Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:10]2=[CH:11][C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH:21]=[C:9]2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33](Br)=[CH:32][CH:31]=2)=[CH:26][CH:25]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][C:33]([N:13]3[C:12]4[CH:11]=[C:10]5[C:2]([CH3:22])([CH3:1])[C:3]6[C:8]([C:9]5=[CH:21][C:20]=4[C:19]4[C:14]3=[CH:15][CH:16]=[CH:17][CH:18]=4)=[CH:7][CH:6]=[CH:5][CH:4]=6)=[CH:32][CH:31]=2)=[CH:28][CH:29]=1
Reactant: Brc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccccc13
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4ccc(-c5ccc(Br)cc5)cc4)c3cc21
Yield: 43.1 %

Procedure:
20 g (70.58 mmol) of 12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]-fluorene and 33 g (105.87 mmol) of 4,4′-dibromobiphenyl are dissolved in toluene and degassed by introduction of a protective gas. 4.94 ml (4.94 mmol/1 M solution in toluene) of tri-tert-butylphosphine, 633.8 mg (2.82 mmol) of Pd(OAc)2 and 10.2 g (105.87 mmol) of NaOtBu are subsequently added. The solids are degassed in advance, the reaction mixture is subsequently degassed and then stirred under reflux for 5 h. The warm reaction solution is filtered through Alox B (activity grade 1), washed with water, dried and evaporated. Crystallisation from toluene gives 15.6 g (30.4 mmol) (43%) of the product as a white solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].CO[CH:11](OC)[CH2:12][CH2:13][C:14]#[N:15].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH:23]=O.[Cl-].[NH4+]>C1COCC1>[CH3:18][O:19][C:20]1[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=[C:22]2[C:21]=1[CH:11]=[CH:12][C:13]([C:14]#[N:15])=[CH:23]2
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: COC(CCC#N)OC
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc2cc(C#N)ccc2c(OC)c1OC
Temperature: -75 °C
Reaction time: 1 h

Procedure:
2.0 M Lithium diisopropylamide (2.55 mL) was added to dry THF (5 mL) at −75° C. under an argon atmosphere, and a solution of 3-cyanopropionaldehyde dimethylacetal (672 mg) in dry THF (5 mL) was then added dropwise to the mixture, and the resulting mixture was stirred at −75° C. for 1 hour. A solution of 3,4,5-trimethoxy-benzaldehyde (1.0 g) in dry THF (5 mL) was then added dropwise to the reaction mixture. After the mixture was warmed to room temperature and stirred for 1 hour, a saturated aqueous solution of ammonium chloride was added to the reaction mixture to conduct extraction with ethyl acetate. The resultant organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant residue was dissolved in methanol (6 mL), sulfuric acid (1 mL) was slowly added to the solution, and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was weakly alkalified with an aqueous solution of 4 M potassium hydroxide at 0° C. to conduct extraction with chloroform. The resultant organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:3 to 1:1) to obtain the title compound.
Reaction SMILES: C([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5](=[O:13])[CH:4]=1)=O.[C:14]([NH:17][CH2:18][C:19]([OH:21])=[O:20])(=O)[CH3:15].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[O:13]=[C:5]1[CH2:4][C:3](=[C:18]2[C:19](=[O:20])[O:21][C:14]([CH3:15])=[N:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6]1
Reactant: CC(=O)NCC(=O)O
Reactant: O=Cc1cc(=O)[nH]c2ccccc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC1=NC(=C2CC(=O)Nc3ccccc32)C(=O)O1

Procedure:
17 Grams of 4-formylcarbostyril, 18 g of N-acetylglycine, 7 g of anhydrous sodium acetate and 100 ml of acetic anhydride were heated at 110° C. to make a homogeneous solution, further the solution was refluxed for 1.5 hours. After cooled the reaction mixture, the reaction mixture was poured in a cold water and the crystals precipitated were collected by filtration. The crystals were washed with cold water, then recrystallized from ethanol-chloroform to obtain 10 g of 4-(1,2-dihydro-2-oxo-4-quinolyliden)-2-methyl-5-oxazolone.1/2-hydrate.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH:4]=O.C(=O)([O-])[O-].[K+].[K+].[F:17][C:18]([F:27])([F:26])/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C)C=O>[Cl:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[NH:1][CH:19]([C:18]([F:17])([F:27])[F:26])[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:4]2
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: Nc1ccc(Cl)cc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(Cl)ccc2NC1C(F)(F)F
Temperature: 100 °C
Yield: 55.7 %

Procedure:
The 2-amino-5-chlorobenzaldehyde from Step 1 (15.0 g, 96 mmol), anhydrous potassium carbonate (27.6 g, 200 mmol), and ethyl 4,4,4-trifluorocrotonate (34 mL, 200 mmol) were mixed in anhydrous dimethyformamide (60 mL) and heated at 100° C. for 7 hours. The contents were allowed to cool and partitioned between ethyl acetate (200 mL) and water (200 mL). The aqueous layer was extracted with ethyl acetate (1×100 mL). The ethyl acetate extracts were combined and washed with brine (1×200 mL), dried over MgSO4, and concentrated in vacuo leaving a dark oil which solidified upon standing. The solid was purified by flash chromatography (silica gel; ethyl acetate-hexanes, 1:9). Fractions containing the desired product were combined, concentrated in vacuo and the residue recrystallized from ethyl acetate-hexanes to afford the ethyl 6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate as a yellow solid (16.36 g, 56%): mp 132.6-134.2° C. 1H NMR (CDCl3, 300 MHz) 7.61 (s, 1H), 7.10 (m, 2H), 6.55 (d, 1H, J=8.0 Hz), 5.10 (q, 1H, J=6.0 Hz), 4.55 (brs, 1H), 4.23 (m, 2H), 1.32 (t, 3H, J=7.0 Hz). FABHRMS m/z 306.0468 (M+H+, Calc'd 306.0509). Anal. Calc'd for C13H11NO2F3Cl: C, 51.08; H, 3.63; N, 4.58. Found: C, 50.81; H, 3.49; N, 4.72.
Reaction SMILES: [C:1]([N:5]1[C:9]2[N:10]=[CH:11][N:12]=[CH:13][C:8]=2[C:7]([C:14]([C:16]2[CH:17]=[C:18]([NH:22][C:23](=[O:32])[CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:19]=[N:20][CH:21]=2)=[O:15])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:35]I.[Cl-].[NH4+]>C1COCC1>[C:1]([N:5]1[C:9]2[N:10]=[CH:11][N:12]=[CH:13][C:8]=2[C:7]([C:14]([C:16]2[CH:17]=[C:18]([N:22]([CH3:35])[C:23](=[O:32])[CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:19]=[N:20][CH:21]=2)=[O:15])=[CH:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(F)cc3)c2)c2cncnc21
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C(=O)Cc1ccc(F)cc1)c1cncc(C(=O)c2cn(C(C)(C)C)c3ncncc23)c1
Reaction time: 0.17 h
Yield: 46 %

Procedure:
To a stirred solution of N-[5-(7-tert-Butyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin-3-yl]-2-(4-fluoro-phenyl)-acetamide (Example 546, 115 mg, 0.27 mmol) in anhydrous THF (4.5 mL), was added NaH (60% in paraffin oil, 10.7 mg, 0.27 mmol) at 0° C. under nitrogen and the resulting mixture stirred for 10 min. MeI (0.017 mL, 0.27 mmol) was then added and the reaction mixture was stirred at room temperature for 1 hour. Aqueous saturated ammonium chloride (5 mL) was added and the mixture extracted with ethyl acetate (2×10 mL). The organic phase was washed with water (10 mL), brine (10 mL), dried over sodium sulphate and evaporated to dryness in vacuo. The crude material was purified via preparative TLC (eluting with 5% methanol in DCM) to afford the title compound as off white solid in 46% yield, 55 mg. 1H NMR (400 MHz, DMSO-D6) δ: 1.79 (s, 9H), 3.28 (s, 3H), 3.58 (br, 2H), 7.08-7.20 (m, 4H), 8.20 (s, 1H), 8.32 (s, 1H), 8.83 (s, 1H), 8.97 (br, 1H), 9.01 (s, 1H), 9.50 (s, 1H); LCMS (system 10): Rt=3.08 min; m/z 446 [M+H]+.
Reaction SMILES: ClCCl.[Br:4][CH2:5][C:6]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:7]=1[C:8](OC)=[O:9].[H-].C([Al+]CC(C)C)C(C)C.CCCCCC.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>COC(C)(C)C>[Br:4][CH2:5][C:6]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:7]=1[CH2:8][OH:9]
Reactant: COC(=O)c1cccc(Cl)c1CBr
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: COC(C)(C)C
Solvent: CCCCCC
Solvent: ClCCl
Product: OCc1cccc(Cl)c1CBr
Reaction time: 1 h
Yield: 98.3 %

Procedure:
Dichloromethane (10 ml) was added to methyl 2-(bromomethyl)-3-chlorobenzoate obtained in Example 10c (500 mg, 1.9 mmol), a 1.04 M diisobutylaluminum hydride/n-hexane solution (4.57 ml, 4.75 mmol) was added at −78° C., followed by stirring for one hour under a nitrogen atmosphere. A saturated aqueous Rochelle salt solution and tert-butyl methyl ether were added, followed by extraction with tert-butyl methyl ether. The organic layer was washed with brine, dried over magnesium sulfate and then allowed to pass through a silica gel pad. The eluate was concentrated to give the title compound (440 mg, yield 98.3%).
Reaction SMILES: [OH-].[Li+].[C:3]1([CH2:14][C:15]([O:17]C)=[O:16])[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.C1COCC1.Cl>O.CO>[CH3:13][O:12][C:10](=[O:11])[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:14][C:15]([OH:17])=[O:16])=[CH:4][CH:5]=1
Reactant: COC(=O)Cc1ccc(CC(=O)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Yield: 43.4 %

Procedure:
A 655 mg portion of lithium hydroxide was dissolved in 32 ml of water and added to 32 ml of a mixture of 6.4 g of dimethyl 2,2′-(1,4-phenylene)diacetate, 32 ml of THF and 32 ml of methanol. After 2Hours of stirring at room temperature, the reaction solution was neutralized with 1 M hydrochloric acid and extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate and concentrated under a reduced pressure. The residue was purified by a silica gel column chromatography (chloroform-methanol) to obtain 2.6 g of [4-(2-methoxy-2-oxoethyl)phenyl]acetic acid. EN: 207.
Reaction SMILES: [OH-].[Na+].CO.[C:5]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18]C)=[O:17])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl>C(OCC)(=O)C.O.O1CCOCC1>[C:5]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([OH:18])=[O:17])(=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
1.2 mL of 2.0 mol/L aqueous sodium hydroxide was added to a suspension of 5 mL of methanol and 2.5 mL of dioxane containing 0.50 g of methyl 2-(benzamido)-4-phenylbenzoate at room temperature and stirred at 50° C. for 30 minutes. After the reaction mixture was cooled to room temperature, 1.0 mol/L hydrochloric acid was added to adjust to pH 3 and water and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. Hexane was added to the obtained, residue and a solid substance was separated by filtration to obtain 0.36 g of 2-(benzamido)-4-phenylbenzoic acid as white solid.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH3:13])=[N:5]1)(=[O:3])[CH3:2].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][Br:14])=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)n1nc(C)c2ccccc21
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)n1nc(CBr)c2ccccc21
Temperature: 70 °C

Procedure:
1-Acetyl-3-methyl-1H-indazole (5.77 g, 33.1 mmol) in CCl4 (150 mL) was treated with N-bromosuccinimide (6.49 g, 36.5 mmol) and benzoyl peroxide (0.80 g, 3.3 mmol) and the mixture was heated at 70° C. for 16 h. The mixture was concentrated and the residue quickly filtered through a plug of flash silica eluting with 0→5% EtOAc in hexane to give the crude title compound contaminated with traces of dibromide and starting material. This was conveniently used directly in subsequent reactions without further purification.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C.[C:19]([Si:21]([CH3:24])([CH3:23])[CH3:22])#[CH:20].O>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[CH2:10]([O:9][C:7]([C:3]1[N:4]=[CH:5][S:6][C:2]=1[C:20]#[C:19][Si:21]([CH3:24])([CH3:23])[CH3:22])=[O:8])[CH3:11]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1ncsc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ncsc1C#C[Si](C)(C)C
Temperature: 90 °C
Reaction time: 1 h

Procedure:
5-Bromo-4-ethoxycarbonylthiazole (18.64 g) was dissolved in 80 ml of DMF. Triethylamine (22 ml), 16.7 ml of ethynyltrimethylsilane, 960 mg of copper(I) iodide, and 1.11 g of bis(triphenylphosphine)palladium(II) dichloride were added in that order to the solution, and the mixture was stirred at 90° C. under an argon atmosphere for one hr. Water (80 ml), 160 ml of ethyl acetate and 160 ml of hexane were added to the reaction solution, and the mixture was washed with (brine+aqueous hydrochloric acid), sodium bicarbonate water, and brine in that order. Activated carbon and anhydrous magnesium sulfate were added to the organic layer, and the mixture was filtered and was concentrated under the reduced pressure to give 16.45 g of the title compound.
Reaction SMILES: [C:1]([N:5]1[C:9]([CH3:10])=[C:8]([C:11]([OH:13])=O)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:19]([CH:22]=1)[C:20]#[N:21].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>O.CN(C)C=O>[C:1]([N:5]1[C:9]([CH3:10])=[C:8]([C:11]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([O:23][CH2:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[C:19]([C:20]#[N:21])[CH:22]=2)=[O:13])[CH:7]=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Reactant: Cc1c(C(=O)O)cnn1C(C)(C)C
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(OCC(C)(C)C)c(C#N)c2)cnn1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.4 %

Procedure:
1-tert-Butyl-5-methylpyrazole-4-carboxylic acid (2 g), 5-amino-2-neopentyloxybenzonitrile (2.2 g), triethylamine (3.3 g) and diethyl cyanophosphate (2.7 g) were added to dimethylformamide (20 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. Methanol was added to the residue to allow crystallization. The crystals were recrystallized from hydrous dimethylformamide to give the title compound (2.2 g), melting point: 143–144° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].N1C=CC=CC=1.Cl[C:19](OCC)=[O:20].Cl>O.C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:19](=[O:20])[NH:9][C:7](=[O:8])[C:6]=2[CH:10]=1
Reactant: NC(=O)c1cc(Cl)ccc1O
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: c1ccncc1
Product: O=c1[nH]c(=O)c2cc(Cl)ccc2o1
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
A solution of 10 g of 5-chloro-2-hydroxybenzamide (58.0 mmol), pyridine (22 ml) and acetonitrile (25 ml) was stirred in an ice bath. Ethyl chloroformate (6.1 ml, 0.0638 mol) was added dropwise. The pink solution was stirred for 30 minutes at <10° C. The ice bath was replaced with an oil bath. The reaction mixture was heated to 95° C. and the volatiles were distilled off (43 ml). The reaction was cooled to room temperature, causing a white solid to form. The mixture was poured into water (100 ml) and acidified with concentrated aqueous hydrochloric acid. The resulting solid was filtered and recrystallized in hot ethanol to give 9.77 g of 6-chloro-2H-1,3-benzoxazine-2,4(3H)-dione.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=1.C(N(C(C)C)CC)(C)C>C(O)C.[Pd]>[F:16][C:13]([F:14])([F:15])[C:4]1[N:3]=[CH:2][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cnc(C(F)(F)F)nc1Cl
Agent: [Pd]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(C(F)(F)F)nc1
Reaction time: 6 h
Yield: 97.7 %

Procedure:
To a solution of ethyl 4-chloro-2-(trifluoromethyl)pyrimidine-5-carboxylate (30.2 g, 119.0 mmol) in ethanol (594 mL) under nitrogen were added palladium (10% on carbon, 50% water wet; 2.58 g, 1.21 mmol) and diisopropylethylamine (50.0 mL, 286.0 mmol). The mixture stirred under hydrogen (1 atm). After 6 h, the mixture was filtered with Celite. The filtrate was concentrated and ethyl acetate was added. The mixture was washed with saturated aqueous sodium bicarbonate (2×), saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated to give the title compound (25.6 g). MS 221.1 (M+1).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=2)=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: 150 °C
Yield: 29939.7 %

Procedure:
6-Chloronicotinic acid (1.57 g, 0.01 mmol), [4-(trifluoromethyl)phenyl]boronic acid (1.9 g, 0.01 mol), tetrakis(triphenylphosphine) palladium (0) (230 mg, 2 mol %), Na2CO3 (2M, 5 ml) in THF (15 ml) were placed in a microwave tube and the contents were heated in the microwave oven for 20 min at 150° C. The cooled mixture was filtered through Hyflo® to remove inorganic material, the Hyflo® was washed with EtOAc and the combined organic extracts were dispersed between aq. NaOH and EtOAc. The aqueous extracts were acidified (aq. HCl) and extracted with EtOAc; the organic extracts were washed with brine, dried (MgSO4) and evaporated to give the product (0.8 g, 30%). 1H NMR (400 MHz, CD3OD) δ: 7.85 (2H, d, J 8.2), 8.10 (1H, dd, J 0.8, 8.4), 8.31 (2H, d, J 8.2), 8.49 (1H, dd, J 2.2, 8.2), 9.26 (1H, dd, J 0.8, 2.1).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[C:8]([OH:12])([CH3:11])([CH3:10])[CH3:9].CN(C)C1C=CC=CC=1.Cl>O.CCOCC>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: O=C(Cl)CCCCl
Reactant: CC(C)(C)O
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CCCCl
Yield: 73.9 %

Procedure:
4-Chlorobutyryl chloride (14.1 g) was added dropwise with stirring under ice-cooling to a mixture of tert-butanol (18.5 g) and dimethylaniline (18.2 g). The resulting mixture was stirred for 2 hours in an oil bath (100° C.). Ether (200 ml), water (100 ml) and 1N hydrochloric acid (50 ml) were added to the reaction mixture and mixed with shaking. The organic layer was washed successively with 1N hydrochloric acid, an aqueous sodium bicarbonate and brine and dried over anhydrous magnesium sulfate. The solvent was distilled off and then the residue was subjected to distillation under reduced pressure to obtain tert-butyl 4-chlorobutyrate (13.2 g).
Reaction SMILES: [CH3:1][O-:2].[Na+].[F:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11](F)[CH:12]=1)[C:8]#[N:9]>CO.CN(C)C=O.CCOCC>[F:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([O:2][CH3:1])[CH:12]=1)[C:8]#[N:9]
Reactant: C[O-]
Reactant: N#Cc1cc(F)cc(F)c1
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1cc(F)cc(C#N)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Sodium methoxide (1.50 ml of a 4.5M solution in methanol, 7.10 mmol) was added dropwise to a stirred solution of 3,5-difluorobenzonitrile (1.00 g, 7.10 mmol) in N,N-dimethylformamide (36 ml) at 0° C. under nitrogen. The reaction was allowed to warm to room temperature and stirred for 14 hours. The reaction was diluted with ether (40 ml), washed with water (3×100 ml) and brine (100 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with cyclohexane:ethyl acetate (95:5, by volume) to provide the title compound (418 mg) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:18]#[N:19])=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[NH:5][C:6]=1[Br:7].C1COCC1.CC([O-])(C)C.[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O.CCOC(C)=O.CCCCCC>[CH2:31]([N:5]1[C:6]([Br:7])=[C:2]([Br:1])[C:3]([C:18]#[N:19])=[C:4]1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:17])[F:16])=[CH:10][CH:9]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: N#Cc1c(-c2ccc(C(F)(F)F)cc2)[nH]c(Br)c1Br
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N#Cc1c(Br)c(Br)n(Cc2ccccc2)c1-c1ccc(C(F)(F)F)cc1

Procedure:
In a 100 mL flask, 1.5 g of 4,5-dibromo-2-(α,α,α-trifluoro-p-tolyl)pyrrole-3-carbonitrile is mixed with 50 mL dry THF to give a clear dark solution. 1 eq of KOtBu is added with stirring. After a few minutes the solution clears. Benzyl bromide (0.65 g) is added by syringe. The mixture is heated at reflux overnight. The following day TLC (50/50 EtOAc/hexane) indicates the presence of both starting material and product. The reaction is worked up in the following manner; 50 mL of water is added and the mixture is extracted with 4×50 mL CHCl3. The organic phases are combined and washed with 4×50 mL 10% aq. NAOH. The organic phase is dried with MgSO4 and stripped. This gives a brown solid which is crystallized from EtOAc/hexane, mp 145°-147° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:25])[CH:11]=[CH:12][C:13]2[C:18]([O:19][CH3:20])=[CH:17][C:16]([O:21][CH3:22])=[CH:15][C:14]=2[O:23][CH3:24])=[CH:5][C:4]=1[N+:26]([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].O.C(OCC)(=O)C>CC(C)=O.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:25])/[CH:11]=[CH:12]/[C:13]2[C:14]([O:23][CH3:24])=[CH:15][C:16]([O:21][CH3:22])=[CH:17][C:18]=2[O:19][CH3:20])=[CH:5][C:4]=1[NH2:26]
Reactant: COc1cc(OC)c(C=CC(=O)Nc2ccc(OC)c([N+](=O)[O-])c2)c(OC)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(OC)c(/C=C/C(=O)Nc2ccc(OC)c(N)c2)c(OC)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A solution of N-(4-methoxy-3-nitrophenyl)-3-(2,4,6-trimethoxyphenyl) -2-propenamide (example 5) (1.3mmol) in acetone/water (10:5) was heated to 50° C. After 30 min, sodium hydrosulfite (Na2S2O4) 26.3 mmol) was added slowly. The resulting mixture was heated at reflux (50° C.) for one hour. The mixture was then cooled to room temperature and water was added. The product was isolated by extraction with ethyl acetate. The organic layer washed with 10% aqueous NaHCO3 and then dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The crude product thereby obtained was recrystallized from 2-propanol to yield the title compound, melting point 92-94° C., in 48% yield.