Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.Cl.Cl[CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1.O>C1COCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[C:6]([C:11]([F:14])([F:12])[F:13])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S)c(C(F)(F)F)c1
Reactant: ClCc1cccnc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(SCc2cccnc2)c(C(F)(F)F)c1
Yield: 52.1 %

Procedure:
4-nitro-2-(trifluoromethyl)benzenethiol (3.0 g) was dissolved in THF (60 ml), and to this solution was added triethylamine (5.25 ml) and then, 3-(chloromethyl)pyridine hydrochloride (2.65 g), and the mixture was stirred for 1 hour at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was washed with hexane/ethyl acetate, to give 3-[[[4-nitro-2-(trifluoromethyl)phenyl]sulfanyl]methyl]pyridine (2.2 g).
Reaction SMILES: C([O:3][C:4]([CH:6]([O:8][C:9]1[CH:25]=[CH:24][C:12]2[C:13](=[O:23])[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][O:16][C:11]=2[CH:10]=1)[CH3:7])=[O:5])C.O1CCOCC1.Cl>O>[OH:5][C:4]([CH:6]([O:8][C:9]1[CH:25]=[CH:24][C:12]2[C:13](=[O:23])[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][O:16][C:11]=2[CH:10]=1)[CH3:7])=[O:3]
Reactant: CCOC(=O)C(C)Oc1ccc2c(=O)c(-c3ccccc3)coc2c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(Oc1ccc2c(=O)c(-c3ccccc3)coc2c1)C(=O)O
Temperature: 0 °C
Yield: 93.2 %

Procedure:
A mixture of 20 g of 7-(1-ethoxycarbonylethyl)oxy-3-phenyl-4H-1-benzopyran-4-one, 200 ml of dioxane, 70 ml of hydrochloric acid and 150 ml of water was refluxed for 4 hours and poured into ice water. The resulting crystalline precipitate was collected by filtration and recrystallized from ethanol to give 17.1 g of 7-(1-hydroxycarbonylethyl)oxy-3-phenyl-4H-1-benzopyran-4-one as white crystals. m.p. 223° C.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.C[Mg]I.[C:18](#N)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>C1COCC1>[CH2:18]([C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(Oc1ccc(Br)cc1)C(=O)O
Reactant: N#Cc1ccccc1
Agent: C[Mg]I
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(Oc1ccc(Cc2ccccc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
26 g (0.1 mole) of 2-[(para-bromo)-phenoxy]-2-methyl-propionic acid is dissolved in 200 cc of anhydrous THF and placed in a 500 cc flask. The mixture is cooled in an ice bath and 0.2 mole of methylmagnesium iodide (prepared in solution of THF) is added slowly. After this addition, the temperature is allowed to rise and the mixture stirred at ambient temperature for 11/2 hours. Then slowly and drop by drop a solution of 4.1 g (0.1 mole) of benzonitrile in 20 cc of THF is added and the mixture is stirred for 2 hours 30 minutes at ambient temperature. The reaction mixture is poured on to 500 cc of 10% hydrochloric acid, cooled by 500 g of ice, and vigorously stirred. The reaction mixture is extracted with ether and the ethereal phases are washed, dried and decolorised. The ether solvent is evaporated under vacuum and the oily residue placed in a desiccator under vacuum. 2-[(para-benzoyl)-phenoxy]-2-methylpropionic acid slowly crystallises (22 g). The yield is 77% and the melting point 130° C.
Reaction SMILES: Cl.[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5].[CH3:14][C:15]([CH:17]1[C:23](=[O:24])[CH2:22][C:21]([CH3:26])([CH3:25])[CH2:20][C:18]1=[O:19])=O>CO>[CH3:26][C:21]1([CH3:25])[CH2:22][C:23](=[O:24])[C:17](=[C:15]([NH:5][C@@H:4]2[C@@H:6]([OH:7])[C@H:8]([OH:9])[C@@H:10]([CH2:12][OH:13])[O:11][C@@H:3]2[OH:2])[CH3:14])[C:18](=[O:19])[CH2:20]1
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CC(=O)C1C(=O)CC(C)(C)CC1=O
Agent: Cl
Solvent: CO
Product: CC(N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O)=C1C(=O)CC(C)(C)CC1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 188.5 %

Procedure:
Glucosamine hydrochloride (50 g, 231 mmol) was suspended in anhydrous methanol (500 mL), then 2-acetyl-dimedone sodium salt (47.3 g, 231 mmol) was added. The reaction mixture was stirred at room temperature for 10 minutes, then 2-acetyl-dimedone (21.1 g, 115.9 mmol) was added. The reaction mixture was stirred under reflux for 2.5 hours and monitored by tlc. At the completion of the reaction (TLC: MeCN—H20, 10:2), the reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated and the resulting solid residue was washed on a funnel with ether (3×500 mL) and dried to give crude product (75 g, 94%). No further purification was required for the next reaction.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[N:19]=[CH:20][CH:21]=[CH:22][N:23]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: C[C@@H]1CCCN(C(=O)c2ccccc2-c2ncccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2ccccc2-c2ncccn2)[C@@H]1CNc1ncc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A316 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(2-(pyrimidin-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 457 [M+1]+. 1H NMR (500 MHz, CD3OD) δ 9.05-6.85 (m, 9H), 5.15-3.00 (m, 5H), 2.10-0.75 (m, 8H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4](CC([O-])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([CH3:12])=[CH2:11].C1(C)C=CC=CC=1.C([SnH](CCCC)CCCC)CCC.[OH-:37].[Na+].Cl>C(OCC)(=O)C.O.CO>[CH3:12][C:10]1([CH3:11])[C:6]2[CH:5]=[C:4]([OH:37])[CH:3]=[CH:2][C:7]=2[O:8][CH2:9]1
Reactant: [OH-]
Reactant: C=C(C)COc1ccc(CC(=O)[O-])cc1Br
Agent: CCCC[SnH](CCCC)CCCC
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1(C)COc2ccc(O)cc21
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of [3-bromo-4-(2-methylallyloxy)phenyl]acetate (Intermediate 43, 190 mg, 0.67 mmol) in toluene (5 mL) azobisisobutyronitrile (0.13 g, 0.80 mmol) and tributylstannane (0.39 g, 1.33 mmol) were added and the reaction mixture was stirred for 2 hours at 90° C. Methanol (5 mL), water (3 mL) and sodium hydroxide 2M solution in water (0.67 ml, 1.33 mmol) were added and the reaction mixture was stirred for 1 hour at room temperature. A 2N aqueous solution of HCl was added while the pH was allowed to reach ˜3-4 and ethyl acetate (30 ml) was added. Two phases were separated and a 10% w/w solution of KF was added to the organic phase and the mixture was stirred for 1 hour at room temperature. The solid was filtered off and the solution was dried (Na2SO4), and evaporated. The residue was purified by flash chromatography (Biotage system) on silica gel using a SNAP 25 g as column and cyclohexane/ethyl acetate from 100:0 to 70:30 as eluent affording the title compound (95 mg) as white solid.
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([NH:33]C(=O)OC(C)(C)C)([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:22][CH:23]4[CH2:28][CH2:27][CH:26]([C:29]([F:32])([F:31])[F:30])[CH2:25][CH2:24]4)[C:14]=3[C:18]([F:21])([F:20])[F:19])[CH:9]=2)[CH2:4][O:3]1.CO.Cl.O>>[NH2:33][C:5]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:22][CH:23]3[CH2:28][CH2:27][CH:26]([C:29]([F:30])([F:31])[F:32])[CH2:25][CH2:24]3)[C:14]=2[C:18]([F:20])([F:21])[F:19])[CH:9]=1)([CH2:6][OH:7])[CH2:4][OH:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc3c(C(F)(F)F)c(OC4CCC(C(F)(F)F)CC4)ccc3c2)COC(C)(C)OC1
Agent: Cl
Solvent: O
Solvent: CO
Product: NC(CO)(CO)c1ccc2c(C(F)(F)F)c(OC3CCC(C(F)(F)F)CC3)ccc2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 106.8 %

Procedure:
Tert-butyl 2,2-dimethyl-5-(5-(trifluoromethyl)-6-(4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)-1,3-dioxan-5-ylcarbamate (1000.1 mg, 0.0016906 mol) (impure, assume 100% purity) was dissolved in methanol (30 mL, 0.73 mol), followed by 1 M of hydrogen chloride in water (30 mL, 0.030 mol). The reaction mixture was then heated at 80° C. for 2.5 hours. The solvent was removed under reduced pressure and the crude residue was treated with 4 N HCl in 1,4-dioxane. The solution was stirred for 1 hour and the solvent was then removed under reduced pressure. Ethyl ether was then added and the resulting solid was removed via filtration to give 815 mg of the desired product a white solid (64%). ESI-MS: 417 (M-16)+ 1H NMR (400 MHz, DMSO-d6) δ=8.21-7.97 (m, 3 H), 7.82-7.61 (m, 2 H), 5.57-5.41 (m, 4 H), 5.10 (br. s., 0.61 H), 4.98-4.88 (m, 0.32 H), 3.97-3.72 (m, 1 H), 2.15-1.91 (m, 2 H), 1.82-1.08 (m, 6 H)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([NH2:11])=[N:7]1)[CH3:2].[Cl:13][C:14]1[S:18][C:17]([C:19](O)=[O:20])=[CH:16][CH:15]=1>C1COCC1>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([NH:11][C:19]([C:17]2[S:18][C:14]([Cl:13])=[CH:15][CH:16]=2)=[O:20])=[N:7]1)[CH3:2]
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: CCOC(=O)Cn1ccc(N)n1
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ccc(NC(=O)c2ccc(Cl)s2)n1

Procedure:
57.2 Using general method A, with THF instead of DMF as solvent, (3-amino-pyrazol-1-yl)-acetic acid ethyl ester was coupled with 5-chlorothiophene-2-carboxylic acid to give {3-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrazol-1-yl}-acetic acid ethyl ester. Light yellow solid. MS 314.0 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[CH:16]/[C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([Cl:12])[CH:14]=2)/[C:9]#[N:10])=[C:4]([F:11])[CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1F
Reactant: O=Cc1cccc(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#C/C(=C\c1cccc(Cl)c1)c1ccc(Cl)cc1F
Yield: 85.6 %

Procedure:
In a manner similar to the method described in Example 1b, 4-chloro-2-fluorophenylacetonitrile (4.5 g, 26 mmol) was reacted with 3-chlorobenzaldehyde (Aldrich) (4.4 g, 32 mmol), methanolic solution (25 wt %) of sodium methoxide (6.6 mL, 29 mmol) in methanol (150 mL) at 50° C. for 3 h to give (Z)-2-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-phenyl)-acrylonitrile as a white powder (6.5 g, 84%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=2)=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[CH2:25][OH:26])=[CH:19][CH:18]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=2)=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20](/[CH:23]=[CH:24]/[CH:25]=[O:26])=[CH:21][CH:22]=1
Reactant: Cc1cccc(-c2nc(CCOc3ccc(/C=C/CO)cc3)c(C)o2)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1cccc(-c2nc(CCOc3ccc(/C=C/C=O)cc3)c(C)o2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
Activated manganese dioxide (2.8 g) was added to a solution of (E)-3-[4-[2-[5-methyl-2-(3-methylphenyl)-4-oxazolyl]ethoxy]phenyl]-2-propen-1-ol (1.4 g) in dichloromethane (50 ml). The mixture was stirred for 2 hours at room temperature, which was subjected to filtration through celite. The filtrate was concentrated to give (E)-4-[2-[5-methyl-2-(3-methylphenyl)-4-oxazolyl]ethoxy]cinnamaldehyde (1.27 g, 91%). Recrystallization from dichloromethane-isopropyl ether gave colorless needles, m.p.110-111° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([O:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:10]#N.CCCCCC.CO.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=[O:28].[Na+].[K+]>C(Cl)Cl.[H-].C([Al+]CC(C)C)C(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([O:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[O:28]
Reactant: C[Si](C)(C)OC(C#N)c1c(Cl)cccc1Cl
Reactant: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CCCCCC
Product: C[Si](C)(C)OC(C=O)c1c(Cl)cccc1Cl
Yield: 96.7 %

Procedure:
To a solution of 2-(2,6-dichlorophenyl)-2-((trimethylsilyl)oxy)acetonitrile (1.372 g, 5.00 mmol) in DCM (23.16 ml), diisobutylaluminum hydride 1.0 M solution in hexane (7.50 ml, 7.50 mmol) was added at −78° C. dropwise over 20 min. Reaction was carefully quenched first with MeOH (1 ml, 24.97 mmol) and then with Rochelle salt 1.5 M (5.00 ml, 7.50 mmol). The flask was removed from the bath and allowed to reach ambient temperature and extracted with EtOAc (20 ml). The organic layer was separated and washed with brine, filtered through celite pad and concentrated to obtain 2-(2,6-dichlorophenyl)-2-((trimethylsilyl)oxy)acetaldehyde (1.34 g, 97%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[CH:3]=1.[CH2:10]([Mg]Br)[CH2:11][CH3:12].[Cl-].[NH4+].O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:10][CH2:11][CH3:12])[CH:3]=1
Reactant: BrCc1cccc(Br)c1
Reactant: CCC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under nitrogen stream, to a solution of 1-bromo-3-bromomethylbenzene (25 g) in tetrahydrofuran (200 ml) were sequentially added dropwise n-propylmagnesium bromide (60 ml, 2M solution in tetrahydrofuran) and lithium tetrachlorocuprate (5 ml, 0.1M solution in tetrahydrofuran) at −78° C. Then, this reaction mixture was stirred at 0° C. for 2 hours. Under ice-cooling, to this reaction mixture were sequentially added a saturated aqueous solution of ammonium chloride (100 ml) and water (100 ml), and the mixture was extracted with ethyl acetate (200 ml). The resulting aqueous layer was again extracted with ethyl acetate (100 ml), the combined organic layer was washed with a saturated aqueous solution of sodium chloride (100 ml), and dried over anhydrous sodium sulfate. This organic layer was concentrated under reduced pressure, the resulting residue was purified by silica gel chromatography (eluent: n-hexane/ethyl acetate=1/0 to 100/1) to give the titled compound (8.5 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[F:16][C:17]1[CH:18]=[C:19]([C:23]2[N:24]=[C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:26][CH:27]=2)[CH:20]=[CH:21][CH:22]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:16][C:17]1[CH:18]=[C:19]([C:23]2[N:24]=[C:25]([N:28]3[CH2:29][CH2:30][N:31]([C:8]([NH:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:15])[CH2:32][CH2:33]3)[S:26][CH:27]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Fc1cccc(-c2csc(N3CCNCC3)n2)c1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1cccnc1)N1CCN(c2nc(-c3cccc(F)c3)cs2)CC1
Temperature: 70 °C
Reaction time: 4 h
Yield: 50.4 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (225 mg, 0.835 mmol), 1-[4-(3-fluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.760 mmol) and diisopropylethylamine (0.265 ml, 1.52 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 4 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and ethyl acetate to give the desired product (147 mg, 50.5%) as a solid.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([O:12][CH3:13])[CH:5]=[CH:4][C:3]=1/[CH:14]=[CH:15]\[C:16]([O:18][CH2:19][CH3:20])=[O:17]>[C].[Pd].CO>[F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([O:12][CH3:13])[CH:5]=[CH:4][C:3]=1[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)/C=C\c1ccc(OC)c(C(F)(F)F)c1F
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1ccc(OC)c(C(F)(F)F)c1F
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed ethyl (2Z)-3-[2-fluoro-4-methoxy-3-(trifluoromethyl)phenyl]prop-2-enoate (200 mg, 0.68 mmol, 1.00 equiv), Palladium carbon (300 mg), methanol (15 mL). The solution was subjected to 2 atm of H2. The resulting solution was stirred overnight at 30° C. The reaction progress was monitored by LCMS. The solids were collected by filtration. The resulting mixture was concentrated under vacuum. This resulted in 0.21 g of ethyl 3-[2-fluoro-4-methoxy-3-(trifluoromethyl)phenyl]propanoate as yellow oil. Mass spectrum (ESI, m/z): Calcd. for C13H14F4O3, 295.1 (M+H). found 295.1.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.[F-].[K+].[Cl:28][C:29]1[C:34](B(O)O)=[CH:33][CH:32]=[CH:31][N:30]=1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>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].O1CCOCC1>[Cl:28][C:29]1[C:34]([C:2]2[CH:3]=[N:4][N:5]([C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=2)=[CH:33][CH:32]=[CH:31][N:30]=1
Reactant: OB(O)c1cccnc1Cl
Reactant: Brc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Product: Clc1ncccc1-c1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 100 °C

Procedure:
To an argon purged 48 mL sealed pressure vessel was added 1,4-dioxane (2.6 mL), 4-bromo-1-trityl-1-H-pyrazole (1.00 g, 2.60 mmol), potassium fluoride (0.492 g, 8.48 mmol), 2-chloropyridine-3-boronic acid (0.808 g, 5.14 mmol), tris(dibenzylideneacetone)dipalladium (0)(0.176 g, 0.193 mmol) and tri-t-butylphosphonium tetrafluoroborate (0.168 g, 0.578 mmol). The vessel was purged with argon and heated to 100° C. for 5 hours. The mixture was cooled to RT, filtered through a pad of silica gel using EtOAc and concentrated. The crude was purified using normal phase silica gel chromatography eluting with 15-70% EtOAc/Hexanes. The product fractions were concentrated to yield 2-chloro-3-(1-trityl-1H-pyrazol-4-yl)pyridine as an off-white solid. MS m/z=422 [M+1]+. Calc'd for C27H20ClN3: 421.92.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[N:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH:17]2[CH2:19][CH2:18]2)[N:11]=1.Cl.N>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:10]2[N:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH:17]3[CH2:19][CH2:18]3)[N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(F)c1
Reactant: Cc1cc(C2CC2)nc(Cl)n1
Agent: Cl
Agent: N
Solvent: CCO
Product: Cc1cc(C2CC2)nc(Nc2cccc(F)c2)n1
Temperature: 25 °C

Procedure:
A solution of 5.5 g (50 mmol) of 3-fluoroaniline and 9.3 g (55 mmol) of 2-chloro-4-methyl-6-cyclopropylpyrimidine in 100 ml of ethanol is adjusted to pH 1 with 5 ml of concentrated hydrochloric acid, with stirring, and is then heated under reflux for 18 hours. After the brown emulsion has been cooled to room temperature, it is rendered alkaline with 10 ml of 30% ammonia, poured onto 100 ml of ice-water and extracted twice with 150 ml of diethyl ether each time. The combined extracts are washed with 50 ml of water, dried over sodium sulfate and filtered, and the solvent is evaporated. The yellowish crystals which remain are purified by recrystallisation from diisopropyl ether/petroleum ether (b.p. 50°-70° C.). The white crystals melt at 87°-89° C.; yield: 8.3 g (34 mmol; 68% of the theoretical yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CCOCCc1ccc(Br)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCOCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl 3-[2-(4-bromophenyl)ethoxy]propanoate (Example 10a), 1.0 g) was dissolved in dichloromethane (10 mL) and treated with trifluoroacetic acid (2.5 mL). The mixture was stirred at room temperature for 3 hours, then concentrated in vacuo and azeotroped with dichloromethane (2×10 mL). The residue was taken up in dichlormethane (10 mL) and extracted with 1M sodium hydroxide (20 mL). The basic layer was washed with dichloromethane (20 mL) then acidified with 2M hydrochloric acid. The acidic layer was extracted with dichloromethane (2×20 mL). The organic layers were combined, washed with brine, dried over anhydrous magnesium sulphate, filtered and concentrated to yield the sub-titled compound (0.81 g) as an oil.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[C@@H:6]([CH3:8])[NH2:7])[CH3:3].C(N(CC)CC)C.[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:19]=1[CH2:20]Br>C(O)C>[CH2:2]([O:4][C:5](=[O:9])[C@@H:6]([CH3:8])[NH:7][CH2:20][C:19]1[C:22]([N+:26]([O-:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=1[Cl:17])[CH3:3]
Reactant: CCOC(=O)[C@@H](C)N
Reactant: O=[N+]([O-])c1cccc(Cl)c1CBr
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H](C)NCc1c(Cl)cccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
A mixture of 18.24 g of D-alanine ethyl ester hydrochloride in 60 ml of ethanol was added dropwise to a mixture of 25 ml of triethylamine in 60 ml of ethanol and the resulting mixture was heated to 80° C. The solution obtained was added dropwise at this temperature to a solution of 15 g of 2-chloro-6-nitrobenzyl bromide in 60 ml of ethanol. The mixture was stirred at 80° C. overnight and then evaporated to dryness. The residue was treated with 150 ml of deionised water and extracted twice with 100 ml of methylene chloride. The methylene chloride extracts were washed with water, dried over sodium sulphate and evaporated. The resulting product was purified by chromatography on silica gel with methylene chloride/5% methanol. There were obtained 16 g (93% of theory) of N-(2-chloro-6-nitrobenzyl)-D-alanine ethyl ester; nD25 =1.5247; [α]D =-6.9° (c=1% in ethanol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[CH:7]=1)[CH3:2].[Cu](C#N)[C:15]#[N:16].CN1CCCC1=O>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:15]#[N:16])[CH:7]=1)[CH3:2]
Reactant: N#C[Cu]C#N
Reactant: CCOC(=O)Cc1cccc(Br)c1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCOC(=O)Cc1cccc(C#N)c1
Temperature: 120 °C
Yield: 88.7 %

Procedure:
A mixture of (3-bromo-phenyl)-acetic acid ethyl ester (9.15 g, 37.6 mmol), copper cyanide (5.06 g, 56.5 mmol), and 1-methyl-2-pyrrolidinone (80 mL) was placed into an oil bath heated at 120° C. behind a protective shield. The reaction was heated to 200° C. for 1 h and additional copper cyanide (spatula tip) was added. After heating for an additional 0.5 h, the reaction was cooled to room temperature. The reaction was diluted with EtOAc and the organic solution was washed with water/ammonium hydroxide solution (2:1 v/v) until the aqueous solution was no longer blue. The organic solution was washed with brine, dried (MgSO4), filtered, and concentrated. Flash chromatography (9:1 hexanes:EtOAc) provided (3-cyano-phenyl)-acetic acid ethyl ester (6.31 g) as a clear oil which solidified on standing. 1H NMR (400 MHz, CDCl3) δ 7.57–7.50 (m, 3H), 7.42 (m, 1H), 4.15 (q, 2H), 3.63 (s, 2H), 1.24 (t, 3H).