Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].I([O-])(=O)(=O)=[O:32].[Na+]>CO.O>[CH2:1]([S:13]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25](=[O:30])[C:26]([F:27])([F:28])[F:29])=[CH:19][CH:18]=1)=[O:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCSCCOc1ccc(CCC(=O)C(F)(F)F)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCS(=O)CCOc1ccc(CCC(=O)C(F)(F)F)cc1
Temperature: 22 °C
Reaction time: 18 h
Yield: 95.3 %

Procedure:
A solution of 4-[4-[2-(dodecylthio)ethoxy]phenyl]-1,1,1-trifluoro-2-butanone (0.340 g, 0.76 mmol) in methanol (15 ml) was treated with a solution of sodium periodate (0.165 g, 0.77 mmol) in water (3 ml) and the resulting mixture was stirred at 22° C. for 18 h. The solid formed was filtered and washed with methanol. This filtrate was then concentrated under reduced pressure and then partitioned between water and ethyl acetate. The organic phase was then dried (magnesium sulfate) and concentrated. The residue was chromatographed on silica gel (elution toluene-ethyl acetate 1:1) to give 0.335 g (90%) of 4-[4-[2-(dodecylsulfinyl)ethoxy]phenyl]-1,1,1-trifluoro-2-butanone as a white solid. By 1HNMR this product was a 6:4 mixture of trifluoromethyl ketone and hydrated trifluoromethyl ketone. The pure hydrate precipitates from ethyl acetate-hexane: m.p. 98-100° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[F:16][C:17]([F:21])([F:20])[CH2:18]O.S(=O)(=O)(O)O>>[F:16][C:17]([F:21])([F:20])[CH2:18][O:13][C:12](=[O:14])[CH:11]([C:8]1[CH:7]=[CH:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:10][CH:9]=1)[CH3:15]
Reactant: OCC(F)(F)F
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Agent: O=S(=O)(O)O
Product: CC(C)Cc1ccc(C(C)C(=O)OCC(F)(F)F)cc1
Temperature: 100 °C

Procedure:
A mixture of 4.12 g of 2-(p-isobutylphenyl)propionic acid, 15 ml of 2,2,2-trifluoroethyl alcohol and 4.9 g of concentrated sulfuric acid was heated at 100° C. for 12 hours. After the reaction was complete, the mixture was poured into ice-water and the resulting mixture was extracted with ether. The ether layer separated was washed sufficiently with successive 5% sodium carbonate solution and water, and dehydrated. The ether was removed by distillation to give an oily product. Distillation of the product in vacuo yielded 4.95 g of 2-(p-isobutylphenyl)propionic acid-2,2,2-trifluoroethyl ester as a pale yellow oil, boiling at 73°-74° C./0.12 mmHg. Analysis-Calculated for C15H19F3O2 : C, 62.48; H, 6.64. Found: C, 62.31; H, 6.61.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])=[C:6]([Cl:18])[N:5]=[CH:4][N:3]=1.[F:19][C:20]([F:32])([F:31])[C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:18][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:30][S:27]([C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:32])[F:31])=[CH:26][CH:25]=2)(=[O:28])=[O:29])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[O:16][CH3:17]
Reactant: COc1ccc(F)cc1Oc1c(Cl)ncnc1Cl
Reactant: NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Product: COc1ccc(F)cc1Oc1c(Cl)ncnc1NS(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
The N-[6-chloro-5-(5-fluoro-2-methoxy-phenoxy)pyrimidin-4-yl]-4-trifluoromethyl-benzenesulfonamide (m.p. 185°-186° C.) was prepared from 4,6-dichloro-5-(5-fluoro-2-methoxy-phenoxy)-pyrimidine and 4-trifluoromethylbenzenesulfonamide K.
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=[CH:9][C:2]=12.C(Cl)(=O)C(Cl)=O.[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:23][CH2:22]1>C(Cl)Cl.CN(C)C=O>[N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]([NH:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:23][CH2:22]3)=[O:12])[CH:8]=[CH:9][C:2]=12
Reactant: O=C(O)c1ccc2nonc2c1
Reactant: NCC1CCN(CCc2ccccn2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCC1CCN(CCc2ccccn2)CC1)c1ccc2nonc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
To a suspension of benzofurazan-5-carboxylic acid (150 mg, 0.91 mmol) in methylene chloride (3.3 ml) was added dimethylformamide (1 drop) followed by dropwise addition of oxalyl chloride (89 μl, 1.0 mmol). The resulting solution was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The brown oil was redissolved in methylene chloride (3.3 ml) and was added to a cooled (0° C.) solution of 4-(aminomethyl)-1-(2-pyridylethyl)piperidine (0.21 g, 0.95 mmol) in methylene chloride (1.6 ml). The reaction mixture was stirred at 0° C. for 11/2 hours. Solvent evaporation, flash chromatography (silica gel, chloroform-methanol-ammonium hydroxide, 95/5/1/2) and trituration with hexane-ethyl acetate gave 4-[N-(benzofurazan-5-carbonyl)aminomethyl]-1-(2-pyridylethyl)piperidine (133 mg, 40%);
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[C:36]([NH:39][C@@H:40]1[CH2:44][CH2:43][NH:42][CH2:41]1)(=[O:38])[CH3:37]>C(Cl)Cl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:42]3[CH2:43][CH2:44][C@@H:40]([NH:39][C:36](=[O:38])[CH3:37])[CH2:41]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCC(F)(F)CC1
Reactant: CC(=O)N[C@@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N[C@@H]1CCN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCC(F)(F)CC2)C1

Procedure:
Following the same procedure in Example 1, step A, using 2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (300 mg, 0.74 mmol), N,N-diisopropylethylamine (0.5 mL, 3 mmol) and (3R)-(+)-3-acetamidopyrrolidine (142 mg, 1.1 mmol) in (1 mL) methylene chloride. The crude product was purified by LCMS using high pH column 40-70% acetonitrile gradient to give 15 mg (4% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.51-1.65 (m, 3 H), 1.69 (s, 9 H), 1.71-1.77 (m, 4 H), 1.78 (s, 3 H), 1.93-2.12 (m, 3 H), 2.21-2.33 (m, 1 H), 3.15 (dd, J=10.35, 4.69 Hz, 1 H), 3.21-3.28 (m, 1 H), 3.37-3.49 (m, 2 H), 4.00-4.11 (m, 1 H), 4.58 (d, J=7.42 Hz, 2 H), 7.91 (d, J=8.59 Hz, 1 H), 8.09 (d, J=8.79 Hz, 1 H), 8.12 (s, 1 H); MS (ESI) (M+H)+=496.6; Anal. Calc. for C24H34F2N4O3S+4.2 TFA+2.9H2O+2.4 CH3CN: C, 39.67; H, 4.58; N, 7.16. Found: C, 39.69; H, 4.61; N, 7.96.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]1.[C:16](O)(=[O:19])[CH2:17][CH3:18].CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH:11]([C:16](=[O:19])[CH2:17][CH3:18])[C:10](=[O:15])[CH2:9]1
Reactant: O=C1CC(=O)CC(c2ccccc2Cl)C1
Reactant: CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Product: CCC(=O)C1C(=O)CC(c2ccccc2Cl)CC1=O
Temperature: 25 °C
Reaction time: 13 h
Yield: 53.5 %

Procedure:
To a solution of 5-(2-chlorophenyl)cyclohexane-1,3-dione (1.0 g), propionic acid (0.60 g) and dimethylaminopyridine (0.82 g) in dimethylformamide (30 ml) was added dicyclohexylcarbodiimide (1.2 g), and the mixture was stirred at room temperature for 13 hours. Under reduced pressure, the solvent was evaporated, and to the residue was ethyl acetate. The mixture was washed with 1N hydrochloric acid and water, and to the mixture was added 1N sodium hydroxide solution. The aqueous layer was washed with diethylether, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was recrystallized from diisopropylether and hexane to give colorless crystals of 5-(2-chlorophenyl)-2-propionylcyclohexane-1,3-dione (0.67 g).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[F:22].C(N(CC)CC)C.[Cl:30][CH2:31][C:32](Cl)=[O:33]>ClCCl>[Cl:30][CH2:31][C:32]([NH:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH2:11][CH2:12]2)=[CH:4][C:3]=1[F:22])=[O:33]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)c(F)c2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)CCl)c(F)c2)CC1
Yield: 64 %

Procedure:
tert-Butyl 4-(4-amino-3-fluoro phenoxy)piperidine-1-carboxylate (7.54 g, 0.024 moles) was dissolved in dichloromethane (100 mL) and added triethylamine (3.6 g, 0.036 moles) at room temperature. To the resulting mass, a solution of chloro acetyl chloride (2.9 g, 0.026 moles) in dichloromethane (15 mL) was added drop wise at room temperature. After completion of the reaction, the organic mass was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude residue, which was further purified by flash chromatography using (ethyl acetate:hexane, 1:5) to afford the title compound 5.94 g (Yield: 64%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[CH:17]=[C:18]([N:22]5[CH2:27][CH2:26][CH:25]([NH:28]C(=O)OC(C)(C)C)[CH2:24][CH2:23]5)[CH:19]=[N:20][CH:21]=4)=[N:14][N:13](C4CCCCO4)[C:10]3=[CH:11][N:12]=2)[CH:2]=1.C(Cl)Cl.FC(F)(F)C(O)=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[CH:17]=[C:18]([N:22]5[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]5)[CH:19]=[N:20][CH:21]=4)=[N:14][NH:13][C:10]3=[CH:11][N:12]=2)[CH:2]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3nn(C4CCCCO4)c4cnc(-c5cccnc5)cc34)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(c2cncc(-c3n[nH]c4cnc(-c5cccnc5)cc34)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 33 %

Procedure:
To a solution of tert-butyl 1-(5-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-3-yl)piperidin-4-ylcarbamate in methylene chloride (1.00 mL, 15.6 mmol) was added trifluoroacetic Acid (0.3109 mL, 4.036 mmol). The reaction was stirred at RT for 18 hours. The reaction was concentrated then submitted for rHPLC (reverse phase HPLC) to give 158 (10 mg, 33% yield). ESI MS m/z=372.1 (M+1). 1H NMR (400 MHz, DMSO) δ 9.39 (s, 1H), 9.24 (s, 1H), 8.72 (s, 1H), 8.61-8.52 (m, 3H), 8.42 (s, 1H), 7.83 (s, 1H), 7.55-7.48 (m, 1H), 3.85 (d, J=13.0 Hz, 2H), 2.98-2.76 (m, 3H), 1.91-1.81 (m, 2H), 1.42 (dd, J=20.7, 10.2 Hz, 2H)
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].C(N(CC)CC)C.[NH:18]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21](=O)[O:20]C1=O>C(O)C>[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH:10][C:21](=[O:20])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:18]
Reactant: NNc1ccccc1F
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1ccccc1C(=O)NNc1ccccc1F
Temperature: 21 °C
Reaction time: 0.33 h
Yield: 40.4 %

Procedure:
A stirred suspension of 845 g (5.03 mole) of 97% (2-fluoro-phenyl)-hydrazine, hydrochloride in 7.6 L of ethanol at 21-22° C. was added in a stream 563 g (5.57 mole) of triethylamine over a 20 minute period. A whitish gas formed initially. The resulting dark mixture was stirred at 21° C. for 20 minutes and then 854 g (5.03 mole) of 96% 1H-benzo[d][1,3]oxazine-2,4-dione was added. The resulting mixture was heated up to reflux (78° C.) over the next 1 hour. During this period, vigorous gas evolution was noted. Reflux was maintained for 2 hours and then the suspension was stirred at room temperature for 16 hours. The solid was collected by filtration, rinsed once with 150 mL of ethanol, then once with 150 mL of ethanol: ethyl acetate (1:1), and pressed dry under suction. Further drying in vacuo at 35° C. for 7 hours provided 498 g (40%) of product. A second crop of 51 g (4%) of material was obtained from the mother liquor.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([OH:16])=[C:11]([O:17][CH3:18])[C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][CH:29]1[CH2:31][O:30]1>C(C(C)=O)C>[CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH2:28][CH:29]2[O:30][CH2:31]2)=[C:11]([O:17][CH3:18])[C:10]=1[O:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCC1CO1
Reactant: COc1c(O)cc(C)c(OCc2ccccc2)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1c(OCC2CO2)cc(C)c(OCc2ccccc2)c1OC

Procedure:
Then, using 3.69 g of the compound of Example 12, 1.82 g of anhydrous potassium carbonate, 1.5 ml of chloromethyloxirane and 100 ml of methyl ethyl ketone, reaction and workup carried out as in Example 1-A gave about 4.5 g of 1-(4-benzyloxy-2,3-dimethoxy-5-methylphenoxy)-2,3-epoxypropane as yellow oil. Using this epoxy compound, 3.05 g of 1-(2-methoxyphenyl)piperazine and 100 ml dioxane, reaction and workup carried out as in Example 1-A followed by purification by column chromatography (silica gel, elution with ethyl acetate:hexane=1:0.5) gave 4.61 g of yellow oil.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([N+:16]([O-:18])=[O:17])=[CH:7][C:6]=2[NH:5][CH2:4]1.[N+:19]([O-])([O-:21])=[O:20].[K+]>OS(O)(=O)=O>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[C:9]=3[C:8]([N+:16]([O-:18])=[O:17])=[CH:7][C:6]=2[NH:5][CH2:4]1
Reactant: O=[N+]([O-])[O-]
Reactant: O=[N+]([O-])c1cc2c(c3ccccc13)C(CCl)CN2
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cccc2c3c(cc([N+](=O)[O-])c12)NCC3CCl
Temperature: 0 °C
Yield: 76.3 %

Procedure:
A stirred solution of 102 (500 mg, 1.90 mmol) in conc. H2SO4 (5 mL) was cooled to −5° C. and treated with powdered KNO3 (288 mg, 2.85 mmol). The mixture was stirred at 0° C. for a further 15, in, then poured into ice-water and the solid was collected and dissolved in CH2Cl2. The solution was filtered through a column of silica gel and the product was recrystallised from EtOAc/iPr2O to give 1-(chloromethyl)-5,6-dinitro-1,2-dihydro-3H-benzo[e]indole (103) (446 mg, 76%) as a red solid: mp 206-207° C.; 1H NMR [(CD3)2SO] δ 8.23 (dd, J=8.7, 1.0 Hz, 1H), 8.00 (dd, J=7.7, 0.9 Hz, 1H), 7.76 (s, 1H), 7.67 (dd, J=8.4, 7.6 Hz, 1H), 6.72 (s, 1H), 4.32-4.22 (m, 1H), 3.94-3.83 (m, 2H), 3.83-3.75 (m, 2). Anal. (C13H10ClN3O4) C, H, N.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:13][N:14]=[C:7]1[CH:6]=[CH:5]2.[CH2:21]([CH:23]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:24][O:25][C:26](=[O:30])[CH2:27][CH2:28][SH:29])[CH3:22].CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:21]([CH:23]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:24][O:25][C:26](=[O:30])[CH2:27][CH2:28][S:29][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:13][N:14]=[C:7]1[CH:6]=[CH:5]2)[CH3:22]
Reactant: CCCCC(CC)COC(=O)CCS
Reactant: Ic1ccc2c(ccc3nnc(-c4ccccn4)n32)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCCCC(CC)COC(=O)CCSc1ccc2c(ccc3nnc(-c4ccccn4)n32)c1
Temperature: 90 °C

Procedure:
5k (890 mg, 2.4 mmol) and 3-mercaptopropionic acid 2-ethylhexyl ester (630 mg, 2.9 mmol) were dissolved in 1,4-dioxane (20 mL) and degassed with N2 for 10 minutes. iPr2NEt (0.86 mL, 4.8 mmol), Pd2dba3 (54 mg, 0.06 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (69 mg, 0.12 mmol) were added, and the mixture was degassed with N2 for an additional 10 minutes. The reaction was heated to 90° C. until no starting material was seen by tlc analysis, and then the mixture was concentrated and purified by silica gel chromatography to give the desired product, 5m.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:6](O)=[O:7])[CH:3]([CH3:5])[CH3:4].CN1CCOCC1.[NH:23]1[CH2:31][CH2:30][CH2:29][C@H:24]1[C:25]([O:27][CH3:28])=[O:26].[ClH:32]>C1COCC1>[NH2:1][C@H:2]([C:6]([N:23]1[CH2:31][CH2:30][CH2:29][C@H:24]1[C:25]([O:27][CH3:28])=[O:26])=[O:7])[CH:3]([CH3:5])[CH3:4].[ClH:32]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)C(C)C
Temperature: -15 °C
Reaction time: 8 h

Procedure:
Boc-Val-OH (3.00 g, 13.8 mmol) was dissolved in 10 ml of dry THF and cooled down to −15° C. To the mixture CAIBE (1.80 ml, 13.8 mmol) and NMM (1.52 ml, 13.8 mmol) where added and the solution was stirred until the formation of the mixed anhydride was complete. Then the mixture was brought to −10° C. and NMM (1.52 ml, 13.8 mmol) was added followed by H-Pro-OMe.HCl (2.29 g, 13.8 mmol). The mixture was allowed to reach room temperature and left overnight. After removing the solvent and the usual workup the resulting ester 1 was taken without further characterisation. The ester 1 was dissolved in HCl/HOAc (5 ml, 6N) and left at 0° C. until the removal of the Boc-group was complete. The solvent was then removed and the resulting oil was treated with diethylether to give a white solid 2.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35].[H-].[Na+].O>CN(C)C=O>[F:28][C:3]1[CH:4]=[C:5]([F:27])[C:6]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)=[CH:9][C:8](=[O:26])[C:7]=2[C:2]=1[NH:1][CH2:30][CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35]
Reactant: CC(C)CCCCBr
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCCCNc1c(F)cc(F)c2oc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)cc(=O)c12
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 71.2 %

Procedure:
853 mg (2.19mmol) of 5-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-1-benzopyran-4-one obtained in Example 66 was dissolved in 20 mL of dimethylformamide under argon atmosphere, 788 mg (4.38 mmol) of 1-bromo-5-methylhexane and 266 mg (6.65mmol) of sodium hydride (60% oil dispersion) were added under ice-cooling and the mixture was stirred at room temperature for 5.5 hours. The reaction solution was cooled on ice, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform: n-hexane=3:1) to give 762 mg of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(5-methylhexylamino)-4H-1-benzopyran-4-one (yield: 71%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[F:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][C:29]([CH3:31])=[N:28][C:27]=2[C:32](O)=[O:33])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:32]([C:27]3[N:28]=[C:29]([CH3:31])[O:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[CH:21]=3)=[O:33])=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3ccc(N)n3)n2)OCCO1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(F)c2)o1
Product: CC(=O)c1csc(Cn2ccc(NC(=O)c3nc(C)oc3-c3cccc(F)c3)n2)n1

Procedure:
Following general procedure B followed by C, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-fluoro-phenyl)-2-methyl-oxazole-4-carboxylic acid. LC-MS-conditions 05: tR=0.89 min; [M+H]+=426.04.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1([NH2:17])[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1.C(N(CC)CC)C>ClCCl>[C:1]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([NH2:17])=[CH:11][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1ccc(NC(=O)c2ccccc2)cc1
Temperature: 25 °C
Yield: 28.3 %

Procedure:
Benzoyl chloride (10.7 ml, 92.5 mmol) was added to a stirred solution of 1,4-phenylenediamine (10.0 g, 92.5 mmol) and triethylamine (14.2 ml, 102 mmol) in dichloromethane (250 ml) at 0° C. The reaction was allowed to warm to ambient temperature over 3 hours, the solid was filtered off and water (100 ml) was added to the filtrate, causing precipitation of a second solid. Collection of this solid by suction filtration and drying in vacuo yielded N-benzoyl 4-aminoaniline (5.55 g, 28% yield) as a white solid:
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[N:4]1.[C:15]1([CH3:27])[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[S:23](Cl)(=[O:25])=[O:24]>CN(C=O)C.O1CCCC1>[CH3:27][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[S:23]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[N:4]1)(=[O:24])=[O:25]
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(C)c(S(=O)(=O)n2nc(C(=O)O)c3ccccc32)c(C)c1
Temperature: 0 °C

Procedure:
NaH (60% in oil, 40 mmol) is washed under argon with petroleum ether and then suspended in 60 ml of anhydrous DMF. An indazole-3-carboxylic acid solution (3.35 g, 20 mmol) in anhydrous DMF (50 ml) is added dropwise to this suspension kept at 0° C. The reaction mixture becomes clear. When the addition is complete, the medium is allowed to react for 30 min at room temperature and then the reaction mixture is again cooled to 0° C. Mesitylenesulphonyl chloride (4.82 g, 22 mmol) in solution in anhydrous tetrahydrofuran (THF) (50 ml) is added. The ice bath is removed and a suspension appears. The medium is allowed to react for 30 min at room temperature. The solvents are evaporated under vacuum and the residue is taken up in 0.1N NaOH solution. The solution obtained is washed with diethyl ether and then acidified with 6N HCl. The compound which separates is filtered, and taken up in AcOEt. The AcOEt solution is dried over Na2SO4 and then evaporated. The residue (6.18 g) is recrystallized from AcOEt/petroleum ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.Br[CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:31]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:16][CH2:17][N:18]([CH:22]4[CH2:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[C:23]4=[O:31])[CH2:19][CH2:20]3)=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(Cc2ccc(C3CCNCC3)cc2)cc1
Reactant: O=C1c2ccccc2CC1Br
Product: O=C1c2ccccc2CC1N1CCC(c2ccc(Cc3ccc(F)cc3)cc2)CC1

Procedure:
The same procedure was followed as in Example 11 using the compound (12) synthesized in Example 5 and 2-bromo-1-indanone to produce the above.