Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([CH3:21])[C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH:2]([CH3:21])[C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:25][CH2:24]1
Reactant: CN1CCNCC1
Reactant: CC(Cl)C(=O)N1c2ccccc2C(=O)Nc2cccnc21
Product: CC(C(=O)N1c2ccccc2C(=O)Nc2cccnc21)N1CCN(C)CC1
Yield: 49 %

Procedure:
Using the procedure of Example 5, the product of Step A was reacted with 1-methyl-piperazine to obtain a 49% yield of 5,11-dihydro-11-[2-(4-methyl-1-piperazinyl)-propionyl]-6-H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one which melted at 223°-224° C. after crystallization from ethyl acetate.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:14])=[CH:10][C:11]=2[Cl:13])[CH2:6][CH2:5]1)(=O)C.[OH-].[K+]>C(O)C.O>[Br:14][C:9]1[CH:8]=[C:7]2[C:12](=[C:11]([Cl:13])[CH:10]=1)[NH:4][CH2:5][CH2:6]2
Reactant: CC(=O)N1CCc2cc(Br)cc(Cl)c21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Clc1cc(Br)cc2c1NCC2
Yield: 87.8 %

Procedure:
1-acetyl-5-bromo-7-chloroindoline (1.17 g) was dissolved in a mixture of ethanol (15 mL) and water (8 mL) containing KOH (0.5 g) and heated to reflux for 2 h. The reaction was partitioned between EtOAc (100 mL) and water (20 mL). The organic extract was washed with brine (20 mL), dried and stripped in vacuo to give 5-bromo-7-chloroindoline (0.87 g).
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[OH:22])=[C:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].[C:23]([O:30][CH2:31][C:32](Cl)=[O:33])(=[O:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:32](=[O:33])[CH2:31][O:30][C:23](=[O:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3CC[C@]2(C)[C@H]1O
Reactant: CCCCCC(=O)OCC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCCC(=O)OCC(=O)O[C@H]1[C@@H](CC)C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3CC[C@@]21C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 20 ml of toluene are dissolved 1.5 g of 16β-ethyl-17β-hydroxy-4,9(10)-estradien-3-one and 1.92 g of 4-dimethylaminopyridine, and 1.6 ml of n-hexanoyloxyacetyl chloride is added. The mixture is stirred at 50°-60° C. for 3 hours. After cooling to 25° C., the mixture is poured into a mixture of ethyl acetate (200 ml) and saturated aqueous sodium hydrogen carbonate (50 ml). The organic layer is separated and the aqueous layer is extracted with ethyl acetate. These organic layers are combined, washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is chromatographed on a silica gel column. Following passage of diisopropyl ether-n-hexane (1:1), elution is carried out with 1000 ml of a 3:2 mixture of the same solvents. The eluate is evaporated under reduced pressure to remove the solvent, giving 1.69 g of the above-identified compound as a light-yellow viscous oil.
Reaction SMILES: [C:1]([O:13][CH3:14])(=[O:12])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(O)[CH2:16][CH2:17][CH2:18][CH3:19]>CCCCO.CCCCO.CCCCO.CCCCO.[Ti].CO>[C:6]([O:8][CH2:9][CH2:19][CH2:18][CH2:17][CH3:16])(=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([C:1]([O:13][CH2:14][CH2:1][CH2:2][CH2:3][CH3:4])=[O:12])=[CH:3][CH:4]=1
Reactant: CCCCCO
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Agent: [Ti]
Solvent: CO
Solvent: CCCCO
Product: CCCCCOC(=O)c1ccc(C(=O)OCCCCC)cc1
Reaction time: 0.5 h

Procedure:
A 2-liter multineck flask with distillation bridge and reflux divider, 20 cm packed column, stirrer, dip tube, dropping funnel, and thermometer was charged with 679 g (3.5 mol) of dimethyl terephthalate (Oxxynova), 1.7 g of tetrabutyl orthotitanate (0.25% by mass based on DMT, DuPont, Tyzor TnBT) and, to start with, 200 g out of a total of 748 g (8.5 mol) of n-pentanol (>99% purity, FLUKA), and this initial charge was heated slowly until the DMT forms a homogeneous mixture with the alcohol, at which point the stirrer was switched on. The reflux divider was set so that the overhead temperature remained at a constant level of approximately 65° C. (the boiling point of methanol). From a liquid-phase temperature of approximately 185° C., the remaining alcohol was slowly run in at a rate such that the temperature in the flask did not fall below 180° C. and a reflux sufficient for the distillation was maintained. The distillate removed was analyzed by GC for the amount of methanol separated off. After a major fraction of the methanol (approximately 90% of the anticipated 7 mol of methanol) had been taken off, a sample was taken from the reaction flask every 30 minutes and analyzed by GC. Transesterification was at an end when the amount of dimethyl ester and mixed ester(methyl pentyl) in total had dropped below 0.3% by mass (approximately 8 to 9 hours).
Reaction SMILES: [C:1]([C:6]1[C:18]([CH3:19])=[CH:17][C:9]2[N:10]([CH3:16])[C:11]([C:13]([O-:15])=[O:14])=[N:12][C:8]=2[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[C:20](#N)[CH3:21].C(N(CC)CC)C.C(OC(OCC)=O)(=O)OCC>C(OCC)(=O)C>[C:1]([C:6]1[C:18]([CH3:19])=[CH:17][C:9]2[N:10]([CH3:16])[C:11]([C:13]([O:15][CH2:20][CH3:21])=[O:14])=[N:12][C:8]=2[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CC#N
Reactant: CCCC(=O)c1cc2nc(C(=O)[O-])n(C)c2cc1C
Agent: CCOC(=O)OC(=O)OCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCC(=O)c1cc2nc(C(=O)OCC)n(C)c2cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.0 g of 5-butyryl-1,6-dimethyl-benzimidazole-2-carboxylate acid are introduced, in the course of 15 minutes, into a mixture of 150 ml of acetonitrile, 15 ml of triethylamine and 18.5 g of diethyl pyrocarbonate, while stirring at room temperature. The mixture is left to stand overnight, the acetonitrile is stripped off under reduced pressure, the residue is taken up in ethyl acetate and the resulting solution is washed with water, dried over sodium sulphate and evaporated to dryness. Ethyl 5-butyryl-1,6-dimethyl-benzimidazole-2-carboxylate, which is initially obtained as an oil but soon crystallises, is filtered off. When recrystallised from ethyl acetate/cyclohexane, it melts at 106°-108°.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[C:10]([Cl:21])[CH:9]=1)(C)(C)C.O.C([O-])(O)=O.[Na+]>Cl.O1CCOCC1>[Cl:21][C:10]1[CH:9]=[C:8]([NH2:7])[CH:13]=[CH:12][C:11]=1[N:14]1[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]1
Reactant: CN1CCN(c2ccc(NC(=O)OC(C)(C)C)cc2Cl)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN1CCN(c2ccc(N)cc2Cl)CC1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
298 mg (0.92 mmol) of [3-chloro-4-(4-methyl-piperazin-1-yl)-phenyl]-carbamic acid tert-butyl ester (Example 65b) are dissolved in 5 ml of 4 N HCl in dioxane. The solution is stirred for 4 h at 50° C., and after this time water is added and the pH is adjusted to 8 with NaHCO3. The suspension is extracted with n-butanol. The organic phase is washed with water, dried over MgSO4 and evaporated to dryness to provide the title compound. Title compound: ES-MS: 226.2 (M+H)+; analytical HPLC: tret=3.09 minutes (Grad 2).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].Br[CH2:15][CH2:16][CH2:17][OH:18].C(=O)([O-])[O-].[K+:23].[K+].C1OCCOCCOCCOCCOCCOC1.[I-].[K+].C(OC(=O)C)(=O)C>CN(C)C=O.O.C(N(CC)CC)C>[OH:18][CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:3]=[C:4]([C:11]([O-:13])=[O:12])[C:5](=[CH:9][CH:10]=1)[C:6]([O-:8])=[O:7].[K+:23].[K+:23]
Reactant: OCCCBr
Reactant: O=C(O)c1ccc(O)cc1C(=O)O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C([O-])c1ccc(OCCCO)cc1C(=O)[O-]

Procedure:
Five point zero (5.0) grams of 4-hydroxyphthalic acid and 13 g of 3-bromo-1-propanol were allowed to react in dimethylformamide while refluxing with heating in the presence of 10 g of potassium carbonate, a catalytic amount of 18-crown-6 and a catalytic amount of potassium iodide. The reaction was pursued with thin layer chromatography (TLC), heating was stopped when the reaction product became homogeneous and the temperature was lowered to room temperature. The reaction mixture was acetylated by the addition of acetic anhydride and triethylamine. Water was added to the reaction solution thereby the reaction was stopped. This mixture was extracted with ethyl acetate and the organic layer was concentrated. A methanol solution containing potassium hydroxide was added thereto and refluxed with heating, thereby white solids were formed. The solids formed were filtered, washed with ethyl acetate, and then dried, thereby 1.7 g of dipotassium 4-(3-hydroxypropoxy)-phthalate was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH:10]2[CH2:23][OH:24])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:11][CH:10]2[CH2:23][O:24][S:33]([CH3:32])(=[O:35])=[O:34])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CO)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(COS(C)(=O)=O)C1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (6RS,7SR)-7-(3,4-dichlorophenyl)-6-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (735 mg) in THF (10 ml) were added triethylamine (0.41 mL) and methanesulfonyl chloride (0.21 mL) under ice-cooling, and the mixture was stirred for 1 hr. Triethylamine (0.14 ml) and methanesulfonyl chloride (0.076 ml) were added, and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with 1 N hydrochloric acid, distilled water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (863 mg).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](=[O:13])[C:8]([O:10]CC)=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO.O>[Br:1][C:2]1[S:6][C:5]([C:7](=[O:13])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)c1ccc(Br)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C(=O)c1ccc(Br)s1
Yield: 95.2 %

Procedure:
Ethyl 2-(5-bromothien-2-yl)glyoxalate (45.6 g, 173 mmol) from Step A was dissolved in a mixture of 100 mL THF, 100 mL methanol, and 300 mL water, then treated with 10 N NaOH (26 ml, 260 mmol) at room temperature for 20 hours. Volatile solvents were removed by rotary evaporation. The residue was dissolved in 2 L water and extracted with diethyl ether (250 mL). The aqueous layer was acidified to pH 1 with 6 N HCl, and extracted with diethyl ether (3×300 mL). The combined diethyl ether extracts were dried over Na2SO4 and concentrated in vacuo to yield 2-(5-bromothien-2-yl)glyoxalic acid, Intermediate 1 (38.7 g, 95%). The product was then recrystallized from diethyl ether. m.p. 119-120° C.; MS (M−H) 235.1; 1H NMR (300 MHz, CDCl3) d 9.00 (1H, br s), 8.15 (1H, d, J=4.2 Hz), 7.16 (1H, d, J=4.2 Hz); 13C NMR (75 MHz, CDCl3) d 173.80, 159.58, 140.14, 137.17, 132.58, 130.48; IR (KBr) 3326, 3124, 1756, 1634, 1415, 1363, 1308, 1253cm−1;
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=O.Cl.N1CCCCC1.O1CCOCC1.[CH2:20]1[O:28][C:27]2[CH:26]=[CH:25][C:24]([CH2:29][CH2:30][CH:31]=[O:32])=[CH:23][C:22]=2[O:21]1>O>[OH:32][CH:31]1[O:6][C:2](=[O:5])[CH:3]=[C:30]1[CH2:29][C:24]1[CH:25]=[CH:26][C:27]2[O:28][CH2:20][O:21][C:22]=2[CH:23]=1
Reactant: O=CC(=O)O
Reactant: O=CCCc1ccc2c(c1)OCO2
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCNCC1
Solvent: O
Product: O=C1C=C(Cc2ccc3c(c2)OCO3)C(O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.5 %

Procedure:
2.5 g (0.027 mol) of glyoxylic acid hydrate 3.2 g (0.027 mol) of piperidine hydrochloride, and 30 mL of dioxane were mixed with stirring, whereupon water was added in dropwise fashion until a homogeneous solution resulted. 3-(3,4-Methylenedioxyphenyl)propionaldehyde 4.8 g, 0.027 mol) was then introduced and the solution allowed to stir at room temperature for 1 hour, then heated at reflux for 48 hours. At the end of this time the solution was concentrated, diluted with water, and extracted with EtOAc (2×100 mL). The organic layer was separated, dried (MgSO4) then concentrated to afford an oil. The crude oil was chromatographed over silica gel (150 g). Elution with 50% EtOAc-hexane afforded 1.8 g, 28% of the desired product as a light yellow oil.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15][CH2:14]2)(=O)=O)=CC=1.[CH:21]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH3:20][C:16]1([CH3:19])[O:15][CH2:14][CH:13]([CH2:12][NH:26][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:18][O:17]1
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)OC2)cc1
Reactant: NC1CCCC1
Product: CC1(C)OCC(CNC2CCCC2)CO1
Temperature: 80 °C
Yield: 93.8 %

Procedure:
A mixture of 1.5 g (5 mmol) of (2,2-dimethyl-1,3-dioxan-5-yl)methyl 4-methylbenzenesulfonate and 10 mL (101 mmol) of cyclopentylamine is heated for 12 hours at 80° C. The medium is concentrated under reduced pressure and then taken up in 200 mL of Et2O, washed with water (2×50 mL) and then dried over Na2SO4 and concentrated under reduced pressure. 1 g of N-[(2,2-dimethyl-1,3-dioxan-5-yl)methyl]cyclopentanamine is obtained in the form of an oil, which is used without further purification in the following step.
Reaction SMILES: C([N:4]([CH2:8]C)[CH:5]([CH3:7])[CH3:6])(C)C.[B:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)([OH:12])[OH:11].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(O)(=O)C(O)=O.CNC1CC1>CC#N>[CH:5]1([N:4]([CH3:8])[C:17]([C:16]2[CH:15]=[CH:14][C:13]([B:10]([OH:11])[OH:12])=[CH:21][CH:20]=2)=[O:19])[CH2:6][CH2:7]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC1CC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: CN(C(=O)c1ccc(B(O)O)cc1)C1CC1
Reaction time: 0.83 h
Yield: 71.5 %

Procedure:
N,N-Diisopropylethylamine (1.693 mL, 9.69 mmol) was added to a suspension of 4-boronobenzoic acid (321.7 mg, 1.939 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (806.4 mg, 2.121 mmol) in CH3CN (20 mL). After 50 min at room temperature, N-methylcyclopropanamine oxalic acid salt (315.8 mg, 1.960 mmol) was added. After 1.25 h at room temperature, the mixture was purified by reverse phase HPLC (Sunfire S10 30×250 mm column, 30-50% solvent B gradient) to give the expected product (303.6 mg, 72% yield). MS (ES+) m/z: 220 (M+H); LC retention time: 2.40 min (analytical HPLC Method A).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]1=[O:26])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:27][C:28]1([CH3:41])[CH:37]2[O:38][CH:36]2[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:39]#[N:40])[CH:34]=2)[O:29]1>CCCCCC.C1COCC1.N#N.CO>[CH3:27][C:28]1([CH3:41])[CH:37]([OH:38])[CH:36]([C:22]2[C:21](=[O:26])[N:20]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:25]=[CH:24][CH:23]=2)[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:39]#[N:40])[CH:34]=2)[O:29]1
Reactant: O=c1ccccn1Cc1ccccc1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Agent: N#N
Agent: [Li]CCCC
Solvent: CO
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CC1(C)Oc2ccc(C#N)cc2C(c2cccn(Cc3ccccc3)c2=O)C1O
Reaction time: 2 h

Procedure:
6.7 ml of a 15% solution of butyllithium in hexane are added to a solution of 1.4 ml of diisopropylamine in 10 ml of THF while stirring and passing in N2 at 0°. A solution of 1.85 g of N-benzyl-2-pyridone in 10 ml of THF at 0° is then added dropwise. After stirring for 0.5 hours, a solution of 2 g of 2,2-dimethyl-3,4-epoxy-6-cyanochroman in 10 ml of THF is added dropwise at 0°, the mixture is boiled for 2 hours and excess butyllithium is decomposed by adding methanol dropwise. Customary working up gives 2,2-dimethyl-4-(1-benzyl-1,2-dihydro-2-oxo-3-pyridyl)-6-cyano-3-chromanol, m.p. 120°-122°.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1)=[O:5].S(Cl)([Cl:22])=O>>[CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([Cl:22])=[O:12])=[CH:9][CH:8]=1)=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)O)cc1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1

Procedure:
A mixture of 10.3 g of 4-[(2-methylbenzoyl)amino]benzoic acid and 32 ml of thionyl chloride is refluxed for 1.5 hours. The solution is concentrated under vacuum. Toluene is added and the solvent removed under vacuum. Toluene is added and the mixture chilled and filtered to give a yellow solid, m.p. 135°-141° C.
Reaction SMILES: [Br:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5](=[O:12])[NH:4][CH:3]=1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH4+].[Cl-]>CN(C=O)C.O>[CH2:15]([N:4]1[CH:3]=[C:2]([Br:1])[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]1=[O:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]cc(Br)c2ncccc12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2cccnc2c(Br)cn1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 85.7 %

Procedure:
To a solution of 8-bromo-1,6-naphthyridin-5(6H)-one (0.225 g, 1.0 mmol) in anhydrous DMF (6 mL) was added sodium hydride (60% dispersion in mineral oil, 0.052 g, 1.3 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 45 min and then benzyl bromide (0.205 g, 1.2 mmol) was added slowly. The reaction mixture was stirred at 0° C. for 2 h, then allowed to warm to rt and stirred for 17 h. After that time, saturated NH4Cl solution (5 mL) and water (5 mL) were added and the mixture was extracted with ethyl acetate (2×25 mL). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol to 97:3 dichloromethane/methanol) to give 6-benzyl-8-bromo-1,6-naphthyridin-5(6H)-one (0.270 g, 86%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 9.04 (dd, J=4.5, 1.8 Hz, 1H), 8.71-8.77 (m, 1H), 7.65 (s, 1H), 7.50 (dd, J=8.0, 4.5 Hz, 1H), 7.30-7.41 (m, 5H), 5.22 (s, 2H); ESI MS m/z 315 [M+H]+ and 317 [M+H]+.
Reaction SMILES: O.Cl.CS[C:5]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=1)([CH3:9])[C:6]([OH:8])=[O:7]>[Zn].C(OCC)C>[O:16]([C:12]1[CH:11]=[C:10]([CH:5]([CH3:9])[C:6]([OH:8])=[O:7])[CH:15]=[CH:14][CH:13]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CSC(C)(C(=O)O)c1cccc(Oc2ccccc2)c1
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: CCOCC
Product: CC(C(=O)O)c1cccc(Oc2ccccc2)c1
Yield: 100.3 %

Procedure:
Water (1.5 ml) and 1.5 ml of conc. hydrochloric acid were added to 432 mg of α-methylthio-α-(m-phenoxyphenyl)propionic acid, and then 300 mg of zinc powder was added. With stirring, the mixture was heated under reflux for 2.5 hours. Water (10 ml) and 30 ml of diethyl ether were added to the reaction mixture. The insoluble matter was separated by filtration. The filtrate was extracted three times with 80 ml of diethyl ether. The organic layer was washed with 10 ml of water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford 364 mg of α-(m-phenoxyphenyl)propionic acid as an oil. The yield was 100%.
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=O.[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[CH2:20][C:21](=[O:27])[NH:22]2.N1CCCCC1.C(O)(=O)C>C(O)C>[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20](=[CH:1][C:3]1[NH:4][C:5]3[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=3[C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:21](=[O:27])[NH:22]2
Reactant: Cc1cccc2c1CC(=O)N2
Reactant: O=Cc1[nH]c2c(c1CCC(=O)O)CCCC2
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cccc2c1C(=Cc1[nH]c3c(c1CCC(=O)O)CCCC3)C(=O)N2
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A mixture of 3-(2-formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid (5.4 g), 3.2 g of 4-methyl-2-oxindole and 2.7 g of piperidine in 25 mL of ethanol was refluxed for 4 hours. Upon slow addition of acetic acid (8 mL), a precipitate formed. The mixture was refluxed for 5 minutes and cooled to ambient temperature. The precipitate was collected by vacuum filtration and washed with 20 mL of ethanol. The solids were slurry-washed in 30 mL of refluxing ethanol, cooled, collected by vacuum filtration, washed with 30 mL of ethanol and dried under vacuum to give 6.2 g (80% yield) of 3-[2-(4-methyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionic acid as an orange solid.
Reaction SMILES: C([O:4][CH2:5][C:6](=O)[CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:17])/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])(=O)C.[OH2:19]>O1CCCC1.[OH-].[K+].C(O)C>[OH:4][CH2:5]/[C:6](/[CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:17])/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:15])[CH3:16])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:17])=[CH:11]/[CH2:12][OH:19]
Reactant: CC(=O)OCC(=O)CC/C=C(\C)CCC=C(C)C
Reactant: O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/CC/C(=C\CC/C(C)=C/CO)CO
Temperature: -20 °C
Reaction time: 2 h

Procedure:
In 30 ml of anhydrous tetrahydrofuran was suspended 5.4 g of (E)-4-methyl-6-acetoxy-4-hexen-1-yltriphenylphosphonium iodide, and to this suspension was added dropwise two molar equivalents of a n-butyllithium-hexane solution at -20° C. in a stream of nitrogen. The mixture was stirred at -20° C. for 2 hours, and to this was further added 2.5 g of (E)-6,10-dimethyl-2-oxo-5,9-undecadien-1-ol acetate (prepared in Referential example 2) in 10 ml of anhydrous tetrahydrofuran. The resulting mixture was again stirred at room temperature for 3 hours and, after addition of ice-water, extracted with ether, and from the extract was obtained an oil. The so obtained crude oil was dissolved in 25 ml of a 5% potassium hydroxide-ethanol solution under ice-cooling, and allowed to stand for 2 hours. This was, after addition of water, extracted with ether and treated in the usual way. The resultant was then chromatographed on silica gel to yield 0.95 g of the desired product.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][CH:16]([CH:19]=O)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1>>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][CH:16]([CH2:19][N:21]4[CH2:26][CH2:25][S:24][CH2:23][CH2:22]4)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CSCCN1
Reactant: O=CC1CCN(c2ccc(CN3CCCC3)cc2)CC1
Product: c1cc(N2CCC(CN3CCSCC3)CC2)ccc1CN1CCCC1

Procedure:
Prepared from the product of Example 16 and thiomorpholine.