Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[O:26][C:25]([NH:27][CH2:28][C@@H:29]3[C@H:34]([CH3:35])[CH2:33][CH2:32][CH2:31][NH:30]3)=[N:24][C:23]=2[CH:36]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[O:26][C:25]([NH:27][CH2:28][C@@H:29]3[C@H:34]([CH3:35])[CH2:33][CH2:32][CH2:31][N:30]3[C:7]([C:6]3[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[C:11]3[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=3)=[O:9])=[N:24][C:23]=2[CH:36]=1
Reactant: Cc1ccc(-c2ccnc(C)c2)c(C(=O)O)c1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1nc2cc(Cl)ccc2o1
Product: Cc1ccc(-c2ccnc(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 5-methyl-2-(2-methylpyridin-4-yl)benzoic acid and 5-chloro-N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 489 [M+1]+.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][S:6]([OH:9])(=O)=[O:7].[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17].FC(F)(F)S(O)(=O)=O>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([S:6]([CH3:5])(=[O:9])=[O:7])=[CH:13][C:12]=1[F:17]
Reactant: Fc1ccccc1F
Reactant: CS(=O)(=O)O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=S(Cl)Cl
Product: CS(=O)(=O)c1ccc(F)c(F)c1
Temperature: 80 °C
Yield: 59 %

Procedure:
A mixture of thionyl chloride (12.73 mL, 0.175 mol) and methanesulfonic acid (28.4 mL, 0.438 mol) was heated at reflux overnight and then cooled to 80° C. 1,2-Difluorobenzene (8.64 mL, 88 mmol) was and trifluoromethanesulfonic acid (0.675 mL, 8.8 mmol) were added dropwise. The reaction mixture was then heated at 120° C. for 3 h, cooled to room temperature and poured into ice-water (200 mL). The mixture was extracted three times with ethyl acetate and the combined organic extracts were dried (sodium sulfate), filtered, evaporated, and purified by flash chromatography, eluting with 15% ethyl acetate/hexanes, to give 1,2-difluoro-4-methanesulfonyl-benzene (9.98 g, 59%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 3.27 (s, 3H), 7.70-7.84 (m, 2H), 8.02-8.09 (m, 1H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2)=[O:5].C(N(CC)CC)C.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[C:29](Cl)=[O:30]>O1CCCC1>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[C:29]([NH:2][CH2:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2)=[O:5])=[O:30]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: NCC(=O)c1ccc2c(c1)CCC(=O)N2
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)NCC(=O)c2ccc3c(c2)CCC(=O)N3)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 50569.4 %

Procedure:
3 g of 6-α-aminoacetyl-3,4-dihydrocarbostyril monohydrochloride was suspended in 60 ml of tetrahydrofuran. Thereto were added 7 ml of triethylamine and 2.8 mg of 3,4-dimethoxybenzoyl chloride. The mixture was stirred at room temperature. After 3 hours, the resulting crystals were collected by filtration, methanol-washed and dried to obtain 2.6 g of 6-[2-(3,4-dimethoxybenzoylamino)acetyl]-3,4-dihydrocarbostyril as white acicular crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[N:19]=[CH:20][C:21]([C:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH:26]=[N:25][CH:24]=4)=[CH:22][C:14]2=3)=[O:12])[CH:5]=[C:6]([Br:10])[C:7]=1[O:8]C.B(Br)(Br)Br.[OH-].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[N:19]=[CH:20][C:21]([C:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH:26]=[N:25][CH:24]=4)=[CH:22][C:14]2=3)=[O:12])[CH:5]=[C:6]([Br:10])[C:7]=1[OH:8]
Reactant: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4cncc5ccccc45)cc32)cc1Br
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(c1cc(Br)c(O)c(Br)c1)N1CCOc2ncc(-c3cncc4ccccc34)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.7 %

Procedure:
Under nitrogen atmosphere, in a 10 ml flask, (3,5-dibromo-4-methoxy-phenyl)-(7-isoquinolin-4-yl-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl)-methanone (11.3 mg, 0.020 mmol) was dissolved in dichloromethane, and then cooled to 0□. 1.0M Boron tribromide dissolved in dichloromethane (0.2 ml, 0.203 mmol) was added thereto and then stirred at room temperature for 18 hours. After adjusting to pH 6 with 1N NaOH solution, the mixture was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. Diethyl ether was added to the formed solid and stirred for 30 minutes and then filtered to obtain the target compound 61 as white solid (3.0 mg, 27%).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[C:4]([I:12])[C:3]=1[OH:13].[CH:14]#[C:15][CH2:16][CH3:17]>N1C=CC=CC=1.Cl>[CH2:16]([C:15]1[O:13][C:3]2[C:4]([I:12])=[CH:5][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=2[CH:14]=1)[CH3:17]
Reactant: C#CCC
Reactant: CS(=O)(=O)c1cc(I)c(O)c(I)c1
Agent: Cl
Solvent: c1ccncc1
Product: CCc1cc2cc(S(C)(=O)=O)cc(I)c2o1
Temperature: 130 °C
Reaction time: 3 h
Yield: 48.4 %

Procedure:
To a solution of 2,6-diiodo-4-methylsulfonylphenol (1.00 g, 2.36 mmol) in pyridine (10 mL) at 25° C. was added but-1-yne (128 mg, 2.36 mmol) and Cu2O (135 mg, 0.944 mmol). The mixture was stirred at 130° C. for 3 h under a nitrogen atmosphere. The residue was cooled to 25° C., diluted with 1N HCl (200 ml) and extracted with EtOAc (30 mL×2). The combined organic layers were washed by brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (PE:EA=10:1 to 5:1) to afford the title compound (400 mg, 48%) as a solid. 1H NMR (CDCl3, 400 MHz) δ 8.14 (d, J=1.6 Hz, 1H), 8.06 (d, J=1.6 Hz, 1H), 6.62 (s, 1H), 3.09 (s, 3H), 2.90 (q, J=7.6 Hz, 2H), 1.38 (t, J=7.6 Hz, 3H). LCMS: 350.9 (M+H+)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26]([C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](Cl)=[O:32])#[N:27]>C(#N)C>[C:26]([C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1)=[O:32])#[N:27]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: CN1CCN(c2cccc3ccc(N)cc23)CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3ccc(NC(=O)c4cccc(C#N)c4)cc23)CC1
Yield: 60 %

Procedure:
The title product was prepared following the procedure of example 3 from 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.213 g, 0.883 mmol) and triethylamine (0.258 mL, 1.94 mmol) and 3-cyanobenzoyl chloride (0.322 g, 1.94 mmol) in acetonitrile (10 mL) with stirring at reflux for 2 hours and then at room temperature overnight. The mixture was concentrated and the residue was taken up in methylene chloride. This organic solution was washed with 0.5N sodium hydroxide, dried over calcium sulfate and concentrated. The product was isolated by silica gel flash chromatography and recrystallization from isopropyl alcohol to yield 0.184 g of (60%) of the title compound: mp 220°-222° C. Analysis calculated for C23H22N4O: C, 74.57; H, 5.99; N, 15.12. Found: C, 74.42; H, 5.78; N, 14.96.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([CH2:30][O:31][C:32]1[CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=[CH:36][CH:37]=1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28](=[O:29])[CH2:30][O:31][C:32]1[CH:37]=[C:36]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:9]/[C:10](=[N:11]\[OH:12])/[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:4][CH:3]=2)[CH:35]=[CH:34][CH:33]=1)[CH3:26]
Reactant: O/N=C(\CC(c1ccccc1)c1ccc(Br)cc1)c1ccncc1
Reactant: CCOC(=O)COc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Product: CCOC(=O)COc1cccc(-c2ccc(C(C/C(=N\O)c3ccncc3)c3ccccc3)cc2)c1

Procedure:
In analogy to example 22, from (E)-3-(4-bromo-phenyl)-3-phenyl-1-pyridin-4-yl-propan-1-one oxime (example 5) and 3-(ethoxycarbonyl)methoxyphenylboronic acid pinacol ester was prepared the title compound as a colorless oil, MS (ESI+): m/z=481.3 ([M+H]+).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]([NH2:8])=[O:7])[CH2:4][OH:5].[C:9]([O:24][C@H:25]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:26][C:27](O)=[O:28])(=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(N(CC)CC)C.CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1>C(Cl)Cl>[C:9]([O:24][C@H:25]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:26][C:27]([NH:8][C:6](=[O:7])[C@H:3]([CH2:4][OH:5])[NH2:2])=[O:28])(=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)O
Reactant: NC(=O)[C@@H](N)CO
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)NC(=O)[C@@H](N)CO
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
A suspension of L-serinamide hydrochloride (0.157 g, 1.18 mmol) and (R)-3-tetradecanoyloxytetradecanoic acid (0.61 g, 1.34 mmol) in CH2Cl2 (6 mL) was treated with triethylamine (0.18 mL, 1.3 mmol) and the resulting solution was stirred with 4 Å molecular sieves for 30 min. EEDQ (0.437 g, 1.77 mmol) was then added and the mixture was stirred for 16 h at room temperature. The product that precipitated was collected and washed with CH2Cl2 (2×25 mL) to give 0.455 g (71%) of N-[(R)-3-tetradecanoyloxytetradecanoyl]-L-serinamide as a colorless powder: mp 126-130° C.; 1H NMR (CDCl3) δ0.88 (t, 6H, J=~7 Hz), 1.15-1.7 (m, 42 H), 2.31 (t, 2 H, J=7.5 Hz), 2.51 (d, 2 H, J=6.3 Hz), 3.56 (br s, 1 H), 3.65 (dd, 1 H, J=11.2, 5.5 Hz), 3.86 (dd, 1 H, J=11.2, 4.5 Hz), 4.21 (s, 2 H), 4.40 (m, 1 H), 5.22 (m, 1 H).
Reaction SMILES: Cl.Cl.[NH2:3][NH2:4].[Cl:5][C:6]1[CH:7]=[C:8]([C:12](=O)/[CH:13]=[C:14](\O)/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:9]=[CH:10][CH:11]=1.C(O)(=O)C>C(O)C>[Cl:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[C:14](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[NH:4][N:3]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: NN
Reactant: O=C(/C=C(O)/C=C/c1ccc(O)cc1)c1cccc(Cl)c1
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: Oc1ccc(/C=C/c2cc(-c3cccc(Cl)c3)n[nH]2)cc1
Temperature: 80 °C
Yield: 41 %

Procedure:
Hydrazine dihydro-chloride (0.263 g, 2.50 mmol) was added to a sealed tube charged with (2Z,4E)-1-(3-chlorophenyl)-3-hydroxy-5-(4-hydroxyphenyl)penta-2,4-dien-1-one (0.717 g, 2.39 mmol) in absolute ethanol (8 mL) and a catalytic amount of acetic acid. The reaction tube was sealed and heated to 80° C. After 12 hours the reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in a small amount of methanol and precipitated with water, and the solid was collected by vacuum filtration to provide the title compound in (288 mg, 41% yield) as a yellow solid: 1H NMR (400 MHz, CD3OD): δ 7.79 (bs, 1H), 7.68 (bd, J=7.6 Hz, 1H), 7.37 (m, 3H), 7.29 (bd, J=7.6 Hz, 1H), 7.12 (d, J=16.4 Hz, 1H), 6.86 (d, J=16.4 Hz, 1H), 6.81 (bs, 1H), 6.77 (m, 2H); MS (EI) for C17H13 ClN2O: 297.1 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([O:15][CH3:16])=[CH:7][C:8]2[N:12]=[C:11]([SH:13])[NH:10][C:9]=2[CH:14]=1)=[O:4].[ClH:17].[Cl:18][CH2:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22]>>[ClH:18].[ClH:17].[NH2:22][C:21]1[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=1[CH2:19][S:13][C:11]1[NH:10][C:9]2[CH:14]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:6]([O:15][CH3:16])=[CH:7][C:8]=2[N:12]=1
Reactant: COC(=O)c1cc2[nH]c(S)nc2cc1OC
Reactant: Nc1ccccc1CCl
Agent: Cl
Product: COC(=O)c1cc2[nH]c(SCc3ccccc3N)nc2cc1OC

Procedure:
To a mixture of 29.0 g (0.16 mole) of methyl-4-amino-2-methoxybenzoate, 0.5 g of 4-dimethylaminopyridine, and 16.0 gm (0.16 mole) of triethylamine in 500 ml of dichloromethane was added in batches 22 ml (ca. 0.23 mole) of acetic acid. After two hours the reaction mixture was neutralized with sodium bicarbonate (in solution and as a solid). The organic phase was washed successively with aqueous sodium bicarbonate. The organic phase was washed successively with aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Recrystallization from toluene gave 30 g of methyl-4-acetamido-2-methoxybenzoate. To 100 ml of fuming nitric acid, stirred at −40° C., was slowly added 22.3 g (0.10 mole)of the acetylated intermediate. After about twenty minutes the mixture was warmed to 0° C. and stirred for another twenty minutes. The mixture was poured onto one liter of ice and the resultant precipitate was collected. Recrystallization from toluene/ethanol gave 14.2 g of the nitrated and deacetylated compound, methyl-4-amino-2-methoxy-5-nitrobenzoate. (Under similar conditions in which the acetyl group is not removed, saponification with methanolic sodium hydroxide gives the same product.) Hydrogenation of the nitro intermediate in tetrahydrofuran using Raney nickel as catalyst gave methyl-4,5-diamino-2-methoxybenzoate. A mixture of 4.83 g (24.6 mmole) of the diamine and 7.08 g (49.2 mmole) of potassium ethylxanthate was heated at reflux under argon in 40 ml of water. The resultant product mixture was chromatographed on silica gel to give 1.5 g of methyl-2-mercapto-5-methoxy-1H-benzimidazole-6-carboxylate. (Analysis. Calc'd. for C10H10N2O3S: C, 50.41; H, 4.23; N, 11.76; S, 13.46. Found: C, 50.30; H, 4.19; N, 11.71; S, 13.12.) The title compound was then prepared by the method of Example 1 using 1.19 g (5.0 mmole) of methyl-2-mercapto-5-methoxy-1H-benzimidazole-6-carboxylate instead of 2-mercaptobenzimidazole and 0.97 g (5.5 mmole)of 2-(chloromethyl)aniline hydrochloride instead of 2-(chloromethyl)-N,N-dimethylaniline. Analysis. Calc'd. for C17H17N3O3S*2HCl: C, 49.05; H,4.60; N, 10.09; S, 7.70; C1, 17.03. Found: C, 49.37; H, 4.77; N, 9.72; S, 7.43; C1, 16.77.
Reaction SMILES: N1CCCC1.[F:6][C:7]1[C:8]([OH:16])=[C:9]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:11][CH:12]=1.[O:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.Cl>C1(C)C=CC=CC=1>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:8]=1[O:16][C:20]1([CH2:21][CH2:22][O:17][CH2:18][CH2:19]1)[CH2:14][C:13]2=[O:15]
Reactant: O=C1CCOCC1
Reactant: CC(=O)c1cccc(F)c1O
Agent: Cl
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: O=C1CC2(CCOCC2)Oc2c(F)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
Pyrrolidine (4.8 ml, 58 mmol) was added to a stirred solution of 1-(3-fluoro-2-hydroxyphenyl)ethanone (28) (5.9 g, 39 mmol) and tetrahydro-4h-pyran-4-one (4.6 ml, 50 mmol) in toluene (40 mL) at rt. After the exotherm subsided, the reaction mixture was stirred at rt for 1 h. then subjected to Dean-Stark reflux conditions for 6 h. The reaction mixture was cooled, poured into ice and 2 N HCl aqueous solution, and extracted with EtOAc (2×). The combined organics were washed with 2 N HCl aqueous solution (1×), 2 N NaOH aqueous solution (2×), brine (1×), and dried over Na2SO4. Concentration in vacuo gave 8-fluoro-2′,3′,5′,6′-tetrahydrospiro[chromene-2,4′-pyran]-4(3H)-one (29) (4.4 g, 48% yield) which was taken onto the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.51-7.60 (2H, m), 7.00-7.07 (1H, m), 3.60-3.73 (4H, m), 2.93 (2H, s), 1.71-1.92 (4H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Br)([O-:3])=[O:2].[N+:12]([C:15]1C=C[CH:18]=[CH:17][C:16]=1C)([O-])=O.[N+](C1C=CC=CC=1C(Br)Br)([O-])=O.N1CCCC1.OS(O)(=O)=O.[O-]S([O-])(=O)=O.[Mg+2]>ClC1C=CC=CC=1.C(Cl)Cl>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][N:12]1[CH2:15][CH2:16][CH2:17][CH2:18]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: Cc1ccccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: O=[N+]([O-])c1ccccc1C(Br)Br
Solvent: ClCCl
Solvent: C1CCNC1
Solvent: Clc1ccccc1
Product: O=[N+]([O-])c1ccccc1CN1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of the crude 2-nitrobenzyl bromide (185 g, containing approximately 21% by weight of the 2-nitrobenzyl bromide (approximately 39 g, 180 mmol) besides the starting material 2-nitrotoluene and by-products of its bromination such as 2-nitrobenzal bromide) in chlorobenzene were added methylene chloride (500 ml) and pyrrolidine (28.1 g, 395 mmol). The solution was stirred at room temperature overnight. Then, the solution was cooled to 0° C. and aqueous solution of H2SO4 (200 g, 10% per weight) were added. The aqueous phase was extracted four times with methylene chloride (30 ml each). The aqueous phase was then treated with saturated aqueous solution of K2CO3 until the gas evolution had ceased. Then, it was extracted four times with methylene chloride (30 ml each). The combined organic phases were washed with water and brine and dried over MgSO4 affording a yellow liquid (yield: 89%). The product obtained was sufficient pure (>95%) for subsequent steps without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([CH3:15])[N:7]=1>[Zn].C(O)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([CH3:15])[N:7]=1
Reactant: COCCNc1ccc([N+](=O)[O-])c(C)n1
Agent: [Zn]
Solvent: CC(=O)O
Product: COCCNc1ccc(N)c(C)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 38.6 %

Procedure:
To a suspension of (2-methoxy-ethyl)-(6-methyl-5-nitro-pyridin-2-yl)-amine (421 mg, 2 mmol) and 5 ml of acetic acid, Zn dust (781 mg, 12 mmol) was added at 0° C. The mixture was stirred at 60° C. for 1 hour. Zn dust was filtered through celite and the residue was purified by HPLC to provide N2-(2-Methoxy-ethyl)-6-methyl-pyridine-2,5-diamine as an oil (140 mg, 39%). Exact mass calculated for C9H15N3O 181.12 found 182.2 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([N:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20](O)=[O:21])=[CH:12]1)[CH3:10].[F:23][CH2:24][CH2:25][NH2:26].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([N:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20]([NH:26][CH2:25][CH2:24][F:23])=[O:21])=[CH:12]1)[CH3:10]
Reactant: CC(c1c(F)cccc1F)n1cc(C(=O)O)c2ncccc21
Reactant: NCCF
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(c1c(F)cccc1F)n1cc(C(=O)NCCF)c2ncccc21
Reaction time: 0.08 h

Procedure:
See FIG. 16(a). 1-(1-(2,6-difluorophenyl)ethyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (0.090 g, 0.30 mmol), 2-fluoroethanamine (0.019 g, 0.30 mmol) and triethylamine (0.166 mL, 1.19 mmol) was taken in DCM (15 mL) under N2 and stirred. After 5 min, 1-Propanephosphonic acid cyclic anhydride (0.379 g, 1.19 mmol) was added. The resulting reaction was stirred at rt for 40 min. LCMS analysis showed formation of required product. Reaction was diluted with DCM and water. DCM layer was extracted and washed with brine and dried over sodium sulphate and concentrated. Purification was done on Waters RP system to get product 1-(1-(2,6-difluorophenyl)ethyl)-N-(2-fluoroethyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (0.040 g, 38.7%) as a solid. ES+MS m/z: 348.40. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.05 (d, J=6.97 Hz, 3 H ) 3.67 (q, J=5.21 Hz, 1 H ) 3.71-3.82 (m, 1 H ) 4.49 (t, J=4.90 Hz, 1 H ) 4.65 (t, J=4.99 Hz, 1 H ) 6.22 (q, J=7.16 Hz, 1 H ) 7.13 (t, J=8.57 Hz, 2 H ) 7.29 (dd, J=8.48, 4.71 Hz, 1 H ) 7.34-7.52 (m, 1 H ) 7.80 (d, J=8.29 Hz, 1 H ) 8.41 (s, 1 H ) 8.50 (d, J=4.71 Hz, 1 H) 8.92 (t, J=5.75 Hz, 1 H ).
Reaction SMILES: [NH:1]([C:6]([O:8][CH2:9][CH:10]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])[CH2:2][C:3](O)=[O:4].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.[CH3:52][O:53][C:54](=[O:74])[CH:55]([NH2:73])[CH:56]([C:61]1[CH:66]=[CH:65][C:64]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)=[CH:63][CH:62]=1)[C:57]([O:59][CH3:60])=[O:58]>CN(C)C=O>[CH3:60][O:59][C:57](=[O:58])[CH:56]([C:61]1[CH:62]=[CH:63][C:64]([C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)=[CH:65][CH:66]=1)[CH:55]([NH:73][C:3](=[O:4])[CH2:2][NH:1][C:6]([O:8][CH2:9][CH:10]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[C:17]2[C:22]1=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:7])[C:54]([O:53][CH3:52])=[O:74]
Reactant: COC(=O)C(N)C(C(=O)OC)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C(NC(=O)CNC(=O)OCC1c2ccccc2-c2ccccc21)C(C(=O)OC)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 54 %

Procedure:
A solution of Fmoc-Gly-OH (from Bachem) (1.66 g., 5.6 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (from Aldrich, 39391) (1.1 g., 5.7 mmol), 1-hydroxybenzotriazole (from Aldrich, 54804) (0.76 g., 5.6 mmol) and triethylamine (0.4 mL, 2.8 mmol) in dimethylformamide (50 mL) was stirred at room temperature for 1 hour. A solution of 2-amino-3-biphenyl-4-yl-succinic acid dimethyl ester hydrochloride (0.98 g., 2.8 mmol) in dimethylformamide (10 mL) was added and the reaction mixture was stirred at room temperature for a further 14 hours. The solvent was removed in vacuo and the residue partitioned between ethylacetate (100 mL) and sodium bicarbonate (100 mL, saturated solution in water). The aqueous layer was washed with ethylacetate (2×100 mL), the organics combined, dried over magnesium sulphate and concentrated in vacuo to afford a crude residue. The crude product was purified using flash chromatography (SiO2) eluting with ethylacetate/isohexane (3:1) to afford 2-biphenyl-4-yl-3-[2-(9H-fluoren-9-ylmethoxycarbonylamino)-acetylamino]-succinic acid dimethyl ester as a white crystalline solid (0.89 g., 54% yield). 1HNMR (CDCl3) δH (ppm); 3.71-3.73 (m, 7H), 3.81 0.2H (d, CH J=5.6 Hz), 3.86, 0.3H (d, CH J=5.8 Hz), 3.9, 0.3H (d, CH J=5.3 Hz), 3.94, 0.2H (d, CH J =5.8 Hz), 4.13-4.24 (m, 1H), 4.28-4.44 (m, 2.5H), 4.5 (d, 0.5H J=4.4 Hz), 5.1-5.4 (m, 2H), 6.4 (d, NH J=8.5 Hz), 7.19 (d, NH J=9.4 Hz), 7.23-7.34, 5H (m, Ar—H), 7.35-7.42, 4H (m, Ar—H), 7.47-7.60, 6H (m, Ar—H), 7.74, 2H (d, Ar—H J=7.6 Hz); LCMS analysis (solvent MeCN/H2O/0.1% HCO2H, 5-95% gradient/H2O 2.5 min, 95% 4 min., Phenomenex C18 reverse phase, flow rate 1 mL/min.) HPLC retention times 5.33 and 5.47 min. (diastereoisomers); mass found 593 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[O:7][C:6](=[O:8])[C:5](=[C:9]([OH:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])C(=O)O1.[C:28](O)(C)(C)C>C1C=CC=CC=1>[O:25]=[C:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][C:6]([O:7][C:2]([CH3:1])([CH3:27])[CH3:28])=[O:8]
Reactant: CCCCCCCCCCCCCCCC(O)=C1C(=O)OC(C)(C)OC1=O
Reactant: CC(C)(C)O
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCC(=O)CC(=O)OC(C)(C)C
Yield: 99.8 %

Procedure:
2,2-Dimethyl-5-(1-hydroxyhexadecylidene)-1,3-dioxane-4,6-dione (200 g) and tert-butyl alcohol (170 g) were refluxed in benzene (1 l) for 4 hours. Evaporation of the solvent gave crude tert-butyl 3-oxooctadecanoate (185 g) as an oil.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:30]=[N:29][CH:28]=[CH:27][C:4]=1[C:5]([NH:7][C:8]1[S:9][C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[C:11]([C:13]([O:15]C)=[O:14])[N:12]=1)=[O:6].FC1C=CC=C(F)C=1C(NC1SC(C2C=CC=C(C(F)(F)F)C=2)=C(C(O)=O)N=1)=O>>[CH3:2][C:3]1[CH:30]=[N:29][CH:28]=[CH:27][C:4]=1[C:5]([NH:7][C:8]1[S:9][C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[C:11]([C:13]([OH:15])=[O:14])[N:12]=1)=[O:6]
Reactant: COC(=O)c1nc(NC(=O)c2ccncc2C)sc1-c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: O=C(O)c1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Product: Cc1cnccc1C(=O)Nc1nc(C(=O)O)c(-c2cccc(C(F)(F)F)c2)s1

Procedure:
Compound 112 was prepared from Compound 111 by hydrolysis similarly as described for the preparation of Compound 66.