Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[C:9]2[O:10][C@@H:11]([CH2:14][O:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][C:5]=1[N+:26]([O-])=O)[CH:2]=[CH2:3].O.O.[Sn](Cl)Cl>C(OCC)(=O)C>[CH3:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([O:15][CH2:14][CH:11]2[O:10][C:9]3[C:4]([CH2:1][CH:2]=[CH2:3])=[C:5]([NH2:26])[CH:6]=[CH:7][C:8]=3[O:13][CH2:12]2)(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: C=CCc1c([N+](=O)[O-])ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCc1c(N)ccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Temperature: 25 °C

Procedure:
(2R)-Toluene-4-sulfonic acid 8-allyl-7-nitro-2,3-dihydro-benzo(1,4)dioxin-2-ylmethyl ester (5.3 g, 13 mmole) and tin (II) chloride dihydrate (14.7 g, 65 mmole) were combined in 500 mL of ethyl acetate and the mixture refluxed for 3 hours under nitrogen. The reaction was allowed to cool to room temperature and was quenched by the addition of 300 mL of saturated aqueous sodium bicarbonate. The biphasic mixture was filtered through celite, the phases separated and the aqueous back-extracted with 200 mL of ethyl acetate. The combined organic phases were washed with 250 mL portions of water and saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel with methylene chloride as eluant to give 2.2 g of the (R)-enantiomer of the title compound as an orange oil. 1H-NMR (CDCl3): doublet 7.8 δ (2H); doublet 7.35 δ (2H); doublet 6.6 δ (1H); doublet 6.25 δ (1H); multiplet 5.8 δ (1H); singlet 5.05 δ (1H); doublet 5.0 δ (1H); multiplet 4.4 δ (1H); multiplet 4.2 δ (3H); doublet of doublets 4.0 δ (1H); doublet 3.25 δ (2H); singlet 2.45 δ (3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([C:25]3[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=3)[C:16]3[C:21]([C:22]=2[CH:23]=[O:24])=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([C:25]3[CH:30]=[CH:29][C:28]([C:35]4[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=4)=[CH:27][CH:26]=3)[C:16]3[C:21]([C:22]=2[CH:23]=[O:24])=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(C=O)c3ccccc3n2-c2ccc(I)cc2)CC1
Reactant: OB(O)c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2c(C=O)c3ccccc3n2-c2ccc(-c3ccncc3)cc2)CC1
Yield: 70 %

Procedure:
4-[3-Formyl-1-(4-iodophenyl)-1H-indol-2-yl]-piperazine-1-carboxylic acid tert-butyl ester is reacted with 4-pyridylboronic acid as described in Example 65 to afford 4-[3-formyl-1-[(4-pyridin-4-yl)-phenyl]-1H-indol-2-yl]-piperazine-1-carboxylic acid tert-butyl ester (70% yield) as a yellow solid. ESI/MS 483 (M+1); NMR (CDCl3) 10.30 (1H, s); 8.76 (2H, d); 8.28 (1H, d, J=6 Hz); 7.89 (2H, d, J=9 Hz); 7.64 (5H, m); 7.20 (2H, m); 3.36 (8H, m); 1.58 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:13][C:12]([C:14]([O:16]CC)=[O:15])=[CH:11][C:10](=[O:19])[CH:9]=1>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:13][C:12]([C:14]([OH:16])=[O:15])=[CH:11][C:10](=[O:19])[CH:9]=1
Reactant: CCOC(=O)c1cc(=O)cc(-c2ccccc2Cl)o1
Agent: Cl
Product: O=C(O)c1cc(=O)cc(-c2ccccc2Cl)o1

Procedure:
A mixture of ethyl 6-(2-chlorophenyl)-4-oxo-4H-pyran-2-carboxylate (3.9 g) and concentrated hydrochloric acid (40 ml) was heated under reflux for 2 hours. The reactant dissolved on warming and a solid began to precipitate. Water (40 ml) was added to the cooled mixture and the resulting buff solid yielded the title product as off-white needles (mp 241°-246° C. with decomposition).
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:8]([CH2:12][OH:13])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].Cl[CH2:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[NH:31][C:32](=[O:38])[O:33][CH2:34][CH2:35][O:36][CH3:37]>CC(C)=O>[CH3:37][O:36][CH2:35][CH2:34][O:33][C:32]([NH:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=1[CH2:23][O:1][C:2]1[C:3]2[N:4]([C:8]([CH2:12][OH:13])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1)=[O:38]
Reactant: Cc1nc2c(O)cccn2c1CO
Reactant: COCCOC(=O)Nc1cccc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COCCOC(=O)Nc1cccc(C)c1COc1cccn2c(CO)c(C)nc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.8 %

Procedure:
A mixture of 178 mg (1.0 mmol) of 8-hydroxy-2-methylimidazo[1,2-a]pyridine-3-methanol, 117 mg (1.1 mmol) of anhydrous sodium carbonate, 15 mg (0.1 mmol) of sodium iodide and 283 mg (1.1 mmol) of 2-methoxyethyl 2-chloromethyl-3-methylphenylcarbamate in 5 ml of acetone is stirred at RT for 48 h, worked up analogously to Example 2 and chromatographed by means of ethyl acetate/isopropyl alcohol (9:1). 247 mg (62%) of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].N1C=CC=CC=1.[Cl:20][CH2:21][C:22](Cl)=O>ClC(Cl)C.C(Cl)(Cl)Cl>[Cl:20][CH2:21][C:22]1[NH:13][C:12]2[CH:11]=[CH:10][CH:9]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]=2[N:1]=1
Reactant: CCOC(=O)c1cccc(N)c1N
Reactant: O=C(Cl)CCl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cccc2[nH]c(CCl)nc12
Reaction time: 8 h
Yield: 47.7 %

Procedure:
To a solution of ethyl 2,3-diaminobenzoate (4.72 g) and pyridine (2.49 g) in dichloroethane (50 ml) was added chloroacetyl chloride (3.11 g) in chloroform (10 ml) at −70° C. and the reaction mixture was stood overnight. After the reaction mixture was concentrated in vacuo, the residue was diluted with ethnaol (50 ml). To the solution was added p-toluenesulfonic acid (249 mg) and the reaction mixture was refluxed for 2 hours. After the reaction mixture was concentrated in vacuo, the reside was diluted with ethyl acetate and satureated sodium hydrogen carbonate aqueous solution. The organic layer was separated and washed with brine. The solution was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give ethyl 2-chloromethyl-1H-benzimidazole-4-carboxylate (2.98 g).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[F:10].[BH4-].[Na+].CO>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[F:10]
Reactant: O=Cc1ccc(Br)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1ccc(Br)c(F)c1
Yield: 96.8 %

Procedure:
To a solution of 4-bromo-3-fluorobenzaldehyde (10 g, 49.3 mmol) and NaBH4 (3.73 g, 99 mmol) in THF (100 mL) was added MeOH (100 mL) dropwise at 20° C. After LCMS analysis showed the starting material had disappeared, the solvent was removed in vacuo. The residue was dissolved in DCM (200 mL) and washed with H2O (60 mL) and brine (60 mL). The organic layer was dried over Na2SO4, filtered and concentrated to yield a white solid of (4-bromo-3-fluorophenyl)methanol (9.8 g, 47.7 mmol, 97.0% yield): 1H NMR (400 MHz, CD3OD) δ 7.54 (t, J=7.8 Hz, 1H), 7.18 (d, J=9.6 Hz, 1H), 7.06 (d, J=7.2 Hz, 1H), 4.56 (s, 2H); ES-LCMS m/z 188.9 (M-17).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:40](=[O:41])[N:6]2[C:7]([C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=3)=[O:28])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([C:19]([C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[O:20])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[F:42][C:43]([F:50])([F:49])[S:44]([O:47]C)(=[O:46])=[O:45]>ClCCl>[F:42][C:43]([F:50])([F:49])[S:44]([O-:47])(=[O:46])=[O:45].[OH:1][C@@H:2]([C@H:4]1[C:40](=[O:41])[N:6]2[C:7]([C:27]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=3)=[O:28])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([C:19]([C:21]5[CH:22]=[N+:23]([CH3:43])[CH:24]=[CH:25][CH:26]=5)=[O:20])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cccnc5)c4s3)[C@H](C)[C@H]12
Solvent: ClCCl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5ccc[n+](C)c5)c4s3)[C@H](C)[C@H]12
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (240 mg) was suspended in 10 ml of dichloromethane to prepare a suspension. Methyl trifluoromethanesulfonate (0.047 ml) was added to the suspension, and the mixture was stirred at room temperature for 20 min. The reaction solution was concentrated under the reduced pressure to give 333 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(1-methylpyridinium-3-yl)carbonylimidazo-[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate trifluoromethanesulfonate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]2[O:14][C:13](=[O:15])[NH:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[H-].[Na+].[CH:18]1(Br)[CH2:22][CH2:21][CH2:20][CH2:19]1>CN(C)C=O>[CH:18]1([O:1][C:2]2[CH:3]=[C:4]([CH:10]3[O:14][C:13](=[O:15])[NH:12][CH2:11]3)[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1ccc(C2CNC(=O)O2)cc1O
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C2CNC(=O)O2)cc1OC1CCCC1
Reaction time: 2 h
Yield: 70 %

Procedure:
7.2 mmol of 5-(3-hydroxy-4-methoxyphenyl)-2-oxazolidinone is dissolved in 10 ml. of absolute dimethylformamide and stirred with 7.9 mmol of sodium hydride for 1 hour at 50°. After cooling, the mixture is combined with 8.6 mmol of cyclopentyl bromide and then agitated for 2 hours at 80°. After the reaction is terminated, the dimethylformamide is withdrawn under vacuum at 40°. The residue is taken up in 100 ml. of 2 N sodium hydroxide solution and extracted three times with 150 ml. of chloroform. The combined chloroform phases are washed with water, dried, filtered, and concentrated. The residue is recrystallized from ethyl acetate/ether, thus obtaining in a 70% yield 5-(3-cyclopentoxy-4-methoxyphenyl)-2-oxazolidinone, m.p. 111°-112°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)(O)[O-].[Na+].Cl[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19]>O>[CH:21]([O:20][C:18]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)=[O:19])([CH3:23])[CH3:22]
Reactant: Nc1ccc(N)c([N+](=O)[O-])c1
Reactant: CC(C)OC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)OC(=O)Nc1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
A stirred suspension of 2,5-diaminonitrobenzene (60 g.) in a solution of sodium bicarbonate (49.4 g) in water (780 ml) at 10° C. was treated dropwise with isopropyl chloroformate (48 g) and the mixture was stirred at room temperature for 3 hours. The crude brown solid was filtered off, washed well with water and dried to give 4-isopropoxycarbonylamino-2-nitroaniline (90.0 g), m.p. 158°-160° C., which was used in the next stage of the synthesis without further purification being necessary. Recrystallisation of a sample from toluene gave pure 2-nitro-4-isopropoxycarbonylaminoaniline, m.p. 161°-163° C.
Reaction SMILES: C[O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([CH2:15][C:16]3[CH:32]=[CH:31][C:19]4[N:20]=[C:21]([NH:23][C@@H:24]5[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]5[OH:30])[S:22][C:18]=4[CH:17]=3)=[CH:13][N:14]=[C:8]2[CH:7]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([CH2:15][C:16]3[CH:32]=[CH:31][C:19]4[N:20]=[C:21]([NH:23][C@@H:24]5[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]5[OH:30])[S:22][C:18]=4[CH:17]=3)=[CH:13][N:14]=[C:8]2[CH:7]=1
Reactant: COCCOc1ccn2c(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)cnc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: OCCOc1ccn2c(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)cnc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.9 %

Procedure:
To a stirred solution of (1R,2R)-2-((6-((7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (45 mg, 0.099 mmol) from Example 153 in 2 mL of DCM at −10° C. was added BBr3 in DCM (1.0 M, 110 μL, 0.11 mmol). The resulting mixture was stirred at rt for 30 min before it was cooled to −10° C. and additional BBr3 in DCM (1.0 M, 100 μL, 0.10 mmol) was added. After stirring at rt overnight, BBr3 in DCM (1.0 M, 100 μL, 0.10 mmol) was added and stirring was continued for 1 d. The resulting mixture was quenched with MeOH and the mixture was purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford (1R,2R)-2-((6-((7-(2-hydroxyethoxy)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (16 mg, 37%). 1H NMR (500 MHz, DMSO-d6) δ 8.00 (d, J=7.9 Hz, 1H), 7.91 (d, J=7.4 Hz, 1H), 7.49 (s, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.22 (s, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.90 (d, J=2.0 Hz, 1H), 6.57 (dd, J=2.5, 7.4 Hz, 1H), 4.79 (br s, 1H), 4.22 (s, 2H), 4.02 (t, J=4.7 Hz, 2H), 3.72 (t, J=4.7 Hz, 2H), 3.50 (br s, 2H), 2.04 (d, J=12.8 Hz, 1H), 1.87 (d, J=11.3 Hz, 1H), 1.54-1.68 (m, 2H), 1.10-1.37 (m, 4H). LCMS (ESI) m/z 439 (M+H)+.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH2:11]([C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH3:21])[C:14]=1[NH2:15])[CH3:12]>ClCCl>[CH:1]([NH:15][C:14]1[C:16]([CH2:20][CH3:21])=[CH:17][CH:18]=[CH:19][C:13]=1[CH2:11][CH3:12])=[O:3]
Reactant: O=CO
Reactant: CCc1cccc(CC)c1N
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CCc1cccc(CC)c1NC=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
A mixture of formic acid (14.361 g, 0.312 mol) and acetic anhydride (12.659 g, 0.124 mol) was stirred at room temperature for 1 h under an argon atmosphere. This mixture was added to a solution of 2,6-diethylaniline (14.924 g, 0.1 mol) in dry dichloromethane (60 ml) at such a rate that the temperature of the reaction mixture was kept between 5 and 10° C. The reaction was stirred at room temperature for 16 h and then refluxed for 4 h. The solvent was evaporated under reduced pressure, the residue was dissolved in CHCl3 (200 mL) and washed with a saturated aqueous NaHCO3 solution (3×200 mL), and water (200 mL). The organic layer was dried over Na2SO4 and the solvent was evaporated under reduced pressure. The remaining yellow solid was washed with hot diethyl ether (2×50 mL) to afford N-formyl-2,6-diethylaniline 8d as a white solid (13.16 g, 74%). 1H NMR (CDCl3, 300 MHz): δ=8.15-8.02 (m, 1H, CHO), 7.86 (broad s, 1H, NH), 7.25-7.06 (m, 3H), 2.65 (q, J=7 Hz, 2H), 2.53 (q, J=7 Hz, 2H), 1.20 (t, J=7 Hz, 3H), 1.14 (t, J=7 Hz, 3H); 13C{1H} NMR (CDCl3, 75 MHz): δ=165.97, 161.00, 142.13, 141.52, 132.15, 131.66, 128.65, 128.37, 127.09, 126.49, 25.18, 25.04, 15.00, 14.62; HRMS (EI+) calculated for C11H15NO [M]+ 177.1154, observed 177.1159.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:32]([NH:31][C:28]1[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=1)=[O:33]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(Cl)c3)c2cc1OC
Temperature: 60 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline 50 mg) was dissolved in chloroform (5 ml), and p-fluorophenyl isocyanate (21 μl) was then added to the solution. The mixture was stirred at 60° C. for one hr. The precipitated crystal was collected by filtration and was washed to give 57 mg (yield 81%) of the title compound.
Reaction SMILES: CO[C:3](=[O:13])[CH2:4][CH2:5][O:6][N:7]=[C:8]([O:10][CH2:11][CH3:12])[CH3:9].[CH2:14]([NH2:17])[CH2:15][CH3:16]>CO>[CH2:11]([O:10][C:8](=[N:7][O:6][CH2:5][CH2:4][C:3](=[O:13])[NH:17][CH2:14][CH2:15][CH3:16])[CH3:9])[CH3:12]
Reactant: CCCN
Reactant: CCOC(C)=NOCCC(=O)OC
Solvent: CO
Product: CCCNC(=O)CCON=C(C)OCC
Temperature: 55 °C
Reaction time: 15 h
Yield: 86 %

Procedure:
To a known compound, 3-(1-ethoxy-ethylideneaminooxy)-propanoic acid methyl ester (CAS No. 97164-30-2, 300 mg, 1.585 mmol) were added methanol (3 ml) and n-propylamine (1.3 ml), and the mixture was stirred at 55° C. for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give N-(2-propylcarbamoyl-ethoxy)-acetimidic acid ethyl ester (296 mg, 86% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[Cl:10][C:11]1[N:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:10][C:11]1[N:16]=[CH:15][C:14]([C:2]2[CH:3]=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: Cn1cc(Br)ccc1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2ccc(Cl)nc2)ccc1=O
Temperature: 110 °C
Yield: 72.7 %

Procedure:
A mixture of 5-bromo-1-methylpyridin-2(1 H)-one (2.2 g, 11.7 mmol), 6-chloropyridin-3-ylboronic acid (1.57 g, 9.98 mmol), Na2CO3 (2.2 g, 20.76 mmol), and tetrakis(triphenylphosphine)palladium (0) (500 mg, 0.05 mmol) in dioxane:water (15:1, 20 ml) was degassed and heated at 110° C. in a microwave for 1 hr. The reaction was diluted with EtOAc and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by silica gel chromatography (AcOEt-Hexanes) to provide title compound, 5-(6-Chloropyridin-3-yl)-1-methylpyridin-2(1 H)-one (1.6 g, 73% yield).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:3]1=[O:23].Br[CH:25]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(OCC)(=O)C>C(Cl)Cl>[CH2:29]([O:28][C:26]([CH:25]([NH:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:3]1=[O:23])[CH2:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:27])[CH3:30]
Reactant: CC(C)(C)OC(=O)CN1CC(c2ccccc2)SCC(N)C1=O
Reactant: CCOC(=O)C(Br)CCc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CCc1ccccc1)NC1CSC(c2ccccc2)CN(CC(=O)OC(C)(C)C)C1=O

Procedure:
0.22 g of the isomer of t-butyl α-[6-amino-5-oxo-2-phenylperhydro-1,4-thiazepin-4-yl]acetate [prepared as described in step (h) above] was subjected to N-alkylation with 0.28 g of ethyl 2-bromo-4-phenylbutyrate in the same manner as described in Example 1(h). The resulting product was subjected to silica gel column chromatography, using a 1:20 by volume mixture of ethyl acetate and methylene chloride as the eluent. From the fraction first eluted was obtained 0.14 g of t-butyl α-{6-[1-ethoxycarbonyl-3-phenylpropylamino]-5-oxo-2-phenylperhydro-1,4-thiazepin-4-yl}acetate as an oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([O:21][CH3:22])[CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[C:15]2[CH3:20])=[O:8].[CH3:23][CH:24]([CH3:34])[CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH:29]([CH3:33])[CH2:28]1.C(N(CC)CC)C.O>C1C=CC=CC=1>[CH3:22][O:21][C:12]1[CH:13]=[C:14]2[C:19](=[C:10]([NH:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:30]3[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][CH:24]([CH3:34])[CH3:23])[CH2:28][CH:29]3[CH3:33])[CH:11]=1)[N:18]=[CH:17][CH:16]=[C:15]2[CH3:20]
Reactant: COc1cc(NC(=O)CCCCCBr)c2nccc(C)c2c1
Reactant: CC(C)CCN1CCNC(C)C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: c1ccccc1
Product: COc1cc(NC(=O)CCCCCN2CCN(CCC(C)C)CC2C)c2nccc(C)c2c1
Yield: 44.3 %

Procedure:
A mixture of 6 g (0.0164 mole) of 6-bromo-N-(6-methoxy-4-methyl-8-quinolinyl)hexanamide, 3 g (0.017 mole) of 1-(3-methyl-butyl)-3-methylpiperazine and 3 ml of triethylamine in 100 ml of benzene was heated under reflux for 30 hr, allowed to cool and filtered to remove triethylamine hydrobromide. The filtrate was combined with 1 ml of triethylamine and heated under reflux for 28 hr. The cooled reaction mixture was combined with water and additional benzene. The benzene layer was separated, washed, dried and concentrated to dryness. The residue dissolved in ethyl acetate and chromatographed over 200 g of silica gel first with ethyl acetate, then with a 7% solution of methanol in ethyl acetate and finally with a 10% solution of methanol in ethyl acetate. Fractions containing product, Rf (15% methanol/ethyl acetate)=0.12, were combined and concentrated to afford 3.3 g (44%) of the desired product as an oil, which was used in the next step without further purification. The structure was confirmed by IR and NMR spectra.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[F:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][CH2:23][CH2:22][CH2:21][CH2:20][F:19])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: NCCCCF
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NCCCCF

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.94 mmol) was treated with 4-fluoro-butylamine following general procedure B to afford 4-(4-fluoro-butylamino)-8-methoxy-quinoline-3-carboxylic acid ethyl ester (244 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid using general procedure D and then transformed into the corresponding ethylamide (150 mg) following general procedure E. The above ethylamide (145 mg, 0.45 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 3-ethyl-1-(4-fluoro-butyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (95 mg). LCMS: m/z 346 [M+1]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][OH:6].[N+:7]([C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([N+]([O-])=O)[C:11]=1[C:12]#[N:13])([O-:9])=[O:8]>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:14]1[CH:15]=[CH:16][CH:17]=[C:10]([N+:7]([O-:9])=[O:8])[C:11]=1[C:12]#[N:13]
Reactant: COCCCO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: COCCCOc1cccc([N+](=O)[O-])c1C#N
Yield: 63.6 %

Procedure:
Prepared as in Example 111c from 3-methoxypropan-1-ol and 2,6-dinitrobenzonitrile in 63.6% yield. 1H NMR (400 MHz, CDCl3) δ 2.16 (m, 2H), 3.36 (s, 3H), 3.63 (t, J=5.6 Hz, 2H), 4.29 (t, J=6.4 Hz, 2H), 7.35 (dd, J=8.8, 0.8 Hz, 1H), 7.69 (t, J=8.8 Hz, 1H), (dd, J=8.4, 0.8 Hz, 1H).