Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-:3][CH:4]=O)=O.[Na+].C(#N)C.CN(C)C=O.ClC/[C:17](=[CH:27]/[F:28])/[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1>O>[NH2:3][CH2:4]/[C:17](=[CH:27]/[F:28])/[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1
Reactant: F/C=C(/CCl)CCc1ccc(F)cc1
Reactant: O=C[N-]C=O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: NC/C(=C/F)CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Combine sodium diformylamide (28.8 g, 0.31 mol), acetonitrile (360 g), and N,N-dimethylformamide (48 g). Add (E)-1-chloro-2-(fluoromethylene)-4-(p-fluorophenyl)butane (50.6 g, 0.23 mol). Heat to reflux. After 5 hours, cool to ambient temperature. Add water (466 g) and stir for 15 minutes. After 30 minutes, the aqueous layer is removed. Evaporate the organic layer in vacuo to give the title compound. 1H NMR (CDCl3, 300 MHz) δ 2.28 (m, 2H), 2.72 (m, 2H), 4.07 (d, J=3Hz, 2H), 6.74 (d, J=81Hz, 1H), 6.94 (m, 2H), 7.13 (m, 2H), 8.73 (s, 2H).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34](C(O)=O)[CH2:33][CH:32]1[CH3:40])=[O:30])([CH3:27])([CH3:26])[CH3:25].N[C@H](CC1C=CC2C(=CC=CC=2)C=1)C(N(C)[C@@H](C1ON=C(C)N=1)CC1C=CC2C(=CC=CC=2)C=1)=O.FC(F)(F)C([O-])=O.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]1[CH3:40])=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC1CC(C(=O)O)CCN1C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cc1noc([C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)[C@H](N)Cc2ccc3ccccc3c2)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC1CCCCN1C(=O)OC(C)(C)C

Procedure:
N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.46 g, 2.42 mmol) and 1-hydroxy-benzotriazole monohydrate(0.37 g, 2.41 mmol) were added to a solution of 2-methylpiperidine-1,4-dicarboxylic acid-1-tert-butylester (0.59 g, 2.42 mmol) in N,N-dimethylformamide (8 mL). After 30 min at 20° C. a solution of (2R)-2-amino-N-methyl-N-[(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(2-naphthyl)ethyl]-3-(2-naphthyl)propionamide (as a trifluoroacetate) (1.0 g, 1.73 mmol) and diisopropylethylamine (0.22 g, 1.73 mmol) in N,N-dimethylformamide (4 mL) was added. After 18h at 20° C. the reaction mixture was poured on water (100 mL) and extracted several times with ethyl acetate (total 60 mL). The collected organic phases were washed with aqueous citric acid (10%, 20 mL), a saturated solution of sodium hydrogen carbonate (20 mL) and water (3×20 mL). After drying (magnesium sulfate) the solution was concentrated in vacuo to give 1.25g of crude 4-(1-{methyl-[1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(2-naphthyl)ethyl]carbamoyl}-2-(2-naphthyl)ethyl)-carbamoyl)-2-methylpiperidine-1-carboxylic acid tert-butyl ester that was used for the next step without further purification.
Reaction SMILES: [CH:1]1[C:2](=[O:16])[CH:3]=[CH:4][C:5]2=[N:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]=[CH:10][C:11]=12.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)(Cl)Cl.O>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][C:2]=1[OH:16]
Reactant: O=c1ccc2nc3ccccc3ccc-2c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Oc1ccc2c(c1)C=Cc1ccccc1N2
Reaction time: 3 h
Yield: 64.1 %

Procedure:
Title compound 374 (170 mg, 0.82 mmol) was solubilized in CHCl3 (5 mL) and a saturated solution of Na2S2O4 in water was added (20 mL). The mixture was stirred for 3 hours. The 2 layers were split and the organic layer was dried over sodium sulfate, filtered and evaporated to afford title compound 375 (110 mg, 65%). MS (m/z): 209.9 (M+H).
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl-].[NH4+]>C(Cl)(Cl)Cl.[Pd](Cl)Cl.C(#N)C.C(#N)C>[C:22]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:5][CH:4]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CCN(c2cccc3ccc([Sn](C)(C)C)cc23)CC1
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CN1CCN(c2cccc3ccc(C(=O)c4ccccc4)cc23)CC1
Temperature: 25 °C

Procedure:
7-Trimethylstannyl-1-(4-methyl-1-piperazinyl)-naphthalene (0.1 g, 0.27 mmol), benzoyl chloride (0.031 mL, 0.27 mmol) and bis (acetonitrile) palladium chloride (0.007 g, 0.027 mmol) were combined in chloroform (5 mL) and heated to 60° to 65° C. for 15 minutes. The reaction was cooled to room temperature and saturated aqueous ammonium chloride (10 mL) and chloroform (10 mL) were added, Phases were separated and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated to a milky oil. The oil was purified by flash chromatography on silica gel (1×6 inches), the product eluting with 5% methanol/ethyl acetate as a yellow oil (0.07 g, 79%). The oil was crystallized from ether to obtain a bright yellow solid: mp 124°-124.5° C. Analysis calculated for C22H22N2O: C, 79.97; H, 6.71; N, 8.48. Found: C, 79.74; H, 6.69; N, 8.46.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][C:9]([C:11]#[C:12][Si](C)(C)C)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:1][C:2]1[C:3]2[S:10][C:9]([C:11]#[CH:12])=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[Si](C)(C)C#Cc1cc2ncnc(Cl)c2s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cc2ncnc(Cl)c2s1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of compound 48.1 (5.0 mmol) in THF (50 mL) was tetrabutylammonium fluoride (“TBAF”; 5.0 mmol; 1.0 M in THF) at 0° C. After stirring at 0° C. for 5 minutes, the reaction mixture was concentrated, diluted with EtOAc, washed with saturated sodium bicarbonate, brine and dried. The solvent was removed and the residue purified by flash column chromatography on silica gel to provide 4-chloro-6-ethynyl-thieno[3,2-d]pyrimidine (compound 48.2) in 92% yield. EIMS (m/z): calcd. for C8H3ClN2S (M+)+H 194.97. found 195.00.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10](Br)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+].Cl>C1(=O)CCCCC1>[F:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCBr
Reactant: Oc1ccc(Br)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C1CCCCC1
Product: CCCCCCOc1ccc(Br)cc1F
Reaction time: 7 h
Yield: 83.7 %

Procedure:
A reaction vessel was charged with 19.4 g of 2-fluoro-4-bromophenol, 16.8 g of hexyl bromide, 23.3 g of potassium carbonate and 510 ml of cyclohexanone and the reaction was effected with stirring at 120°-140° C. for 7 hours. The reaction liquid was poured into dilute hydrochloric acid and the mixture was extracted with benzene. The benzene layer was washed with water and dried over Glauber's salt, and the benzene was distilled off. The residue was purified by way of column chromatography on silica gel (eluent: hexane) to obtain 23.4 g (yield 83.6%) of 3-fluoro-4-hexyloxybromobenzene.
Reaction SMILES: Cl([O-])=O.[Na+].[OH2:5].P([O-])(O)(O)=O.[Na+].[Cl:12][C:13]1[N:14]=[C:15]([CH:20]2[CH2:22][CH2:21]2)[NH:16][C:17]=1[CH:18]=[O:19].CC(=CC)C>O.C1COCC1.C(O)(C)(C)C>[Cl:12][C:13]1[N:14]=[C:15]([CH:20]2[CH2:21][CH2:22]2)[NH:16][C:17]=1[C:18]([OH:5])=[O:19]
Reactant: O=Cc1[nH]c(C2CC2)nc1Cl
Reactant: O
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: O=C(O)c1[nH]c(C2CC2)nc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.5 %

Procedure:
A solution of sodium chlorite (1.5 g, 16.6 mmol) and sodium dihydrogen phosphate monohydrate (1.3 g, 9.4 mmol) in water (3.7 mL) was added to a stirred solution of 4-chloro-2-cyclopropyl-1H-imidazole-5-carbaldehyde (0.282 g, 1.6 mmol), 2-methyl-2-butene (10 mL of a 2M solution in THF, 20.0 mmol), and tert-butanol (1.2 mL) in THF (5.0 mL). The reaction mixture was stirred at RT for 6 h. The aqueous phase was separated and extracted with EtOAc (4×10 mL). The combined extracts were dried (Na2SO4), filtered, concentrated and the residue was triturated with diethyl ether to provide the title compound (0.285 g, 95%) as light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.95 (br. s., 1H), 1.90-2.00 (m, 1H), 0.89-0.98 (m, 2H), 0.82-0.89 (m, 2H). ES-LCMS: m/z 187.0 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].Cl[CH2:23][CH2:24][N:25]([CH2:33][CH2:34]Cl)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:1]([O:3][C:4]([C:5]1([S:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:13][CH:14]=2)(=[O:7])=[O:8])[CH2:23][CH2:24][N:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:33][CH2:34]1)=[O:21])[CH3:2]
Reactant: ClCCN(CCCl)Cc1ccccc1
Reactant: CCOC(=O)CS(=O)(=O)c1ccc(OCCC(C)C)cc1
Product: CCOC(=O)C1(S(=O)(=O)c2ccc(OCCC(C)C)cc2)CCN(Cc2ccccc2)CC1

Procedure:
1-Benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from [4-(3-methyl-butoxy)-phenylsulfonyl]-acetic acid ethyl ester (6.2 g, 20 mnmol) and bis-(2-chloro-ethyl)-benzyl amine (6.44 g, 24 mmol). Yield 8 g (84%); yellow oil; MS: 474 (M+H)+
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[CH:15]=[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][N:9]2[N:8]=1.[C:16](=O)([O-])[O-:17].[K+].[K+]>CN(C)C=O>[CH:16]([C:15]1[C:7]([CH3:6])=[N:8][N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12)=[O:17]
Reactant: Cc1cc2ccccn2n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nn2ccccc2c1C=O
Temperature: 0 °C

Procedure:
To 116.6 ml of dimethylformamide was added 105 ml of phosphorus oxychloride, followed by 99 g of 2-methylpyrazolo[1,5-a]pyridine under stirring at keeping the temperature below 20° C. The reaction mixture was stirred at 50°-60° C. for 1 hours, then poured into ice water. Acidic aqueous solution was neutralized with potassium carbonate, then extracted with dichloromethane, washed with salt water, dried over anhydrous sodium sulfate and then concentrated. The resulting residue was recrystallized from methanol to give the title compound in a yield of 54.8 g (46%) as colorless crystals, mp 77°-79° C.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])=[CH:8][CH:7]=1)(=O)C.[OH-].[K+].Cl>CO>[F:19][C:14]([F:20])([C:15]([F:16])([F:17])[F:18])[CH2:13][CH2:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][OH:4])=[CH:11][CH:10]=1
Reactant: CC(=O)OCc1ccc(CCC(F)(F)C(F)(F)F)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: OCc1ccc(CCC(F)(F)C(F)(F)F)cc1
Yield: 87 %

Procedure:
4-(3,3,4,4,4-Pentafluorobutyl)benzenemethanol acetate (525 mg, 1.42 mmol) was heated to reflux with aqueous potassium hydroxide solution (40%; 399 μL, 2.84 mmol) in methanol (6 mL) for two hours. The residue was acidified with 1 M aqueous hydrochloric acid, and extracted with ethyl acetate. The combined organic layers were concentrated under reduced pressure. Flash chromatography gave 314 mg of 4-(3,3,4,4,4-pentafluorobutyl)benzenemethanol; 1H NMR (300 MHz, CDCl3) δ 7.33 (d, 2H), 7.21 (d, 2H), 4.68 (dbr, 2H), 2.91 (m, 2H), 2.32 (m, 2H), 1.71 (tbr, 1H) ppm.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[CH:36]=O)[CH:29]=[CH:28]1>>[CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:36][C:34]3[CH:33]=[CH:32][CH:31]=[C:30]4[C:35]=3[N:27]([CH3:26])[CH:28]=[CH:29]4)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1ccc2cccc(C=O)c21
Reactant: Nc1cccc(-c2c(Cc3ccccc3)nnc3c(Cl)cccc23)c1
Product: Cn1ccc2cccc(CNc3cccc(-c4c(Cc5ccccc5)nnc5c(Cl)cccc45)c3)c21

Procedure:
The title compound was prepared from 3-(3-benzyl-8-chloro-cinnolin-4-yl)-phenylamine and 1-methyl-1H-indole-7-carbaldehyde according the procedure of Example 5 Step 5. MS (ESI) m/z 489.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:13][CH3:14])=[N:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8](O)=[O:9])[CH3:2].F[B-](F)(F)F.O=C1C=CC=C[N:22]1OC(N(C)C)=[N+](C)C.O.OC1C2N=NNC=2C=CC=1.N.O1CCOCC1.C(N(C(C)C)C(C)C)C>ClCCl.O>[CH2:1]([C:3]1[C:4]([O:13][CH3:14])=[N:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8]([NH2:22])=[O:9])[CH3:2]
Reactant: CN(C)C(On1ccccc1=O)=[N+](C)C
Reactant: CCc1cc(C(=O)O)c(C)nc1OC
Agent: F[B-](F)(F)F
Agent: N
Agent: Oc1cccc2[nH]nnc12
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(C(N)=O)c(C)nc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 122.4 %

Procedure:
A round bottom flask under a nitrogen atmosphere is charged with 5-ethyl-6-methoxy-2-methyl-nicotinic acid (1.00 g, 5.13 mmol) of Step 2, Example 14 dissolved in dichloromethane (50 mL). To this is added O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.676 g, 5.64 mmol) followed by hydroxybenzotriazole hydrate (785 mg, 5.13 mmol). The resulting mixture is stirred at rt for 30 min then treated with a solution of ammonia in 1,4-dioxane (0.5 M, 10.3 mL, 5.15 mmol) followed by N-ethyl-diisopropylamine (2.32 mL, 13.3 mmol) to give a suspension. After stirring at rt for 23 hr, LC/MS shows the reaction to be incomplete. A solution of ammonia in 1,4-dioxane (0.5 M, 10 mL, 5.00 mmol) is added and stirred for an additional period of 24 hr. LC/MS shows the reaction is still incomplete and so more ammonia (0.5 M, 5 mL, 2.5 mmol) is added and allowed to stir for 68 hr to give a solution. LC/MS shows the reaction to be complete. The reaction is diluted with water and the mixture is extracted with seven portions of dichloromethane. The combined extract is dried over magnesium sulfate, filtered and evaporated. The crude product is purified by flash chromatography on a 10-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (1:0, increasing to 1:2). Fractions containing the product are combined and re-purified by flash chromatography on a 10-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (1:0, increasing to 1:2). Fractions containing the product are combined, the solvent evaporated and the residue triturated with ether to give 5-ethyl-6-methoxy-2-methyl-nicotinamide (1.22 g) as a fluffy, pink solid. MS: m/e=195 (M+H); 1H NMR (CDCl3, δ, ppm): 7.50 (1H, s), 5.77 (2H, s), 3.96 (3H, s), 2.61 (3H, s), 2.56 (2H, q), 1.18 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[C:4]([F:11])[CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][N:14]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>FC(F)(F)C([O-])=O.[Pd+2].FC(F)(F)C([O-])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]2[CH:17]=[CH:18][C:13]([NH2:12])=[N:14][CH:15]=2)=[C:4]([F:11])[CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: Nc1ccc(Br)cn1
Agent: [Pd+2]
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1ccc(-c2ccc(Cl)cc2F)cn1
Temperature: 80 °C
Yield: 71.2 %

Procedure:
Solid 4-chloro-2-fluorobenzeneboronic acid (10.0 g, 57.4 mmol), 2-amino-5-bromopyridine (9.92 g, 57.4 mmol), palladium (II) trifluoroacetate (0.381 g, 1.15 mmol), and triphenylphosphine (0.602 g, 2.29 mmol) were combined in a 1 L flask under nitrogen, then toluene (150 mL), EtOH (150 mL), and 2 M Na2CO3 (100 mL) were added. The mixture was sparged with nitrogen for 30 min using a gas dispersion tube, then heated at 80° Celsius for 20 hours with vigorous stirring. The mixture was cooled to rt, diluted with EtOAc (200 mL), and transferred to a separatory funnel. The aqueous phase was removed, and the organic phase washed with brine. The combined aqueous phases were extracted with an equal volume of EtOAc, and the combined organic phases were dried and concentrated to dryness. The residue was subjected to FCC to provide 5-(4-chloro-2-fluorophenyl)pyridin-2-amine (9.10 g, 71%). MS (CI): mass calcd. for C11H8CFN2, 222.04; m/z found, 223.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.54-8.22 (s, 2H), 8.22-8.18 (d, J=2.1, 1H), 8.15-8.10 (m, 1H), 7.68-7.58 (m, 2H), 7.48-7.38 (m, 1H), 7.16-7.06 (d, J=9.3, 1H).
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[CH:7][C:6]=1[CH3:20].[CH3:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=[O:26].[Cl-].[NH4+]>O1CCCC1>[Si:13]([O:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([CH:25]([OH:26])[C:24]2[CH:27]=[CH:28][CH:29]=[C:22]([CH3:21])[CH:23]=2)=[C:6]([CH3:20])[CH:7]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: Cc1cc(CO[Si](C)(C)C(C)(C)C)ccc1Br
Reactant: Cc1cccc(C=O)c1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1cccc(C(O)c2ccc(CO[Si](C)(C)C(C)(C)C)cc2C)c1
Reaction time: 2 h
Yield: 63.9 %

Procedure:
Magnesium (0.84 g, 34.6 millimol) was suspended in tetrahydrofuran (30 ml), and thereto was added a small amount of iodine. Under nitrogen atmosphere, a solution of 2-bromo-5-t-butyldimethylsilyloxymethyltoluene (10 g, 31.6 millimol) in tetrahydrofuran (10 ml) was added. When the mixture was heated for some time, the reaction was started, and heat generated. After stirring for 2 hours as it was, m-methylbenzaldehyde (3.16 g, 26.3 millimol) was added. After stirring for 2 hours, to the mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure. The residue was separated and purified by using a silica-gel column chromatography (ethyl acetate:n-hexane=1:6) to give the title compound (6 g, 16.8 millimol, 64%).
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH3:11])[CH2:4][C:5]([CH3:9])([CH3:8])[CH2:6][NH2:7])[CH3:2].[C:12](O)(=[O:15])[CH:13]=[CH2:14].P(=O)(O)(O)O>C1C=CC(NC2C=CC(NC3C=CC=CC=3)=CC=2)=CC=1>[CH2:10]([N:3]([CH2:1][CH3:2])[CH2:4][C:5]([CH3:9])([CH3:8])[CH2:6][NH:7][C:12](=[O:15])[CH:13]=[CH2:14])[CH3:11]
Reactant: CCN(CC)CC(C)(C)CN
Reactant: C=CC(=O)O
Agent: O=P(O)(O)O
Agent: c1ccc(Nc2ccc(Nc3ccccc3)cc2)cc1
Product: C=CC(=O)NCC(C)(C)CN(CC)CC
Yield: 59.1 %

Procedure:
Proceeding as in Example 1, 60 g 3-diethylamino-2,2-dimethylpropylamine; 27.3 g acrylic acid; 1.0 g N,N'-diphenyl-p-phenylenediamine; and 1 ml 85% phosphoric acid were mixed. 47.5 g (59%) N-(3-diethylamino-2,2-dimethylpropyl)acrylamide, boiling point 139° to 141° C. at 1.33 Pa, were isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][CH3:12])[C:8]([N+:13]([O-:15])=[O:14])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:16][C:17]([F:22])([F:21])[CH2:18][CH2:19][NH2:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[F:16][C:17]([F:22])([F:21])[CH2:18][CH2:19][NH:20][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([N+:13]([O-:15])=[O:14])[C:9]([NH:11][CH3:12])=[CH:10][C:2]=1[Cl:1]
Reactant: CNc1cc(Cl)c(C(=O)O)cc1[N+](=O)[O-]
Reactant: NCCC(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cc(Cl)c(C(=O)NCCC(F)(F)F)cc1[N+](=O)[O-]

Procedure:
The sub-title compound is prepared in analogy to 5c from 2-chloro-4-methylamino-5-nitro-benzoic acid (900 mg, 3.9 mmol), 3,3,3-trifluoro-propylamine (0.58 g, 3.9 mmol), TBTU (1.38 g, 4.2 mmol), DIPEA (2.0 mL, 11.7 mmol) and THF (20 mL).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[CH2:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=2)[CH2:9]1)[CH3:7]>>[CH2:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N+:1]([O-:4])=[O:2])=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=2)[CH2:9]1)[CH3:7]
Reactant: CCN1Cc2ccc(NC(C)=O)cc2C1
Reactant: O=[N+]([O-])[O-]
Agent: [K+]
Product: CCN1Cc2cc(NC(C)=O)c([N+](=O)[O-])cc2C1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 49.8 %

Procedure:
KNO3 (1.33 g, 13.2 mmol) was added in small portions, over 10 min, to a stirred solution of acetamide 246 (2.45 g, 12.0 mmol) in CH2SO4 (50 mL) at 0° C. and the reaction mixture was stirred at 0° C. for a further 45 min. The mixture was poured onto ice, made basic with cNH3 and extracted with DCM (3×100 mL). The solvent was evaporated to give a brown oil which was purified by chromatography on neutral Al2O3, eluting with a gradient (0-20%) of EtOAc/pet. ether, to give nitroacetamide 247 (1.49 g, 50%) as a yellow solid: mp EtOAc/pet. ether) 85-87° C.; 1H NMR δ 10.43 (br s, 1H, NH), 8.62 (s, 1H, H-7), 8.03 (s, 1H, H-4), 3.96 (s, 2H, CH2N), 3.92 (s, 2H, CH2N), 2.79 (q, J=7.2 Hz, 2H, CH2N), 2.28 (s, 3H, COCH3), 1.21 (t, J=7.2 Hz, 3H, CH3); HRMS (FAB+) calcd for C12H16N3O3 (MH+) m/z 250.1192, found 250.1195. Anal. calcd for C12H15N3O3: C, 57.8; H, 6.0; N, 16.9. Found: C, 57.9; H, 5.9; N, 16.7%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@@H:4]([NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[O:35]([C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:34])[C@@H:4]([NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:45]2[CH:46]=[CH:47][C:42]([O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:43][CH:44]=2)=[CH:8][CH:7]=1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1ccc(NCc2cccc3ccccc23)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(Oc3ccccc3)cc2)cc1)NC(=O)c1ccc(NCc2cccc3ccccc23)cc1
Temperature: 80 °C
Yield: 33.3 %

Procedure:
(S)-3-(4-Bromo-phenyl)-2-{4-[(naphthalen-1-ylmethyl)-amino]-benzoylamino}-propionic acid methyl ester (273 mg, 0.53 mmol), Pd (PPh3)4 (96 mg, 0.11 mmol), and 4-phenoxyphenylboronic acid (226 mg, 1.1 mmol) were dissolved in 5 mL of toluene, a 1M Na2CO3 solution (1.3 mL, 1.3 mmol) added and the mixture heated at 80° C. for 16 h. The reaction mixture was evaporated to dryness and the crude mixture purified over silica gel (8:2, DCM-hexanes) to give (S)-2-{4-[(naphthalen-1-ylmethyl)-amino]-benzoylamino}-3-(4′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester (107 mg).