OH2:51]>O1CCCC1>[OH:51][C:2]1[C:15]2[C:14](=[O:16])[CH2:13][CH2:12][C@H:11]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:10]=2[C:9]([O:27][CH3:28])=[C:8]2[C:3]=1[C:4]([O:33][CH2:34][O:35][CH3:36])=[C:5]([CH:30]=[O:46])[C:6]([CH3:29])=[CH:7]2
Reactant: O
Reactant: C/C=C/c1c(C)cc2c(OC)c3c(c(O)c2c1OCOC)C(=O)CC[C@@H]3OCc1ccc(OC)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: COCOc1c(C=O)c(C)cc2c(OC)c3c(c(O)c12)C(=O)CC[C@@H]3OCc1ccc(OC)cc1
Temperature: 23 °C
Reaction time: 0.17 h

Procedure:
Potassium osmate dihydrate (29 mg, 0.079 mmol, 0.05 equiv) was added to an ice-cooled mixture of (S,E)-9-hydroxy-10-methoxy-4-(4-methoxybenzyloxy)-8-(methoxymethoxy)-6-methyl-7-(prop-1-enyl)-3,4-dihydroanthracen-1-one (780 mg, 1.58 mmol, 1 equiv), 2,6-lutidine (369 μL, 3.17 mmol, 2.0 equiv), and sodium periodate (1.36 g, 6.33 mmol, 4.0 equiv) in a mixture of tetrahydrofuran (20 mL) and water (10 mL). After 10 min, the cooling bath was removed and the reaction flask was allowed to warm to 23° C. After 1.5 h, the reaction mixture was partitioned between water (100 mL) and ethyl acetate (150 mL). The layers were separated. The organic layer was washed with aqueous sodium chloride solution (50 mL) and the washed solution was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by flash-column chromatography (20% ethyl acetate-hexanes) to provide 498 mg of the product, (S)-9-hydroxy-10-methoxy-5-(4-methoxybenzyloxy)-1-(methoxymethoxy)-3-methyl-8-oxo-5,6,7,8-tetrahydroanthracene-2-carbaldehyde, as an orange foam (65%). 1H NMR (500 MHz, CDCl3): 15.17 (s, 1H), 10.74 (s, 1H), 7.66 (s, 1H), 7.27 (d, 2H, J=8.5 Hz), 6.86 (d, 2H, J=8.6 Hz), 5,30-5.18 (m, 3H), 4.63 (d, 1H, J=11.1 Hz), 4.52 (d, 1H, J=12.0 Hz), 3.86 (s, 3H), 3.79 (s, 3H), 3.62 (s, 3H), 3.22 (m, 1H), 2.75 (s, 3H), 2.63 (m, 1H), 2.54 (m, 1H), 2.08 (m, 1H). 13C NMR (125 MHz, CDCl3): 204.9, 193.2, 163.2, 161.7, 159.2, 144.4, 141.7, 137.0, 130.1, 129.4, 120.7, 117.9, 113.8, 110.0, 102.8, 70.4, 67.2, 62.9, 58.3, 55.2, 32.3, 26.3, 22.2. FTIR, cm−1 (thin film): 2936 (m), 2907 (m), 1684 (s), 1611 (s), 1377 (s), 1246 (s). HRMS (ESI): Calcd for (C27H28O8+K)+:519.1416; Found 519.1368. TLC (20% ethyl acetate-hexanes): Rf=0.17 (CAM)
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:11][C@H:12]([CH3:15])[CH2:13]I)[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[CH2:18]([CH:22]1[CH2:28][CH:27]2[NH:29][CH:24]([CH2:25][CH2:26]2)[CH2:23]1)[CH2:19][CH2:20][CH3:21]>CC#N>[CH2:18]([CH:22]1[CH2:23][CH:24]2[N:29]([CH2:13][C@@H:12]([CH3:15])[CH2:11][N:6]3[C:5]4[CH:16]=[CH:17][C:2]([F:1])=[CH:3][C:4]=4[O:9][CH2:8][C:7]3=[O:10])[CH:27]([CH2:26][CH2:25]2)[CH2:28]1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCC1CC2CCC(C1)N2
Reactant: C[C@H](CI)CN1C(=O)COc2cc(F)ccc21
Solvent: CC#N
Product: CCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)COc2cc(F)ccc21
Yield: 33.7 %

Procedure:
A microwave vial was charged with (S)-7-fluoro-4-(3-Iodo-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one (111MF20) (0.047 g, 0.13 mmol) and 3-butyl-8-azabicyclo[3,2,1]octane (0.039 g, 0.23 mmol) in MeCN (2 mL) and sealed. After microwave irradiation, 100° C., 60 min, the reaction mixture was purified by cation exchange CC followed by flash CC (SiO2; CH2Cl2/MeOH 50:1) to give the title compound (112KK05) (0.017 g, 33%). 1H NMR (CD3OD) δ 7.34-7.30 (m, 1H), 6.80-6.75 (m, 2H), 4.61 (ABq, J=18.8 Hz, J=15.1 Hz, CH2), 4.04 (dd, J=14.3 Hz, J=5.9 Hz, 1H), 3.93 (dd, J=14.3 Hz, J=8.2 Hz, 1H), 3.18-3.10 (m, 2H), 2.36-2.23 (m, 2H), 2.03-1.85 (m, 3H), 1.62-1.45 (m, 5H), 1.36-1.14 (m, 8H), 0.92-0.87 (m, 2 CH2); 13C NMR (CD3OD) δ 166.2, 160.4 (d, J=242.3 Hz), 148.1 (d, J=11.9 Hz), 126.3 (d, J=2.9 Hz), 118.1 (d, J=9.7 Hz), 109.8 (d, J=22.9 Hz), 105.7 (d, J=26.5 Hz), 68.6, 62.5, 61.2, 58.3, 46.4, 39.0, 37.9, 32.1, 30.2, 29.0, 27.8, 27.2, 23.9, 17.2, 14.4.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[C:19]([Cl:18])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1C1CCCCC1
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCCC1
Temperature: 60 °C

Procedure:
A mixture of rac-6-chloro-3-cyclohexyl-1,3-dihydro-indol-2-one (0.11 g, 0.44 mmol) (from Example 19b supra), 3-chlorobenzyl bromide (0.11 g, 0.53 mmol) (Aldrich), potassium iodide (87 mg, 0.53 mmol) and potassium carbonate (0.13 g, 0.95 mmol) in acetone (3 mL) was heated at 60° C. for 2 days in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate and extracted with water and brine. Aqueous layers were back washed with ethyl acetate. Organic layers were combined, dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography (ethyl acetate-dichloromethane, 5:95, V/V) to give rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexyl-1,3-dihydro-indol-2-one as a white solid. (Yield 30 mg, 18%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][C:26]([O:28]C)=[O:27])=[CH:19][CH:18]=2)=[O:15])=[N:11][N:10]=1.CO.[OH-].[Na+].Cl>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:19][CH:18]=2)=[O:15])=[N:11][N:10]=1
Reactant: COC(=O)CCCc1ccc(NC(=O)c2nnc(Nc3ccccc3F)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCCc1ccc(NC(=O)c2nnc(Nc3ccccc3F)o2)cc1
Reaction time: 8.5 h
Yield: 55.6 %

Procedure:
Methyl 4-{4-[({5-[(2-fluorophenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]phenyl}butanoate (Example 483) (174 mg, 0.44 mmol) was stirred in THF: MeOH (8 mL of a 1:1 mixture) and NaOH (2.5 mL of 2M aqueous solution) was added. The mixture was stirred for 8.5 h then acidified (2M HCl), allowed to stand overnight, then concentrated in vacuo. The precipitate was filtered and washed with water and then Et2O to give the title compound (94 mg, 56%) as a solid; 1H NMR δ 1.77-1.84 (2H, m), 2.22 (2H, t), 2.59 (2H, t), 7.14-7.21 (3H, m), 7.25-7.34 (2H, m), 7.70-7.72 (2H, m), 8.02-8.07 (1H, m), 10.74 (1H, s), 10.94 (1H, s), 11.98 (1H, s); MS m/e MH+ 385.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([S:8]([O:11][C:12]2[CH:13]=[C:14]([CH:21]=[C:22]([CH3:24])[CH:23]=2)[O:15][CH2:16][CH2:17][CH2:18][O:19][NH2:20])(=[O:10])=[O:9])[CH:7]=1.Cl.[N:28]1([C:33](N)=[NH:34])C=CC=N1>CN(C)C=O>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([S:8]([O:11][C:12]2[CH:13]=[C:14]([CH:21]=[C:22]([CH3:24])[CH:23]=2)[O:15][CH2:16][CH2:17][CH2:18][O:19][NH:20][C:33]([NH2:34])=[NH:28])(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Oc1cc(C)cc(OCCCON)c1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1S(=O)(=O)Oc1cc(C)cc(OCCCONC(=N)N)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96 %

Procedure:
A mixture of 3-[3-(5-chloro-2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propoxyamine (265 mg, 0.66 mmol, prepared in the preceding step) and 1H-pyrazole-1-carboxamidine hydrochloride (196 mg, 1.33 mmol) in anhydrous N,N-dimethylformamide (3 mL) was stirred at ambient temperature for 2.5 h. Additional 1H-pyrazole-1-carboxamidine hydrochloride (97 mg, 0.66 mmol) was added and the reaction was stirred at ambient temperature for 3 days. N,N-Dimethylformamide was removed in vacuo, then acetonitrile (1 mL) was added to precipitate excess 1H-pyrazole-1-carboxamidine hydrochloride. The mixture was filtered and the filtrate was concentrated in vacuo. The residual oil was partitioned between diethyl ether (20 mL) and water (20 mL). The aqueous layer was washed with diethyl ether (2×20 mL). The aqueous layer was neutralized (pH 7) with 2N NaOH and extracted with ethyl acetate (2×30 mL). The ethyl acetate extracts were washed with pH 7 buffer (2×20 mL) and brine (30 mL), dried over Na2SO4, filtered, and evaporated to give the free base of the title compound (281 mg, 96%) as a colorless oil. Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C18H22CIN3O6S: 444.1 (M+H), 466.1 (M+Na). Found 444.6, 466.7.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.CN.[BH3-][C:19]#[N:20].[Na+].C(O)(=O)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:20][CH3:19])[CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: O=C(CN1CCCC1)c1ccc(Br)cc1
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNC(CN1CCCC1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 100 %

Procedure:
1-(4-Bromophenyl)-2-(1-pyrrolidinyl)ethanone (4.45 g, 16.6 mmol) and methyl amine (33 mL, 66.4 mmol of 2 M solution in THF) were dissolved in 75 mL THF and maintained for 15 minutes at room temperature. NaBH3CN (3.13 g, 49.8 mmol) was added and the reaction mixture was treated with 1 mL acetic acid and stirred at room temperature for 4 days. The solvent was removed under reduced pressure. The residue was dissolved in 100 mL of EtOAc and washed with sodium bicarbonate (100 mL) and then brine (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give 4.7 g (99%) of the title compound as a yellow oil. MS (ES) m/e 284 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]2[CH3:22])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>CN(C)C=O>[ClH:1].[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:2]2[N:11]=[C:10]([N:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]3[CH3:22])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:26][CH:25]=1
Reactant: CC1c2ccccc2CCN1c1nc(Cl)nc2ccccc12
Reactant: Nc1ccc(F)cc1
Solvent: CN(C)C=O
Product: CC1c2ccccc2CCN1c1nc(Nc2ccc(F)cc2)nc2ccccc12
Product: Cl
Yield: 93 %

Procedure:
In accordance with the same procedures as in Example 18, except that to a mixture of 1.26 g of the compound (4.07 mM) prepared in Example 2 and 15 ml of dimethylform-amide, 0.81 ml of 4-fluoroaniline(8.54 mM) was added, 1.59 g of the title compound was prepared.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C@@H:26]4[CH2:30][CH2:29][CH2:28][NH:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:31])[NH:6]2.[C:32](Cl)(=[O:36])[CH:33]([CH3:35])[CH3:34]>>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C@@H:26]4[CH2:30][CH2:29][CH2:28][N:27]4[C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:31])[NH:6]2
Reactant: CC(C)C(=O)Cl
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@@H]1CCCN1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@@H]1CCCN1C(=O)C(C)C
Yield: 53.6 %

Procedure:
Using an analogous procedure to that described for the preparation of Example 19, 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2S)-pyrrolidin-2-ylmethoxy]quinazoline (150 mg, 0.36 mmol), (prepared as described for the starting material in Example 12), was reacted with isobutyryl chloride (45 μl, 0.43 mmol). The product was purified by column chromatography, eluting with methanol/methylene chloride (2/98) to give 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-7-{[(2S)-1-isobutyrylpyrrolidin-2-yl]methoxy}-6-methoxyquinazoline (95 mg, 54%).
Reaction SMILES: [ClH:1].Cl.[CH2:3]1[N:8]([CH2:9][CH2:10][CH2:11][C:12]([NH:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)=[O:13])[CH2:7][CH2:6][N:5]2[CH2:27][CH2:28][CH2:29][CH2:30][CH:4]12.[CH3:31]C(C)([O-])C.[K+].CI>O1CCCC1>[ClH:1].[ClH:1].[CH3:31][N:14]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][N:8]1[CH2:7][CH2:6][N:5]2[CH2:27][CH2:28][CH2:29][CH2:30][CH:4]2[CH2:3]1
Reactant: CC(C)(C)[O-]
Reactant: COc1cc(NC(=O)CCCN2CCN3CCCCC3C2)cc(OC)c1OC
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1cc(N(C)C(=O)CCCN2CCN3CCCCC3C2)cc(OC)c1OC
Reaction time: 1 h

Procedure:
0.9 g of the compound obtained in Example 2 is dissolved in 50 ml of tetrahydrofuran and, under argon, there are added 0.265 g of potassium tert-butoxide and then, after 1 hour's stirring, 0.15 ml of methyl iodide. Stirring is maintained for 1 hour and the solvent is removed in vacuo. The residue is taken up in a mixture of water/dichloromethane, extracted, decanted and then dried over Na2SO4 and evaporated to dryness in vacuo. The product is converted to the hydrochloride using ethanolic hydrogen chloride.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[N:3]=[CH:2]1.[C:9]1([C:15](Cl)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1.CN(C=O)C>[C:15]([N:1]1[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[N:3]=[CH:2]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)c1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
To a RT solution of 1H-imidazole-4-carboxylic acid (1.12 g, 9.99 mmol) in pyridine (15 mL) and DMF (30 mL) was added triphenylmethyl chloride (3.06 g, 11.0 mmol). The reaction mixture was stirred at RT overnight, then was partitioned between EtOAc (500 mL) and H2O (50 mL). The organic phase was washed with H2O (20 mL), 10% citric acid (20 mL) and brine (5 mL), dried (MgSO4) and concentrated in vacuo. The residue was triturated with EtOAc to afford 1-trityl-1H-imidazole-4-carboxylic acid (2.78 g, 79% yield) as a white solid. LCMS Method A (ESI, positive ion spectrum): (M+H)/z=not observed, tR=3.27 min.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].CN1C=CN=C1.[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].C(N(CCCC)CCCC)CCC>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[C:1]([NH:4][C@H:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:20](=[O:21])[C:19]1[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=1[CH3:17])(=[O:3])[CH3:2]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CCOC(=O)CNC(C)=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)[C@@H](NC(C)=O)C(=O)c1ccccc1C
Temperature: -45 °C
Reaction time: 0.17 h

Procedure:
A solution of ethyl N-acetylglycinate (98%, 7.41 g, 50.0 mmol) and 1-methyl-1H-imidazole (99%, 4.81 mL, 60.0 mmol) in dichloromethane (100 mL) was cooled to −45° C. and treated with 2-methylbenzoyl chloride (99%, 6.59 mL, 50.0 mmol). The reaction was stirred at −45° C. for 10 minutes. Titanium(IV) chloride (19.2 mL, 175 mmol) was added, followed by tri-n-butylamine (98%, 48.6 mL, 200 mmol), and stirring was continued at the same temperature for 30 minutes. The reaction was quenched with water and extracted with diethyl ether; the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (Eluents: 1:5 ethyl acetate/heptane followed by 1:2 ethyl acetate/heptane) afforded the product. Yield: 6.00 g, 22.8 mmol, 46%. APCI m/z 264.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.93 (dd, J=7.8, 1.2 Hz, 1H), 7.44 (ddd, J=7.6, 7.5, 1.4 Hz, 1H), 7.26-7.34 (m, 2H), 6.89 (br d, J=7 Hz, 1H), 6.05 (d, J=7.2 Hz, 1H), 4.04-4.19 (m, 2H), 2.45 (br s, 3H), 2.11 (s, 3H), 1.06 (t, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:10]([CH2:12][C:13]1[S:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]2)[CH:14]=1)[CH3:11])[CH3:9].CN[CH2:43][CH3:44]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:39]([S:36]([N:33]1[CH2:34][CH2:35][CH:30]([C:21]2[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=[C:18]([C:15]4[CH:14]=[C:13]([CH2:12][N:10]([CH3:11])[CH2:8][CH:9]5[CH2:2][CH2:3][O:5][CH2:44][CH2:43]5)[S:17][CH:16]=4)[CH:19]=3)[NH:23][CH:22]=2)[CH2:31][CH2:32]1)(=[O:37])=[O:38])[CH3:40]
Reactant: CCNC
Reactant: CCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)CC5CCOCC5)c4)cc23)CC1
Yield: 16.4 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting methyl(tetrahydro-2H-pyran-4-ylmethyl)amine (129 mg, 1.0 mmol) for N-methylethanamine to afford 11.0 mg of the title compound (16.4%).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[CH3:21][O:22][C:23]1[CH:32]=[CH:31][C:26]([O:27][CH2:28][CH2:29][NH2:30])=[CH:25][CH:24]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15](=[O:17])[NH:30][CH2:29][CH2:28][O:27][C:26]2[CH:31]=[CH:32][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: COc1ccc(OCCN)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: COc1ccc(OCCNC(=O)COc2ccc(C[C@H](OC)C(=O)O)cc2)cc1

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 2-(4-methoxy-phenoxy)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C21H25NO7 [M+H]+: 404.