Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH3:10][O:11][CH2:12][CH2:13][O:14][C:15](Cl)=[O:16].O>[OH-].[Na+]>[CH3:10][O:11][CH2:12][CH2:13][O:14][C:15]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:16]
Reactant: COCCOC(=O)Cl
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCCOC(=O)N[C@@H](CC(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.5 %

Procedure:
L-Leucine (25 g, 0.19 mol) was dissolved in a 2M aqueous sodium hydroxide solution (0.12 L), to which chloroformic acid 2-methoxyethyl ester (30 g, 0.22 mol) and a 1M aqueous sodium hydroxide solution were simultaneously and slowly added under ice-cold conditions. This solution was stirred at room temperature for 18 hours, followed by dilution with water (600 mL) and washing with diethyl ether (2×200 mL). The aqueous layer was cooled in an ice bath, and the pH was adjusted to 3 with 6M hydrochloric acid. This solution was extracted with ethyl acetate (5×150 mL). The organic layer was dehydrated with anhydrous magnesium sulfate and concentrated in vacuo to yield N-((2-methoxyethoxy)carbonyl)-L-leucine (41 g, 92%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1.[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[N:6]=[CH:5][CH:4]=[C:3]2[O:2][CH3:1]
Reactant: COc1ccnc2c(C)cccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccnc2c(CBr)cccc12

Procedure:
4-Methoxy-8-methylquinoline (346 mg, 2 mmole), N-bromosuccinimide (365 mg, 2.05 mmole) and benzoyl peroxide (10 mg) in CCl4 (8 ml) were heated under reflux for 2.5 hours. The mixture was cooled and the succinimide was filtered off. The filtrate was washed with dilute aqueous NaHCO3 (1×) and water (1×), dried (Na2SO4) and evaporated to yield the sub-title compound as a pale yellow solid which was recrystallised from petroleum ether-cyclohexane to give colourless needles.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24]([O:26]C)=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10].[Li+].[OH-].Cl>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: COC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)c1cc2c(s1)-c1ccc(C(=O)O)cc1OCC2)c1ccccc1Cl
Temperature: 50 °C

Procedure:
To a solution of methyl 2-((2-chlorophenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylate 138 (45 mg, 0.11 mmol) in 1.0 mL THF and 1.0 mL water in a 20 mL scintillation vial was added LiOH (monohydrate, 200 mg). The vessel was sealed and heated at 50° C. over night. The reaction mixture was cooled to room temperature, acidified to pH 2 with 2N HCl, and extracted with ethylacetate. The combined organic extracts were dried over Na2SO4 and concentrated to give the crude 2-((2-chlorophenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid.
Reaction SMILES: [CH2:1]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[CH2:25][CH2:26][OH:27])[CH2:2][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].Br[CH2:29][CH2:30][CH2:31][CH2:32][Cl:33].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:33][CH2:32][CH2:31][CH2:30][CH2:29][O:27][CH2:26][CH2:25][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][N:19]1[CH2:1][CH2:2][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]
Reactant: ClCCCCBr
Reactant: CCCCCCCCCCCCCCCCCCN1CCCCC1CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCN1CCCCC1CCOCCCCCl

Procedure:
2-(1-Octadecyl-2-piperidyl)ethan-1-ol and 1-bromo-4-chlorobutane are reacted in acetone in the presence of potassium carbonate at reflux temperature to obtain 2-[2-(4-chlorobutoxy)ethyl]-1-octadecylpiperidine.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:10]=[CH:9][O:8][C:7]=1[C:11](=[O:13])[CH3:12])(=[O:3])[CH3:2].[Br-:14].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[C:1]([O:4][CH2:5][C:6]1[CH:10]=[CH:9][O:8][C:7]=1[C:11](=[O:13])[CH2:12][Br:14])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1ccoc1C(C)=O
Reactant: [Br-]
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: CC(=O)OCc1ccoc1C(=O)CBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
3-Acetoxymethyl-2-acetylfuran (1.7 g, 9.3 mmol, prepared according to the procedure described in Acta. Chemica. Scandinavia, 1990, 44, 916) was dissolved in acetic acid (30 ml). To the solution was added pyridinium tribromide (3.3 g, 10.2 mmol) and the resulting mixture was stirred at room temperature for 3 h. The mixture was cooled to 0° C. and saturated aqueous sodium bicarbonate added dropwise until the solution was basic. The mixture was extracted with ethyl acetate (100 ml). The organic extract was washed with brine (100 ml), dried (MgSO4) and concentrated to give 2.3 g (95%) of the title compound. 1H-NMR (CDCl3) δ: 7.54 (1 H, d, J=1.6 Hz), 6.65 (1 H, d, J=1.6 Hz), 5.38 (2 H, s), 4.37 (2 H, s), 2.09 (3 H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][N:11](C([C@@]34C(C)(C)[C@@](C)(CC3)C(=O)O4)=O)[CH2:10][C@@H:9]2[O:27][CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[CH:4][CH:3]=1.CNC(NCCC[C@H](N)C(O)=O)=NC.C(O)(=O)C>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]2[O:27][CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)[C@@]2(C)CC[C@]1(C(=O)N1CC[C@H](c3ccc(Br)cc3)[C@@H](OCc3ccc4ccccc4c3)C1)OC2=O
Agent: CN=C(NC)NCCC[C@H](N)C(=O)O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Brc1ccc([C@H]2CCNC[C@@H]2OCc2ccc3ccccc3c2)cc1
Temperature: -40 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
A solution of 736 mg (1.28 mmol) of (3R,4R)-4-(4-bromophenyl)-3-(naphthalen-2-ylmethoxy)-1-[(1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carbonyl]-piperidine in 32 ml of absolute tetrahydrofuran was cooled to -70° C. Thereto there was added dropwise a solution of 1.86 ml (6.5 mmol) of sodium dihydrido-bis-(2-methoxyethoxy)-aluminate (70% in toluene, about 3.5M) in 32 ml of tetrahydrofuran. The mixture was warmed to -40° C., stirred at -40° C. for 8 hours, thereafter cooled to -78° C. and treated dropwise with a solution of 0.5 ml of glacial acetic acid in 10 ml of tetrahydrofuran. For the working-up, the reaction mixture was partitioned between 200 mg of ethyl acetate and 200 ml of aqueous 5% sodium hydrogen carbonate solution. The organic phase was separated and the aqueous phase was back-extracted three times with 50 ml of ethyl acetate each time. The combined organic phases were dried over magnesium sulphate and finally the solvent was distilled off under reduced pressure. The crude product (800 mg) was purified by chromatography on silica gel with a 9:1 mixture of methylene chloride and methanol as the eluent. There were obtained 344 mg (68% of theory) of (3R,4R)-4-(4-bromophenyl)-3-(naphthalen-2-ylmethoxy)-piperidine as a colourless solid; MS: 396, 398 (M+H)+.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.B(O)(O)[C:17]1[CH:22]=[CH:21][C:20]([C:23]#[CH:24])=[CH:19][CH:18]=1>>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)=[CH:18][CH:19]=1)#[CH:24]
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: C#Cc1ccc(B(O)O)cc1
Product: C#Cc1ccc(-c2c(-c3cc(C#N)ccn3)ncn2C)cc1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-(dihydroxyborophenyl)acetylene according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C18H12N4, 285. Found, 285.
Reaction SMILES: [N+:1]([C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:14][C:15](=[O:17])[CH3:16])([O-:3])=[O:2].[C:18]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:18][N:14]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([F:11])([F:12])[F:13])[C:4]=1[N+:1]([O-:3])=[O:2])[C:15](=[O:17])[CH3:16]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)Nc1cccc(C(F)(F)F)c1[N+](=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(=O)N(C)c1cccc(C(F)(F)F)c1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
N-(2-Nitro-3-trifluoromethyl-phenyl)-acetamide (Helvetica 1947, p. 107) (2.0 g) was dissolved in DMF (15 ml) prior to the addition of K2CO3 (2.07 g) and MeI (0.71 ml). After 2 h, the solution was concentrated and 1N HCl solution (aq) was added. The solution was extracted with EtOAc. The organic layer was washed with brine, dried, filtered, and concentrated. Filtration through a plug of silica of the resulting residue gave N-methyl-N-(2-nitro-3-trifluoromethyl-phenyl)-acetamide. This material (2 g) was dissolved in EtOH prior to the addition of a solution of NaOH (2 g) in H2O (2 ml). The mixture was heated to reflux for 2 h, cooled to rt, and neutralized with 1N HCl, and extracted twice with EtOAc. The organic extracts were combined, washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was dissolved in MeOH (50 ml) prior to the addition of 10% Pd/C (2.07 g). This solution was placed on a Parr apparatus under H2 (50 psi) for 2 h. The Pd/C was filtered off and the solution was concentrated. The resulting residue was dissolved in diethyl malonate. The reaction was heated at 160° C. oil bath for 45 min. After cooling to rt, flash chromatography of the crude reaction gave (1-methyl-4-trifluoromethyl-1H-benzoimidazol-2-yl)-acetic acid ethyl ester (1.05 g). A portion (200 mg) of this material was dissolved in THF (17 ml) prior to the addition of a solution of LiOH (31 mg) in H2O (6 ml). MeOH (6 ml) was added. After 2 h at rt, the reaction was concentrated and freeze-dried to provide (1-methyl-4-trifluoromethyl-1H-benzoimidazol-2-yl)-acetic acid lithium salt (189 mg). MS found: (M+H)+=259.2
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[C:13](I)[C:12]([Cl:16])=[CH:11][N:10]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]#[CH:31])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O.[Cu]I.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>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]#[C:31][C:13]2[C:12]([Cl:16])=[CH:11][N:10]=[C:9]([Cl:8])[CH:14]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: Clc1cc(I)c(Cl)cn1
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2cc(Cl)ncc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Copper(I) iodide (0.50 g), bis-(triphenylphosphine)-palladium(II) chloride (0.50 g), and triethylamine (3.4 mL) are added successively to a solution of 2,5-dichloro-4-iodo-pyridine (6.54 g) in N,N-dimethylformamide (45 mL) under Ar atmosphere at room temperature. The resulting mixture is stirred at room temperature for 1 h prior to the addition of 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (5.15 g). The mixture is stirred at 55° C. for 2 h. The solvent is evaporated and the residue is diluted with ethyl acetate. The resulting mixture is washed with water and brine, dried (Na2SO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 85:15→50:50) to give the title compound. LC (method 3): tR=1.66 min; Mass spectrum (ESI+): m/z=355/357/359 (2 Cl) [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][C:20]([N:23]([CH3:25])[CH3:24])=[CH:21][CH:22]=[C:17]3[N:16]([CH3:26])[C:15]2=[O:27])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:24][N:23]([CH3:25])[C:20]1[N:19]=[C:18]2[N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:15](=[O:27])[N:16]([CH3:26])[C:17]2=[CH:22][CH:21]=1
Reactant: CN(C)c1ccc2c(n1)n(C1CCN(C(=O)OC(C)(C)C)CC1)c(=O)n2C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1ccc2c(n1)n(C1CCNCC1)c(=O)n2C
Reaction time: 0.58 h
Yield: 96 %

Procedure:
To a stirring solution of 1.07 g (0.0028 mol) of 4-(5-dimethylamino-1-methyl-2-oxo-1,2-dihydro-imidazo[4,5-b]pyridin-3-yl)-piperidine-1-carboxylic acid tert-butyl ester in CH2Cl2 (7 mL) was added 7 mL of TFA. After 35 min, the solvent was removed. The residue was partitioned between EtOAc (200 mL) and 1 N NaOH (150 mL). The aqueous layer was extracted with EtOAc (3×100 mL) and the combined organic layers were dried over Na2SO4 and concentrated to afford 0.74 g (96%) of 5-dimethylamino-1-methyl-3-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one as a white/pink solid. 1H NMR (400 MHz, CDCl3): 6.95 (d, J=8.3 Hz, 1H), 6.08 (d, J=8.3 Hz, 1H), 4.35 (tt, J=12.1 Hz, 4.0 Hz, 1H), 3.25 (s, 3H), 3.14 (d, J=12.4 Hz, 2H) 2.97 (s, 6H), 2.66 (td, J=12.9 Hz, 1.3 Hz, 2H), 2.53 (qd, J=12.4 Hz, 4.0 Hz, 2H), 1.69 (d, J=11.9 Hz, 2H).
Reaction SMILES: CS(O[CH:6]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=1)[CH2:7][C:8]#[N:9])(=O)=O.[I-].[Na+].O.C(OCC)C>COCCOC.[Zn]>[C:18]1([C:14]2[CH:13]=[C:12]([CH2:11][CH2:10][CH:6]=[CH:7][C:8]#[N:9])[CH:17]=[CH:16][CH:15]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CS(=O)(=O)OC(CC#N)CCc1cccc(-c2ccccc2)c1
Agent: [I-]
Agent: [Na+]
Agent: [Zn]
Solvent: CCOCC
Solvent: O
Solvent: COCCOC
Product: N#CC=CCCc1cccc(-c2ccccc2)c1

Procedure:
A stirred mixture of 3.4 grams (0.010 mole) of 3-methylsulfonyloxy-5-(3-phenylphenyl)pentanenitrile, 3.4 grams (0.023 mole) of sodium iodide, 3.4 grams (0.052 mole) of zinc powder, and 3.4 mL of water in 50 mL of ethylene glycol dimethyl ether was heated at reflux for about 22 hours. The reaction mixture was cooled, and 150 mL of diethyl ether was added. The mixture was filtered, and the filtrate was washed in succession with water, an aqueous 5% hydrochloric acid solution, an aqueous 5% sodium bicarbonate solution, an aqueous 5% sodium bicarbonate solution, an aqueous 5% sodium thiosulfate solution, and finally with water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. NMR analysis of the residual oil indicated that it was impure. The oil was dissolved in 10:1 petroleum ether and diethyl ether, and the solution was passed through a column of silica gel. Early fractions of eluate were combined and concentrated under reduced pressure, yielding an intermediate product, 5-(3-phenylphenyl)-2-pentenenitrile. Later fractions of the eluate were combined and concentrated under reduced pressure, yielding the intended product, 5-(3-phenylphenyl)pentanenitrile. The intermediate was hydrogenated in a manner analogous to that of Example 3, Step B, yielding an additional amount of 5-(3-phenylphenyl)pentanenitrile. All samples of the pentanenitrile were combined, yielding 1.4 grams of that product. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: O1CCCC1.Br[C:7]1[CH:16]=[N:15][C:10]2[O:11][CH2:12][CH2:13][NH:14][C:9]=2[CH:8]=1.[CH3:17][O:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:17][O:18][C:19]1[CH:24]=[C:23]([C:7]2[CH:16]=[N:15][C:10]3[O:11][CH2:12][CH2:13][NH:14][C:9]=3[CH:8]=2)[CH:22]=[N:21][CH:20]=1
Reactant: Brc1cnc2c(c1)NCCO2
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cncc(-c2cnc3c(c2)NCCO3)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To 3 ml of tetrahydrofuran/0.5 ml of distilled water, 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (80.0 mg, 0.37 mmol), 3-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolane-2-yl)-pyridine (105 mg, 0.45 mmol), potassium carbonate (103 mg, 0.74 mmol) and tetrakis triphenylphosphine palladium (129 mg, 0.11 mmol) were added and stirred at 80° C. for 4 hours. After completion of the reaction, the mixture was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on amine silica eluting with a solvent of dichloromethane:methanol=40:1. The fractions containing the product were collected and evaporated to obtain 7-(5-methoxy-pyridin-3-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine as white solid (72 mg, 80%).
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][O:7][C:8]2[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=2[CH2:10][CH2:11][NH:12][CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.Br[CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].C(=O)(O)[O-].[Na+].O>C(#N)C>[Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][O:7][C:8]2[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=2[CH2:10][CH2:11][N:12]([CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)[CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(CNCCc2ccccc2OCc2ccc(Br)cc2)cc1
Reactant: CCOC(=O)CCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CCCCN(CCc1ccccc1OCc1ccc(Br)cc1)Cc1ccc(C(=O)OC)cc1

Procedure:
5.00 g (11.0 mmol) of methyl 4-[({2-[(4-bromobenzyl)oxy]phenethyl}amino)-methyl]benzoate from Ex. VIII, 2.30 g (11.0 mmol) of ethyl 5-bromovalerate and 1.109 g (13.21 mmol) of sodium bicarbonate in 30 ml of acetonitrile are heated at reflux for 18 hours. The reaction mixture is admixed with water and extracted with methylene chloride. The organic phase is washed with saturated sodium chloride solution and dried over magnesium sulphate and the solvent is distilled off under reduced pressure. The residue is purified by chromatography over silica gel using the mobile phase methylene chloride/methanol 100/1.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]/[C:16]([O:18]C)=[O:17])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+]>CO>[C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COC(=O)/C=C/CCCCCNC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCCC/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.2 %

Procedure:
A solution of 10.7 g (39.4 mmoles) of (8) in 30 mL methanol was chilled in an ice bath and 59 mL of 1N sodium hydroxide was added. The ice bath was removed and the mixture was stirred at room temperature for 20 h. After evaporation of most of the methanol, the solution was acidified to pH 3 with 1N potassium bisulfate. The mixture was extracted with ether, and washed with water and brine. After drying over sodium sulfate and removal of solvent in vacuo, the residue was crystallized from ether - hexane to provide 9.55 g of the title compound (9), mp 76°-78° C. Anal. Calcd. for C13H23NO4 : C, 60.68; H, 9.01; N, 5.44. Found: C, 60.50; H, 9:00; N, 5.40.
Reaction SMILES: [NH2:1][C:2]1[NH:7][CH2:6][C:5]2=[C:8]([CH3:14])[N:9]=[C:10]([CH2:11][CH2:12][CH3:13])[N:4]2[N:3]=1.[C:15]([Cl:18])(=[O:17])[CH3:16]>C(O)(=O)C>[ClH:18].[CH3:14][C:8]1[N:9]=[C:10]([CH2:11][CH2:12][CH3:13])[N:4]2[C:5]=1[CH2:6][NH:7][C:2]([NH:1][C:15](=[O:17])[CH3:16])=[N:3]2
Reactant: CC(=O)Cl
Reactant: CCCc1nc(C)c2n1N=C(N)NC2
Solvent: CC(=O)O
Product: CCCc1nc(C)c2n1N=C(NC(C)=O)NC2
Product: Cl

Procedure:
2-Amino-3,4-dihydro-5-methyl-7-propylimidazo[ 5,1-f]-as-triazine (Example 1a) (1.9 g.) and acetyl chloride (1.8 g.) in acetic acid (20 ml., glacial) were heated at 100° for 3 hours. The solution was evaporated under reduced pressure and the residue was crystallised from a mixture of ethanol and ethyl acetate to give a white solid m.p. 302°.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:12])[CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[Cl:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1.[OH-].[Na+]>C(O)C>[Cl:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:2][CH:3]([OH:12])[CH2:4][CH2:5][C:6]3[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=3)=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: Oc1ccc(-c2cccc(Cl)c2)cc1
Reactant: OC(CCl)CCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OC(CCc1cccnc1)COc1ccc(-c2cccc(Cl)c2)cc1

Procedure:
Prepared according to the method described in Example 24b) from (±)-α-(chloromethyl)-3-pyridinepropanol (1.0 g), 3'-chlorobiphenyl-4-ol (1.4 g), ethanol (30 ml) and aqueous sodium hydroxide (1.5 M, 5 ml) to give the title compound after purification as a white solid (0.34 g).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[OH:28][C@@H:29]([CH2:42][NH2:43])[CH2:30][O:31][C:32]1[C:40]2[NH:39][C:38](=[O:41])[NH:37][C:36]=2[CH:35]=[CH:34][CH:33]=1>>[OH:28][C@H:29]([CH2:30][O:31][C:32]1[C:40]2[NH:39][C:38](=[O:41])[NH:37][C:36]=2[CH:35]=[CH:34][CH:33]=1)[CH2:42][NH:43][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=3)(=[O:16])=[O:17])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidine-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S. Pat. No. 5,786,356/1998) according to the procedure of Example 255 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.60-1.80 (m, 2H), 2.00-2.15 (m, 2H), 2.06 (s, 3H), 2.50-2.70 (m, 2H), 2.90-3.20 (m, 3H), 3.60-3.75 (m, 2H), 4.15-4.25 (m, 1H), 5.70 (brs, 1H), 6.61 (t, J=8.7 Hz, 1H), 6.80-6.92 (m, 5H), 7.60 (d, J=9.0 Hz, 2H), 7.70 (d, J=9.0 Hz, 2H), 9.72 (brs, 1H), 10.42 (s, 1H), 10.65 (s, 1H), 10.80 (s, 1); MS (ES) m/z: 595.2 (MH+); HRMS Calcd. for C29H35N6O6S(MH+): 595.2339. Found: 595.2332.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=2)[CH2:9][CH3:10])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=2)[CH2:9][CH3:10])=[CH:6][CH:7]=1
Reactant: CCN(CCCOc1ccc(C(=O)OC)cc1)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCN(CCCOc1ccc(C(=O)O)cc1)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 13 h
Yield: 91.3 %

Procedure:
Methyl 4-[3-[N-(4-chlorophenyl)-N-ethylamino]propoxy]benzoate (1.37 g) was dissolved in methanol (20 ml), and a solution of sodium hydroxide (0.48 ml) in water (5 ml) was added thereto, the mixture was heated with stirring at 60° C. for 13 hours. The reaction mixture was cooled, and was added a neutralization amount of conc. hydrochloric acid thereto, then the mixture was concentrated under reduced pressure. The residue was suspended in water, and collected by filtration, and washed with water to give the desired product (1.20 g). mp. 146°-149° C.