Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])[N:20]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])[N:20]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cc(OCc2ccc(-c3cc(OC)ccc3F)c(OCC(C)C)n2)ncn1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(COc3cc(C(CC(=O)O)C4CC4)ncn3)nc2OCC(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(6-((5-(2-fluoro-5-methoxyphenyl)-6-isobutoxypyridin-2-yl)methoxy)pyrimidin-4-yl)propanoate (198 mg) in THF (3.0 mL) and methanol (1.5 mL) was added 1N aqueous sodium hydroxide solution (3.0 mL), and the mixture was stirred at room temperature for 30 min. 1N Hydrochloric acid (3.0 ml) was added to the reaction mixture at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give the title compound (180 mg) as a white amorphous solid.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]([C:23]1[CH:27]=[C:26]([NH:28][C:29]([NH:31][C@@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C@H:35]([O:42][C:43]3[CH:44]=[CH:45][C:46]4[N:47]([C:49]([N:52]5[CH2:57][CH2:56][CH2:55][CH2:54][C@@H:53]5[CH3:58])=[N:50][N:51]=4)[CH:48]=3)[CH2:34][CH2:33]2)=[O:30])[N:25]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([O:65][CH2:66][CH2:67][OH:68])[CH:60]=2)[N:24]=1)([CH3:22])[CH3:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:78][S:79](Cl)(=[O:81])=[O:80]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:78][S:79]([O:68][CH2:67][CH2:66][O:65][C:61]1[CH:62]=[CH:63][CH:64]=[C:59]([N:25]2[C:26]([NH:28][C:29](=[O:30])[NH:31][C@@H:32]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[C@H:35]([O:42][C:43]4[CH:44]=[CH:45][C:46]5[N:47]([C:49]([N:52]6[CH2:57][CH2:56][CH2:55][CH2:54][C@@H:53]6[CH3:58])=[N:50][N:51]=5)[CH:48]=4)[CH2:34][CH2:33]3)=[CH:27][C:23]([C:20]([CH3:21])([CH3:22])[CH2:19][O:18][Si:1]([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:24]2)[CH:60]=1)(=[O:81])=[O:80]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)CO[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)CO[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Yield: 57.6 %

Procedure:
A solution of Intermediate 153h (214 mg, 0.23 mmol) in DCM (2.3 mL) was treated with DIPEA (0.12 mL, 0.69 mmol) then methanesulfonyl chloride (0.037 mL, 0.48 mmol). After 30 mins the mixture was diluted with DCM and saturated aqueous sodium bicarbonate solution. The phases were separated and the aqueous layer was extracted with DCM (×2). The combined organic phase was washed with water, saturated aqueous sodium bicarbonate solution and brine, dried (Na2SO4) and concentrated in vacuo to an orange gum. The gum was purified by FCC, using 0-8% MeOH in DCM, to give the title compound as a pale brown glass (134 mg, 58%). LCMS (Method 3): Rt 5.18 min, m/z 1011.7 [MH+].
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[C:9]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]CC)=[O:21])=[CH:15][CH:14]=2)=[O:11])=[C:8]([F:25])[C:7]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)=[CH:6][CH:5]=1.O>O1CCOCC1>[Cl:3][C:4]1[C:9]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=2)=[O:11])=[C:8]([F:25])[C:7]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2c(Cl)ccc(OCc3cccc(Cl)c3)c2F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)Cc1ccc(NC(=O)c2c(Cl)ccc(OCc3cccc(Cl)c3)c2F)cc1
Yield: 32 %

Procedure:
Lithium hydroxide monohydate (12 mg, 0.281 mmol) was added to a solution of ethyl (4-{[(6-chloro-3-{[(3-chlorophenyl)methyl]oxy}-2-fluorophenyl)carbonyl]amino}phenyl)acetate (91 mg, 0.192 mmol in dioxane (2 ml) and water (1 ml) and the reaction was stirred at room temperature overnight. The solvent was evaporated, the residue dissolved in water (5 ml) and acidified (2M HCl, pH˜1). The aqueous layer was extracted with ethyl acetate, the organics dried (Na2SO4) and the solvent evaporated to afford a colourless solid which was collected by filtration. This was purified by mass directed auto-prep (MDAP) to afford the title compound as a colourless solid (28 mg, 32%).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.CN1CCOCC1.[Br:25][C:26]1[C:31]([F:32])=[CH:30][C:29]([S:33](Cl)(=[O:35])=[O:34])=[C:28]([F:37])[CH:27]=1>ClCCl>[Br:25][C:26]1[C:31]([F:32])=[CH:30][C:29]([S:33]([NH:14][C:13]2[CH:15]=[C:9]([N:4]3[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]3)[CH:10]=[CH:11][C:12]=2[O:16][CH3:17])(=[O:34])=[O:35])=[C:28]([F:37])[CH:27]=1
Reactant: O=S(=O)(Cl)c1cc(F)c(Br)cc1F
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1N
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1cc(F)c(Br)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)aniline (D4) (500 mg, 2.12 mmol) in dichloromethane (30 ml) was treated with morpholinomethyl-polystyrene HL resin (1 g, 4 mmol/g loading, 4.24 mmol) followed by 4-bromo-2,5-difluorobenzene sulfonyl chloride (930 mg, 3.2 mmol). The resulting solution was stirred room temperature for 18 hours and was then filtered, washing with dichloromethane, and the filtrate concentrated in vacuo. The residue was then purified using an SCX ion exchange cartridge (Varian bond-elute) eluting with methanol followed by ammonia (0.5M to 2M in methanol). The appropriate fractions were combined and reduced in vacuo to afford a crude product which was purified further by trituration with methanol to afford the desired product D37. MS (ES+) m/e 490/492 [M+H]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:34][CH2:35][C:36]1[CH:37]=[C:38]([S:42][C:43]2[CH:44]=[CH:45][C:46]([C:49]#[N:50])=[N:47][CH:48]=2)[CH:39]=[CH:40][CH:41]=1.[OH:51][C:52]1[C:57]([CH3:58])=[C:56](O)[CH:55]=[CH:54][C:53]=1[C:60](=[O:62])[CH3:61]>C1COCC1.C(OCC)(=O)C>[C:60]([C:53]1[CH:54]=[CH:55][C:56]([O:34][CH2:35][C:36]2[CH:37]=[C:38]([S:42][C:43]3[CH:44]=[CH:45][C:46]([C:49]#[N:50])=[N:47][CH:48]=3)[CH:39]=[CH:40][CH:41]=2)=[C:57]([CH3:58])[C:52]=1[OH:51])(=[O:62])[CH3:61]
Reactant: N#Cc1ccc(Sc2cccc(CO)c2)cn1
Reactant: CC(=O)c1ccc(O)c(C)c1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OCc2cccc(Sc3ccc(C#N)nc3)c2)c(C)c1O
Reaction time: 8 h
Yield: 73 %

Procedure:
Add triphenylphosphine (1.84 g, 7.02 mmol) and diisopropylazodicarboxylate (1.42 g, 7.02 mmol) to a solution of 5-(3-(hydroxymethyl)phenylthio)picolinonitrile (1.70 g, 7.02 mmol) and 1-(2,4-dihydroxy-3-methylphenyl)ethanone (1.17 g, 7.02 mmol) in THF (35.1 mL). Stir overnight. Dilute with ethyl acetate. Wash the mixture with water and brine. Dry, filter and concentrate to afford the title compound (2.00 g, 73%). Use as is. MS (APCI-neg) m/z (rel intensity): 390 (M+H, 100%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[Cl:15])[O:11][C:10]([CH3:27])([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=1)[CH2:9][C:8]2=[O:28])(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+]>C(O)(=O)C.[Zn]>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[Cl:15])[O:11][C:10]([CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=1)([CH3:27])[CH2:9][C:8]2=[O:28])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc2c(cc1Cl)OC(C)(COc1ccc([N+](=O)[O-])cc1)CC2=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(=O)Oc1cc2c(cc1Cl)OC(C)(COc1ccc(N)cc1)CC2=O
Reaction time: 2 h
Yield: 40.9 %

Procedure:
1 g of zinc powder was added in portions to a solution of 740 mg of 6 -acetoxy-7-chloro-2-methyl-2-(4-nitrophenoxymethyl)-4-oxochroman (prepared as described in Preparation 35) dissolved in 15 ml of acetic acid. The reaction mixture was stirred for 2 hours, after which it was poured into a saturated aqueous solution of sodium bicarbonate whilst ice-cooling, and the mixture was then extracted with benzene. The extract was washed with water and dried over anhydrous sodium sulfate, after which the solvent was removed by evaporation under reduced pressure. The residue was subjected to column chromatography through silica gel, eluted with a 1:1 by volume mixture of benzene and ethyl acetate, to afford 280 mg of the title compound as a pale yellow oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([F:13])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].N1C=CC=CC=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:20]([NH:2][C:3]1[C:4]([F:13])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1cccc(N)c1F
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cccc(NC(=O)c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
Methyl 3-amino-2-fluorobenzoate hydrochloride (7.77 g, 0.037 mol) was suspended in methylene chloride (100 ml), and pyridine (6.94 g, 0.085 mol) was added dropwise thereto. Benzoyl chloride (5.78 g, 0.041 mol) was added dropwise to this reaction mixture under cooling, and the mixture was agitated overnight at room temperature. After completion of the reaction, the reaction mixture was washed sequentially with a 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, and saturated saline, and the reaction mixture was dried over anhydrous sodium sulfate. The sodium sulfate was filtered away, and then the filtrate was concentrated under reduced pressure. The concentration residue was recrystallized from ethyl acetate, as a result of which 8.79 g (yield: 85%) of the indicated compound was obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([CH3:36])=[C:11]([CH2:13][N:14]3[C:22]4[C:17](=[CH:18][C:19]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:20][CH:21]=4)[C:16]([CH2:33]O)=[C:15]3[CH3:35])[N:12]=2)[CH:5]=[CH:6][CH:7]=1>CO.[Pd]>[CH3:35][C:15]1[N:14]([CH2:13][C:11]2[N:12]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=3)[O:9][C:10]=2[CH3:36])[C:22]2[C:17]([C:16]=1[CH3:33])=[CH:18][C:19]([C:23]([OH:32])([C:28]([F:29])([F:30])[F:31])[C:24]([F:27])([F:26])[F:25])=[CH:20][CH:21]=2
Reactant: Cc1oc(-c2cccc(Cl)c2)nc1Cn1c(C)c(CO)c2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc21
Agent: [Pd]
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1Cn1c(C)c(C)c2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc21
Reaction time: 8 h

Procedure:
A solution of 25 mg of 2-{1-[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-3-hydroxymethyl-2-methyl-1H-indol-5-yl}-1,1,1,3,3,3-hexafluoro-propan-2-ol in 1 mL of MeOH was treated with Pd/C (10% Pd) and stirred under H2 at atmospheric pressure for 8 hrs. Filtration and evaporation of the solvent yielded 2-[2,3-dimethyl-1-(5-methyl-2-phenyl-oxazol-4-ylmethyl)-1H-indol-5-yl]-1,1,1,3,3,3-hexafluoro-propan-2-ol, light brown solid, 483 (MH+).
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:14]([O:16]CC)=[O:15])[C:5]1=[O:19])([CH3:3])[CH3:2].[OH-].[Na+].C(O)C>O>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:14]([OH:16])=[O:15])[C:5]1=[O:19])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc2ccccc2n(C(C)C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)n1c(=O)c(C(=O)O)cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
A solution of 1.55 g of ethyl 1-isopropyl-2(1H)-quinolone-3-carboxylate and 0.28 g of sodium hydroxide in a solvent mixture of 10 ml of ethanol and 2 ml of water was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and after addition of dil. hydrochloric acid, the precipitated solid was collected by filtration, washed with water and dried to give 1.22 g of 1-isopropyl-2(1H)-quinolone-3-carboxylic acid. m.p. 168°-169° C. (ethyl acetate)
Reaction SMILES: [C:1]1([CH:7]([CH2:12][C:13]([OH:15])=O)[CH2:8][C:9](O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:16]C(N)=O>>[C:1]1([CH:7]2[CH2:12][C:13](=[O:15])[NH:16][C:9](=[O:10])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC(CC(=O)O)c1ccccc1
Reactant: NC(N)=O
Product: O=C1CC(c2ccccc2)CC(=O)N1

Procedure:
29.0 g (139 mmol) 3-phenylglutaric acid and 8.4 g (139 mmol) urea are stirred at 150° C. for 1.5 hours. After cooling, the reaction mixture is recrystallized from methanol: Yield 20.9 g (79%).
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=1>CN(C=O)C.O>[CH3:18][C:17]1[C:12]([S:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: SCc1ccccc1
Reactant: Cc1cccnc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccnc1SCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of NaH (2.4 g, 99 mmol) in 100 mL of DMF cooled to 0° C. is added benzylmercaptan (12.3 g, 99 mmol). The solution was allowed to warm to room temperature than recooled to 0° C. 2-Fluoro-3-methylpyridine in 10 mL DMF was added dropwise and stirred at room temperature overnight. The solution was diluted with H2O, extracted twice with Et2O, twice with EtOAc, and the combined organics washed twice with saturated NaHCO3, dried and concentrated. The resulting oil was flash chromatographed (10% Et2O/hexane (v/v)) to yield 16.3 g of the desired product. NMR (200 MHz, CDCl3) δ 2.24 (s, 3H), 4.50 (s, 2H), 6.9 (dd, 1H), 7.2 (m, 5H), 7.4 (d, 1H) and 8.3 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH:5]=[C:6]2[CH2:9][CH2:10]O.C(Br)(Br)(Br)[Br:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:14][CH2:10][CH2:9][C:6]1[CH:7]2[CH2:8][CH:3]([CH2:4][CH:5]=1)[C:2]2([CH3:12])[CH3:1]
Reactant: CC1(C)C2CC=C(CCO)C1C2
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1(C)C2CC=C(CCBr)C1C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
A mixture of 2-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)ethanol (0.835 g, 4.87 mmol), CBr4 (1.83 g, 5.5 mmol) and PPh3 (1.44 g, 5.5 mmol) in anhydrous CH2Cl2 (10 ml) was stirred for 2 h at room temperature. The solvent was evaporated to dryness and the residue was treated with EtOAc (10 ml) and filtered through a SiO2 bead to give the title compound (1.03 g; 90%), as colourless oil. 1H-NMR (CDCl3) 0.82 (s, 3H); 1.26 (s, 3H); 1.99-2.37 (m, 6H); 2.5 (tr, 2H, J=7.88 Hz); 3.34 (tr, 2H, J=7.27 Hz); 5.31 (broad s, 1H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=O)=[CH:5][CH:4]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[N:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1>>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:23][C:20]2[CH:21]=[N:22][C:17]([C:16]([F:25])([F:15])[F:24])=[CH:18][CH:19]=2)=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(CCNc2ccc(C(F)(F)F)nc2)cc1

Procedure:
In analogy to example 33, step 1, (4-trifluoromethyl-phenyl)-acetic acid (commercially available) was coupled with 6-trifluoromethyl-pyridin-3-ylamine (commercially available) to give the title compound MS m/e: 335.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](Cl)=[O:5].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([CH3:17])[CH:11]=1.O>C(#N)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:4](=[O:5])[CH2:3][C:2]([CH3:8])([CH3:7])[CH3:1])=[C:12]([CH3:17])[CH:11]=1
Reactant: Cc1cc(Br)ccc1N
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CC#N
Solvent: O
Product: Cc1cc(Br)ccc1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
3,3-Dimethylbutanoyl chloride (724 mg, 0.75 mL, 5.4 mmol) was added to a solution of 4-Bromo-2-methyl-phenylamine (1.0 g, 5.4 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature overnight. Water was added to the mixture and the precipitate formed collected to give the title compound as a powder (830 mg, 56% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:5]=1[CH3:11].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:31]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:5]=1[CH2:11][Br:31]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(Br)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(Br)c1CBr
Temperature: 90 °C

Procedure:
3-Bromo-2-methyl-benzoic acid methyl ester (2.0 g, 8.73 mmol) is dissolved in carbon tetrachloride (35 mL). The solution is kept under an inert atmosphere by bubbling nitrogen through the mixture while benzoyl peroxide (106 mg, 0.44 mmol) and N-bromosuccinimide (1.55 g, 8.73 mmol) are added. The mixture is purged with vacuum and nitrogen, and is then refluxed at 90° C. for 2 hours. The reaction mixture is cooled to 0° C. and filtered. The filtrate is evaporated to yield the title compound, which is used as such for the next step.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]2[C:3]=1[CH2:4][N:5]([CH3:15])[C:6]2=[O:14].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:15][N:5]1[CH2:4][C:3]2[C:7](=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=2[N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:6]1=[O:14]
Reactant: CN1Cc2c(Br)ccc([N+](=O)[O-])c2C1=O
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1Cc2c(N3CCOCC3)ccc([N+](=O)[O-])c2C1=O
Temperature: 90 °C

Procedure:
A mixture of 4-Bromo-2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one (100.0 mg, 0.3689 mmol), morpholine (321.7 uL, 3.689 mmol), DIPEA (642.6 uL, 3.689 mmol) in DMF (4 mL) were mixed in sealed tube under an atmosphere of argon and heated at 90° C. for 4 days. The crude material was purified by MDP directly under basic conditions the desired product. MS (ES+): m/z 278.24 (100) [MH+]; HPLC: tR=0.81 min (UPLC, analytical).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][CH2:21][CH3:22])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]([Br:15])=[C:10]([CH:16]([CH3:18])[CH3:17])[N:9]=2)[CH:7]=1.[CH2:23]([N:25]=[C:26]=[S:27])[CH3:24].C(N(CC)CC)C>C(O)C>[CH:16]([C:10]1[N:9]=[C:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([NH:25][CH2:23][CH3:24])=[S:27])[CH:3]=[CH:4][C:5]=2[O:19][CH2:20][CH2:21][CH3:22])[NH:13][C:12](=[O:14])[C:11]=1[Br:15])([CH3:18])[CH3:17]
Reactant: CCCOc1ccc(N)cc1-c1nc(C(C)C)c(Br)c(=O)[nH]1
Reactant: CCN=C=S
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCOc1ccc(NC(=S)NCC)cc1-c1nc(C(C)C)c(Br)c(=O)[nH]1
Yield: 681.7 %

Procedure:
The compound (4.0 g, 10 mmol) of example 34 was suspended in ethanol (10 ml), and added with ethyl isothiocyanate (0.9 g, 1.1 mmol) and triethylamine (1 mL). After refluxed for 3 h, the reaction mixture was concentrated to dryness. The resultant solid was washed with distilled water and recrystallized from ethyl acetate-petroleum ether to give the title compound (3.4 g, yield: 74%). 1H NMR (DMSO-d6) δ: 12.38 (1H, br), 9.41 (1H, br), 7.74 (1H, d), 7.54 (1H, dd), 7.15 (1H, d), 4.04 (2H, t), 3.46 (2H, m), 3.37 (1H, m), 1.75 (2H, m), 1.18 (6H, d), 1.11 (3H, t), 0.97 (3H, t).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[CH2:20][C:21]([OH:23])=[O:22])([O-:12])=[O:11].C(N(CC)CC)C>C(OC(=O)C)(=O)C>[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[C:20](=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1)[C:21]([OH:23])=[O:22])([O-:12])=[O:11]
Reactant: O=Cc1ccc(Br)cc1
Reactant: Cc1ccc([N+](=O)[O-])c(CC(=O)O)c1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc([N+](=O)[O-])c(C(=Cc2ccc(Br)cc2)C(=O)O)c1
Temperature: 40 °C
Yield: 98.6 %

Procedure:
To a mixture of 4-bromobenzaldehyde (19.5 g, 106 mmol) and 2-nitro-5-methyl-phenylacetic acid (20.6 g, 106 mmol; J. G. Atkinson et. al., Tetrahedron Lett., 2857, 1979) in 100 ml of acetic anhydride was added triethylamine (14.7 ml, 106 mmol) and the resulting reddish solution was heated at 40° C. for 70 hours. Most of the acetic anhydride was evaporated under vacuum and the residue was diluted with ethyl acetate and washed with sat. NH4Cl, H2O, and brine. Drying (MgSO4) and evaporation yielded 37.87 g (99%) of product as a yellow solid which was used in the next reaction without purification.
Reaction SMILES: [CH:1](=[N:8][N:9]([C:18]1[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=1[C:20](OC)=[O:21])[C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]CC.[Na+].O.Cl>C(O)C>[OH:21][C:20]1[C:19]2[C:18](=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:9]([N:8]=[CH:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10](=[O:17])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CC(=O)N(N=Cc1ccccc1)c1ccccc1C(=O)OC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(O)c2ccccc2n(N=Cc2ccccc2)c1=O
Temperature: 50 °C
Yield: 91.9 %

Procedure:
The product of Example 226B (5.17 g, 14.59 mmol) in ethanol (100 mL) was reacted with sodium ethoxide (21% by weight in ethanol, 5.50 mL, 14.60 mmol) at 25° C. then heated at 50° C. for 1 hour. After cooling to 25° C., the reaction mixture was poured into water, acidified to pH 4 with 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent removed under vacuum to give the title compound (4.51 g, 96%). MS (DCI) m/z 323 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.73 (s, 3 H) 7.21 (m, 1 H) 7.56 (m, 5 H) 7.95 (m, 2 H) 8.03 (d, J=7.72 Hz, 1 H) 9.08 (s, 1 H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[C:15]([O:34][CH3:35])=[CH:16][CH:17]=[C:18]2[C:23]=1[O:22][C:21](=[O:24])[CH:20]=[C:19]2[NH:25][C:26]1[C:31]([Cl:32])=[CH:30][N:29]=[CH:28][C:27]=1[Cl:33]>>[Cl:33][C:27]1[CH:28]=[N:29][CH:30]=[C:31]([Cl:32])[C:26]=1[NH:25][C:19]1[C:18]2[C:23](=[C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[C:15]([O:34][CH3:35])=[CH:16][CH:17]=2)[O:22][C:21](=[O:24])[CH:20]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCBr
Reactant: C1COCCN1
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCN1CCOCC1

Procedure:
The title compound was prepared from morpholine and 8-(5-bromopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 28) following the procedure outlined in Example 52. 1H NMR (400 MHz, DMSO-d6): δ 9.52 (br s, 1H), 8.80 (s, 2H), 7.94 (d, 1H), 7.19 (d, 1H), 4.62 (s, 1H), 3.98 (t, 2H), 3.91 (s, 3H), 3.55 (br, 4H), 2.51-2.15 (br, 6H), 1.69 (m, 2H), 1.47 (m, 4H); MS (ESI): 507.9.