Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([CH:6]1[CH2:12][CH2:11][N:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:9]2[CH:23]=[CH:24][CH:25]=[CH:26][C:8]=2[C:7]1=[O:27])=O)C.CC(O)=O.Cl.[OH-].[Na+]>O>[C:19]1([CH3:22])[CH:18]=[CH:17][C:16]([S:13]([N:10]2[CH2:11][CH2:12][CH2:6][C:7](=[O:27])[C:8]3[CH:26]=[CH:25][CH:24]=[CH:23][C:9]2=3)(=[O:15])=[O:14])=[CH:21][CH:20]=1
Reactant: CCOC(=O)C1CCN(S(=O)(=O)c2ccc(C)cc2)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)N2CCCC(=O)c3ccccc32)cc1
Temperature: 0 °C
Yield: 60 %

Procedure:
To the mixture of 5-Oxo-1-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester thus obtained, were added AcOH (2.4 l), conc.HCl (800 ml) and H2O (240 ml). The mixture was heated at reflux for 5 h and poured into ice water. The pH was adjusted to about 7-8 by adding diluted aqueous NaOH. The mixture was extracted with CH2Cl2. The organic layer was separated, dried over MgSO4, concentrated, and the residue was crystallized from the mixture (4:1 n-hexane:AcOEt) to give 1-(Toluene-4-sulfonyl)-1,2,3,4-tetrahydro-benzo[b]azepin-5-one (278 g, 60%) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH:12]=[CH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:23])C=1.C(OC(=O)C)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH:12]2[CH:11]([O:23]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC=CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2OC2CC1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
To a stirred solution of 16.4 g 2,3,6,7-tetrahydro-azepine-1-carboxylic acid tert-butyl ester in 420 ml dichloromethane was added at −60° C. 35.8 g m-chloroperbenzoic acid (70% purity). The mixture was allowed to slowly warm to room temperature overnight, 1 l ethylacetate was added and the solution was extracted with aqueous sodium bicarbonate, 1N aqueous sodium hydroxide and brine. Evaporation of the solvent and chromatography yielded 14.5 g (82%) 8-oxa-4-aza-bicyclo[5.1.0]octane-4-carboxylic acid tert-butyl ester as colorless liquid; MS (EI): m/e=213 (M+,5%), 158 (22%), 140 (12%), 57 (100%). To a solution of 14.3 g 8-oxa-4-aza-bicyclo[5.1.0]octane-4-carboxylic acid tert-butyl ester in 750 ethanol was added 150 ml water, 35.8 g ammonium chloride and 43.6 g sodium azide. The mixture was stirred at 75° C. over night, the solvents were greatly removed by distillation under vacuum and the residue was suspended in ethanol and filtered. The ethanol was distilled off and the residue was suspended in ethylacetate and filtered. Removal of the solvent and chromatography on silicagel with ethylacetate/hexane 1:1, yielded 13.5 g (79%) 4-azido-5-hydroxy-azepane-1-carboxylic acid tert-butyl ester as a viscous oil; MS (ISP): m/e=257 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:10]=[O:11])=[C:7]([OH:9])[CH:8]=1)[CH3:2].[CH3:12][C:13]([Si:16]([CH3:22])([CH3:21])[O:17][CH2:18][CH2:19]Br)([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:10]=[O:11])=[C:7]([O:9][CH2:19][CH2:18][O:17][Si:16]([C:13]([CH3:15])([CH3:14])[CH3:12])([CH3:22])[CH3:21])[CH:8]=1)[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CCc1ccc(C=O)c(O)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCc1ccc(C=O)c(OCCO[Si](C)(C)C(C)(C)C)c1

Procedure:
This compound was prepared in a manner analogous to that of Step (b) of Example 1, using 17.0 grams (0.113 mole) of 5-ethyl-2-formylphenol, 27.7 grams (0.116 mole) of 2-(1,1-dimethylethyldimethylsilyloxy)ethyl bromide, 19.2 grams (0.139 mole) of potassium carbonate, and a catalytic amount of 18-crown-6 in 200 mL of THF. The yield of the subject compound was 12.7 grams, following purification by column chromatography on silica gel. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=O)[CH2:9][CH2:10][C:11](=O)[CH:12]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[N:6][CH:7]=1.C([O-])(=O)C.[NH4+:36]>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:36][C:11]([CH:12]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH2:13][CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: [NH4+]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ccc(Br)cn2)cc1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(Br)cn3)[nH]2)cc1
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 85.5 %

Procedure:
To a solution of 1-(5-bromopyridin-2-yl)-5-[4-(methylsulfonyl)phenyl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (3.89 g) in acetic acid (40 mL) was added ammonium acetate (9.50 g), and the mixture was stirred at 110° C. for 45 min. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (3.20 g, yield 86%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 491 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:9]([CH:10]=[N:11][C@@H:12]([CH3:16])[C:13]([NH2:15])=[O:14])=[CH:8][CH:7]=1.FC1C=CC=CC=1CC1C=C(C=CC=1OCC1C=CC=CC=1F)CN[C@@H](C)C(N)=O>>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][NH:11][C@@H:12]([CH3:16])[C:13]([NH2:15])=[O:14])=[CH:17][CH:18]=1
Reactant: C[C@H](N=Cc1ccc(OCc2ccccc2F)cc1)C(N)=O
Agent: C[C@H](NCc1ccc(OCc2ccccc2F)c(Cc2ccccc2F)c1)C(N)=O
Product: C[C@H](NCc1ccc(OCc2ccccc2F)cc1)C(N)=O
Yield: 93 %

Procedure:
(S)-2-[4-(2-Fluorobenzyloxy)benzylamino]propanamide is prepared in a 93% yield from (S)-2-[4-(2-fluorobenzyloxy)benzylideneamino]propanamide by following the same procedure of Example 8, step b). The content of (S)-2-[3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)-benzylamino]propanamide is 0.02% by weight determined by HPLC (see Example 17B).
Reaction SMILES: [NH2:1][CH:2]([CH:8]=[C:9]([CH2:15][P:16]([OH:19])([OH:18])=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[C:3]([O:5]CC)=[O:4]>O>[NH2:1][CH:2]([CH:8]=[C:9]([CH2:15][P:16]([OH:19])([OH:18])=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(N)C=C(CCCCO)CP(=O)(O)O
Solvent: O
Product: NC(C=C(CCCCO)CP(=O)(O)O)C(=O)O
Reaction time: 48 h
Yield: 63.8 %

Procedure:
1.0 g (3.4 mmol) ethyl 2-amino-4-phosphonomethyl-8-hydroxy-oct-3-enoate (Example 20) in 10 ml of water are refluxed, while stirring, for 48 hours. The reaction mixture is evaporated to dryness yielding after drying 0.58 g (64% yield) of 2-amino-4-phosphonomethyl-8-hydroxy-oct-3-enoic acid, m.p. 152°-155°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]1[C:22](=[O:27])[O:23][C:24](=[O:26])[CH2:25][C:5]2=1.[OH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]([C:22]([OH:23])=[O:27])=[C:5]2[CH2:25][C:24]([N:32]1[CH2:33][CH2:34][CH:29]([OH:28])[CH2:30][CH2:31]1)=[O:26]
Reactant: OC1CCNCC1
Reactant: O=C1Cc2c(n(Cc3cccc4ccccc34)c3ccc(F)cc23)C(=O)O1
Product: O=C(O)c1c(CC(=O)N2CCC(O)CC2)c2cc(F)ccc2n1Cc1cccc2ccccc12

Procedure:
6-Fluoro-9-naphthalen-1-ylmethyl-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione (from example 34.1.) was ring opened with 4-hydroxypiperidine at 22° C. to give the title compound as a white solid. MS: 461.0 ([M+H]+).
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[C:21]([OH:24])(=[O:23])[CH3:22].OO.C(OC(=O)C)(=O)C>O>[C:21]([O:24][CH:9]1[C:10]2[N:1]=[C:2]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)(=[O:23])[CH3:22]
Reactant: CCOC(=O)c1cc2c(nc1C(=O)OCC)CCCC2
Reactant: CC(=O)O
Agent: OO
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cc2c(nc1C(=O)OCC)C(OC(C)=O)CCC2
Temperature: 75 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
A mixture comprising 2.8 g of diethyl 5,6,7,8-tetrahydroquinoline-2,3-dicarboxylate, 10 ml of acetic acid and 1.1 ml of a 35% hydrogen peroxide aqueous solution, was stirred at 75° C. for 3 hours under heating. 1.0 ml of a 35% hydrogen peroxide aqueous solution was added thereto, and the mixture was further reacted at 75° C. for 9 hours. After cooling the mixture, water was added thereto, and the mixture was extracted with chloroform. The organic layer was dried, and then the solvent was distilled off to obtain an oily substance. This oily substance was added to 50 ml of acetic anhydride under reflux, and refluxed for 15 minutes. The solvent was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with diethyl ether. The organic layer was dried, and then the solvent was distilled off. The residue was purified by column chromatography to obtain 2.3 g (yield: 69%) of diethyl 8-acetoxy-5,6,7,8-tetrahydroquinoline-2,3-dicarboxylate.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:29])[CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([O:21][Si](C(C)(C)C)(C)C)[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1.Cl.C(OCC)(=O)C.O>C1COCC1>[OH:1][NH:2][C:3](=[O:29])[CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([OH:21])[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCC=CC(=O)NO)c1ccc2ccccc2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(C=CCCCCC(O)c1ccc2ccccc2c1)NO
Temperature: 30 °C
Reaction time: 3 h
Yield: 33 %

Procedure:
To a solution of the silyl ether 186 (300 mg, 0.725 mmol) in THF (3 mL) at room temperature was added 1N aqueous solution of hydrochloric acid (3 mL). The mixture was stirred for 3 hours at 30° C. and then added a large volume of ethyl acetate and water. The water layer was washed with ethyl acetate and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude residue was purified by flash chromatography (75% to 100% ethyl acetate/hexane) affording unsatisfactory purity. So the compound was purified again using 8% methanol in dichloromethane affording the title compound 187 in 33% yield (77 mg). 1H NMR: (300 MHz, CD3OD) δ: 7.87-7.71 (m, 4H), 7.52-7.40 (m, 3H), 6.77 (dt, J=15.1, 6.9 Hz, 1H), 5.75 (d, J=15.1 Hz, 1H), 4.76 (t, J=6.9 Hz, 1H), 2.17-2.10 (m, 2H), 1.84-1.77 (m, 2H), 1.49-1.27 (m, 4H) 1.88-1.75 (m, 4). MS (ESI)=282 (M+−OH), 322 (M++Na).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[N:11]=[CH:10][NH:9][C:8]2=[S:23].[CH3:24]I.Cl>O1CCCC1.O>[CH3:24][S:23][C:8]1[C:7]2[C:12](=[CH:13][C:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[C:5]([O:4][CH3:3])[CH:6]=2)[N:11]=[CH:10][N:9]=1
Reactant: CI
Reactant: COc1cc2c(=S)[nH]cnc2cc1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(SC)ncnc2cc1OCc1ccccc1
Yield: 94.4 %

Procedure:
Sodium hydroxide (1.0 N, 200 ml) was added to a solution of 6-methoxy-7-benzyloxy-3,4-dihydroquinazolin-4-thione (30 g, 0.1 mol) in tetrahydrofuran (100 ml) and then methyl iodide (7.5 ml, 0.12 mol) was slowly added at ambient temperature over 30 minutes. The pH of the solution was then adjusted to 7 with hydrochloric acid (2.0 N), the reaction was diluted with water and the solid was recovered by suction filtration. Drying in vacuo yielded 4-(methylthio)-6-methoxy-7-benzyloxyquinazoline (29.5 g, 94% yield):
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.N1(C2C=C[C:24]([CH:25]=[O:26])=CC=2)C=CC=N1>>[F:1][C:2]1[CH:9]=[C:8]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[CH:24][CH:25]=[O:26]
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccc(-c2ncccn2)cc1F
Product: O=CC=Cc1ccc(-c2ncccn2)cc1F

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 2-fluoro-4-(2-pyrimidinyl)benzaldehyde (prepared as described in Reference Example 15) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 229 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[C:11]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[C:10]([O:17][CH3:18])[N:9]=[CH:8][N:7]=1.[H-].[Na+].COS(OC)(=O)=O.[CH3:31][O:32][CH2:33]COC>C(OC)=O.CCOCC>[CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[C:11]([C:12](=[CH:31][O:32][CH3:33])[C:13]([O:15][CH3:16])=[O:14])=[C:10]([O:17][CH3:18])[N:9]=[CH:8][N:7]=1
Reactant: COCCOC
Reactant: COC(=O)Cc1c(OC)ncnc1Oc1cccc(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COS(=O)(=O)OC
Solvent: COC=O
Product: COC=C(C(=O)OC)c1c(OC)ncnc1Oc1cccc(C)c1

Procedure:
Methyl 4-(3-methylphenoxy)-6-methoxy-pyrimidin-5-yl-acetate (12.1 g, 42 mmol)is dissolved in a mixture of 1,2-dimethoxyethane (120 ml) and methyl formate (50 ml). Sodium hydride (2.5 g, 80% in oil, 84 mmol) is added in one portion, the temperature being kept at room temperature. After 5 hours dimethylsulfate (6.6 ml, 70 mmol) is added with cooling. After an additional 5 hours the reaction mixture is diluted with ether and washed with brine. Drying and chromatography on silicagel (eluant: hexane/ethyl acetate 1:1) gives the E-isomer of methyl α-[4-(3-methylphenoxy)-6-methoxy-pyrimidin-5-yl)-β-methoxyacrylate as a crystalline solid, m.p. 107° C.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[I-].[Na+].[Br:15][C:16]1[C:17]([C:28]#[N:29])=[N:18][N:19]([CH2:26][CH3:27])[C:20]=1[CH2:21][CH2:22][CH2:23][CH2:24]Cl>C(Cl)(Cl)Cl.O.CN(C=O)C>[Br:15][C:16]1[C:17]([C:28]#[N:29])=[N:18][N:19]([CH2:26][CH3:27])[C:20]=1[CH2:21][CH2:22][CH2:23][CH2:24][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: CCn1nc(C#N)c(Br)c1CCCCCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCn1nc(C#N)c(Br)c1CCCCN1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Yield: 71.1 %

Procedure:
Potassium phthalimide (954 mg, 5.15 mmol), sodium iodide (130 mg, 0.86 mmol), and DMF (5 mL) were added to 4-bromo-5-(4-chlorobutyl)-1-ethyl-1H-pyrazole-3-carbonitrile (1.0 g, 3.4 mmol, prepared as described in Parts A-E of Example 19), and the reaction was heated at 100° C. for 45 minutes under a nitrogen atmosphere and allowed to cool to ambient temperature. Water (50 mL) was added, and the resulting mixture was stirred at 0° C. A precipitate formed, was isolated by filtration, and was dissolved in chloroform. The resulting solution was dried over sodium sulfate, filtered, and concentrated under reduced pressure. An analysis by nuclear resonance spectroscopy (NMR) indicated that starting material was present. The solid was treated with potassium phthalimide (1.27 g, 6.88 mmol), sodium iodide (130 mg, 0.86 mmol), and DMF (5 mL) and heated at 90° C. for three hours. Water (50 mL) was added, and the resulting solid was isolated by filtration to provide 0.97 g of 4-bromo-1-ethyl-5-(4-phthalimidobutyl)-1H-pyrazole-3-carbonitrile as a gray, crystalline solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[C:4]([C:6]1[CH:20]=[CH:19][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17]C)=[CH:8][CH:7]=1)=[O:5])[CH3:2].B(Br)(Br)Br>ClCCl>[CH2:21]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:20]=[CH:19][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])=[CH:8][CH:7]=1)=[O:5])[CH3:22]
Reactant: CCN(CC)C(=O)c1ccc(Cc2ccccc2OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(Cc2ccccc2O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
The obtained 2-(4-diethylcarbamoylbenzyl)anisole was dissolved in dichloromethane (280 ml), added with boron tribromide (25.0 g) and stirred at room temperature for 3 hours. After the reaction mixture was slowly poured into ice (300 g) with ice cooling to quench the reaction and the layers were separated, the aqueous layer was extracted with dichloromethane (300 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=1:1) to obtain 10.15 g of the title compound. Yield: 79% (for the three steps).
Reaction SMILES: CO[C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[CH:5]=1.C(C1C=C(B(O)O)C=CC=1)(O)=O.BrC1C(C)=NC=CC=1.O=S(Cl)Cl.[C:42]([O:46][C:47](=[O:64])[CH2:48]C(C1C=CC=C(C2C=CN=C(C)C=2)C=1)=O)([CH3:45])([CH3:44])[CH3:43]>C(#N)C.C([O-])([O-])=O.[Na+].[Na+]>[C:42]([O:46][C:47](=[O:64])[CH2:48][C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[CH:5]=1)=[O:17])([CH3:45])([CH3:44])[CH3:43]
Reactant: COC(=O)c1cccc(-c2ccc(C)nc2)c1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Agent: Cc1ncccc1Br
Agent: O=C(O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: Cc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1

Procedure:
Compound K3 was prepared from 3-(6-methyl-pyridin-3-yl)-benzoic acid methyl ester [prepared by the following procedure: A mixture of 3-carboxyphenylboronic acid (4.82 g, 29.07 mmol) and 3-bromo-2-methylpyridine (5.00 g, 29.07 mmol) in acetonitrile (145 mL) and 0.4M Na2CO3-solution (145 mL) was degassed and Pd(Ph3P)4 (1.68 g, 5 mol %) was added. The reaction mixture was refluxed for 16 h, evaporated to dryness (cf. Synlett 6:829–831 (2000). The residue was suspended in MeOH (400 mL) and SOCl2 (10.5 mL, 145 mmol) was added dropwise at 23° C. and the reaction mixture was refluxed for 4 h. Evaporated to dryness, taken up in EtOAc, washed with sat. NaHCO3-solution and brine, dried over Na2SO4. Removal of the solvent in vacuum left a brown oil, which was purified by silica gel column chromatography with cyclohexane/EtOAc.] (3.87 g, 17.0 mmol) by treatment with lithium tert-butyl acetate according to general procedure K (method b). Starting from 3-(2-methyl-pyridin-4-yl)-benzoic acid methyl ester, prepared in analogy to the method described above, 3-[3-(2-Methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Compound K4) was prepared in analogy to the above method.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:13])=[CH:9][C:10]=2[CH3:12])[O:5][C:4](=[O:14])[CH:3]=1.[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH:18]=O>CO>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:13])=[CH:9][C:10]=2[CH3:12])[O:5][C:4](=[O:14])[C:3]=1[CH:18]1[C:3]2[C:4](=[O:14])[O:5][C:6]3[CH:7]=[C:8]([OH:13])[CH:9]=[C:10]([CH3:12])[C:11]=3[C:21]=2[O:20][CH:17]1[O:16][CH3:15]
Reactant: COC(C=O)OC
Reactant: Cc1cc(O)cc2oc(=O)cc(O)c12
Solvent: CO
Product: COC1Oc2c(c(=O)oc3cc(O)cc(C)c23)C1c1c(O)c2c(C)cc(O)cc2oc1=O
Temperature: 25 °C
Yield: 92 %

Procedure:
4,7-Dihydroxy-5-methylcoumarin (200 mg; 1.04 mmole) was dissolved in methanol (5 mL). A 60% aqueous dimethoxyacetaldehyde solution (792 μL; 8.7 mmole) was added and the reaction mixture was refluxed for 5 hours. By cooling to room temperature a white precipitate was precipitated, which was filtered off and washed with methanol. Obtained was the title compound in a 92% yield and of sufficient purity to be used in the next synthesis step:
Reaction SMILES: [F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([CH:8]([CH:18]([CH3:20])[CH3:19])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28]([CH3:34])=[N:29]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([CH:8]([CH:18]([CH3:20])[CH3:19])[CH2:9][C:10]([C:13]([F:15])([F:14])[F:16])([OH:17])[CH:11]=[N:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[CH:27][C:28]([CH3:34])=[N:29]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc2c(N)cccc2n1
Reactant: COc1c(F)cccc1C(CC(O)(C=O)C(F)(F)F)C(C)C
Agent: [Ti+4]
Agent: CC[O-]
Product: COc1c(F)cccc1C(CC(O)(C=Nc1cccc2nc(C)ccc12)C(F)(F)F)C(C)C

Procedure:
In the same way as in Example 61, 200 mg (0.62 mmol) of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-5-methyl-2-(trifluoromethyl)hexanal, 125 mg (0.80 mmol) of 5-amino-2-methylquinoline and 0.3 ml of titanium tetraethoxide are reacted to give 4-(3-fluoro-2-methoxyphenyl)-1-[(2-methylquinolin-5-yl)imino]-5-methyl-2-(trifluoromethyl)hexan-2-ol. 229 mg of imine purified by column chromatography (silica gel, hexane/ethyl acetate 0-35%) are cyclized in the same way as in Example 61 at −20° C. with 5 ml (5 mmol) of 1 M boron tribromide solution in dichloromethane to give the desired product. Column chromatography on silica gel (hexane/2-propanol 0-15%) and subsequent preparative HPLC (SunFire C18, water/methanol) yield 11 mg of product.
Reaction SMILES: N.[O:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]1[CH2:13][CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]([O:26]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH:22]=2)[NH:17][CH:16]=1.C[N:37](C)C=O>O>[O:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]1[CH2:13][CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]([NH2:37])=[O:26])[CH:22]=2)[NH:17][CH:16]=1
Reactant: CN(C)C=O
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Agent: N
Solvent: O
Product: NC(=O)c1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Ammonia (0.88, 0.2 ml) was added to a solution of 3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) ethyl]-1H-indole-5-carboxylic acid, 4-nitrophenyl ester (0.3 g) in warm (50° C.) dimethylformamide (3 ml). The mixture was stirred at 50° C. for 4 hours., poured into water (40 ml) and stirred for a further 0.5 hours. The precipitate (0.21 g) was collected and crystallised from ethanol to give the title compound (0.12 g) as an off-white solid m.p. 254°-6° C. T.L.C. Silica, Ethyl acetate:2-propanol:water:ammonia (25:15:8:2) Rf 0.75.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[C:3]=1[CH3:15].Br.[C:17](O)(=[O:19])[CH3:18]>>[C:17]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:4]1[CH:5]=[CH:6][C:7](=[O:8])[C:2]([OH:1])=[C:3]1[CH3:15])(=[O:19])[CH3:18]
Reactant: CC(=O)O
Reactant: Cc1c(O)c(=O)ccn1CCCCCO
Agent: Br
Product: CC(=O)OCCCCCn1ccc(=O)c(O)c1C
Yield: 65 %

Procedure:
3-Hydroxy-1-(5'-hydroxypentyl)-2-methylpyrid-4-one, prepared as described under (N), (2 g) is dissolved in glacial acetic acid containing about 1% w/v of hydrogen bromide and the solution is refluxed for 2 hours. The resultant mixture is subjected to rotary evaporation and the residue crystallised from aqueous ethonal to give 1-(5'-acetoxypentyl)-3-hydroxy-2-methylpyrid-4one in 65% yield, m.p. 132°-133° C., δmax (nujol) 1520, 1540, 1580, 1635, 1735 cm-1 and δ(d6DMSO), 1.6 (m, 6H), 2.1 (s, 3H), 2.4 (s, 3H), 4.05 (m, 4H), 6.4 (d, 1H), 7.3 (d, 1H).