Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(N(CC)CC)C.[C:16]([O:20][C:21]([NH:23][C@H:24]([C:27](O)=[O:28])[CH2:25][Cl:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:27](=[O:28])[C@H:24]([CH2:25][Cl:26])[NH:23][C:21]([O:20][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:22])[CH3:3]
Reactant: CCOC(=O)CN
Reactant: CC(C)(C)OC(=O)N[C@@H](CCl)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CNC(=O)[C@H](CCl)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.2 %

Procedure:
To a solution of 0.28 g (2 mmol) of glycine ethyl ester hydrochloride and 0.28 mL (2 mmol) of triethylamine in 10 mL of chloroform, 0.52 g (2 mmol) of N-(tert-butoxycarbonyl)-3-chloro-L-alanine in 6 mL of chloroform and 0.42 g (2 mmol) of dicyclohexylcarbodiimide were added at 0° C. The reaction mixture was stirred for 16 hours at room temperature. The resultant precipitate was removed by filtration and the filtrate was washed successively with 0.5N hydrochloric acid, water and 3% aqueous sodium bicarbonate, then was dried over anhydrous sodium sulfate. Removal of the solvent left a crystalline residue which was recrystallized from a mixture of ethyl acetate and n-hexane to give 0.415 g (60%) of the pure product melting at 71.5°-72.0° C. The identity of the product, which has the structural formula ##STR76## was confirmed by IR and NMR analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:9][CH3:10].Cl[S:12]([OH:15])(=[O:14])=[O:13]>ClC1C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH2:9][CH3:10])=[CH:4][C:5]([OH:8])=[C:6]([S:12]([OH:15])(=[O:14])=[O:13])[CH:7]=1
Reactant: O=S(=O)(O)Cl
Reactant: CCc1cc(O)ccc1Cl
Solvent: Clc1ccccc1
Product: CCc1cc(O)c(S(=O)(=O)O)cc1Cl

Procedure:
In a 1-liter four-necked glass flask is prepared a solution mixture of 100 g of 4-chloro-3-ethylphenol and 200 g of monochlorobenzene. While the mixture is maintained at a temperature of 25°-30° C., 80 g of chlorosulfonic acid is added dropwise. After the mixture is maintained at the same temperature for 3 hours, the reaction mass of 5-chloro-4-ethyl-2-hydroxybenzenesulfonic acid is obtained and 75.1 g of acetic acid is added to the reaction mass. After 1.33 g of aluminium chloride and 0.67 g of sulfur chloride are added, 110 g of sulfuryl chloride is added dropwise. After the addition is completed, the temperature of the mixture is raised to 35° C. and the mixture is maintained at the temperature for 5 hours. In a 2-liter flask is charged 960 g of water, and the reaction mass is poured into the flask under stirring. The reaction mixture is separated into an aqueous layer and an oil layer, and the lower oil layer is removed to obtain aqueous solution of 3,5-dichloro-4-ethyl-2-hydroxybenzenesulfonic acid. After cooling to 20° C., 184 g of a 70% nitric acid solution is added dropwise, maintaining the temperature at 20°-25° C. After the addition is completed, the reaction mixture is heated to 45° C. and maintained at the temperature for 4 hours. The reaction mixture is cooled to 20° C. and filtered. The product is washed with water and dried to give 2,4-dichloro-3-ethyl-6-nitrophenol.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.Cl[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:27]=[CH:26][C:25]2[N:24]=[C:23]([NH2:28])[C:22]3[N:29]=[C:30]([CH2:35][O:36][CH3:37])[N:31]([CH2:32][CH2:33][CH3:34])[C:21]=3[C:20]=2[CH:19]=1.CN(C=O)C>O>[CH3:37][O:36][CH2:35][C:30]1[N:31]([CH2:32][CH2:33][CH3:34])[C:21]2[C:20]3[CH:19]=[C:18]([O:17][CH2:16][CH2:15][CH2:14][N:7]4[CH2:12][CH2:11][O:10][CH2:9][CH2:8]4)[CH:27]=[CH:26][C:25]=3[N:24]=[C:23]([NH2:28])[C:22]=2[N:29]=1
Reactant: CCCn1c(COC)nc2c(N)nc3ccc(OCCCCl)cc3c21
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c(COC)nc2c(N)nc3ccc(OCCCN4CCOCC4)cc3c21
Temperature: 50 °C
Reaction time: 3 h
Yield: 9.1 %

Procedure:
Potassium carbonate (530 mg, 3.84 mmol), morpholine (92 mg, 1.06 mmol), and 8-(3-chloropropoxy)-2-methoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine (350 mg, 0.96 mmol) were added to 15 mL of DMF and heated to 50° C. for 18 hours. Analysis by LC/MS indicated the presence of two peaks and the reaction mixture was cooled and poured into 500 mL of deionized water. After three hours, no precipitation was observed. Sodium chloride (250 g) was added to the mixture and the mixture was stirred vigorously overnight. The precipitate was collected by filtration, dissolved in dichloromethane, and purified by chromatography on a HORIZON HPFC system (eluting with a gradient of methanol/dichloromethane (20:80) in dichloromethane from 0:100 to 40:60). The resulting material was concentrated under reduced pressure, crystallized from acetonitrile, and dried under high vacuum to yield 36 mg of 2-methoxymethyl-8-(3-morpholin-4-ylpropoxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine as tan crystals, mp 193-196° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23]4[C:28]([C:29](=[O:38])[C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23]4[C:28]([C:29](=[O:38])[C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)[C:3]=12
Reactant: COc1ccc(-c2nn(C(C)c3oc4ccccc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2ccc(O)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 33 %

Procedure:
To a solution of Example 88 (0.150 g, 0.295 mmoles) in dichloromethane (4 ml), BBr3 (1M in dichloromethane, 1.5 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N HCl solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as off-white solid (0.048 g, 33% yield). MP: 244-247° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 9.79(s,1H), 8.04(s, 1H), 8.04(dd, J=8.5,1.4 Hz, 1H), 7.85(m,1H), 7.68(d, J=8.5Hz, 1H), 7.53(t, J=7.6Hz, 1H), 7.42(d, J=8.5Hz, 2H), 7.28(br s,1H), 7.06(t, J=8.5 Hz, 1H), 6.91(d, J=8.5Hz, 2H), 6.91(br s,2H), 6.00(q, J=7.1 Hz, 1H),1.88(d, J=7.0 Hz, 3H). Mass: 492.69(M+−1).
Reaction SMILES: C[O:2][C:3](=[O:25])[C@@H:4]([N:9]([CH2:11][C:12]1[CH:13]([CH:23]=[O:24])[O:14][C:15]2[C:20]([CH:21]=1)=[C:19]([Cl:22])[CH:18]=[CH:17][CH:16]=2)[CH3:10])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1.O>[Cl:22][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:20]=1[CH2:21][C:12]([CH2:11][N:9]([CH3:10])[C@@H:4]([CH2:5][CH:6]([CH3:7])[CH3:8])[C:3]([OH:25])=[O:2])=[C:13]([CH:23]=[O:24])[O:14]2
Reactant: COC(=O)[C@H](CC(C)C)N(C)CC1=Cc2c(Cl)cccc2OC1C=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)O)N(C)CC1=C(C=O)Oc2cccc(Cl)c2C1
Yield: 88.6 %

Procedure:
A solution of (S)-2-[(5-chloro-2-formyl-2H-chromen-3-ylmethyl)-methyl-amino]-4-methyl-pentanoic acid methyl ester (2.0 g, 5.71 mmol) and lithium hydroxide monohydrate (0.312 g, 7.40 mmol) was stirred at 25° C. for 2 hours in tetrahydrofuran-water (3:1) mixture (90 mL). The reaction mixture was concentrated in vacuo to remove tetrahydrofuran, and the residue was acidified with 2N hydrochloric acid, and diluted with water. The resulting solution was extracted with ethyl acetate (3×). The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to afford (S)-2-[(5-chloro-2-formyl-4H-chromen-3-ylmethyl)-methyl-amino]-4-methyl-pentanoic acid (1.78 g, 93.6%).
Reaction SMILES: OC1C=CC2CCCCN(CC)C=2C=1.C[O:16][C:17]1[CH:26]=[CH:25][C:24]2[CH2:27][CH2:28][CH2:29][CH2:30][N:22]3[C:23]=2[C:18]=1[CH2:19][CH2:20][CH2:21]3>>[OH:16][C:17]1[CH:26]=[CH:25][C:24]2[CH2:27][CH2:28][CH2:29][CH2:30][N:22]3[C:23]=2[C:18]=1[CH2:19][CH2:20][CH2:21]3
Reactant: COc1ccc2c3c1CCCN3CCCC2
Agent: CCN1CCCCc2ccc(O)cc21
Product: Oc1ccc2c3c1CCCN3CCCC2

Procedure:
The title compound was synthesized in a similar manner as 8-hydroxy-2,3,4,5-tetrahydro-1-ethylbenzo[b]azepine from 11-methoxy-2,3,5,6,7,8-hexahydro-1H-azepino[3,2,1-ij]quinoline: 1H NMR (DMSO-d6) δ 8.82 (s, 1H), 6.64 (d, 1H); 6.22 (d, 1H), 3.03-2.99 (m, 2H), 2.87-2.83 (m, 2H), 2.55-2.50 (m, 2H), 2.53-2.49 (m, 2H), 1.68-1.61 (m, 4H), 1.45-1.37 (m, 2H); MS expected 204 (C13H18NO, M+1), found 204.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[C@@H:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.[CH3:27][O+](C)C.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C>ClCCl>[CH2:1]([O:8][C:9](=[O:21])[C@@H:10]([NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:11][O:12][CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[O+](C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)OCc1ccccc1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.6 %

Procedure:
To a solution of the compound of Formula XII(a), (S)-2-tert-butoxycarbonylamino-3-hydroxy-propionic acid benzyl ester (1.7 g, 5.76 mmol) in dichloromethane (50 mL) was added trimethyloxonium tetrafluoroborate (1.11 g, 7.50 mmol), followed by the portion-wise addition of proton sponge (1.61 g, 7.50 mmol). After stirring for 24 hrs at RT, the solution was concentrated, and the residue was dissolved in ethyl acetate, and the solution filtered through a pad of celite. The filtrate was washed with 1 M HCl and brine. The organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Silica-gel flash chromatography with 5% to 15% ethyl acetate in hexanes afforded the compound of Formula XIII(b), (S)-2-tert-butoxycarbonylamino-3-methoxy-propionic acid benzyl ester (1.24 g, 69.6%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ (ppm) 7.35-7.29 (m, 5H), 4.90-4.87 (m, 1H), 4.51 (s, 2H), 3.92-3.87 (m, 1H), 3.80-3.78 (m, 1H), 3.56 (dd, 2H), 3.42 (dd, 1H), 3.33 (s, 3H), 1.42 (s, 9H).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:29]Br.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC3C=CC(F)=C(F)C=3)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:29][C:28]3[CH:31]=[CH:32][C:33]([F:34])=[C:26]([F:25])[CH:27]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: Fc1ccc(CBr)cc1F
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: CC(C)(C)OC(=O)N1CCc2nn(Cc3ccc(F)c(F)c3)c(-c3ccc(Cl)cc3)c2CC1
Product: Fc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)cc1F

Procedure:
The title compound (0.002 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.07 g) using 3,4-difluorobenzyl bromide (0.4 mL) in place of benzyl chloride. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-(3,4-difluoro-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C20H18ClF2N3, 373.12. found, m/z 374.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.41-7.38 (m, 2H), 7.36-7.33 (m, 2H), 7.22-7.20 (m, 1H), 7.07-7.02 (m, 1H), 6.96-6.92 (m, 1H), 5.26 (s, 2H), 3.06-3.02 (m, 4H), 2.94-2.91 (m, 2H), 2.87-2.84 (m, 2H).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[C:15]([F:16])=[C:14]([CH2:17][CH3:18])[N:13]=[CH:12][N:11]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[C:27](=[O:34])[CH2:28][N:29]1[CH:33]=[N:32][CH:31]=[N:30]1>C1COCC1>[Cl:9][C:10]1[C:15]([F:16])=[C:14]([CH:17]([CH3:18])[C:27]([C:21]2[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=2[F:19])([OH:34])[CH2:28][N:29]2[CH:33]=[N:32][CH:31]=[N:30]2)[N:13]=[CH:12][N:11]=1
Reactant: CCc1ncnc(Cl)c1F
Reactant: O=C(Cn1cncn1)c1ccc(F)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(c1ncnc(Cl)c1F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: -70 °C
Reaction time: 3 h

Procedure:
To a solution of LDA (20 mmol) in THF1 (50 ml) (prepared by a similar method to that used in Example 1) under a nitrogen atmosphere and at -70° C. was added dropwise a solution of the product of part (ii) (3.2 g, 20 mmol) in THF1 (30 ml) over 15 minutes. The resulting mixture was stirred at this temperature for 3 hours. To the resulting solution was added a solution of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (4.46 g, 20 mmol) in THF (50 ml) and the mixture was maintained at -70° C. for 1 hour and then at -50° C. for a further 1 hour. The reaction was quenched by the addition of a solution of glacial acetic acid (1.2 g) in water (10 ml) and the mixture was allowed to warm to room temperature. The organic phase was separated, the aqueous phase extracted with ethyl acetate (20 ml) and the combined organic layers were dried over magnesium sulphate and concentrated under reduced pressure. Column chromatography of the residue on silica using 3:2 ethyl acetate/diethyl ether as the eluant first gave, after combination and evaporation of appropriate fractions and trituration with diethyl ether, the title compound, enantiomeric pair B (0.94 g, 12%), m.p. 92° C. Found: C,49.93; H,3.57; N,18.17; C16H13ClF3N5O requires: C50.06; H,3.39; N,18.25%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[CH2:23][CH2:22][C@H:21]([CH3:24])[N:20](C(=O)C(OC)(C4C=CC=CC=4)C(F)(F)F)[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:15]3[CH2:23][CH2:22][C@H:21]([CH3:24])[NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(C(=O)N1c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c2CC[C@@H]1C)(c1ccccc1)C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: C[C@H]1CCc2c(ncnc2N2CCN(C(=O)OC(C)(C)C)CC2)N1
Temperature: 25 °C
Reaction time: 96 h
Yield: 62.7 %

Procedure:
To a solution of (7S)-4-[7-Methyl-8-(3,3,3-trifluoro-2-methoxy-2-phenyl-propionyl)-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (84 mg, 0.153 mmol) in MeOH (5 mL) was added LiOH (3M, 4 mL). The mixture was stirred at room temperature for 4 days and then neutralized with 2N HCl. The solvent was removed and the residue was subject to column chromatography, eluted by ethyl acetate—DCM/MeOH (20:1) to afford (7S)-4-(7-Methyl-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (32 mg, 63%). 1H NMR (CDCl3, 400 MHz) δ 8.11 (s, 1H), 5.20 (s, 1H), 3.54 (m, 5H), 3.30 (m, 4H), 2.57 (m, 2H), 1.95 (m, 1H), 1.48 (s, 9H), 1.40 (m, 1H), 1.27 (d, J=6.4 Hz, 3H). MS (APCI+) [M+H]+334.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]([CH2:7][N:8]1[N:12]=[N:11][C:10](/[CH:13]=[C:14]2\[CH2:15][N:16]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:18][C:19]\2=[O:20])=[N:9]1)=[O:6]>O1CCCC1>[CH3:3][O:4][C:5]([CH2:7][N:8]1[N:12]=[N:11][C:10](/[CH:13]=[C:14]2\[CH2:15][N:16]([C:21]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:17][CH2:18][CH:19]\2[OH:20])=[N:9]1)=[O:6]
Reactant: COC(=O)Cn1nnc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2=O)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)Cn1nnc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2O)n1
Reaction time: 2 h
Yield: 29 %

Procedure:
Sodium borohydride (400 mg) was added to a solution of (E)-3-{[2-(methoxycarbonylmethyl)-2H-tetrazol-5-yl]methylidene}-1-(triphenylmethyl)piperidin-4-one (5.18 g) in tetrahydrofuran (100 ml) at 0° C. After the mixture was stirred at the same temperature for 2 hours, the reaction was quenched by addition of a saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, and the extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure, and the objective material that emerged was collected by filtration. The mother liquor was concentrated and the residue was purified by silica gel chromatography using hexane, ethyl acetate, and dichloromethane (1:1:1) as an eluent to afford an additional amount of the title compound as a colourless amorphous solid. Total amount: 1.5 g, total yield: 29%.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[O:24][CH:25]([CH2:27][CH3:28])[CH3:26])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH:25]([O:24][C:18]1[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)=[O:29])([CH2:27][CH3:28])[CH3:26]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC(C)CC)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC(C)Oc1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
The mixture of 2-(2-sec-butoxy-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (12) (176 mg, 0.44 mmol) and KOH (500 mg, 8.93 mmol) is dissolved in EtOH (6 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate came out of the water. The precipitate is filtered to give a pure product (13) as white solid (162 mg, 100%).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([I:8])[C:5]([OH:9])=[CH:4][CH:3]=1.CI.[C:12](=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[N:7]=[C:6]([I:8])[C:5]([O:9][CH3:12])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)nc1I
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COc1ccc(F)nc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
6-Fluoro-2-iodo-pyridin-3-ol (50 mg) was dissolved in acetonitrile (2 ml) to prepare a solution. Methyl iodide (148 mg) and potassium carbonate (87 mg) were added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous magnesium sulfate, the solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform to give 6-fluoro-2-iodo-3-methoxypyridine (52 mg, yield 100%).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[H-].[Na+].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[C:14]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1Nc2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C(=O)N(C(=O)c2ccccc2)c2ccccc21
Reaction time: 0.17 h
Yield: 79.6 %

Procedure:
14.7 g (0.10 mole) of isatin (dissolved in 100 ml of N,N-dimethylformamide) are added to 2.6 g (0.11 mole) of sodium hydride in 100 ml of N,N-dimethylformamide, while stirring. After the mixture has been stirred for one hour at room temperature, 14.1 g (0.10 mole) of benzoyl chloride are added dropwise at 0° C. Stirring is then continued for 10 minutes at 0° C. and the mixture is poured onto ice. The precipitate which separates out is filtered off under suction and dried to give 20 g (80%) of N-benzoylisatin as yellow crystals.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7](=[O:12])[C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[C:13]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)([OH:15])=[O:14]>CN(C=O)C>[F:9][C:8]([F:11])([F:10])[C:7]([C:5]1[S:6][C:2]([C:19]2[CH:20]=[CH:21][C:16]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=2)=[CH:3][CH:4]=1)=[O:12]
Reactant: O=C(c1ccc(Br)s1)C(F)(F)F
Reactant: O=C(O)c1ccc(B(O)O)cc1
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(-c2ccc(C(=O)C(F)(F)F)s2)cc1

Procedure:
The titled compound was prepared from 1-(5-bromo-2-thienyl)-2,2,2-trifluoroethanone (C2) (1.0 eq) and the corresponding 4-carboxyphenylboronic acid (1.3 eq) in DMF (1.0M) following the general procedure for Suzuki cross-coupling described in example 3 step 1. After completation of the reaction the solution mixture was concentrated under reduced pressure and 1N HCl solution was added. The resulting precipitate formed was washed several times with DCM and used in the next coupling reaction without further purification. 1H NMR (400 MHz, DMSO, 300K) δ 13.14 (1H, broad s), 8.18 (1H, broad s), 8.06-8.00 (4H, m), 7.95 (1H, d, J=4.2 Hz). MS (ES) C13H7F3O3S requires: 300, found: 301 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:35][CH:36]1[CH:43]2[CH2:44][CH:39]3[CH2:40][CH:41]([CH2:45][CH:37]1[CH2:38]3)[CH2:42]2>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([NH:35][CH:36]1[CH:37]2[CH2:45][CH:41]3[CH2:40][CH:39]([CH2:44][CH:43]1[CH2:42]3)[CH2:38]2)=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NC1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold (ca. -78°) solution of 106 g (0.4 mole) of t-butoxycarbonyl-L-phenylalanine (Boc-Phe) and 88 ml (ca. 0.8 mole) of N-methylmorpholine in 300 ml of dichloromethane, stirred over 30 g of 4 A molecular sieves, was added dropwise 52.4 ml (ca. 0.4 mole) of isobutyl chloroformate. The mixture was allowed to warm slowly to 5° and then recooled to about -78°. After adding 75 g (0.4 mole) of 2-aminoadamantane, the mixture was allowed to warm to room temperature and to stir overnight. The mixture was clarified by filtration and washed with several portions of 0.5M sodium bisulfate. The organic layer was heated at reflux over activated charcoal, filtered, dried over sodium sulfate, and concentrate in vacuo to dryness. The resultant title compound was used without further purification in subsequent reactions.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[OH-].[Na+].CO.Cl>O>[C:3]1([CH:8]=[CH:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: CC(=O)c1ccccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(C=Cc1ccccc1)c1ccccc1

Procedure:
A solution of 2.50 g (19.0 mmol) of 2'-hydroxyacetophenone, 2.42 g (18.6 mmol) of phenylpropargyladehyde, 3.44 g NaOH (in 9 mL of water) and 50 mL MeOH was stirred for 16 hours before the solution was poured into 500 mL water. The resulting mixture was neutralized with dilute HCl and extracted with CH2Cl2. The solvent was removed from the organic phase. Column separation with CH2Cl2 -petroleum ether (1:1) gave a pure intermediate chalcone product. Further oxidation of the above chalcone was carried out with excess H2O2 (30%) in basic (NaOH aq.) MeOH solution for 18 hours. This solution was poured into water, and neutralized with dilute HCl. The resulting light yellow precipitate was collected by filtration and the pure desired product was obtained by recrystallization from MeOH with 2% overall yield. MP: 153°-154° C. Quantum yield (relative to 3-hydroxyflavone in CH2Cl2) 1.6. Extinction coefficient εmax (M-1 cm-1) 21,000. λmax (abs)=372 nm and λmax (em)=540 nm.