Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:6][C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:2]=[CH2:3].[H][H]>[Pd].C(O)C>[CH2:1]([C:4]1[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:6][C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:2][CH3:3]
Reactant: [H][H]
Reactant: C=CCc1c(C(=O)OCC)nc2ccccc2c1O
Agent: [Pd]
Solvent: CCO
Product: CCCc1c(C(=O)OCC)nc2ccccc2c1O

Procedure:
A solution of 49.0 parts of ethyl 3-allyl-4-hydroxy-quinoline-2-carboxylate in 600 parts of boiling ethanol was stirred for 5 minutes in 3 parts of 3% palladium-on-carbon catalyst, then filtered and the filtrate together with 5 parts of fresh catalyst was charged to a stainless steel autoclave and hydrogen added at room temperature to a pressure of 50 atmospheres. After stirring at 16 hours 1.38 moles of hydrogen had been absorbed. The reaction mixture was dissolved in hot ethanol, filtered to remove catalyst, and evaporated to give 39.3 parts of ethyl 3-n-propyl-4-hydroxyquinoline-2-carboxylate, pale yellow needles, m.pt. 155°-157°C which were collected and dried; a further 4.8 parts of less pure product m.pt. 140°-146°C were recovered from the ethanolic mother liquors after concentration in vacuo. After repeated recrystallisation from ethanol very pale yellow prismatic needles, m.pt. 158°-159.5°C were obtained. (Found: C 69.3; H 6.3; N 5.2%. C15H17NO3 requires C 69.5; H 6.6; N 5.4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:19]2[C@@H:18]3[C@H:8]([C@H:9]4[C@@:13]([CH2:16][CH2:17]3)([CH2:14][CH3:15])[C:12](=[O:22])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([CH2:37][C:38]([O-])=[O:39])(C)=C>C(OCC)(=O)C>[C:38]([O:22][C:12]1[C@:13]2([CH2:16][CH2:17][C@H:18]3[C@@H:8]([CH2:7][CH2:6][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:21]=[CH:20][C:19]=43)[C@@H:9]2[CH2:10][CH:11]=1)[CH2:14][CH3:15])(=[O:39])[CH3:37]
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: C=C(C)CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Product: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC=C2OC(C)=O

Procedure:
30 g of 3-methoxy-18-methyl-1,3,5(10)-estratrien-17-one [J. Org. Chem. 40 (1975) 681] is stirred for 22 hours at 120° C. in 200 ml of isopropenylacetate with 1.5 g of p-toluenesulfonic acid. It is then diluted with ethyl acetate, washed with sodium carbonate and a common salt (NaCl) solution, dried over sodium sulfate and concentrated. After chromatography, 27.6 g of 17-acetoxy-3-methoxy-18-methyl-1,3,5(10),16-estratetraene with a melting point of 105°-106° C. is obtained.
Reaction SMILES: [OH:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1=[O:25]>C(#N)C>[CH2:10]([O:9][C:7]([C:4]1[CH:3]=[C:2]([O:1][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]2=[O:25])[NH:6][N:5]=1)=[O:8])[CH3:11]
Reactant: O=C1CCCCC1Cl
Reactant: CCOC(=O)c1cc(O)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(OC2CCCCC2=O)[nH]n1
Temperature: 25 °C
Yield: 48.8 %

Procedure:
To the stirred suspension of ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (6.25 g, 40 mmol) and 22.1 g of potassium carbonate in 500 ml of acetonitrile was added 6.35 g of 2-chlorocyclohexanone, and refluxed for 16 hours. The reaction mixture was allowed to cool to room temperature, then filtered, the solid was washed with acetonitrile. The filtrate was concentrated to an oil. The residue was dissolved in ethyl acetate and extracted with water. The organic phase was dried over MgSO4 and evaporated to dryness. The product was purified by silics-gel column chromatography by eluting it with 1:1 ethyl acetaet;hexane. 4.92 g (49%) of the desired product was obtained as a white solid. M.Pt. 122-124° C.; (M+H) 253.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][NH:5][CH2:4][C@H:3]1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:9].C(N(CC)CC)C.Cl[C:23]1[N:28]=[C:27]([NH2:29])[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][N:24]=1>C(#N)C>[NH2:29][C:27]1[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][N:24]=[C:23]([N:5]2[CH2:6][CH2:7][C@H:2]([CH3:1])[C@H:3]([C:8]([N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)=[O:9])[CH2:4]2)[N:28]=1
Reactant: C[C@H]1CCNC[C@H]1C(=O)N1CCCC1
Reactant: Nc1nc(Cl)ncc1[N+](=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@H]1CCN(c2ncc([N+](=O)[O-])c(N)n2)C[C@H]1C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.3 %

Procedure:
To a solution of cis-(4-methylpiperidin-3-yl)(pyrrolidin-1-yl)methanone (1.7 g, 8.60 mmol) in acetonitrile (20 mL) was added triethylamine (3.65 mL, 26.02 mmol). The mixture was stirred for 10 min at room temperature. Then 2-chloro-5-nitropyrimidin-4-amine (1.19 g, 6.9 mmol) was added and the reaction mixture was stirred at 80° C. for 3 h. The mixture was cooled to room temperature and stirred for 1 h. Ice cold water was added and the mixture was extracted with ethyl acetate. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via column chromatography (40-100% ethyl acetate in petroleum ether) to afford cis-(1-(4-amino-5-nitropyrimidin-2-yl)-4-methylpiperidin-3-yl)(pyrrolidin-1-yl)methanone (1.6 g). MS (ES+) (M+H) 335.3.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([C@H:13]1[C@@H:17]([CH2:18][OH:19])[O:16][C:15](=[O:20])[NH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])(O)=O.[Na+].C(OCC)(=O)C>CC(C)=O.CN1CCOCC1>[CH2:6]([C@H:13]1[C@@H:17]([CH2:18][O:19][S:2]([CH3:1])(=[O:4])=[O:3])[O:16][C:15](=[O:20])[NH:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)[C@@H](CO)O1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CS(=O)(=O)OC[C@H]1OC(=O)N[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A solution of 4.7 ml of methanesulphonyl chloride in 10 ml of acetone is added at 25° C. to a suspension of 10.4 g of the alcohol from Example 8 in 20 ml of acetone and 6.1 ml of N-methylmorpholine and the suspension is stirred at 25° C. for 3 hours. A further 1.1 ml of N-methylmorpholine are added and the mixture is stirred for 1 hour. The suspension is shaken with 80 ml of semi-saturated NaHCO3 solution and ethyl acetate and the separated aqueous phase is extracted with ethyl acetate. The ethyl acetate extracts are washed with water, dried and filtered. The filtrate is concentrated to give 14.3 g (100%) of crude methanesulphonic acid (4S,5S)-4-benzyl-2-oxo-oxazolidin-5-ylmethyl ester, TLC (SiO2 ethyl acetate): Rf =0.4; MS (El): 286 (M+H+).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:26])([CH3:25])[O:6][C@@H:7]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:8](O[Si](C(C)(C)C)(C)C)=[O:9])([CH3:4])[CH3:3].C(Cl)(=O)C([Cl:30])=O>CN(C)C=O.C(Cl)Cl>[CH3:1][C:2]([Si:5]([CH3:26])([CH3:25])[O:6][C@@H:7]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:8]([Cl:30])=[O:9])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OC(=O)[C@H](Cc1ccccc1)O[Si](C)(C)C(C)(C)C
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](Cc1ccccc1)C(=O)Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
To a solution of 21.0 g (53 mmol) of (1,1-dimethylethyl)-dimethylsilyl (2S)-2-((1,1-dimethylethyl)dimethylsilyloxy)-3-phenylpropanoate (3) and five drops of N,N-dimethylformamide in methylene chloride at 0° C. was added 29.3 mL (59 mmol) of a 2.0M solution of oxalyl chloride in methylene chloride over a 30 min period. The cooling bath was removed and the reaction mixture was allowed to stir at room temperature for 18 hours. The solvent and excess oxalyl chloride were removed by rotary evaporation resulting in a yellow liquid. Purification by vacuum distillation afforded 12.7 g (80%) of (2S)-2-((1,1-dimethylethyl)-dimethylsilyloxy)-3-phenylpropanoyl chloride (4) as a clear liquid: bp 88°-90° C. (0.2 mm Hg); 1H NMR (CDCl3) δ-0.215 (s, 3 H), -0.0339 (s, 3 H), 0.840 (s, 9 H), 2.94-3.01 (m, 1 H), 3.23-3.29 (m, 1 H), 4.52-4.56 (m, 1 H), 7.25-7.35 (m, 5 H); 13C NMR (CDCl3) δ175.7, 135.9, 129.8, 128.4, 127.1, 81.1, 40.8, 25.5, 18.0, -5.40, -5.76.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH:11]=2)=[O:8])=[CH:4][CH:3]=1.[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:5]2[O:6][C:2]([C:28]3[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=3)=[CH:3][CH:4]=2)=[O:8])=[CH:11][C:12]=1[N:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1
Reactant: OB(O)c1ccncc1
Reactant: COc1ccc(NC(=O)c2ccc(Br)o2)cc1N1CCN(C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(NC(=O)c2ccc(-c3ccncc3)o2)cc1N1CCN(C)CC1

Procedure:
5-bromo-N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]furan-2-carboxamide (0.3 g;0.76 mmol) was stirred with 4-pyridylboronic acid (0.094 g;0.76 mmol), tetrakis(triphenylphosphine)palladium(0) (0.045 g;5 mol %) and anhydrous sodium carbonate (0.089 g;0.84 mmol) in water (14 ml) and DME (14 ml) and the whole heated at reflux under Ar (18 hours). The reaction mixture was poured into 10% Na2CO3 (aq) (30 ml) and extracted into CHCl3. The organic extracts were combined, dried over Na2 SO4, filtered and the filtrate evaporated in vacuo to a brown oil which crystallised on standing. The brown solid was purified by flash silica-gel chromatography and eluted with 3%MeOH/CHCl3 to yield the title compound as a lemon solid (0.22 g;74%), mp=157°-159° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.C1N2CCN(CC2)C1.[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[CH:19]=[CH2:20]>>[CH2:23]([O:22][C:18](=[O:21])[C:19]([CH:8]([OH:9])[C:5]1[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[CH2:20])[CH3:24]
Reactant: C=CC(=O)OCC
Reactant: Cc1ccc(C=O)cn1
Agent: C1CN2CCN1CC2
Product: C=C(C(=O)OCC)C(O)c1ccc(C)nc1
Reaction time: 8 h
Yield: 62 %

Procedure:
To a solution of 6-methylpyridine-3-carbaldehyde (5.0 g, 41 mmol) in ethyl acrylate (10 mL) at room temperature was added DABCO (1.0 g, 9 mmol), and the mixture was stirred overnight. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography (SiO2, hexane to 40% ethyl acetate), to give the title compound (5.6 g, 62%) as a yellow oil. LCMS (ES+) 222.2 (M+H)+, RT 0.98 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@@H:13]([OH:15])[CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C:13](=[O:15])[CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](O)CN(C(=O)OCc2ccccc2)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC(=O)CN(C(=O)OCc2ccccc2)C1
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of (3S,5R)-benzyl 3-(tert-butoxycarbonylamino)-5-hydroxypiperidine-1-carboxylate (1 eq) in 10 mL dichloromethane was added Dess-Martin periodinane (1.2 eq) at room temperature. The reaction mixture was stirred at that temperature overnight. The mixture was diluted with ethyl acetate, washed with brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (EtOAc:hexanes=1:2) to yield (S)-benzyl 3-(tert-butoxycarbonylamino)-5-oxopiperidine-1-carboxylate (81%). LC/MS (m/z): 249.1 (MH+-100), Rt: 0.83 min. HPLC: Rt: 3.26 min.
Reaction SMILES: [CH2:1]([O:13][C:14]([C:16]1[CH:17]=[C:18]2[C:23](=O)[O:22][C:20](=[O:21])[C:19]2=[CH:25][CH:26]=1)=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl.[NH2:28][OH:29].N1C=CC=CC=1>O>[CH2:1]([O:13][C:14]([C:16]1[CH:17]=[C:18]2[C:23](=[O:22])[N:28]([OH:29])[C:20](=[O:21])[C:19]2=[CH:25][CH:26]=1)=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOC(=O)c1ccc2c(c1)C(=O)OC2=O
Reactant: NO
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCOC(=O)c1ccc2c(c1)C(=O)N(O)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 500-ml flask equipped with a stirrer, a thermometer and a dropping funnel, 100 g (277.43 mmol) of 4-dodecyloxycarbonylphthalic anhydride, 21.21 g (305.17 mmol) of hydroxylamine hydrochloride and 250 g of pyridine were placed and were stirred at room temperature in an atmosphere of nitrogen gas for 30 minutes, followed by stirring at 90° C. for further 3 hours. The resulting reaction mixture was added dropwise to 3000 g of pure water over 30 minutes with stirring and thereby yielded a crystal of 4-dodecyloxycarbonyl-N-hydroxyphthalimide. The mixture was stirred for further 1 hour, the precipitate was separated by filtration and was rinsed with pure water. The resulting solid was stirred and rinsed in a solvent mixture of 640 g of n-hexane and 160 g of ethyl acetate for 3 hours, the resulting slurry was filtrated, was rinsed with n-hexane, was dried at 60° C. under reduced pressure and thereby yielded 90.88 g (242.04 mmol) of target 4-dodecyloxycarbonyl-N-hydroxyphthalimide as a white powder. The yield was 87.2% on the basis of 4-dodecyloxycarbonylphthalic anhydride.
Reaction SMILES: [F:1][C:2]1([F:25])[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]([C:14](=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH2:4][CH2:3]1.[OH-].[Na+]>C(O)(=O)C>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]([N:5]2[C:6]3[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=3[C:8](=[O:9])[C:2]([F:25])([F:1])[CH2:3][CH2:4]2)=[O:24])=[CH:16][CH:17]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCC(F)(F)C(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1ccc(C(=O)N2CCC(F)(F)C(=O)c3ccccc32)cc1
Yield: 82.8 %

Procedure:
4,4-Difluoro-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one (940 mg) was dissolved in 20 ml of acetic acid, 3.07 g of stannous chloride was added to the solution at room temperature and then the resulting mixture was heated under reflux for 5 hours. The reaction solution was ice-cooled and adjusted to a basic range with 1N sodium hydroxide. Then, after separating the organic layer, the water layer was extracted with ethyl acetate. The resulting organic layer was dried over anhydrous potassium carbonate and the solvent was evaporated under a reduced pressure. The thus prepared residue was recrystallized from chloroformhexane to obtain 711 mg of 1-(4-aminobenzoyl)-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])N[C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.[OH-].[Na+].N>O.[Zn]>[NH2:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:11][CH:12]=1)[C:6](=[O:7])[O:10][CH2:9]2
Reactant: Nc1ccc2c(c1)C(=O)NC2=O
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc2c(c1)COC2=O
Reaction time: 0.5 h

Procedure:
Twenty grams of 4-aminophthalimide was added to a mixture of 41 gm zinc and 122 gm sodium hydroxide in 50 ml water (with good stirring) over 30 minutes. The mixture was stirred another 30 minutes, then heated to 60°. When ammonia ceased to be evolved the mixture was heated for an additional 60 minutes, then cooled to about 30°. The zinc residues were filtered off and the solution was acidified with 30 ml concentrated hydrochloric acid. The solution was heated to 90° for 45 minutes, then cooled and neutralized with 20 gm solid sodium carbonate, which brought the pH to 8-9. The product was filtered, washed with water and air dried. Wt=16.8 gm, m.p.=177°-189°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].O>C(O)(=O)C>[C:12]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(CC(=O)O)cc1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(CC(=O)O)cc1

Procedure:
A mixture of (4-amino-phenyl)-acetic acid (25 g) in acetic acid (200 mL) was treated with acetic anhydride (31.3 mL). The mixture was heated on a steam bath for 4 hours, then cooled, then treated with water (20 mL) and then evaporated. The residue was dried under vacuum to give the title compound (30.4 g) as a beige coloured solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.[CH:33](OC(=O)C)=[O:34]>>[CH:33]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1)=[O:34]
Reactant: CC(=O)OC=O
Reactant: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCNCC4)c[nH]c13)OCO2
Product: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCN(C=O)CC4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-butoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A179) and acetic formic anhydride the title compound was obtained as colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:35])[C@@H:9]([CH3:34])[C:10]([NH:12][C@@H:13]([CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[C:14]([N:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18][C@H:17]1[C:25]([OH:27])=O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[F:60][C:61]1[CH:67]=[CH:66][CH:65]=[C:64]([CH3:68])[C:62]=1[NH2:63].OS([O-])(=O)=O.[K+]>C(Cl)Cl>[F:60][C:61]1[CH:67]=[CH:66][CH:65]=[C:64]([CH3:68])[C:62]=1[NH:63][C:25]([C@H:17]1[N:16]([C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([N:8]([CH3:35])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH3:34])[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18]1)=[O:27]
Reactant: Cc1cccc(F)c1N
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1c2ncccc2C[C@H]1C(=O)O)C1CCOCC1)N(C)C(=O)OC(C)(C)C
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc(F)c1NC(=O)[C@@H]1Cc2cccnc2N1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C1CCOCC1
Reaction time: 0.08 h
Yield: 41 %

Procedure:
To a solution of (S)-1-((S)-2-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (60 mg, 122 pilot, Eq: 1.00) and diisopropylethylamine (64 μL, 367 μmol, Eq: 3) in DCM (1.8 mL) was added diphenylphosphinic chloride (63.7 mg, 51 μL, 269 μmol, Eq: 2.2). After stirring for 5 min, 2-fluoro-6-methylaniline (18.4 mg, 147 μmol, Eq: 1.2) was added and the resulting solution stirred at rt for 2 d. The reaction mixture was poured into aqueous 0.1 M KHSO4 (20 mL) and the resulting mixture was extracted with EtOAc. The combined organic layers were concentrated in vacuo and the crude material was purified by flash chromatography (silica gel, 4 g, 10% to 50% EtOAc in hexanes) to give tert-butyl (S)-1-((S)-2-((S)-2-(2-fluoro-6-methylphenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylamino)-1-oxopropan-2-yl(methyl)carbamate (30 mg), m/z=598 (M+H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[C:15]1(C)C=CC(S(O)(=O)=O)=C[CH:16]=1.C(=O)(O)[O-].[Na+]>C(O)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCCCCCCCCCBr
Yield: 3476.4 %

Procedure:
This example is a method of synthesis for inventive compound no. 3556. A solution of 11-bromoundecanoic acid (available from Aldrich, 5.70 g, 22 mmol) and p-toluenesulfonic acid (0.1 g) in absolute ethanol (100 ml) was refluxed for 3 hours. Saturated aqueous sodium bicarbonate solution (40 ml) was added and the reaction mixture was extracted with dichloromethane (3×70 ml). The combined extracts were washed with water (50 ml) and saturated aqueous salt solution (50 ml), and then the solvent was evaporated to a colorless oil. Ethyl 11-bromoundecanoate (5.92 g, 94% yield) was collected during distillation (2 mm) at 135° C. A solution of the bromoester (5.92 g, 20 mmol) and 1-sodiotheobromine (4.08 g, 20 mmol) in dimethylsulfoxide (80 ml) was stirred for 18 hours at ambient temperature. The mixture was added to water (100 ml) and dichloromethane (100 ml). The aqueous layer was extracted with dichloromethane (2×80 ml). The combined organic layers were washed with water (80 ml) and saturated aqueous salt solution (80 ml), dried over magnesium sulfate, and evaporated under vacuum to a white solid. The residue was recrystallized in dichloromethane/ether/hexane, yielding 4.95 g of 1-(ethyl 11-yl-undecanoate)-3,7-dimethylxanthine (62% yield).
Reaction SMILES: [NH2-].[Li+].N.[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH:9]([O:13][CH3:14])[CH2:10][C:11]#[CH:12].Br[CH2:16][CH2:17][CH2:18][C:19]([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:21]>O1CCCC1>[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH:9]([O:13][CH3:14])[CH2:10][C:11]#[C:12][CH2:16][CH2:17][CH2:18][C:19]([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:21]
Reactant: COC(CCCBr)(OC)OC
Reactant: C#CCC(OC)c1ccco1
Agent: N
Agent: [Li+]
Agent: [NH2-]
Solvent: C1CCOC1
Product: COC(CC#CCCCC(OC)(OC)OC)c1ccco1
Yield: 120.9 %

Procedure:
To a stirred solution of 4.09 g of lithium amide and 200 ml of liquid ammonia was added dropwise a solution of 24.3 g of 4-(2-furyl)-4-methoxy-1-butyne in 20 ml of tetrahydrofuran during 10 minutes. The mixture was stirred under reflux for 30 minutes and then treated dropwise with a solution of 40.4 g of 1-bromo-4,4,4-trimethoxybutane (U.S. Pat. No. 3,864,387) in 40 ml of tetrahydrofuran during 10 minutes. This solution was stirred under reflux for 60 minutes, the ammonia was allowed to evaporate over one hour and the resulting solution stirred at 20° C. for 10 minutes. The solution was then partitioned between ether and water, the organic layer separated, washed with brine, dried and concentrated, giving 58 g of crude 8-(2-furyl)-1,1,1,8-tetramethoxy-5-octyne as a liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[O:11][C:12](=O)[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[OH:15])([O-])=O.O>CO.[Ni].C1(C)C(C)=CC=CC=1>[Cl:10][C:8]1[CH:7]=[CH:6][C:5]2[O:11][C:12]3[CH:13]=[CH:19][CH:18]=[CH:17][C:16]=3[C:14](=[O:15])[NH:1][C:4]=2[CH:9]=1
Reactant: O=C(Oc1ccc(Cl)cc1[N+](=O)[O-])c1ccccc1O
Agent: [Ni]
Solvent: O
Solvent: Cc1ccccc1C
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2Oc2ccccc21
Reaction time: 20 h
Yield: 47.1 %

Procedure:
A solution of 33.74 g of O-(2-nitro-4-chlorophenyl)salicylic acid in 150 mL of methanol was hydrogenated over Raney nickel (6.8 g) at room temperature and 30 psi pressure with stirring for 20 hours. The crude amino acid obtained on evaporation of the methanol was refluxed in 150 mL of xylene for 20 hours with continuous removal of water. The xylene solution was cooled and the xylene was removed, the residue was washed with THF, filtered and dried to provide 8-chloro-10H-dibenzo[b,f][1,4]oxazepin-11-one as gray solid (13.3 g, 40%), mp 260-261°. 1H NMR (300 MHz, DMSO-d6), δ 7.15-7.2 (m, 2H), 7.3-7.4 (m, 3H), 7.64 (ddd, 1H, J=1.9, 7.8 and 8.4 Hz), 7.78 (dd, 1H, J=1.5 and 7.7 Hz), 10.589 (s, 1H, —NH).