Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:27]1[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][C:28]=1[O:38][CH3:39].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][C:27]2[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][C:28]=2[O:38][CH3:39])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCC2CCN(C(=O)OC(C)(C)C)CC2)c(OC)c1
Temperature: 95 °C
Reaction time: 2.5 h
Yield: 89 %

Procedure:
1-(tert-Butoxycarbonyl)-4-(4-methylphenylsulphonyloxymethyl)piperidine (40 g, 0.11 mol), (prepared as described for the starting material in Example 1), was added to a suspension of ethyl 4-hydroxy-3-methoxybenzoate (19.6 g, 0.1 mol) and potassium carbonate (28 g, 0.2 mol) in dry DMF (200 ml). After stirring at 95° C. for 2.5 hours, the mixture was cooled to ambient temperature and partitioned between water and ethyl acetate/ether. The organic layer was washed with water, brine, dried (MgSO4) and evaporated. The resulting oil was crystallised from petroleum ether and the suspension was stored overnight at 5° C. The solid was collected by filtration, washed with petroleum ether and dried under vacuum to give ethyl 4-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-3-methoxybenzoate (35 g, 89%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[C:11]1([C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][N:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O>[C:11]1([C:17]2[CH:22]=[CH:21][C:20]([C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][CH:5]=3)=[CH:19][N:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1ccccc1B(O)O
Reactant: Brc1ccc(-c2ccccc2)nc1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(-c2ccc(-c3ccccc3)nc2)c1
Yield: 77.5 %

Procedure:
2-methylphenyl boronic acid (5.1 g, 37.59 mmol), 2-phenyl-5-bromopyridine (8.0 g, 34.17 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (561 mg, 1.366 mmol), and potassium phosphate tribasic (23.50 g, 102.51 mmol), 250 mL of toluene and 25 mL of water were placed in a 1 L round-bottom flask. Nitrogen was bubbled directly into the mixture for 30 min after which tris(dibenzylideneacetone)dipalladium(0) (312 mg, 0.341 mmol) was added. Nitrogen was then bubbled for another 15 minutes and the reaction mixture was heated to reflux for 16 h under nitrogen. The mixture was cooled and the organic layer was separated from the aqueous layer. The organic layer was washed with saturated brine solution, dried over magnesium sulfate, filtered, and the solvent removed under vacuum to give an off-white solid as the crude. The crude was purified by column chromatography using silica gel as the stationary phase and 2% ethyl acetate in hexanes as the mobile phase. 6.5 g of desired product was obtained after purification (78% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:18]2[S:22][C:21]([C:23]3([O:27][CH2:28][O:29][CH3:30])[CH2:26][CH2:25][CH2:24]3)=[N:20][CH:19]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH3:31][N:32]([CH3:37])[CH2:33][C:34](O)=[O:35].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:18]2[S:22][C:21]([C:23]3([O:27][CH2:28][O:29][CH3:30])[CH2:24][CH2:25][CH2:26]3)=[N:20][CH:19]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([NH:15][C:34](=[O:35])[CH2:33][N:32]([CH3:37])[CH3:31])=[CH:16][CH:17]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN(C)CC(=O)O
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5ccc(N)cc5)cc34)s2)CCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5ccc(NC(=O)CN(C)C)cc5)cc34)s2)CCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 4-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)aniline (Example 23B) (20 mg, 0.045 mmol) and dimethyl glycine (5.61 mg, 0.054 mmol) in N,N-dimethylformamide (0.5 mL) was treated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (10.43 mg, 0.054 mmol), and 1-hydroxybenzotriazole hydrate (8.34 mg, 0.054 mmol). The reaction was stirred for 4 hours at ambient temperature. The reaction was treated with 4-(dimethylamino)pyridine (5.50 mg, 0.045 mmol), and the reaction was stirred 4 hours at ambient temperature. The reaction was diluted with ethyl acetate and washed with water, saturated sodium bicarbonate solution, and brine. The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 2 to 10% methanol in dichloromethane, to give the title compound. MS ESI(+) m/z 526.0 [M+H]+.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:7]=[C:8]([OH:16])[C:9]([CH3:15])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12].[CH3:17]O>>[Cl:5][C:6]1[CH:7]=[C:8]([OH:16])[C:9]([CH3:15])=[C:10]([CH:14]=1)[C:11]([O:13][CH3:17])=[O:12]
Reactant: Cc1c(O)cc(Cl)cc1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Cl)cc(O)c1C
Temperature: 25 °C
Yield: 64.7 %

Procedure:
To cold (0° C. ice bath) methanol (200 mL) with stirring was added drop-wise thionyl chloride (12 mL, 164 mmol). The reaction was maintained for 15 minutes, at which time 5-chloro-3-hydroxy-2-methylbenzoic acid (6.5 g, 34.8 mmol) was added. The reaction was allowed to warm to room temperature and maintained overnight. The reaction was evaporated to dryness under vacuum and the residue was purified by silica gel chromatography (Analogix, SF40-150 g, 50 to 100% CH2Cl2 in hexanes). An overlap fraction containing a close faster running impurity was combined and repurified to give more pure product. The combined pure fractions were evaporated to dryness to give methyl 5-chloro-3-hydroxy-2-methylbenzoate (4.52 g, 22.53 mmol, 64.7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 7.18 (d, J=2.02 Hz, 1H), 7.01 (d, J=2.27 Hz, 1H), 3.82 (s, 3H), 2.25 (s, 3H). MS(ES) [M+H]+ 201.0.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:6])=[O:5].[CH2:11](O)[CH3:12]>>[C:4]([O:6][CH2:11][CH3:12])(=[O:5])/[CH:3]=[CH:2]\[C:1]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)/C=C\C(=O)[O-]
Reactant: CCO
Product: CCOC(=O)/C=C\C(=O)OCC

Procedure:
The column reactor of Example 1 was used to investigate the esterification of monoethyl maleate (MEM) with ethanol (EtOH) to form diethyl maleate (DEM). The resin loadings of the trays were the same as in Example 3. The acid feed to tray No. 2 had the following composition in mole %: H2O 25.9; EtOH 20.3; DEM 10.4; diethyl fumarate (DEF) <0.1; MEM 39.4; monoethyl fumarate (MEF) 0.1; maleic acid (MAC) 3.9; fumaric acid (FAC) <0.1; diethyl ethoxysuccinate (EDES) <0.1. A wet ethanol replaced the dry methanol used in Examples 1 to 3; this had the following composition in mole %: EtOH 84.2; H2O 15.8. The residence time in the column reactor was approximately 2.7 hours. The feed rates were 680 g/hr acid feed and 390 g/hr EtOH. The results are shown in Table IV.
Reaction SMILES: [CH:1]([CH:19]1[CH2:24][C:23](=[O:25])[NH:22][C:20]1=[O:21])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C=O.[C:28](=O)(O)[O-:29].[Na+].Cl>O.CCCCCCC>[OH:29][CH2:28][N:22]1[C:23](=[O:25])[CH2:24][CH:19]([CH:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:20]1=[O:21]
Reactant: CCCCCCCCCCCCCCCCC=CC1CC(=O)NC1=O
Reactant: O=C([O-])O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCCCCCC
Product: CCCCCCCCCCCCCCCCC=CC1CC(=O)N(CO)C1=O
Temperature: 70 °C

Procedure:
In a reaction vessel was placed 1 liter of heptane and 550 gms of octadecenyl succinimide. The mixture was heated to 70° C. with stirring and a mixture of 137 gms of 36% aqueous formaldehyde and 22 gms of sodium bicarbonate was added. This mixture was stirred at reflux for 4 hours. Then 300 ml of water was added and the mixture neutralized with hydrochloric acid. The aqueous layer was separated and removed, then 500 ml butanol was added to the organic layer and the mixture washed with hot water. The organic layer was separated and heptane, butanol and residual water distilled off leaving as the product N-hydroxymethyl-n-octadecenyl succinimide.
Reaction SMILES: C1(O)CCCC1.[H-].[Na+].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]=[CH:15][N:16]=[C:17]([O:20][CH:21]3[CH2:26][CH2:25]O[CH2:23][CH2:22]3)[C:18]=2[N:19]=1>CN(C=O)C.O>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]=[CH:15][N:16]=[C:17]([O:20][CH:21]3[CH2:26][CH2:25][CH2:23][CH2:22]3)[C:18]=2[N:19]=1
Reactant: Clc1ccc2ncnc(OC3CCOCC3)c2n1
Agent: OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc2ncnc(OC3CCCC3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a solution of cyclopentanol (0.050 ml, 0.550 mmol) in DMF (2.500 ml) was added NaH (0.026 g, 55% dispersion in mineral oil, 0.600 mmol) at 0° C. The reaction mixture was stirred for 30 min. at room temperature, 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.1 g, 0.500 mmol) was added to the mixture at 0° C. After being stirred for 2 hours at room temperature, the reaction mixture was diluted with water, and extracted with EtOAc. The organic layers were dried over MgSO4 filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=5:1) to give 6-chloro-4-(cyclopentyloxy)pyrido[3,2-d]pyrimidine (0.04 g, 32%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz): δ 1.63-1.74 (2H, m), 1.86-1.96 (2H, m), 1.99-2.07 (2H, m), 2.12-2.20 (2H, m), 5.72-5.77 (1H, m), 7.72 (1H, d, J=8.8 Hz), 8.18 (1H, d, J=8.8 Hz), 8.83 (1H, s).
Reaction SMILES: C([BH3-])#N.[Na+].[Si:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26])=[CH:15][C:14]=1[CH2:27][O:28][C:29]1[CH:37]=[CH:36][C:32]([CH:33]=[N:34][OH:35])=[CH:31][CH:30]=1)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].O1CCOCC1.Cl>CO.C1COCC1>[Si:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([CH3:26])=[CH:21][CH:22]=[CH:23][C:24]=2[CH3:25])=[CH:15][C:14]=1[CH2:27][O:28][C:29]1[CH:37]=[CH:36][C:32]([CH2:33][NH:34][OH:35])=[CH:31][CH:30]=1)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]
Reactant: Cc1cccc(C)c1-c1ccc(O[Si](C)(C)C(C)(C)C)c(COc2ccc(C=NO)cc2)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cccc(C)c1-c1ccc(O[Si](C)(C)C(C)(C)C)c(COc2ccc(CNO)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Hydroxylamine hydrochloride and a sodium acetate aqueous solution were added to an ethanol solution of 4-[(4′-chloro-2′-methylbiphenyl-3-yl)methoxy]benzaldehyde, followed by stirring at room temperature for 18 hours to obtain 4-[(4-{[tert-butyl(dimethyl)silyl]oxy}-2′,6′-dimethylbiphenyl-3-yl)methoxy]benzaldehyde oxime. Sodium cyanoborohydride was added to a methanol-THF mixed solution of the resulting 4-[(4-{[tert-butyl(dimethyl)silyl]oxy}-2′,6′-dimethylbiphenyl-3-yl)methoxy]benzaldehyde oxime, and then a 4 M hydrogen chloride dioxane solution was dropwise added thereto, followed by stirring at room temperature for 1 hour to obtain N-{4-[(4-{[tert-butyl(dimethyl)silyl]oxy}-2′,6′-dimethylbiphenyl-3-yl)methoxy]benzyl)hydroxylamine.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)=[N:9][CH:10]=1)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][N:18]=1>C(#N)C>[N:11]1([C:8]2[CH:7]=[CH:6][C:5]([C:3]3[N:16]=[C:17]4[CH:22]=[CH:21][C:20]([I:23])=[CH:19][N:18]4[CH:2]=3)=[CH:10][N:9]=2)[CH:15]=[CH:14][CH:13]=[N:12]1
Reactant: O=C(CBr)c1ccc(-n2cccn2)nc1
Reactant: Nc1ccc(I)cn1
Solvent: CC#N
Product: Ic1ccc2nc(-c3ccc(-n4cccn4)nc3)cn2c1
Temperature: 100 °C
Yield: 55.3 %

Procedure:
100.0 mg (corresponding to 0.38 mmol) of 5-(2-bromoacetyl)-2-(pyrazole-1-yl)pyridine and 83.6 mg (corresponding to 0.38 mmol) of 2-amino-5-iodopyridine were dissolved in 3.8 mL of acetonitrile. The resulting solution was heated under reflux for 4 hours in an oil bath at 100° C. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered. The precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 50 mL of water and 50 mL of methanol. Then, about 50 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for an hour using an ultrasonic washing machine. Precipitates were filtered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 80.2 mg (corresponding to 0.21 mmol) of 2-[2-(pyrazole-1-yl)pyridine-5-yl]-6-iodoimidazo[1,2-a]pyridine (FIG. 5, step 3).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[CH:3]=[CH:2]1.O[N:14]=[C:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.N>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:12][N:22]=[C:15]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:14]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2occc2c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: c1cncc(-c2noc(-c3ccc4occc4c3)n2)c1

Procedure:
The title compound was prepared according to Method C using benzofuran-5-carboxylic acid (Aldrich) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 7.20 (dd, J=2.0, 1.0 Hz, 1H), 7.66 (ddd, J=7.9, 4.8, 0.8 Hz, 1H), 7.91 (dt, J=8.6, 1.0, 0.8 Hz, 1H), 8.14-8.24 (m, 2H), 8.47 (dt, J=7.9, 2.0 Hz, 1H), 8.60 (d, J=1.4 Hz, 1H), 8.82 (dd, J=4.7, 1.7 Hz, 1H), 9.28 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 264 (M+H)+.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]([F:35])[CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].I[CH3:37].[OH-].[Na+].Cl>CS(C)=O.C1COCC1.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]([F:35])[CH:22]=[C:23]4[C:27]=3[N:26]([CH3:37])[CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]
Reactant: CI
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)cc(F)cc12
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)Oc1ncc(-c2nc(-c3cc(F)cc4c(CCC(=O)O)cn(C)c34)no2)cc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Potassium hydroxide (90 mg) was added to a solution of ethyl 3-[7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-5-fluoro-1H-indol-3-yl]propanoate (D139) (189 mg) and iodomethane (0.25 mL) in DMSO (3 mL) at RT. The reaction mixture was stirred at RT for 5 hours. Then the reaction was quenched with saturated ammonium chloride, and extracted with EA for 3 times. The combined organic solution was washed with brine and dried over anhydrous sodium sulfate. The dried solution was concentrated to afford the crude product as a yellow oil. This oil was dissolved in THF (3 mL) and water (3 mL). Sodium hydroxide (40 mg) was then added to the mixture. The reaction mixture was stirred at 90° C. for 1 hour, and at RT for another 24 hours. Then 0.5 M HCl was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by MDAP to afford 3-[7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-5-fluoro-1-methyl-1H-indol-3-yl]propanoic acid (E102) (112 mg) as an off-white solid. δH (DMSO-d6, 400 MHz): 1.38 (6H, d), 2.58 (2H, t), 2.93 (2H, t), 3.62 (3H, s), 5.42-5.48 (1H, m), 7.29 (1H, s), 7.30 (1H, dd), 7.65 (1H, dd), 8.59 (1H, d), 8.96 (1H, d), 12.13 (1H, br s). δF (DMSO-d6, 376 MHz): −125.6. MS (ES): C22H20ClFN4O4 requires 458; found 459.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:10](=[O:16])[C@@H:9]([CH2:17][C:18](O)=[O:19])[O:8][C@H:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:6]=2[CH:28]=1.[Cl-].[NH4+].Cl.C([N:34]=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:10](=[O:16])[C@@H:9]([CH2:17][C:18]([NH2:34])=[O:19])[O:8][C@H:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:6]=2[CH:28]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)CN1C(=O)[C@@H](CC(=O)O)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CN1C(=O)[C@@H](CC(N)=O)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
1.0 g of trans-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid and 0.5 g of ammonium chloride were dissolved in 8 ml of dimethylformamide, and 0.46 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 0.7 ml of triethylamine were added, followed by stirring at room temperature for 30 minutes. After water was added, the solution was extracted with ethyl acetate, followed by washing with water, after which the solvent was removed and the residue was recrystallized to yield 0.75 g of a crystal.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]2[N:21]3[C:22]4[N:13]([C:14](=[O:24])[CH:15]=[CH:16][C:17]=4[CH:18]=[CH:19][C:20]3=[O:23])[CH2:12]2)[CH2:6][CH2:5]1.C(N(CC)CC)C.[S:32]1[C:40]2[CH:39]=[C:38]([CH:41]=O)[N:37]=[CH:36][C:35]=2[O:34][CH2:33]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[ClH:1].[S:32]1[C:40]2[CH:39]=[C:38]([CH2:41][NH:3][CH:4]3[CH2:5][CH2:6][N:7]([CH2:10][C@H:11]4[N:21]5[C:22]6[N:13]([C:14](=[O:24])[CH:15]=[CH:16][C:17]=6[CH:18]=[CH:19][C:20]5=[O:23])[CH2:12]4)[CH2:8][CH2:9]3)[N:37]=[CH:36][C:35]=2[O:34][CH2:33]1
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Reactant: O=Cc1cc2c(cn1)OCS2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=c1ccc2ccc(=O)n3c2n1C[C@H]3CN1CCC(NCc2cc3c(cn2)OCS3)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
A suspension of (1R)-1-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione dihydrochloride (impure product) (575 mg, 1.540 mmol) in chloroform (20 ml) and methanol (1 ml) at rt under argon was treated with triethylamine (0.644 ml, 4.62 mmol) and stirred at rt for 0.25 h. The solution was then treated with [1,3]oxathiolo[5,4-c]pyridine-6-carbaldehyde (for a synthesis see WO2004058144 Example 61) (258 mg, 1.540 mmol) and stirred for a further 0.5 h. The solution was then treated with NaBH(OAc)3 (979 mg, 4.62 mmol) and stirred at rt for 0.5 h. The reaction was then treated with saturated aqueous NaHCO3 (100 ml) and extracted with 20% methanol/DCM (3×200 ml). The combined organic extracts were dried (MgSO4), filtered, evaporated and chromatographed (0-20% methanol/DCM) to give the free base of the title compound as a light brown solid (574 mg, 1.273 mmol, 83%).
Reaction SMILES: [NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[C:15]([Br:17])=[CH:16][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1.[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23].C(O)(=O)C.CO>O>[NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([S:18]([N:24]([CH2:25][CH3:26])[CH2:22][CH3:23])(=[O:20])=[O:19])[C:15]([Br:17])=[CH:16][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: Nc1nc2c(c(=O)[nH]1)-c1cc(S(=O)(=O)Cl)c(Br)cc1CC2
Reactant: CCNCC
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CCN(CC)S(=O)(=O)c1cc2c(cc1Br)CCc1nc(N)[nH]c(=O)c1-2
Yield: 59 %

Procedure:
3-Amino-8-bromo-5,6-dihydrobenzo[f]quinazolin-1(2H)-one-9-sulfonylchloride (1.10 g, 2.8 mmole) and diethylamine(5 ml) were dissolved in water(15 ml) and heated to reflux for 30 minutes. The reaction mixture was cooled to room temperature and neutralized with dilute acetic acid. The collected precipitate was suspended in boiling methanol, the suspension allowed to cool, and the solid filtered off and dried under high vacuum to give 3-amino-8-bromo-N,N-diethyl-5,6-dihydrobenzo[f]quinazolin-1(2H)-one-9-sulfonamide (0.708 g, 59%). 1H NMR (DMSO-d6, 200 MHz) δ: 1.07 (t, J=7 Hz, 6H, ethyl CH3), 2.54-2.62 (m, 2H, Ar CH2), 2.81-2.88 (m, 2H, Ar CH2), 3.26 (q, J=7 Hz, 4H, ethyl CH2), 6.83 (br s, 2H, NH2) 7.60(s, 1H, Ar), 9.13 (s, 1H, Ar), 10.95 (br s, 1H, NH). Anal Calculated for C16H19BrN4O3S: C,44.97; H,4.48; Br,18.70; N,13.11; S,7.50. Found: C,44.90; H,4.49; Br,18.65; N,13.03; S,7.57.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.N1CCNCC1.C(Cl)(=O)C1C=CC(OC)=CC=1.Cl[CH2:35][C:36]([N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)=[O:37].N1CCOCC1.ClCC(Cl)=O>C(O)(=O)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH2:35][C:36]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[O:37])[CH2:11][CH2:10]2)=[O:8])=[CH:15][CH:16]=1
Reactant: O=C(CCl)N1CCOCC1
Reactant: COc1ccc(C(=O)N2CCNCC2)cc1
Agent: C1CNCCN1
Agent: COc1ccc(C(=O)Cl)cc1
Agent: O=C(Cl)CCl
Solvent: C1COCCN1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)N2CCN(CC(=O)N3CCOCC3)CC2)cc1

Procedure:
The N-(4-methoxybenzoyl)-piperazine used as a starting substance was obtained as a viscous oil by reacting 1 mol of piperazine with 0.5 mol of anisic acid chloride in glacial acetic acid. The chloroacetic acid morpholide used as a starting substance was obtained as a colourless oil by reacting 2 mol of morpholine with 1 mol of chloroacetyl chloride in toluene.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].[CH:12](O)(C)[CH3:13].[OH-].[Na+].C(Br)C>C1OCCOCCOCCOCCOCCOC1.O>[CH2:12]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11])[CH3:13]
Reactant: COc1cc(C=O)ccc1O
Reactant: CC(C)O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCBr
Product: CCOc1ccc(C=O)cc1OC
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 91 %

Procedure:
A 1-liter four-necked flask fitted with thermometer, mechanical stirrer, and reflux condenser was charged with 62 g 4-hydroxy-3-methoxybenzaldehyde (0.41 mol) and 400 ml isopropyl alcohol. The mixture was stirred for 20 min, and then a 120 ml water solution containing 5 g 18-crown-6 ether and 106.3 g sodium hydroxide (2.66 mol) was gradually dropped thereto using a constant pressure funnel. After dropping, the mixture was stirred for 30 min, and then heated to 60° C. At this temperature, 67.3 g ethyl bromide (0.62 mol) was introduced within 5-6 hours and the reaction was monitored with TLC. After the reaction finished, the mixture was cooled to 15° C., and 400 ml water was then added to quench the reaction. The resulting mixture was extracted three times with ether (300 ml×3). The organic layer was washed with water to pH=7, and dried with anhydrous magnesium sulfate. Part of the ether was removed by flash distillation and then large amount of petroleum ether was added to precipitate crude product. The crude product was recrystallized from diethyl ether/petroleum ether to give 67 g 4-ethoxy-3-methoxybenzaldehyde in a yield of 91%. 1H-NMR (ppm) δ: 9.87 (1H, s; —CHO); 7.31 (1H, m; 2-ArH); 7.26 (1H, m; 6-ArH); 6.86 (1H, m; 5-ArH); 3.98 (2H, q; —CH2); 3.73 (3H, s; —OCH3); 1.42 (3H, t; —CH3). MS (m/Z): 180 (M+).