Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[O:9][CH2:10][C:11]([OH:13])=O)=[O:5])C.[C@@H:17]1([NH2:21])[CH2:19][C@@H:18]1[NH2:20]>>[C@@H:17]1([NH:21][C:11](=[O:13])[CH2:10][O:9][C:8]2[CH:7]=[C:6]([CH:16]=[CH:15][CH:14]=2)[C:4]([OH:3])=[O:5])[CH2:19][C@@H:18]1[NH:20][C:11](=[O:13])[CH2:10][O:9][C:8]1[CH:7]=[C:6]([CH:16]=[CH:15][CH:14]=1)[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cccc(OCC(=O)O)c1
Reactant: N[C@@H]1C[C@@H]1N
Product: O=C(COc1cccc(C(=O)O)c1)N[C@H]1C[C@H]1NC(=O)COc1cccc(C(=O)O)c1

Procedure:
By following the processes described in stages A to C of Example R13, Example R36 is prepared by dimerization of [3-(ethoxycarbonyl)phenoxy]acetic acid with 1,2-cis-cyclopropanediamine (CAS 365996-16-3). A white powder is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=S)=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[OH:19].O=O.[K+].O>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:19][C:13]3[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=3[N:11]=2)=[CH:4][CH:3]=1
Reactant: S=C=Nc1ccc(Br)cc1
Reactant: Nc1cc(Cl)ccc1O
Agent: O=O
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Clc1ccc2oc(Nc3ccc(Br)cc3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
4-Bromophenyl isothiocyanate (3.639 g, 17.00 mmol) was added to a solution of 2-amino-4-chlorophenol (2.441 g, 17.00 mmol) in acetonitrile (20 mL) and the reaction was stirred at room temperature for 2 h. The resulting brown solution was then added dropwise, via a dropping funnel, to a suspension of potassium superoxide (6.04 g, 85.0 mmol) in acetonitrile (20 mL) pre-cooled to 0° C. in an ice bath. After 20 minutes the initial exotherm had subsided and the reaction was allowed to warm to room temperature for 40 minutes. Water (120 mL) was added dropwise and the resulting off-white solid was collected by filtration, washed with additional water (60 mL) and dried overnight on a lyophilizer to afford N2-(4-bromophenyl)-5-chloro-1,3-benzoxazol-2-amine as an off-white solid (4.06 g, 74%); RP-HPLC Rt 17.229 min, 99% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 321 (M−H)− and 323 (M−H)−; 1H NMR (400 MHz, d6-DMSO) 7.17 (1H, dd, J 8.5 and 1.9 Hz), 7.53 (4H, m), 7.71 (2H, d, J 8.8 Hz), and 10.95 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])=[CH:7][CH:6]=1)=[O:4].F[B-](F)(F)F.[O:22]=[N+:23]=[O:24]>ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])=[C:9]([N+:23]([O-:24])=[O:22])[CH:10]=1)=[O:4]
Reactant: COC(=O)c1ccc(N2CCCC2=O)cc1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(N2CCCC2=O)c([N+](=O)[O-])c1
Temperature: 10 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
An ice-cold mixture of the above ester (2.0 g, 9.1 mmol) in 30 mL of dichloromethane was treated with nitronium tetrafluoroborate (2.5 g, 18.8 mmol). The resulting mixture was stirred at 10° C. for 2 h and then at ambient temperature for 4 h. The reaction mixture was quenched with water (20 mL) and the organic layer was evaporated under vacuum. The white solid precipitate was collected by filtration, washed with water and dried to give 2.2 g (92%) of 1-(4-methoxycarbonyl-2-nitrophenyl)pyrrolidin-2-one, mp 159-161° C. (chloroforn/ether).
Reaction SMILES: F[C:2](F)(F)CC[Mg]Br.[CH2:9]([O:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1)[CH3:10]>O1CCCC1>[CH2:9]([O:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])([CH3:2])[CH3:21])=[CH:16][CH:15]=1)[CH3:10]
Reactant: FC(F)(F)CC[Mg]Br
Reactant: CCOCOc1ccc(C(C)=O)cc1
Solvent: C1CCOC1
Product: CCOCOc1ccc(C(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
In a 500 milliliter, three-necked oven-dried round bottom flask equipped with a magnetic stirrer and charged with 200 milliliters of 0.50 M (3,3,3-trifluoropropyl)magnesium bromide in tetrahydrofuran was added 19.4 grams (0.1 mole) of 1-(4-(ethoxymethoxy)phenyl)ethanone and the mixture was stirred at room temperature for 4 hours. The reaction was quenched by slowly pouring the mixture into 400 milliliters saturated ammonium chloride solution and extracting the product into 400 milliliters of ethyl acetate, and washing with brine then water to a neutral pH. The ethyl acetate extracts were then dried over sodium sulfate, filtered, and concentrated in the rotary evaporator affording 20.17 grams (˜96% yield) of 2-(4-(ethoxymethoxy)phenyl)propan-2-ol as an amber oil which was used without further purification. 20 grams (0.096 mole) 2-(4-(ethoxymethoxy)phenyl)propan-2-ol and 11.6 grams (0.11 mole) of triethylamine were dissolved in 40 milliliters of methylene chloride and slowly added to a flask equipped with magnetic stirrer and 11 milliliters (0.105 mole) of methacroyl chloride in 100 milliliters of dichloromethane, which had been cooled to 0° C. The resultant mixture was slowly warmed to room temperature and allowed to stir for 12 hours. Upon completion of the reaction, confirmed by thin layer chromatography, the mixture was quenched by pouring into 400 milliliters of deionized water and the product was extracted into methylene chloride. The methylene chloride extracts were then dried over sodium sulfate, filtered, and concentrated in the rotary evaporator affording 29.3 grams (˜85% yield) of 2-(4-(ethoxymethoxy)phenyl)-5,5,5-trifluoropentan-2-yl methacrylate as an amber oil. The oil was purified further by passing through a silica gel plug eluting with 70/30 hexanes/methylene chloride affording 19 grams of the pure product. 1H NMR (500 MHz, Acetone): δ 7.29-7.26 (d, 2H, 8.5 Hz), 6.98-6.95 (d, 2H, 8 Hz), 6.06 (s, 1H), 5.57 (s, 1H) 5.20 (s, 2H) 3.69-3.66 (q, 2H), 2.48-2.1 (m/m, 4H), 1.884 (s, 3H), 1.80 (s, 3H), 1.17-1.12 (t, 3H).
Reaction SMILES: [CH:1](NC(C)C)(C)C.IC.[C:10]([O:14][C:15](=[O:27])[NH:16][C@@H:17]([C:19]1[N:23]([CH2:24][CH3:25])[C:22]([SH:26])=[N:21][N:20]=1)[CH3:18])([CH3:13])([CH3:12])[CH3:11]>O1CCCC1>[C:10]([O:14][C:15](=[O:27])[NH:16][C@@H:17]([C:19]1[N:23]([CH2:24][CH3:25])[C:22]([S:26][CH3:1])=[N:21][N:20]=1)[CH3:18])([CH3:11])([CH3:12])[CH3:13]
Reactant: CCn1c(S)nnc1[C@@H](C)NC(=O)OC(C)(C)C
Reactant: CC(C)NC(C)C
Solvent: CI
Solvent: C1CCOC1
Product: CCn1c(SC)nnc1[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Diisopropylamine (17.4 ml) and iodomethane (7.7 ml) were added to a tetrahydrofuran (200 ml) solution of the [(R)-1-(4-ethyl-5-mercapto-4H-[1,2,4]triazol-3-yl)ethyl]-carbamic acid t-butyl ester (28.12 g) obtained in Example 8-(3). The mixture was stirred for 1 hour at room temperature, and then precipitated crystals were filtered. The filtrate was concentrated, and the resulting crude crystals were washed with a hexane-ethyl acetate solvent mixture (3:1, 200 ml), followed by drying, to obtain [(R)-1-(4-ethyl-5-methylsulfanyl-4H-[1,2,4]triazol-3-yl)ethyl]-carbamic acid t-butyl ester as a white powder (29.5 g).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([C:11]2[C:12](=[O:27])[NH:13][C:14](=[O:26])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH3:25])[CH:17]=2)=[CH:4][CH:3]=1.[Cl:28]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([C:11]2[C:12](=[O:27])[NH:13][C:14](=[O:26])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH3:25])[C:17]=2[Cl:28])=[CH:4][CH:3]=1
Reactant: Cn1cc(C2=C(c3ccc(O)c4ccoc34)C(=O)NC2=O)c2ccccc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: Cn1c(Cl)c(C2=C(c3ccc(O)c4ccoc34)C(=O)NC2=O)c2ccccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 12.4 %

Procedure:
Dissolve 3-(4-hydroxybenzofur-7-yl)-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione (0.25 g, 0.70 mmol) in 50 mL chloroform under nitrogen. Add 0.093 g (0.70 mmol, 1 equiv) N-chloro succinimide and attach a reflux condenser. Heat to 50° C. and let go overnight. Let cool to room temperature, then extract with ethyl acetate versus water. Wash with brine, then dry over sodium sulfate. Filter and concentrate in vacuo. Purification by column chromatography (20% ethyl acetate: hexanes) yields 0.034 g (12%) product. High Res. Mass Spec (m/z): Calcd 393.0655 Found 393.0642.
Reaction SMILES: N[CH:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].N([O-])=O.[Na+]>C(O)(=O)C>[C:6]([O:8][CH:2]([CH:3]([CH3:5])[CH3:4])[C:6]([OH:8])=[O:7])(=[O:7])[CH3:2]
Reactant: CC(C)C(N)C(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OC(C(=O)O)C(C)C
Temperature: 25 °C
Yield: 152.3 %

Procedure:
Into 300ml of glacial acetic acid there was stirred 11.7g (0.1 moles) of dl-valine. 13.8g of sodium nitrite was added, with stirring, over the duration of 1 hour and the temperature of the reaction medium maintained at room temperature by means of a water bath. After the mixture had been stirred overnight at room temperature, the acetic acid was evaporated off and water (50ml) added. Solvent extraction using diethyl ether then followed. The diethyl ether portion was washed with water, dried over anhydrous magnesium sulphate and the ether evaporated off to yield 12.2g of the title product as a colourless oil.
Reaction SMILES: [C:1]([C:3]1[N:7]2[C:8]3[C:13]([N:14]=[C:15]([NH:16][CH2:17][CH2:18][CH2:19][OH:20])[C:6]2=[N:5][CH:4]=1)=[CH:12][C:11]([C:21]([F:24])([F:23])[F:22])=[CH:10][CH:9]=3)#[CH:2].C[Si]([N:29]=[N+:30]=[N-:31])(C)C>CO>[NH:29]1[C:1]([C:3]2[N:7]3[C:8]4[C:13]([N:14]=[C:15]([NH:16][CH2:17][CH2:18][CH2:19][OH:20])[C:6]3=[N:5][CH:4]=2)=[CH:12][C:11]([C:21]([F:22])([F:23])[F:24])=[CH:10][CH:9]=4)=[CH:2][N:31]=[N:30]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#Cc1cnc2c(NCCCO)nc3cc(C(F)(F)F)ccc3n12
Solvent: CO
Product: OCCCNc1nc2cc(C(F)(F)F)ccc2n2c(-c3cnn[nH]3)cnc12
Temperature: 100 °C
Reaction time: 65 h
Yield: 13 %

Procedure:
A suspension of the 3-{[1-ethynyl-7-(trifluoromethyl)imidazo[1,2-a]quinoxalin-4-yl]amino}propan-1-ol as prepared in example 30 (20 mg, 0.06 mmol) in neat trimethylsilylazide (200 μL) was stirred at 100° C. for 65 h in a reaction vial. The reaction mixture was then stirred at 105° C. for 24 h to go to completion, and was then allowed to cool to room temperature, diluted in methanol (2 mL) and concentrated under vacuum. The crude product was purified by preparative TLC (silica gel, dichloromethane/methanol 90/10) to afford a solid. Further purification by washing with dichloromethane afforded the title compound (3 mg, 13%) as a yellow solid.
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].[CH:5]#[C:6][CH2:7][C:8](=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].Cl>CCOCC>[CH:1]([C:8]([OH:14])([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:7][C:6]#[CH:5])=[CH2:2]
Reactant: C=C[Mg]Cl
Reactant: C#CCC(=O)CCCCC
Agent: Cl
Solvent: CCOCC
Product: C#CCC(O)(C=C)CCCCC

Procedure:
A solution of 130 ml of 2.3 molar vinyl magnesium chloride in 100 ml of ether is cooled to 0° and treated dropwise with 14 g of 1-nonyn-4-one in 50 ml of ether. The reaction mixture is allowed to come to room temperature and poured into ether and dilute hydrochloric acid. The organic layer is separated, washed with water, dried over sodium sulfate, stripped of solvent and the residue is chromatographed on silica gel with 20% ethyl acetate in hexane as eluent to give the title product.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[N:13]2[C:14]3[N:5]([C:6](=[O:26])[CH2:7][N:8]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C:9]=3[CH:10]=[CH:11][C:12]2=[O:15])[CH2:4]1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:34][S:35]([O:1][CH2:2][C@H:3]1[N:13]2[C:14]3[N:5]([C:6](=[O:26])[CH2:7][N:8]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C:9]=3[CH:10]=[CH:11][C:12]2=[O:15])[CH2:4]1)(=[O:37])=[O:36]
Reactant: O=C(OCc1ccccc1)N1CC(=O)N2C[C@@H](CO)n3c2c1ccc3=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@@H]1CN2C(=O)CN(C(=O)OCc3ccccc3)c3ccc(=O)n1c32
Temperature: 25 °C
Yield: 78.6 %

Procedure:
Phenylmethyl (1S)-1-(hydroxymethyl)-3,8-dioxo-1,2,3,4-tetrahydro-5H,8H-2a,5,8a-triazaacenaphthylene-5-carboxylate (242 mg, 0.681 mmol) (for a preparation see Example 13(g)) was dissolved in DCM (10 ml) at room temperature under argon and then treated with triethylamine (0.114 ml, 0.817 mmol). The mixture was then cooled using an ice-water bath. Methanesulfonyl chloride (0.058 ml, 0.749 mmol) was then added and the reaction was allowed to warm up to room temperature. After 1 h the mixture was washed with sat NaHCO3 (10 ml). The aqueous layer was extracted with DCM (2×50 ml) and the combined organic extracts dried on MgSO4, filtered and evaporated to afford the product as a yellow foam (232 mg, 95% purity by LCMS, 74.7%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([O:21][C:22](=[O:55])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][S:30]([CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41]([O:47][Si](C(C)(C)C)(C)C)[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:37][CH:36]=1)(=[O:32])=[O:31])[CH3:20]>C1COCC1.CCOC(C)=O>[CH2:19]([O:21][C:22](=[O:55])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][S:30]([CH2:33][CH2:34][C:35]1[CH:36]=[CH:37][C:38]([CH:41]([OH:47])[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:39][CH:40]=1)(=[O:31])=[O:32])[CH3:20]
Reactant: CCCCCC(O[Si](C)(C)C(C)(C)C)c1ccc(CCS(=O)(=O)NCCCCCCC(=O)OCC)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCC(O)c1ccc(CCS(=O)(=O)NCCCCCCC(=O)OCC)cc1
Reaction time: 16 h
Yield: 92.6 %

Procedure:
Tetrabutylammonium fluoride (0.6 mL of a 1.0 M solution in THF, 0.6 mmol) was added to a solution of the silylether 10 (159 mg, 0.29 mmol) in THF (3.0 mL) at 23° C. The reaction was stirred for 16 h, diluted with EtOAc and washed with water. The organic portion was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. FCC (silica gel, 2:1 hex/EtOAc) afforded 118.6 mg (94%) of the alcohol 11 as a light yellow, viscous oil.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:15][C:16]([F:21])([F:20])[CH:17]([OH:19])[CH3:18]>>[CH3:14][S:11]([C:8]1[CH:9]=[CH:10][C:2]([O:19][CH:17]([CH3:18])[C:16]([F:21])([F:20])[F:15])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: CC(O)C(F)(F)F
Product: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F

Procedure:
Prepared in analogy to Example B1 (b) from 2-chloro-5-methanesulfonyl-benzoic acid (Example B1(a)) and rac-1,1,1-trifluoro-propan-2-ol. The crude material was purified by preparative HPLC to yield the title compound as a white solid. MS (m/e): 311.3 ([M−H]−, 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[NH2:9].[C:10]1([CH3:19])[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O>>[Cl:8][C:6]1[N:5]=[N:4][C:3]([NH2:9])=[C:2]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH3:19])[CH:7]=1
Reactant: Cc1ccccc1B(O)O
Reactant: Nc1nnc(Cl)cc1Br
Product: Cc1ccccc1-c1cc(Cl)nnc1N

Procedure:
The title compound was prepared in analogy to example 1, intermediate b, from 4-bromo-6-chloropyridazin-3-amine (CAS RN 446273-59-2) and o-tolylboronic acid (CAS RN 16419-60-6). Light brown solid (41%). MS (ESI+): m/z=220.064 ([M+H]+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:16])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=1)[NH2:6].[N:17]1[S:21][N:20]=[C:19]2[C:22]([S:26]([NH:29][C:30]3[CH:38]=[C:37]([Br:39])[CH:36]=[CH:35][C:31]=3[C:32](O)=[O:33])(=[O:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=12>>[CH3:2][O:3][C:4](=[O:16])[C@@H:5]([NH:6][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:37]([Br:39])=[CH:38][C:30]=1[NH:29][S:26]([C:22]1[C:19]2=[N:20][S:21][N:17]=[C:18]2[CH:25]=[CH:24][CH:23]=1)(=[O:28])=[O:27])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=1
Reactant: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: COC(=O)[C@@H](N)Cc1ccc(F)c(Br)c1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(F)c(Br)c1)NC(=O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
The title compound was prepared as in EXAMPLE 1, substituting 3-bromo-4-fluoro-L-phenylalanine methyl ester hydrochloride and 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-benzoic acid in Part C. HPLC: RT=10.39 min. MS (ESI−): mass calcd. for C23H17Br2FN4O5S2, 672.34; m/z found, 671 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.42 (s, 1H), 8.37 (d, J=7.1, 1H), 8.22 (d, J=8.8, 1H), 7.88 (s, 1H), 7.75-7.71 (m, 1H), 7.27-7.25 (m, 1H), 7.11 (q, J=8.4, 2H), 7.09-6.94 (m, 2H), 6.56 (d, J=7.0, 1H), 4.94 (q, J=5.8, 1H), 3.82 (s, 3H), 3.25-3.11 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:21])[O:4][C:5]2[CH:18]=[C:17]([CH3:19])[C:16]([Cl:20])=[CH:15][C:6]=2[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14].CN(C)C1C=CC=CC=1.[F:31][C:32]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:33]=1[C:34](Cl)=[O:35]>ClCCl>[Cl:20][C:16]1[C:17]([CH3:19])=[CH:18][C:5]2[O:4][C:3](=[O:21])[C:2]([NH:1][C:34](=[O:35])[C:33]3[CH:37]=[CH:38][C:39]([F:41])=[CH:40][C:32]=3[F:31])=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH3:14])[C:6]=2[CH:15]=1
Reactant: Cc1cc2oc(=O)c(N)c(-c3ccccc3C)c2cc1Cl
Reactant: O=C(Cl)c1ccc(F)cc1F
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: Cc1cc2oc(=O)c(NC(=O)c3ccc(F)cc3F)c(-c3ccccc3C)c2cc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 3-amino-6-chloro-7-methyl-4-(2-methylphenyl)-2H-1-benzopyran-2- one (300 mg), N,N-dimethylaniline (0.13 ml) and dichloromethane (4 ml) was dropwise added 2,4-difluorobenzoyl chloride (0.15 ml). The mixture was stirred for 20 hours at room temperature, washed with water and dried (MgSO4). By distilling off the solvent, 6-chloro-3-(2,4-difluorobenzoylamino)-7-methyl-4-(2-methylphenyl)-2H-1-benzopyran-2-one was obtained as crystals (406 mg, 92.5%). Recrystallization from ethanol gave colorless prisms.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].[N+:11]([O-])([OH:13])=[O:12]>ClCCl>[F:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]=1[OH:10]
Reactant: Cc1ccc(O)c(F)c1F
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])c(O)c(F)c1F
Yield: 91.5 %

Procedure:
To 2,3-difluoro-4-methylphenol (1 g, 6.94 mmol) in dichloromethane at 0° C. was added nitric acid 70% (0.7 mL, 7.77 mmol). After 1 h at room temperature the solution was washed with water, dried and evaporated to give 2,3-difluoro-4-methyl-6-nitrophenol (1.2 g, 6.35 mmol, 91% yield) (D44) as yellow solid.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([C:13]([O:15][CH3:16])=O)[N:4]=1.O[C:18]1[CH:23]=[CH:22][CH:21]=C[C:19]=1[C:24](=[O:26])[CH3:25].Cl>N1C=CC=CC=1>[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([C:13]2[O:15][C:16]3[C:19]([C:24](=[O:26])[CH:25]=2)=[CH:18][CH:23]=[CH:22][CH:21]=3)[N:4]=1
Reactant: COC(=O)c1cc2ccccc2cn1
Reactant: CC(=O)c1ccccc1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: O=c1cc(-c2cc3ccccc3cn2)oc2ccccc12
Temperature: 90 °C
Yield: 88.9 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 227 mg, 5.7 mmol) in dry pyridine (4 ml) was added dropwise a solution of methyl isoquinoline-3-carboxylate (390 mg, 2.08 mmol) and 2′-hydroxy-acetophenone (257 mg, 1.89 mmol) in dry pyridine (4 ml). The mixture was heated at 90° C. for 15 min., cooled to room temperature and poured into an ice cooled 1N hydrochloric acid aqueous solution. The product was extracted in dichloromethane. The organic layers were washed with a 1N hydrochloric acid solution, brine, dried over sodium sulfate and concentrated to dryness. The residue was dissolved in acetic acid (10 ml) and treated with sulfuric acid (40 μl). The solution was heated to 100° C. for 30 min. and cooled to room temperature. The solvents were removed under vacuum distillation. The solid was triturated in water, filtered, washed with a saturated solution of sodium hydrogenocarbonate and water. The solid was dried under vacuum to yield 2-Isoquinolin-3-yl-chromen-4-one (459 mg, 89%) as beige solid.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[CH2:14][C:15](O)=[O:16].C(Cl)Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[F:3][C:4]1[C:5]([CH2:14][CH2:15][OH:16])=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=C(O)Cc1c([N+](=O)[O-])ccc(F)c1F
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)c(F)c1CCO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 108.8 %

Procedure:
19.8 g of the sodium borohydride was added to 60 ml of tetrahydrofuran, and, while the mixed solution was cooled on ice below 10° C., a solution obtained by dissolving 60 g (276 mmol) of 2,3-difluoro-6-nitrophenylacetic acid in 20 ml of tetrahydrofuran was dropped to the mixed solution through I hour. Then, 120 ml of tetrahydrofuran solution dissolving 90 ml of boron trifluoride ethyl ether complex was dropped to the reaction solution through 1 hour below 10° C. The solution was stirred for 15 minutes under cooled on ice and for 20 minutes at room temperature. To 1.5 1 of methylene chloride, 1.2 1 of ice/water, 84 g of sodium hydrogen carbonate was added, and, while well stirring this solution, the reaction solution was slowly added to this solution. The obtained solution was stirred overnight. The organic layer was separated from the solution, and after drying over magnesium sulfate, solvent was removed by distillation to obtain 61 g of oily 3,4-difluoro-2-(2-hydroxyethyl)nitrobenzene. To this oily material, 58 ml (414 mmol) of triethylamine and 500 ml of methylene chloride were added, and while cooling on ice, 100 ml of methylene chloride solution containing 19 ml (331 mmol) of acetyl chloride was dropped to the solution. After stirring for 1 hour and 30 minutes, 5 ml of acetyl chloride was further added to the mixture, and after 30 minutes, the mixture was washed with 200 ml of water twice. After drying over magnesium sulfate, the solvent was removed by distillation to obtain 76.5 g of 2-(2-acetoxyethyl)-3,4-difluoronitrobenzene.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]([CH3:22])([CH3:21])[CH2:7]1)=[O:4].[CH3:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=1[C:31]1[N:36]=[C:35]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][C:38]=2[CH3:44])[N:34]=[C:33]([C:45]2[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][C:46]=2[OH:52])[N:32]=1>>[CH3:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=1[C:31]1[N:36]=[C:35]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][C:38]=2[CH3:44])[N:34]=[C:33]([C:45]2[CH:50]=[CH:49][C:48]([O:51][CH2:2][C:3]([O:5][CH:6]3[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([O:14][CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)[C:8]([CH3:22])([CH3:21])[CH2:7]3)=[O:4])=[CH:47][C:46]=2[OH:52])[N:32]=1
Reactant: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(O)cc3O)n2)c(C)c1
Reactant: CC1(C)CC(OC(=O)CCl)CC(C)(C)N1OC1CCCCC1
Product: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(OCC(=O)OC4CC(C)(C)N(OC5CCCCC5)C(C)(C)C4)cc3O)n2)c(C)c1
Yield: 54 %

Procedure:
The title compound, a yellow solid with mp 105°-109° C., is prepared in 54% yield from 1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-yl chloroacetate and 2,4-bis(2,4-dimethylphenyl)-6-(2,4-dihydroxyphenyl)-s-triazine according to the procedure of Example 8B.