Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=[CH:11][CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[CH:19][N:20]2[CH3:25].C(O)(C(F)(F)F)=O.C([C@@H]1N[C@H](C(C)(C)C)N(C)C1=O)C1C=CC=CC=1>C(Cl)Cl.C(O)(C)C>[CH2:1]([O:8][CH2:9][C@@H:10]([C:18]1[C:17]2[C:21](=[CH:22][CH:23]=[CH:24][C:16]=2[O:15][CH3:14])[N:20]([CH3:25])[CH:19]=1)[CH2:11][CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc2c1ccn2C
Reactant: O=CC=CCOCc1ccccc1
Agent: CN1C(=O)[C@H](Cc2ccccc2)N[C@@H]1C(C)(C)C
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc2c1c([C@@H](CC=O)COCc1ccccc1)cn2C
Yield: 93.7 %

Procedure:
Prepared according to the general procedure from 4-benzyloxy-but-2-enal (285 mg, 1.50 mmol), 4-methoxy-1-methyl-1H-indole (80.5 mg, 0.500 mmol), TFA (7.7 μL, 0.10 mmol) and (2S,5S)-5-benzyl-2-tert-butyl-3-methyl-imidazolidin-4-one (24.6 mg, 0.100 mmol) in CH2Cl2 (0.90 mL) and isopropanol (0.10 mL) at −87° C. for 19.5 h to provide, after silica gel chromatography (20:80 EtOAc/hexanes), the title compound as a colorless oil (158 mg, 90% yield, 94% ee). IR (film) 3081, 2961, 2850, 2730, 1719, 1608, 1582, 1548, 1501, 1466, 1454, 1424, 1381, 1334, 1321, 1274,1261, 1180, 1116, 1073, 1026, 782, 714 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.78 (dd, J=2.4, 2.4 Hz, 1H, CHO), 8.03-8.01 (m, 2H, ArH), 7.59-7.53 (m, 1H, ArH, 7.47-7.41 (m, 2H, ArH), 7.16 (t, J=8.4 Hz, 1H, ArH), 6.92 (dd, J=0.6, 8.4 Hz, 1H, ArH), 6.83 (s, 1H, NCH), 6.52 (d, J=7.5 Hz, 1H, ArH), 4.71 (dd, J=5.1, 10.5 Hz, 1H, CH2O), 4.50 (dd, J=8.4, 10.5 Hz, 1H, CH2O), 4.35 (m, 1H, ArCH), 3.94 (s, 1H, OCH3), 3.71 (s, 3H, NCH3), 2.98 (d, J=2.4 Hz, 1H, CH2CO); 2.96 (d, J=2.7 Hz, 1H, CH2CO); 13C NMR (75 MHz, CDCl3) δ 202.5, 166.3, 154.2, 133.0, 130.3, 129.6, 128.6, 128.4, 125.4, 122.9, 116.8, 113.6, 102.8, 99.4, 68.8, 55.3, 47.3, 33.2, 32.2; HRMS (CI) exact mass calcd for (C21H21NO4) requires m/z 351.1471, found m/z 351.1466. [α]D=−13.9 (c=1.0 CHCl3). The enantiomeric ratio was determined by HPLC analysis of the alcohol, obtained by NaBH4 reduction of the aldehyde, using a Chiracel AD and AD guard column (4:96 ethanol/hexanes, 1 mL/min); S isomer tr=58.7 min and R isomer tr=47.5 min.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:16][C:17]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:18]=1[NH2:19]>>[ClH:1].[CH3:16][C:17]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:18]=1[NH:19][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Product: COc1cc2ncnc(Nc3cc([N+](=O)[O-])ccc3C)c2cc1OC
Product: Cl

Procedure:
Using analogous procedures to those described in the portion of Example 2 which is concerned with the preparation of starting materials, 4-chloro-6,7-dimethoxyquinazoline was reacted with 2-methyl-5-nitroaniline to give 4-(2-methyl-5-nitroanilino)-6,7-dimethoxyquinazoline hydrochloride; Mass: M+H+ 341 and that material was reduced during 5 hours to give 4-(5-amino-2-methylanilino)-6,7-dimethoxyquinazoline; Mass: M+H+ 311.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:7][CH:6]=1)=[O:4].[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH4-].[Na+]>CCO.C(Cl)(Cl)Cl>[CH2:20]([NH:27][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:7][CH:6]=1)[OH:4])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1ccccc1
Reactant: CCCCCCCCOc1ccc(C(=O)CBr)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCCCCCCCOc1ccc(C(O)CNCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.6 %

Procedure:
To a cooled (0° C.) suspension of 2-Bromo-1-(4-octyloxy-phenyl)-ethanone (36.1 g; 110.3 mmol) in EtOH (500 mL) and CHCl3 (100 mL) was added benzylamine (48.2 mL; 441.2 mmol). After 30 minutes the ice-bath was removed and the mixture stirred for another 2 hours at RT. Subsequently the reaction mixture was cooled again to 0° C. and NaBH4 (6.26 g; 165.5 mmol) was added in small portions. The resulting mixture was stirred at 0° C. for 1 hour and thereafter another 4 hours at RT. The reaction mixture was quenched with 1M aqueous HCl (750 mL) at 0° C. and stirred at RT for 1 hour. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and 2 N aqueous NaOH. The organic layer was dried (Na2SO4), filtered, concentrated in vacuo, and purified by column chromatography (SiO2, EtOAc) to give 2-benzylamino-1-(4-octyloxy-phenyl)-ethanol (22.58 g)
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:13])=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9]CC)=[O:8].[OH-].[Na+]>C1COCC1.CO.O>[Cl:1][C:2]1[C:3]([Cl:13])=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
A mixture of ethyl 5,6-dichloronicotinate (1.0 g, 4.5 mmol) and aqueous NaOH (2 N, 6.75 mL, 13.5 mmol) in a mixed solvents of THF/MeOH/water (50 mL, 4/1/1) was stirred at room temperature for 0.5 h. After concentration, the mixture was acidified with 2 N HCl to pH around 2. The resulting mixture was extracted with ether (30 mL×3). The organic layer was washed with water (50 mL×3), dried over Na2SO4, and concentrated to afford 5,6-dichloronicotinic acid (800 mg, 91% yield) as a white solid. LCMS (ESI) m/z: 192.0 [M+H]+.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[N+:8]([C:11]1[CH:12]=[C:13]([CH:36]=[CH:37][CH:38]=1)[CH2:14][C:15]1[C:16](=[O:35])[O:17][C:18]2[CH:28]=[C:27]([O:29][C:30](=[O:34])[N:31]([CH3:33])[CH3:32])[CH:26]=[CH:25][C:19]=2[C:20]=1[CH2:21][C:22]([OH:24])=[O:23])([O-:10])=[O:9].ClCCl.C(O)(=O)C>CO>[CH3:1][O:23][C:22](=[O:24])[CH2:21][C:20]1[C:19]2[CH:25]=[CH:26][C:27]([O:29][C:30](=[O:34])[N:31]([CH3:32])[CH3:33])=[CH:28][C:18]=2[O:17][C:16](=[O:35])[C:15]=1[CH2:14][C:13]1[CH:36]=[CH:37][CH:38]=[C:11]([N+:8]([O-:10])=[O:9])[CH:12]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CN(C)C(=O)Oc1ccc2c(CC(=O)O)c(Cc3cccc([N+](=O)[O-])c3)c(=O)oc2c1
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)Cc1c(Cc2cccc([N+](=O)[O-])c2)c(=O)oc2cc(OC(=O)N(C)C)ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
Trimethylsilyl diazomethane (0.82 mL, 2.0 M in hexane) was added to a solution of {3-(3-nitrobenzyl)-7-dimethylcarbamoyloxy-2-oxo-2H-1-benzopyran-4-yl}acetic acid (compound 7f-1-1COOH) (350 mg, 0.82 mmol) in methanol (5.0 mL)/dichloromethane (8.0 mL), and the mixture was stirred at room temperature for 10 minutes. Acetic acid (2.0 mL) was added to the reaction mixture, and the title compound (338 mg, 94%) was obtained by vacuum concentration as a pale yellow powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]3[CH2:10][CH2:11][CH:12]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]3=[N:7][C:6]=2[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[C:30]([C:39]([F:42])([F:41])[F:40])[CH:29]=1>CN(C=O)C.O>[CH:34]1([C:31]2[CH:32]=[CH:33][C:28]([CH2:27][O:1][C:2]3[CH:3]=[CH:4][C:5]4[N:9]5[CH2:10][CH2:11][CH:12]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]5=[N:7][C:6]=4[CH:19]=3)=[CH:29][C:30]=2[C:39]([F:40])([F:41])[F:42])[CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: CCOC(=O)CC1CCn2c1nc1cc(O)ccc12
Reactant: FC(F)(F)c1cc(CCl)ccc1C1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC1CCn2c1nc1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.4 %

Procedure:
Ethyl 2-(6-hydroxy-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-yl)acetate (0.1 g, 0.384 mmol) was dissolved in DMF (1.0 mL) and cesium carbonate (0.150 g, 0.461 mmol) and 4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (0.111 g, 0.423 mmol) were added. The reaction mixture was stirred at room temperature for 1.5 h and then warmed to 40° C. After stirring for 1 h, the reaction mixture was diluted with water and extracted three times with EtOAc. The combined extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to provide the title compound (126 mg). LCMS m/z=487.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.26 (t, J=7.2 Hz, 3H), 1.55-1.65 (m, 2H), 1.67-1.78 (m, 2H), 1.81-1.91 (m, 2H), 2.04-2.14 (m, 2H), 2.36-2.47 (m, 1H), 2.62 (dd, J=16.4, 9.7 Hz, 1H), 2.97-3.07 (m, 1H), 3.16 (dd, J=16.8, 3.8 Hz, 1H), 3.33-3.43 (m, 1H), 3.64-3.74 (m, 1H), 3.97-4.05 (m, 1H), 4.09-4.21 (m, 3H), 5.09 (s, 2H), 6.87 (d, J=2.4 Hz, 1H), 6.93 (dd, J=8.6, 2.4 Hz, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.56-7.61 (m, 2H), 7.68 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:27][CH:28]([C:33]2[CH:38]=[CH:37][C:36](Br)=[CH:35][C:34]=2[F:40])[C:29]([F:32])([F:31])[F:30])[N:3]=1.[CH3:41][O:42][C:43]1[CH:44]=[N:45][CH:46]=[C:47](B2OC(C)(C)C(C)(C)O2)[CH:48]=1.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:27][CH:28]([C:33]2[CH:38]=[CH:37][C:36]([C:47]3[CH:46]=[N:45][CH:44]=[C:43]([O:42][CH3:41])[CH:48]=3)=[CH:35][C:34]=2[F:40])[C:29]([F:32])([F:31])[F:30])[N:3]=1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(OC(c3ccc(Br)cc3F)C(F)(F)F)nc(N)n2)cc1)C(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1cncc(-c2ccc(C(Oc3cc(-c4ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc4)nc(N)n3)C(F)(F)F)c(F)c2)c1
Temperature: 150 °C
Yield: 38.8 %

Procedure:
A microwave vial (2 ml) was charged with (S)-3-(4-{2-amino-6-[1-(4-bromo-2-fluoro-phenyl)-2,2,2-trifluoro-ethoxy]-pyrimidin-4-yl}-phenyl)-2-tert-butoxycarbonylamino-propionic acid (130 mg, 0.2 mmol), 3-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (70 mg, 0.3 mmol) 1 ml of acetonitrile, and 0.7 ml of water. To this mixture was added 0.4 ml of aqueous sodium carbonate (1M), followed by 14 mg (5 mol %) of dichlorobis(triphenylphosphine)palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness, the residue was dissolved in 2.5 ml of methanol and purified with Prep HPLC to give 51 mg of (S)-3-[4-(2-amino-6-{2,2,2-trifluoro-1-[2-fluoro-4-(5-methoxy-pyridin-3-yl)-phenyl]-ethoxy}-pyrimidin-4-yl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[F:33][C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=1)[NH2:37]>CN(C=O)C.O.CCN(CC)CC>[NH2:1][C:2]1[C:3]([C:9]([NH:37][C:36]2[CH:38]=[CH:39][CH:40]=[C:34]([F:33])[CH:35]=2)=[O:11])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: Nc1ncc(Br)nc1C(=O)O
Reactant: Nc1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1ncc(Br)nc1C(=O)Nc1cccc(F)c1
Reaction time: 6 h
Yield: 70.2 %

Procedure:
3-amino-6-bromopyrazine-2-carboxylic acid (500 mg, 2.29 mmol), HOBT (464 mg, 3.44 mmol) and EDCI (660 mg, 3.44 mmol) were dissolved in dry DMF (20 mL), and the resulting solution was stirred for 6 hours. Then 3-fluoroaniline (305 mg, 2.75 mmol) and Et3N (0.43 mL) was added to the mixture. After being stirred overnight, the mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and evaporated. The crude product was purified by prep-TLC (PE:EtOAc=6:1) to give the pure product of 3-amino-6-bromo-N-(3-fluorophenyl)pyrazine-2-carboxamide (500 mg, yield: 68%). 1H-NMR (CDCl3, 400 MHz) δ 9.44 (s, 1H), 8.22 (s, 1H), 7.59 (d, J=11.2 Hz, 1H), 7.24˜7.27 (m, 2H), 6.79˜6.82 (m, 1H), 3.21 (s, 2H). MS (M+H)+: 311/313.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([CH3:14])[CH:3]=1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:26][CH2:27][CH:28]=[C:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[N:39][C:34]=2[CH2:33][O:32][C:31]2[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:26][CH2:27][CH:28]=[C:29]3[C:35]4[CH:36]=[CH:37][CH:38]=[N:39][C:34]=4[CH2:33][O:32][C:31]4[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]3=4)[CH2:10][CH2:9]2)=[C:4]([CH3:14])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1N1CCNCC1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [I-]
Agent: [K+]
Solvent: Cc1cccc(C)n1
Solvent: CC(C)O
Product: Cc1cc(Cl)ccc1N1CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 54.6 %

Procedure:
To a solution of 1-(4-chloro-2-methyl-phenyl)-piperazine (0.13 g, 0.6 mmol) in isopropanol (6.0 mL) was added 2,6-lutidine (95 uL, 0.802 mmol) and catalytic potassium iodide. This mixture was heated to 80° C., and treated with 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.15 g, 0.4 mmol), added in portions over 2 h. The solution was then stirred at 80° C. for an additional 12h. The reaction mixture was concentrated in vacuo, then purified by flash chromatography on silica gel (gradient elution from 95% ethyl acetate/5% methanol to 90% ethyl acetate/10% methanol) to yield the title compound (0.11 g, 54%). 1H-NMR (DMSO) δ: 1.45 (6H, s), 2.30-2.65 (8H, m), 2.75-2.85 (4H, m), 3.30 (3H, d), 5.30 (2H, br s), 6.20 (1H, t), 6.75 (1H, d), 7.00-7.47 (6H, m), 7.80 (1H, dd), 8.50 (1H, dd). ESI-MS m/z: 504 (M+1), UV retention time: 1.65 min.
Reaction SMILES: Br[CH2:2][CH:3]([C:12]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:30])[NH:17]2)[O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][NH2:40])=[CH:34][CH:33]=1>CS(C)=O.C(OCC)(=O)C>[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][NH:40][CH2:2][C@@H:3]([C:12]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:18]3[C:13]=2[CH:14]=[CH:15][C:16](=[O:30])[NH:17]3)[O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6])=[CH:34][CH:33]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: NCCc1ccc(N)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCc1ccc(N)cc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 100 °C
Yield: 91.6 %

Procedure:
A mixture of 5-(2-bromo-1-(tert-butyl-dimethyl-silanyloxy)-ethyl)-8-benzyloxy-1H-quinolin-2-one (5.0 g, 1.0 equiv) and 2-(4-aminophenyl)ethylamine (2.8 g, 2.0 equiv) in dimethylsulfoxide (10 mL) was heated at 100° C. for 12 h. The reaction mixture was cooled to 20° C., and the resulting red oil was diluted with ethyl acetate (200 mL) and extracted with two portions water (200 mL). The organic layer was washed with two portions of (1:1 10% aqueous acetic acid and saturated aqueous sodium chloride (200 mL). The organic layer was basified by carefully extracting with two portions of saturated sodium bicarbonate (200 mL), followed by saturated sodium chloride (200 mL). The resulting organic solution was treated with anhydrous sodium sulfate, and the solvent was removed under reduced pressure to afford the title intermediate (5.1 g) which was used without further purification.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[N:14]2[C:10](=[N:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=32)[S:9][N:8]=1)=[O:6].Cl>O1CCOCC1>[C:5]([C:7]1[N:14]2[C:10](=[N:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=32)[S:9][N:8]=1)([OH:6])=[O:4]
Reactant: COC(=O)c1nsc2nc3ccccc3n12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1nsc2nc3ccccc3n12
Temperature: 25 °C
Yield: 78.5 %

Procedure:
To a 6 mL solution of 1N NaOH, 3-(methoxycarbonyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole (1.0 g, 4.3 mmole) in 6 mL of dioxane, was added. The reaction mixture was stirred at room temperature until completion. The resulting mixture was then acidified with 3N HCl to pH ~2.0, and stirred at room temperature for an additional 0.5 h. The solid was filtered, washed with water, and dried under vacuum at 60° C. for 24 h to yield 0.74 g (78%) of the title compound as a colourless solid: mp 184-185° C. (dec); 1H NMR (DMSO-d6) δ 13.79 (br s, 1H), 8.59 (d, 1H), 7.78 (d, 1H), 7.51 (t, 1H), 7.40 (t, 1H); IR (KBr) ν 3435, 1705 cm-1 ; MS m/z 193 (M+ -OH), 175 (M+ -CO2)
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH:34]([OH:42])[CH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[F:25][C:18]1[CH:19]=[C:20]([CH3:24])[C:21]([F:23])=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:30][CH2:31][CH2:32][CH2:33][CH:34]([OH:42])[CH2:35][N:36]2[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]2)=[O:29])[S:14][N:13]=1
Reactant: NCCCC(O)CN1CCCCC1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)cc1F
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCC(O)CN3CCCCC3)c2C(N)=O)cc1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 5-amino-1-piperidin-1-yl-pentan-2-ol by the procedure analogous to Example 6. HPLC ret. time: 3.3 minutes. 1H NMR (400 MHz, CD3OD) δ 7.18 (dd, 1H, J=6.0, 9.2 Hz), 7.05 (dd, 1H, J=6.0, 10 Hz), 5.47 (s, 2H), 3.80 (m, 1H), 3.23 (t, 2H, J=6.4 Hz), 2.7-2.4 (m, 7H), 2.25 (s, 3H), 1.8-1.4 (m, nH) ppm; MS (APCl, m/z): 512 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH2:22][CH2:23][NH:24][OH:25])[CH:17]=3)[C:12]2=[O:26])=[CH:4][CH:3]=1.[C:27](Cl)(=[O:29])[CH3:28].[O:31]1CC[CH2:33][CH2:32]1>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH2:22][CH2:23][N:24]([O:25][C:32](=[O:31])[CH3:33])[C:27](=[O:29])[CH3:28])[CH:17]=3)[C:12]2=[O:26])=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: CC(=O)Cl
Reactant: O=C1c2ccc(OCCNO)cc2CCN1CCCc1ccc(F)cc1
Solvent: CCOC(C)=O
Product: CC(=O)ON(CCOc1ccc2c(c1)CCN(CCCc1ccc(F)cc1)C2=O)C(C)=O
Reaction time: 1 h

Procedure:
A solution of 2-[3-(4-fluorophenyl)-propyl]-6-[2-(N-hydroxyamino)-ethoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline (900 mg) in 25 ml of tetrahydrofuran is cooled to 0°. Acetyl chloride (0.50 g) is slowly added and the mixture is stirred for one hour at 0°. The mixture is then diluted with ethyl acetate and washed with aqueous 2N HCl, dried (MgSO4) and evaporated to give 2-[3-(4-fluorophenyl)-propyl]-6-[2-(N-acetyloxy-N-acetylamino)ethoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].[La:24]>CC(O)=O.CN(C=O)C>[La:24].[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[O:22][CH3:23])[N:13]=[CH:12][CH:11]=[C:10]2[O:9][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[CH:3][CH:2]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: [La]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reaction time: 19 h

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline [starting compound A] (415 mg) was dissolved in 10 ml of a 1% AcOH/DMF solution to prepare a solution. Further, aldehyde linker lanthanum (D-series; 28 μmol/unit) (10 units) was added to the solution. The reaction mixture was slowly shaken for 19 hr. Sodium boron triacetoxyhydride (475 mg) was added thereto, and the mixture was further slowly shaken for 24 hr. Lanthanum was taken out of the reaction solution and was washed with alternate N,N-dimethylformamide and dichloromethane each three times, followed by drying under the reduced pressure to give lanthanum with 4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline supported thereon. This lanthanum (3 units) was added to 1 ml of dichloromethane, and a solution of N-(chlorocarbonyl) isocyanate [starting compound B] (55 μl) in dichloromethane (0.2 ml) was added to the mixture at 0° C. The mixture was slowly shaken overnight at room temperature. Further, a mixed solution composed of aniline [starting compound C] (68 μl), diisopropylamine (0.2 ml), and dichloromethane (0.3 ml) was then added thereto at 0° C. The mixture was shaken at room temperature for 7 hr and was then washed with alternate N,N-dimethylformamide and dichloromethane each five times. Drying under the reduced pressure was carried out, a 50% TFA/dichloromethane solution (1 ml) was added thereto, and the mixture was shaken at room temperature for 50 min to take off the product from lanthanum, followed by purification by thin layer chromatography on silica gel to give 6.8 mg of the title compound.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]#[CH:24])[CH:16]=2)=[C:7]([NH:25][C:26]([NH:28][C:29]2[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=2[CH:38]([CH3:40])[CH3:39])=[O:27])[C:6]1=[O:41])[CH2:2][CH2:3][CH3:4].C=O.[CH2:44]([NH:46][CH2:47][CH3:48])[CH3:45].[CH3:49]COCC>O1CCOCC1.[Cu]I>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]#[C:24][CH2:49][N:46]([CH2:47][CH3:48])[CH2:44][CH3:45])[CH:16]=2)=[C:7]([NH:25][C:26]([NH:28][C:29]2[C:30]([CH:38]([CH3:40])[CH3:39])=[CH:31][CH:32]=[CH:33][C:34]=2[CH:35]([CH3:36])[CH3:37])=[O:27])[C:6]1=[O:41])[CH2:2][CH2:3][CH3:4]
Reactant: CCNCC
Reactant: CCOCC
Reactant: C#CCOc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)n(CCCC)c3ncccc23)c1
Agent: [Cu]I
Agent: C=O
Solvent: C1COCCO1
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OCC#CCN(CC)CC)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-[1-butyl-4-{3-(2-propynyloxy)phenyl}-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (1.0 g, 1.82 mmol) in dioxane (10 ml) were added paraformaldehyde (0.37 g), diethylamine (0.26 g, 3.63 mmol) and copper (I) iodide, and the mixture was stirred at room temperature for two hours. To the mixture was added ether, and the mixture was filtered through a cerite pad. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2% methanol in chloroform) to give the title compound (1.05 g, 1.65 mmol).