Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][CH:12]1[CH2:16][C:15](=[O:17])[N:14]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)[C:13]1=[O:26])=O)C1C=CC=CC=1.C(O)(=O)C.[BrH:31]>C(OCC)C>[BrH:31].[NH2:11][CH:12]1[CH2:16][C:15](=[O:17])[N:14]([C:18]2[CH:19]=[C:20]([Cl:25])[CH:21]=[C:22]([Cl:24])[CH:23]=2)[C:13]1=[O:26]
Reactant: O=C(NC1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: NC1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
85 g of 3-(N-benzyloxycarbonylamino)-1-(3,5-dichlorophenyl)pyrrolidine-2,5-dione are mixed with 200 ml of a solution of glacial acetic acid which is saturated with hydrobromic acid, and the mixture is then stirred for 11/2 hours at room temperature. Then 1 liter of diethyl ether is added and the precipitated crystals are rapidly collected by filtration, washed with diethyl ether and dried over potassium hydroxide in vacuo. The hydrobromide is obtained in the form of colourless crystals which melt at 278°-280° C. with decomposition.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:9]2[O:13][CH2:12][CH2:11][O:10]2)[N:5]([CH3:8])[C:6]=1Br.[Li]CCCC.O>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]([CH:9]2[O:13][CH2:12][CH2:11][O:10]2)[N:5]([CH3:8])[CH:6]=1
Reactant: Cn1c(C2OCCO2)nc(Br)c1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(Br)nc1C1OCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
To a solution of 4,5-dibromo-2-(1,3-dioxolan-2-yl)-1-methyl-1H-imidazole (1 g, 3.2 mmol) in dry THF (20 mL) was added n-BuLi (2.5 M in hexane, 1.28 mL, 3.2 mmol) dropwise at −68° C. over 30 min. The reaction mixture was stirred at the same temperature for 2 h and then was allowed to warm to r.t. over 1 h. 10 mL of water was added slowly at 0° C. to quench the reaction. The residue was extracted with EtOAc (50 mL×2) and the combined organic layers were washed with water (20 mL) and brine (20 mL), dried, and concentrated to give a yellow oil (678 mg). MS (ESI): m/z 233 [M+H]+.
Reaction SMILES: [N:1]([C:4]1[C:5]([C:22]2[CH:23]=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)=[N:6][C:7]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11])=[N+]=[N-]>ClC1C=CC=CC=1Cl>[CH3:29][O:28][C:25]1[N:24]=[C:23]2[NH:1][C:4]3[C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)=[N:6][C:5]=3[C:22]2=[CH:27][CH:26]=1
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)nc(-c2ccc(OC)nc2)c1N=[N+]=[N-]
Solvent: Clc1ccccc1Cl
Product: COC(=O)c1cc(-c2ccc(OC)cc2)nc2c1[nH]c1nc(OC)ccc12
Yield: 71 %

Procedure:
A solution of methyl 3-azido-6′-methoxy-6-(4-methoxyphenyl)-2,3′-bipyridine-4-carboxylate (120 mg, 0.31 mmol) in 1,2-dichlorobenzene (4 mL) was heated at 180° C. for 10 min with gas evolution. The solvent was removed under vacuum and the product was purified by silica gel radial chromatography (step gradient elution with hexane containing 50 to 100% methylene chloride). This gave methyl 7-methoxy-2-(4-methoxyphenyl)-5H-pyrido[2′,3′:4,5]pyrrolo[2,3-b]pyridine-4-carboxylate (80 mg, 72% yield) as a yellow solid. MS (ESI) m/z 364.1 (M+H). 1H NMR (CDCl3) δ ppm 9.61 (1H, s), 8.49 (1H, d, J=8.55 Hz), 8.14 (1H, s), 8.07 (2H, d, J=8.85 Hz), 7.02 (2H, d, J=8.85 Hz), 6.73 (1H, d, J=8.55 Hz), 4.06 (3H, s), 4.04 (3H, s), 3.87 (3H, s).
Reaction SMILES: C([O:8][C:9](=[O:35])[CH2:10][NH:11][C:12]([C@H:14]1[CH2:17][C@@H:16]([C:18]([O:20]CC2C=CC=CC=2)=[O:19])[N:15]1CC1C=CC=CC=1)=[O:13])C1C=CC=CC=1.O.[H][H]>CO>[C:18]([C@H:16]1[NH:15][C@@H:14]([C:12]([NH:11][CH2:10][C:9]([OH:35])=[O:8])=[O:13])[CH2:17]1)([OH:20])=[O:19]
Reactant: O=C(CNC(=O)[C@H]1C[C@@H](C(=O)OCc2ccccc2)N1Cc1ccccc1)OCc1ccccc1
Reactant: [H][H]
Solvent: CO
Solvent: O
Product: O=C(O)CNC(=O)[C@H]1C[C@@H](C(=O)O)N1
Yield: 85 %

Procedure:
18.5 mg (39 μmol) of N-[cis-N-benzyl-4-(benzyloxycarbonyl)azetidine-2-carbonyl]glycine benzyl ester in 10 ml of methanol is hydrogenated in a Parr shaker over 34.5 mg of 20% Pd (OH)2 /C (containing 31 % of water) under 4 atm of hydrogen for 4h, 5 ml of water is added, the catalyst is removed by filtration through a double paper filter and washed thoroughly with methanol/water (2:1), and the solution is evaporated. Filtration over SiO2 (isopropanol/water/conc ammonia 14:5:1), evaporation and drying in a vacuum desiccator over P2O5 and KOH affords 6.7 mg (85%) of N-(cis-4-carboxyazetidine-2-carbonyl)glycine as a colorless glass. 1H NMR (D2O):δ4.98 (t, 1H, J =8.5), 4.73 (t, 1H, overlapping), 3.86, 3.74 (AB system, 2H, J =17.5), 3.08 (dt, 1H, J =11.5 (d), 10 (t)), 2.55 (dt, 1H, J =I2 (d), 8.5 (t)).
Reaction SMILES: [Si](O[CH2:9][C@@H:10]([N:17]([CH3:30])[C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[F:29])=[O:19])[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])(C(C)(C)C)(C)C.Cl>CO>[F:29][C:23]1[C:24]([F:28])=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][NH:20][C:18](=[O:19])[N:17]([C@@H:10]([CH3:9])[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH3:30]
Reactant: COC(=O)CC[C@@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)NCc1cccc(F)c1F
Agent: Cl
Solvent: CO
Product: COC(=O)CC[C@H](C)N(C)C(=O)NCc1cccc(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
To a solution of (S)-methyl 5-(tert-butyldimethylsilyloxy)-4-(3-(2,3-difluorobenzyl)-1-methylureido)pentanoate (9.7 g, 21.6 mmol) in MeOH (40 mL) was added HCl (4 N in dioxane, 5.4.0 mL, 21.6 mmol). The resulting solution was stirred at RT for 1 h. The mixture was concentrated and re-dissolved in EtOAc. The organic mixture was washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give (S)-methyl 4-(3-(2,3-difluorobenzyl)-1-methylureido)pentanoate (6.84 g, crude) as a white solid, which was used without further purification. LRMS (M+H+) m/z 331.2.
Reaction SMILES: C(N(CC)[C:4]1[CH:5]=[C:6]([OH:17])[C:7](=[CH:15][CH:16]=1)[CH:8]=[N:9][CH2:10][C:11](C)([NH2:13])C)C.CO[C:22]1[CH:23]=[C:24]([OH:30])[C:25](=[CH:28][CH:29]=1)[CH:26]=O.C(OCC)(=O)C.CO>C(O)C>[CH:16]1[CH:4]=[CH:5][C:6](=[O:17])/[C:7](=[CH:8]/[NH:9][CH2:10][CH2:11][NH:13]/[CH:26]=[C:25]2/[CH:28]=[CH:29][CH:22]=[CH:23][C:24]/2=[O:30])/[CH:15]=1
Reactant: CCN(CC)c1ccc(C=NCC(C)(C)N)c(O)c1
Reactant: COc1ccc(C=O)c(O)c1
Solvent: CO
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1C=CC=C/C1=C/NCCN/C=C1\C=CC=CC1=O
Temperature: 500 °C

Procedure:
A suspension of 13.6 g (0.0517 mol) of N-Mono[4-(diethylamino)salicylidene]-2-methylpropane-1,2-diamine from Example 1 in 50 ml of ethanol is heated with stirring at 500° C. until a clear solution is obtained. 7.87 g (0.0517 mol) of 4-methoxysalicylaldehyde (solid) are added and the mixture is heated at reflux for 2 h. After that time the reaction is complete (TLC monitoring, ethyl acetate/methanol 9:1). Thereafter the reaction solution is carefully concentrated and the residue is dried under a high vacuum. The crude product obtained comprises 20 g of a dark red oil, which slowly solidifies. Purification is by column chromatography (eluent mixture: ethyl acetate/methanol 9:1). The asymmetrically substituted salen derivative is isolated as the diastereomer mixture (structures I and II). Yield: 7 g, reddish oil (34%). The product is characterized by 1H and 13C NMR spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5](=[O:8])[NH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[Br:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:24])=[C:20]([CH:23]=1)[CH2:21]Br.O>C(#N)C>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:24])=[C:20]([CH:23]=1)[CH2:21][N:4]1[C:3]([O:2][CH3:1])=[N:7][NH:6][C:5]1=[O:8]
Reactant: COc1n[nH]c(=O)[nH]1
Reactant: Clc1ccc(Br)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1n[nH]c(=O)n1Cc1cc(Br)ccc1Cl
Temperature: 55 °C
Reaction time: 5 h
Yield: 35.6 %

Procedure:
To a solution of 0.91 g (7.93 mmol) of 5-methoxy-2,4-dihydro-3H-1,2,4-triazol-3-one in 8 ml of dry acetonitrile was added 0.96 g (6.94 mmol) of potassium carbonate. To the mixture was added dropwise a solution of 1.88 g (6.61 mmol) of 5-bromo-2-chlorobenzylbromide in 20 ml of dry acetonitrile at 55° C. After the mixture was stirred at 55° C. for 5 hours, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. To the resultant solid residue (1.90 g) was added cold tert-butyl methyl ether and the solid was thoroughly washed, collected by filtration and dried to obtain 0.75 g of 4-(5-bromo-2-chlorobenzyl)-5-methoxy-2,4-dihydro-3H-1,2,4-triazol-3-one as white powder.
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]1([CH3:20])[CH2:9][C:8]2[C:10]([CH3:19])=[C:11]([NH:16][CH:17]=[O:18])[C:12]([CH3:15])=[C:13]([CH3:14])[C:7]=2[O:6]1.[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH:17]([NH:16][C:11]1[C:12]([CH3:15])=[C:13]([CH3:14])[C:7]2[O:6][C:5]([CH3:20])([CH2:4][S:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:9][C:8]=2[C:10]=1[CH3:19])=[O:18]
Reactant: Sc1ccccc1
Reactant: Cc1c(C)c2c(c(C)c1NC=O)CC(C)(CBr)O2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(C)c2c(c(C)c1NC=O)CC(C)(CSc1ccccc1)O2
Temperature: 80 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
Sodium hydride (60% purity, 1.0 g, 21.1 mmol) was added to a solution of 2-bromomethyl-5-formylamino-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran (6.0 g, 19.2 mmol) and thiophenol in dimethylformamide (50 ml) and the mixture was stirred at 80° C. for 1 hour under an argon atmosphere. After the reaction mixture was cooled, the product was extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled off. The residue was purified by column chromatography on silica gel (isopropyl ether-ethyl acetate, 1:1) and then the purified product was recrystallized from ethanol-isopropyl ether to obtain the desired compound (5.54 g, yield: 83.3% yield), m.p. 130°14 131° C.
Reaction SMILES: C[O:2][C:3](=[O:32])[C@@H:4]([NH:7][C:8]([C:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[S:23][C:24]4[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:25]=4[N:26]=3)=[CH:17][CH:16]=2)[CH:11]=1)=[O:9])[CH2:5][OH:6]>[OH-].[Na+].CO>[F:31][C:29]1[CH:28]=[CH:27][C:25]2[N:26]=[C:22]([NH:21][C:18]3[CH:19]=[CH:20][C:15]([C:12]4[CH:11]=[C:10]([C:8]([NH:7][C@@H:4]([CH2:5][OH:6])[C:3]([OH:32])=[O:2])=[O:9])[O:14][N:13]=4)=[CH:16][CH:17]=3)[S:23][C:24]=2[CH:30]=1
Reactant: COC(=O)[C@H](CO)NC(=O)c1cc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(N[C@@H](CO)C(=O)O)c1cc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)no1
Yield: 53 %

Procedure:
(S)-2-({3-[4-(6-Fluoro-benzothiazol-2-ylamino)-phenyl]-isoxazole-5-carbonyl}-amino)-3-hydroxyl-propionic acid methyl ester was hydrolyzed by IN NaOH in MeOH to obtain the title compound in 53% yield. Mass (ES−): 443 (M++1); IR (KBr): 3435 (br), 3306, 171718, 1683, 1609, 1590, 1571 (br), 1439; 1H NMR (DMSO-d6) δ: 3.83 (m, 2H), 4.47 (m, 1H), 7.20 (m, 1H), 7.66 (m, 1H), 7.73 (s, 1H), 7.78 (m, 1H), 7.94 (br, 4H), 8.95 (d, 1H), 10.89 (br, COOH).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:18][Cl:19])=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8](=O)[NH:9]2)=[CH:4][C:3]=1[O:20][CH3:21].P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:8]1[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]([CH2:18][Cl:19])[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([O:20][CH3:21])[CH:4]=2)[N:9]=1
Reactant: CCOC(=O)c1c(CCl)c2cc(OC)c(Cl)cc2[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(Cl)nc2cc(Cl)c(OC)cc2c1CCl
Reaction time: 0.5 h

Procedure:
A suspension of ethyl 7-chloro-4-(chloromethyl)-6-methoxy-2-oxo-1,2-dihydro-3-quinolinecarboxylate (116.7 g, 50 mmol) in phosphoryl chloride (100 ml) is heated to reflux for 6 hours. The phosphoryl chloride is distilled off. The residue is taken up in water and agitation is carried out for 30 min. The precipitate is filtered out and washed with water until neutrality. The precipitate is taken up in dichloromethane and with a saturated solution of sodium chloride. After filtering through a bed of celite the filtrate is decanted. The organic phase is washed again with a saturated solution of sodium chloride, followed by drying over magnesium sulphate, filtering and evaporating under reduced pressure. 15.88 g of a brown oil is obtained.
Reaction SMILES: C(NCC(O)=O)(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.NC1C=C([N+]([O-])=O)C=CC=1C(C1C=CC=CC=1)=O.[NH2:41][C:42]1[CH:61]=[CH:60][C:45]2[N:46]([CH3:59])[C:47](=[O:58])[CH:48](C)[N:49]=[C:50]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:44]=2[CH:43]=1>>[NH2:41][C:42]1[CH:61]=[CH:60][C:45]2[N:46]([CH3:59])[C:47](=[O:58])[CH2:48][N:49]=[C:50]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:44]=2[CH:43]=1
Reactant: CC1N=C(c2ccccc2)c2cc(N)ccc2N(C)C1=O
Agent: Nc1cc([N+](=O)[O-])ccc1C(=O)c1ccccc1
Agent: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Product: CN1C(=O)CN=C(c2ccccc2)c2cc(N)ccc21

Procedure:
This compound was prepared from Fmoc-glycine and 2-amino-4-nitro-benzophenone using the same procedure used for the enantiomers of 7-amino-1,3-dimethyl-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one. Chemical and physical characteristics of the intermediate and final compounds are reported:
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([CH:12]3[CH2:14][CH2:13]3)[O:11][C:7]=2[C:6]([F:15])=[C:5]([NH:16]C(=O)OC(C)(C)C)[C:4]=1[CH3:24])#[N:2].FC(F)(F)C(O)=O>ClCCl>[NH2:16][C:5]1[C:6]([F:15])=[C:7]2[O:11][C:10]([CH:12]3[CH2:13][CH2:14]3)=[N:9][C:8]2=[C:3]([C:1]#[N:2])[C:4]=1[CH3:24]
Reactant: Cc1c(NC(=O)OC(C)(C)C)c(F)c2oc(C3CC3)nc2c1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(N)c(F)c2oc(C3CC3)nc2c1C#N
Reaction time: 6 h
Yield: 97.3 %

Procedure:
tert-Butyl (4-cyano-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazol-6-yl)carbamate (I-319) (40 mg, 0.12 mmol) was dissolved in dichloromethane (1 ml), then at room temperature, trifluoroacetic acid (1 ml) was added. The solution was stirred at the same temperature for 6 hours, then the solvent was evaporated away under reduced pressure, and the residue was fractionated with dichloromethane and an aqueous saturated sodium hydrogencarbonate solution. The aqueous layer was further extracted twice with dichloromethane. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, then the solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, n-hexane:ethyl acetate=2:1, v/v) to obtain the entitled compound (27 mg, 97%) as a pale brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:20]=[CH:21][CH:22]=2)[CH:4]=[C:5]([O:9]CC2C=CC=CC=2)[C:6](=[O:8])[CH:7]=1>CCO.[Pd]>[NH2:1][C:2]1[N:3]([C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:20]=[CH:21][CH:22]=2)[CH:4]=[C:5]([OH:9])[C:6](=[O:8])[CH:7]=1
Reactant: Nc1cc(=O)c(OCc2ccccc2)cn1-c1cccc(-c2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(=O)c(O)cn1-c1cccc(-c2ccccc2)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of 2-amino-5-(benzyloxy)-1-(biphenyl-3-yl)pyridin-4(1H)-one (2.65 g, 7.19 mmol) and 10% Pd/C (230 mg) in EtOH (300 mL) was stirred under an ¾ balloon for 2 h. After this time, LCMS indicated that the reaction was complete. After evacuation and purge with N2 (3), the EtOH solution was warmed to 50° C. and stirred 1 h at 50° C. The warmed EtOH solution was filtered and the catalyst was washed with warmed EtOH (4×50 mL). The combined EtOH solution was concentrated to give 2-amino-1-(biphenyl-3-yl)-5-hydiOxypyridin-4(1H)-one as slightly yellow solid. ′H NMR (500 MHz, DMSO): δ 7.81 (d, J−7.9 Hz, 1H); 7.76 (d, J=7.7 Hz, 2H); 7.71-7.59 (m, 2H); 7.49 (t, J=7.6 Hz, 2H); 7.43-7.37 (m, 2H); 6.91 (s, 1H); 5.66 (s, 2H); 5.54 (s, 1H). HRMS Calcd for (Ci7H14N202+H)+ 279.1 128. found 279.1 128.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([C@@H:31]([OH:39])[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:27][CH:26]=1.N1C=CC=CC=1>ClCCl>[F:24][C:25]1[CH:26]=[CH:27][C:28]([C@@H:31]([O:39][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:29][CH:30]=1
Reactant: COC(=O)CCC[C@H](O)c1ccc(F)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CCC[C@H](OC1CCCCO1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4.23 ml (45 mmol) of 97% pure 3,4-dihydro-2H-pyran, followed by 762 mg (3.0 mmol) of pyridinium p-toluenesulfonate are added to a solution of 6.80 g (25.8 mmol) of methyl 5-(4-fluorophenyl)-5-(S)-hydroxypentanoate with a purity of 86 area % in 210 ml of dichloromethane in a 2-neck round-bottom flask with magnetic stirrer under nitrogen. The reaction mixture is stirred at room temperature for 24 h. HPLC analysis (system as in Example 5) shows besides pyridine (tret 4.8 min.) and 1.5 area % precursor (tret 9.8 min.), the product in the form of two diastereomers (ratio about 1:1, tret 14.1 and 14.4 min.). The reaction solution is concentrated to 70 ml in vacuo, diluted with 100 ml of diethyl ether and washed with 1×100 ml and 2×50 ml of water. The organic phase was concentrated in vacuo and the residue was dried under HV. 9.70 g of a pale yellowish oil which, according to HPLC, has a purity of 76 area % are obtained. Yield: 23.75 mmol, 92% of theory.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[C:20]([CH3:22])[C:19]([CH3:23])=[CH:18][C:17]=3[C:24](=[O:26])[CH3:25])=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:28][O:27][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:5]=1[O:4][CH2:3][CH2:2][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)[N:12]=[CH:11][CH:10]=[C:9]2[O:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([CH3:23])=[CH:18][C:17]=1[C:24](=[O:26])[CH3:25]
Reactant: C1COCCN1
Reactant: COc1cc2c(Oc3cc(C)c(C)cc3C(C)=O)ccnc2cc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(C)cc3C(C)=O)ccnc2cc1OCCN1CCOCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
1-{2-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-4,5-dimethyl-phenyl}-ethanone (compound 315) (52 mg), morpholine (34 mg), and potassium carbonate (90 mg) were suspended in N,N-dimethylformamide (2 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (18 mg, 31%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH4-].[Na+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH:16]2[CH:11]([CH2:12][N:13]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2cnccc21
Reactant: BrCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC2CN(Cc3ccccc3)CCC21
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
To a solution of 2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (1.0 g, 4.2 mmol) in acetonitrile (20 mL) was added benzyl bromide and the mixture heated at reflux for 2.5 h. The reaction mixture was concentrated in vacuo and the resultant black oil was dissolved in MeOH (50 mL). To this solution was slowly added sodium borohydride (1.2 g, 32.0 mmol) over 10 min, then the mixture was heated at reflux for 2.5 h. After cooling to RT, the reaction mixture was concentrated in vacuo before EtOAc and an aqueous saturated solution of ammonium chloride were added. The reaction mixture was stirred at RT for 1 h. The organic layer was isolated, dried (Na2SO4) and concentrated in vacuo to give the title compound as a cream solid (0.78 g, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[C:23]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:32]#[N:33])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[CH3:34][N:35]([CH3:40])[CH2:36][CH2:37][CH2:38][OH:39]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:39][CH2:38][CH2:37][CH2:36][N:35]([CH3:40])[CH3:34])=[C:23]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:32]#[N:33])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: COCCOc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F
Reactant: CN(C)CCCO
Product: COCCOc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1OCCCN(C)C

Procedure:
Following the procedure of Example 19, 4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-fluoro-6-(2-methoxyethoxy)-3-quinolinecarbonitrile (300 mg, 0.62 mmol) and 2 mL of 3-dimethylamino-1-propanol provides 115 mg of 4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-[3-(dimethylamino)propoxy]-6-(2-methoxyethoxy)-3-quinolinecarbonitrile, mp 194-203° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH2:5]O.[NH:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.O>O1CCOCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH2:5][C:15]1[NH:14][CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1cc(CO)cc(O)c1O
Reactant: c1cc[nH]c1
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1cc(Cc2ccc[nH]2)cc(O)c1O
Temperature: 100 °C

Procedure:
A solution containing 1.0 g of 3,4-dihydroxy-5-nitrobenzyl alcohol and 5.0 ml of pyrrole in 3.0 ml of dioxane was heated for 5 h at 100° C. Water was added and the solution was extracted with dichloromethane. The solvent was evaporated and the residue was purified in a silicagel column using toluene-acetic acid-dioxane (18:1:1) mixture as an eluent. Yield 0.42 g (33%), m.p. 115°-118° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[NH4+]>COCCOC>[CH2:13]([O:12][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([Br:3])=[CH:5][CH:6]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: OCCc1ccc(Br)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: COCCOC
Product: Brc1ccc(CCOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of sodium hydride (60%, 1.09 g) in 1,2-dimethoxyethane (25 mL) was added 2-(4-bromophenyl)ethanol (5 g) under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added benzyl bromide (3.25 mL), and the mixture was stirred at 80° C. overnight. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane-n-hexane/ethyl acetate=50/1-20/1) to give the title compound (6.8 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2.[CH2:17]([SH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([S:24][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1CCc2cc(OCCCBr)ccc2N1
Reactant: SCc1ccccc1
Product: O=C1CCc2cc(OCCCSCc3ccccc3)ccc2N1

Procedure:
Prepared analogous to Example 122 from 6-(3-bromo-propoxy)-3,4-dihydro-carbostyril (m.p.: 142°-147° C.) and benzyl-mercaptan.