Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[CH3:4].I[C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>C1COCC1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:4][C@@H:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[CH2:2][CH2:1][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1
Reactant: CC(C)=CCCC(C)CC[Mg]Br
Reactant: Nc1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: CC(C)=CCC[C@H](C)CCc1ccc(N)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 905.5 %

Procedure:
Citronellylmagnesium bromide [from S-citronellylbromide (14.46 g, 66 mmol) and magnesium (3.20 g, 132 mmol)] in THF (80 mL) was added to a suspension of 4-iodoaniline (4.38 g, 20 mmol) and [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (PdCl2(dppf), 0.150 g, 0.2 mmol) in THF (25 mL) maintained at −78° C. under a nitrogen atmosphere. After stirring for 10 minutes at −78° C., the reaction mixture was heated under reflux for 16 hours and then quenched with 5% hydrochloric acid (HCl). The aqueous solution was then extracted with ether (3×30 mL) and the combined fractions were washed with water, dried over magnesium sulfate (MgSO4), and the solvent was evaporated to give 4-[(3S)-3,7-dimethyl-6-octenyl]aniline as a dark oil (41.9 g) which was used in the next step without additional purification.
Reaction SMILES: [NH:1]1[C:5](=O)[CH2:4][CH2:3][C:2]1=[O:7].[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([CH:5]1[NH:1][C:2](=[O:7])[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCC(=O)N1
Reactant: BrCc1ccccc1
Product: O=C1CCC(Cc2ccccc2)N1

Procedure:
5-Benzylpyrrolidin-2-one is synthesized from pyrrolidine-2,5-dione and benzyl bromide according to S. Lebrun et al. (Tetrahedron Asymmetry 2003, 14, 2625-2632).
Reaction SMILES: [CH2:1]([N:3]([CH2:6]/[CH:7]=[C:8](/[CH3:15])\[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[CH2:4][CH3:5])[CH3:2]>F[B-](F)(F)F.[Rh+].O1CCCC1>[CH2:1]([N:3](/[CH:6]=[CH:7]/[C@H:8]([CH3:15])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:13])[CH3:14])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)C/C=C(/C)CCC=C(C)C
Agent: [Rh+]
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: CCN(/C=C/[C@H](C)CCC=C(C)C)CC
Yield: 100.3 %

Procedure:
A mixture of 2.27 g (10.0 mmol) of (Z)-N,N-diethyl-3,7-dimethyl-2,6-octadienylamine, 36 mg (0.041 mmol) of [θ4 -(Z,Z)-1,5-cyclooctadiene][(R)-6,6'-dimethoxybiphenyl-2,2'-diyl)bis(diphenylphosphine)]rhodium(I) tetrafluoroborate and 5 ml of tetrahydrofuran was heated to 85°-90° C. for 16 hours in a sealed tube. The brownish reaction mixture was evaporated and the residue was distilled in a bulb-tube at about 150° C./0.2 mbar, whereby 2.1 g of (1E, 3R)-N,N-diethyl-3,7-dimethyl-1,6-octadienylamine were obtained as a colourless oil. The distillate obtained was diluted with hexane, treated with 5 ml of 50% acetic acid and the mixture was stirred for 1 hour. The phases were separated and the organic phase was washed with water. 1N HCl, saturated NaHCO3 solution and saturated NaCl solution, dried over Na2SO4, filtered and evaporated. After distillation in a bulb-tube at about 130° C./15 mbar there were obtained 1.38 g (90%) of (R)-citronellal [(R)-3,7-dimethyl-6-octenal] as a colourless liquid.
Reaction SMILES: O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[N:12]1([C:17]2[CH:27]=[CH:26][C:20]([C:21](OCC)=[O:22])=[CH:19][CH:18]=2)[CH:16]=[CH:15][N:14]=[CH:13]1.[OH-].[Na+]>O>[N:12]1([C:17]2[CH:18]=[CH:19][C:20]([CH2:21][OH:22])=[CH:26][CH:27]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: CCOC(=O)c1ccc(-n2ccnc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(-n2ccnc2)cc1
Reaction time: 8 h
Yield: 58 %

Procedure:
To 90 parts of tetrahydrofuran were added 5 parts of lithium aluminum hydride. Then there was added dropwise (slowly) a solution of 35 parts of ethyl 4(1H-imidazol-1-yl)benzoate in 135 parts of tetrahydrofuran: temperature rose to 60° C. Upon completion, stirring was continued first for 1 hour at 60-65° C. and further overnight at room temperature. While cooling, the reaction mixture was decomposed by the successive dropwise additions of 3 parts of water, 10 parts of a sodium hydroxide solution 50% and 10 parts of water. After stirring for a while at room temperature, the precipitate was filtered off and washed with benzene. The filtrate was dried, filtered and evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 16.2 parts (58%) of 4-(1H-imidazol-1-yl)-benzenemethanol; mp. 124.7° C. (intermediate 19).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:33][CH3:34])=[C:16]([CH:22]4[CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]4)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.[ClH:35].O1CCOCC1>C(Cl)Cl>[ClH:20].[ClH:35].[NH:24]1[CH2:23][CH:22]([C:16]2[C:15]([O:33][CH3:34])=[C:14]([CH:12]([N:8]3[C:4]4=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]4[C:10]([CH3:11])=[N:9]3)[CH3:13])[CH:19]=[C:18]([Cl:20])[C:17]=2[CH3:21])[CH2:25]1
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a solution of tert-butyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidine-1-carboxylate (318 mg, 0.653 mmol) (peak 1 from above) in methylene chloride (3.2 mL) was added 4.0 M hydrogen chloride in 1,4-dioxane (1.6 mL, 6.5 mmol). The resulting mixture was stirred at room temperature for 75 minutes. The solvents were evaporated and the residue dried in vacuo to give 0.30 g of the desired product as the bis-HCl salt. LCMS calculated for C19H24ClN6O (M+H)+: m/z=387.2; Found: 387.1.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C:22]([N:24]2[CH2:29][CH2:28][CH:27]([C:30]([O:32]C)=[O:31])[CH2:26][CH2:25]2)=[O:23])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.Cl>CO>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C:22]([N:24]2[CH2:29][CH2:28][CH:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]2)=[O:23])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1CCN(C(=O)c2ccc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C(=O)N4CCC(C(=O)O)CC4)ccc3c2)CC1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 1-(6-(trans-4-tert-butylcyclohexyloxy)-2-naphthoyl)piperidine-4-carboxylate (150 mg, 0.33 mmol) in MeOH (5 mL) was added NaOH (68 mg, 1.7 mmol, 5.0 eq) and H2O (0.5 mL). The reaction mixture was stirred at 85° C. for 2 h. After the reaction was cooled to 0° C., the pH of the solution was adjusted to 6 with 3 N HCl. The mixture was filtered and the yellow solid was the desired product 1-(6-(trans-4-tert-butylcyclohexyloxy)-2-naphthoyl)piperidine-4-carboxylic acid (90 mg, yield: 70%). ESI-MS (M+1)+: 438.3. 1HNMR (400 MHz, CD3OD) δ: 7.83˜7.81 (m, 3H), 7.41 (d, 1H), 7.28 (s, 1H), 7.16 (d, 1H), 4.44˜4.37 (m, 1H), 3.30 (br, 2H), 2.65˜2.60 (m, 1H), 2.29˜2.27 (m, 2H), 1.93˜1.90 (m, 4H), 1.44˜1.41 (m, 3H), 1.32˜1.31 (m, 2H), 1.28˜1.25 (m, 3H), 1.15˜1.12 (m, 1H), 0.92 (s, 9H). HPLC: 98.45%
Reaction SMILES: C1C(C=O)=CC2OCOC=2C=1.C1OC2C=C(Br)C(C=O)=CC=2O1.C([C:26]1[C:27]([Br:40])=[C:28]([C:35]#[C:36][C:37]([O-:39])=[O:38])[CH:29]=[C:30]2[O:34][CH2:33][O:32][C:31]=12)C>>[Br:40][C:27]1[CH:26]=[C:31]2[O:32][CH2:33][O:34][C:30]2=[CH:29][C:28]=1[C:35]#[C:36][C:37]([OH:39])=[O:38]
Reactant: CCc1c(Br)c(C#CC(=O)[O-])cc2c1OCO2
Agent: O=Cc1cc2c(cc1Br)OCO2
Agent: O=Cc1ccc2c(c1)OCO2
Product: O=C(O)C#Cc1cc2c(cc1Br)OCO2

Procedure:
Bromination of piperonal (1) readily gave 6-bromopiperonal (2) which was conveniently converted to ethyl-2-bromo-4,5-methylenedioxyphenylpropiolate (3) by treatment with triethyl phosophonoiodoacetate under the general conditions devised by Wadsworth and Emmons for the synthesis of propiolate esters. The corresponding 2-bromo-4, 5-methylenedioxyphenylpropiolic acid (4) was obtained by alkaline hydrolysis of the ester (crude). Treatment of compound (4) with dicyclohexylcarbodiimide in DMSO to form the anhydride followed by closure of the ring yielded 5-bromo-7,8-methylenedioxy-1-(2′-bromo-4′,5′-methylenedioxyphenyl)napthalene-2,3-dicarboxylic acid anhydride (5), 1-bromo-6,7-methylenedioxy-4-(2′-bromo-4′, 5′-methylenedioxyphenyl)napthalene-2,3-dicarboxylic acid anyhdride (6) and 6,7-methylenedioxy-1-(2′-bromo-4′,5′-methylenedioxyphenyl)napthalene-2,3-dicarboxylic acid anhydride (7). The conversion of the dibromo-anhydride 5 into 2,3-dihydroxymethyl-5-bromo-7,8-methylenedioxy-1-(3′, 4′-methylenedioxyphenyl)napthalene (8) and 2,3-dihydroxymethyl-5,6-methylenedioxy-4-(3′,4′-methylenedioxyphenyl)napthalene (9) was accomplished on using lithium aluminum hydride and aluminum chloride in THF. Selective oxidation of compound 9 using silver carbonate -celite reagent yielded 7,8-methylendioxy-1-(3′,4′-methylenedioxyphenyl)-3-hydroxymethylnapthalene-2-carboxylic acid lactone (10) and 7,8-methylenedioxy-1-(3′,4′-methylenedioxyphenyl)-2-hydroxymethylnaphthalene-3-carboxylic acid lactone (11).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:22][CH2:21][CH2:20][CH:19]3[CH3:23])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[C:24]1([CH3:33])[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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]>[CH3:23][CH:19]1[CH2:20][CH2:21][CH2:22][N:18]1[C:14]1[N:13]=[C:12]([NH:11][C:4]2[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=[C:2]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH3:33])[CH:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Cc1ccccc1B(O)O
Reactant: CC1CCCN1c1cccc(Nc2cc(Cl)nn3ccnc23)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccccc1-c1cc(Nc2cccc(N3CCCC3C)n2)c2nccn2n1
Temperature: 100 °C
Yield: 43.6 %

Procedure:
A mixture of 6-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (0.10 g, 0.304 mmol), o-tolylboronic acid (0.045 g, 0.335 mmol), Pd2(dba)3 (0.017 g, 0.03 mmol), X-phos (0.029 g, 0.06 mmol) and Na2CO3 (0.097 g, 0.912 mmol) in dioxane (20 mL) and water (5 mL) was heated to 100° C. for 16 h in a sealed tube under N2 atmosphere then concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, ethyl acetate:petroleum ether=1:15) to afford N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)-6-o-tolylimidazo[1,2-b]pyridazin-8-amine (51 mg, 44%) as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 8.53 (s, 1H), 7.95 (s, 1H), 7.61 (s, 1H), 7.43-7.25 (m, 5H), 6.28 (d, 1H, J=7.5 Hz), 6.02 (d, 1H, J=8.1 Hz), 4.10-4.06 (m, 1H), 3.55 (s, 1H), 3.45-3.39 (m, 1H), 3.24-3.21 (m, 1H), 2.37 (s, 3H), 2.03-1.89 (m, 3H), 1.61-1.58 (m, 1H), 0.97 (d, 3H, J=6.3 Hz). LC-MS: [M+H]+, 385, tR=1.95 min, HPLC: 99.76% at 214 nm, 100% at 254 nm, tR=4.68 min.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:16][CH2:15][N:14]([C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][N:19]=1>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:25][CH2:24][C:21]3[CH:20]=[N:19][C:18]([CH3:17])=[CH:23][CH:22]=3)[C:6]3[CH:11]4[CH2:16][CH2:15][N:14]([C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4
Reactant: C=Cc1ccc(C)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)N1CCC3CC1
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)C2CCN1CC2

Procedure:
The coupling of 8-methyl-2,3,4,5-tetrahydro-1,4-ethanopyrido[3,2-b]indole (80 mg, 0.38 mmol; Example 211) and 2-methyl-5-vinylpyridine (85 mg, 0.71 mmol; prepared as described in International Publication No. WO 2001017968) was performed according to the procedure described in Example 106A to provide the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 0.87-1.08 (m, 2H), 1.64-1.87 (m, 2H), 2.39 (s, 3H), 2.41 (s, 3H), 2.42-2.52 (m, 2H), 3.07-3.20 (m, 5H), 4.38-4.52 (m, 2H), 6.93 (dd, J=8.2, 1.2 Hz, 1H), 7.09 (d, J=7.9 Hz, 1H), 7.26 (dd, J=5.8, 2.1 Hz, 1H), 7.28 (d, J=8.5 Hz, 1H), 7.36 (s, 1H), 7.77 (d, J=2.1 Hz, 1H); MS (APCI) m/z 332 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](Cl)=[O:31]>>[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:31]
Reactant: O=C(Cl)c1ccco1
Reactant: Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1
Product: O=C(Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1)c1ccco1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.006 mL (0.061 mMol) furoyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: CO[C:3](=[O:17])[C:4]1[CH:9]=[C:8]([CH:10]([OH:13])[CH2:11][OH:12])[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1.[OH:18][CH:19]([CH2:22][OH:23])[CH2:20][NH2:21]>CO>[OH:18][CH:19]([CH2:22][OH:23])[CH2:20][NH:21][C:3]([C:4]1[CH:9]=[C:8]([CH:10]([OH:13])[CH2:11][OH:12])[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1)=[O:17]
Reactant: NCC(O)CO
Reactant: COC(=O)c1cc(C(O)CO)cc([N+](=O)[O-])c1
Solvent: CO
Product: O=C(NCC(O)CO)c1cc(C(O)CO)cc([N+](=O)[O-])c1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
3-Nitro-5-(1,2-dihydroxyethyl)benzoic acid methyl ester (0.40 g, 1.69 mmol) and 2,3-dihydroxypropylamine (0.17 g, 1.86 mmol) were dissolved in methanol (2 ml) and the solution was stirred at 75° C. for 1 h. The pressure was then reduced to 200 mm Hg and stirring was continued at 95° C. for 2 h. The crude reaction mixture was purified by preparative HPLC. Yield: 0.40 g (78%).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1F.[Cl-].[NH4+]>CS(C)=O.C1CCCCC1.C(OCC)(=O)C>[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1[CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: COC(=O)CC(=O)OC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: C1CCCCC1
Product: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1F
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
9.13 g (69.1 mmol) of dimethyl malonate are carefully added dropwise to a suspension of 1.66 g (69.1 mmol) of washed sodium hydride in 70 ml of DMSO. The mixture is heated at 100° C. for 40 min and then cooled to RT, and 5.00 g (31.4 mmol) of 3,4-difluoronitrobenzene are added. The mixture is stirred at RT for 30 min and then heated at 100° C. for one hour. The cooled reaction mixture is poured into a mixture of ethyl acetate (50 ml), cyclohexane (50 ml) and saturated ammonium chloride solution (250 ml). The aqueous phase is extracted twice with in each case 100 ml of ethyl acetate/cyclohexane (1:1). The combined organic phases are washed with water and saturated sodium chloride solution and dried over sodium sulfate. The solvent is removed under reduced pressure, giving an oil which crystallizes after addition of cyclohexane. The crystals are filtered off with suction and washed thoroughly with cyclohexane, giving a solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:12]=[C:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[C:15]([Br:18])[C:16]=1[NH2:17].O>N1C=CC=CC=1>[Br:10][C:11]1[CH:12]=[C:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[C:15]([Br:18])[C:16]=1[NH:17][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1c(Br)cc(-c2ccccc2)cc1Br
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1c(Br)cc(-c2ccccc2)cc1Br)c1ccccc1
Reaction time: 16 h

Procedure:
Benzoyl chloride (4.0 mL, 0.035 mol) was added to a solution of 3,5-dibromobiphenyl-4-amine (10.5 g, 0.032 mol) in pyridine (75 mL). This was stirred for 16 h before being poured into water. The crude solid was filtered, washed with water and chromatographed (silica gel). The column was eluted first with hexanes and dichloromethane (1:1) then dichloromethane to afford the product as a white solid.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][C:15]([OH:17])=[O:16])=[O:7])([CH3:4])[CH3:3].[CH3:18]CN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CO>[Cl-].[Na+].O.CN(C=O)C>[CH3:18][O:16][C:15](=[O:17])[CH2:14][C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][N:8]1[C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CC(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: COC(=O)C[C@@H]1CCCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.4 %

Procedure:
Into a 250 ml round bottom flask ((2S)-1-{[(1,1-dimethylethyl)oxy]carbonyl}-2-piperidinyl)acetic acid (1.00 g, 4.11 mmol), DMF (25 ml), DIPEA (2.15 ml, 12.33 mmol) and TBTU (1.98 g, 6.17 mmol) were added. The mixture was stirred at rt for 20 min and a brown colour was formed. After this time MeOH (0.25 ml, 6.17 mmol) was added and the resulting solution stirred at rt for 30 min. Then it was transferred into e separatory funnel containing brine (20 ml) and extracted with EtOAc (20 ml×2), the combined organic layers were washed with water/ice (5×20 ml). The organic layer was dried (Na2SO4), filtered and concentrated. The crude obtained was purified by column chromatography (Biotage SP1, Cy-EtOAc from 100/0 to 85/15). Collected fractions gave the title compound (1.01 g, 3.92 mmol, 95% yield) as a colorless oil. 1H-NMR (500 MHz, CDCl3) δ(ppm): 4.67-4.75 (m, 1H), 3.96-4.05 (m, 1H), 3.67 (s, 3H), 2.79 (t, 1H), 2.61 (dd, 1H), 2.53 (dd, 1H), 1.60-1.70 (m, 6H), 1.46 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH2:11][OH:12])[O:10][C:6]=2[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34].O>O1CCCC1>[C:33]([O:12][CH2:11][C:9]1[O:10][C:6]2[C:5]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=2[CH:8]=1)(=[O:35])[CH3:34]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c3cc(CO)oc23)c1=O
Reactant: CC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCc1cc2c(Cl)ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Yield: 43.6 %

Procedure:
0.4 g (1.1 mmol) of 3-(4-chloro-2-hydroxymethylbenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil and 0.13 g (1.2 mmol) of triethylamine were dissolved in 20 ml of tetrahydrofuran, and 0.1 g (1.2 mmol) of acetyl chloride was dropwise added thereto under cooling with ice. After completion of the reaction, the reaction solution was poured into water and washed with ethyl acetate. The organic layer was washed sequentially with a 10% hydrochloric acid aqueous solution, water and a saturated sodium chloride aqueous solution, and then, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.2 g (yield: 45.5%) of the desired product as white solid. Melting point: 135-138° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11](Cl)=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH3:15][NH:16][O:17][CH3:18].N1C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([N:16]([O:17][CH3:18])[CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(Cl)C=Cc1ccc(F)c(Br)c1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)C=Cc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.5 %

Procedure:
The unpurified 3-(3-bromo-4-fluoro-phenyl)-acryloyl chloride (3.5 g, 13.3 mmol) prepared in Step 2, N,O-dimethylhydroxylamine hydrochloride (1.4 g, 14.0 mmol), and pyridine (2.4 mL, 29.4 mmol) were added at 0° C. to dichloromethane (20.0 mL). The reaction mixture was stirred at room temperature for 12 hours, quenched with a 1N hydrochloric acid solution, and then extracted with diethyl ether two times. The combined extract was washed with a saturated solution of sodium hydrogen carbonate and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was recrystallized from diethyl ether and n-hexane to give 3.2 g of the titled compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=O)=[CH:17][CH:16]=1)([O-:14])=[O:13].O>COCCOCCOC>[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19]2[O:11][C:3]3[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=3[N:1]=2)=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: COCCOCCOC
Product: O=[N+]([O-])c1ccc(-c2nc3cc([N+](=O)[O-])ccc3o2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
2-Amino-4-nitrophenol (46.2 g, 0.3 mol) was dissolved in diglyme (1250 mL) and added to a 3-necked, 3-liter flask equipped with a condenser, a mechanical stirrer, and a hearer. 4-Nitrobenzoyl chloride (57 g, 0.3 mol) was dissolved in diglyme (250 mL) and added to the flask. The mixture was heated, with stirring, to 120° C. for 1 hour, whereupon polyphosphoric acid (90 g) was added. Heating was continued at 150° C. to 160° C. for an additional 1 hour. The reaction mixture was cooled to 110° C. to 120° C. and deionized water (500 mL) was added over a period of 15 to 30 minutes while the mixture was maintained at 100° C. The reaction mixture was cooled, and the precipitated product was filtered and washed with methanol (300 mL), then dried. The melting point was found to be 253° C. to 255° C. The overall yield was 95 percent with an assay of 100 percent by liquid chromatography.