Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C.[OH-].[Na+]>>[O:8]([CH2:7][CH2:6][CH2:5][C:4]([OH:15])=[O:3])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)CCCOc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCOc1ccccc1

Procedure:
To a solution of phenol (3.16 g, 33.6 mmol) in acetonitrile, was added ethyl 4-bromobutyrate (4.8 ml, 33.6 mmol), potassium carbonate (4.64 g, 33.6 mmol) and tetrabutylammonium iodide (370 mg, 1 mmol). The reaction mixture was stirred vigorously and heated to reflux for 2 days before being cooled, filtered, dried (MgSO4) and concentrated in-vacuo to yield 4-phenoxy-butyric acid ethyl ester. 4-Phenoxy-butyric acid ethyl ester was hydrolyzed to its corresponding carboxylic acid using sodium hydroxide mediated hydrolysis to yield 4-phenoxy-butyric acid. To a solution of 4-phenoxy-butyric acid (7.67 g, 29.6 mmol) in anhydrous dichloromethane was added oxalyl chloride (4.4 ml, 50.3 mmol) and one drop of dimethyl formamide and the reaction mixture stirred at room temperature for 30 minutes. Reaction mixture was concentrated in-vacuo and the residue dissolved in 1,2-dichloroethane (90 ml). This solution was added drop wise to a suspension of aluminum trichloride (4.73 g, 35. 5 mmol) in 1,2-dichloroethane (50 ml) at 0° C. Reaction mixture was left stirring in ice bath which rose to room temperature overnight. The reaction mixture was poured over conc. hydrochloric acid (30 ml) stirred into 10 0 g ice, and then stirred for a further 90 minutes until the ice fully melted. The aqueous phase was washed with dichloromethane 3 times, before the organics were combined, dried (Na2SO4) and concentrated in-vacuo. Purification by triturating with diethylether gave 3,4-dihydro-2H-benzo[b]oxepin-5-one.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[NH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CN(C=O)C>[CH3:12][O:11][C:4]1[N:3]=[C:2]([NH:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:18][CH2:17]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCN)CC1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccc([N+](=O)[O-])c(NCCN2CCC(NC(=O)OC(C)(C)C)CC2)n1
Temperature: 40 °C

Procedure:
A mixture of 2-chloro-6-(methyloxy)-3-nitropyridine (1.9 g, 10 mmol), 1,1-dimethylethyl [1-(2-aminoethyl)-4-piperidinyl]carbamate (2.43 g, 10 mmol) and potassium carbonate (1.4 g, 10 mmol) in acetonitrile (35 ml) and DMF (10 ml) was heated at 40° C. for 30 minutes. The mixture was filtered, washing with acetonitrile, and evaporated. The residue was dissolved in the minimum volume of DCM (15 ml) and washed with water (1 ml). The organic extract was added to a silica column which was then eluted with 0-100% ethyl acetate in hexane affording a yellow solid (3.1 g, 78%).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@@H:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:12]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[C:23]2=[O:38])[O:11][CH:10]1[C@H:39]([OH:71])[C@@H:40]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[NH:41][CH2:42][CH2:43][CH2:44][NH:45][C:46](=[O:63])[C@@H:47]([CH2:59][CH:60]([CH3:62])[CH3:61])[NH:48]C(=O)OCC1C=CC=CC=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:48][C@H:47]([CH2:59][CH:60]([CH3:62])[CH3:61])[C:46]([NH:45][CH2:44][CH2:43][CH2:42][NH:41][C@@H:40]([C@H:39]([CH:10]1[C@@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[C@@H:13]([O:14][Si:15]([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:16])[CH3:17])[C@H:12]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[C:23]2=[O:38])[O:11]1)[OH:71])[C:64]([O:66][C:67]([CH3:69])([CH3:70])[CH3:68])=[O:65])=[O:63]
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@@H](CC(C)C)NC(=O)OCc4ccccc4)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@H](N)CC(C)C)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Yield: 78.5 %

Procedure:
By using an analogous procedure to that described for Example 45, tert-butyl (5R,12S)-12-[(R)-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-isobutyl-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (21 mg, 0.02 mmol, obtained from Example 56) was hydrogenated in methanol (2 ml) using 10% palladium on carbon (10 mg) for 3.5 hours to provide tert-butyl (2S,3R)-2-[(3-{[(2R)-2-amino-4-methylpentanoyl]amino}propyl)amino]-3-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl]-3-hydroxypropanoate (14 mg, 78%) as a white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([N:13]=NC2C=CC=CC=2)=[C:8]([CH3:21])[CH:7]=1)[CH2:2][CH2:3][CH3:4].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([NH2:13])=[C:8]([CH3:21])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(C)c(N=Nc2ccccc2)c(C)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCOc1cc(C)c(N)c(C)c1

Procedure:
To a flask fitted with reflux condenser and stirrer containing 4-butoxy-2,6-dimethylazobenzene (53.4 g, 0.189 mole) was added 50% aqueous ethanol (480 ml). The mixture was heated close to boiling with stirring and sodium hydrosulfite (Na2S2O4, 121.4 g., 697 mole) was added in small portions over a period of 30 min. The mixture was refluxed for 75 min. Most of the alcohol was distilled off and the oily amine layer formed in the operation was taken up in ether. The aqueous phase was made alkaline with sodium hydroxide and was extracted with ether. All the combined ether extracts were dried (Na2SO4), were filtered, and all low-boiling components were evaporated at reduced pressure (solvent and aniline), after which the residue was fractionated by distillation in vacuo. The fraction boiling at 105°-108° (0.1 mm Hg) was collected. Yield: (63%); nD25 =1.5337. [Cf. E. Honkanen, Ann. Acad. Sci. Fennicae, Ser. AII, 99 (1960)].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][NH:7][N:6]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][N:7]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1n[nH]cc1[N+](=O)[O-]
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1nn(CCc2ccccc2)cc1[N+](=O)[O-]
Yield: 65.5 %

Procedure:
430 mg (2.5 mM) of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester was dissolved in 4 ml of N,N-dimethylformamide, to which 0.41 ml (3 mM) of (2-bromoethyl)benzene and 1.6 g (5.0 mM) of cesium carbonate were added dropwise, and the mixture was stirred under a nitrogen atmosphere for a day. The solvent was distilled off under reduced pressure, and the resultant was extracted with ethyl acetate and brine. The organic solvent layer was dried over anhydrous sodium sulfate, filtered, and then distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane:ethyl acetate=5:1), to obtain 506 mg (65.5%) of the title compound and 218 mg (31.2%) of the compound of Preparative Example 10.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:38]I>C(#N)C.CCOCC>[I:38][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=1
Reactant: OCCc1cccc(C(F)(F)F)c1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Product: FC(F)(F)c1cccc(CCI)c1
Reaction time: 4 h

Procedure:
3-(Trifluoromethyl)phenethyl alcohol (10.0 g, 52.6 mmol), triphenylphosphine (17.9 g, 68.4 mmol), and imidazole (5.00 g, 73.6 mmol) were dissolved in acetonitrile (42 mL) and ether (70 mL), then the mixture was cooled to 0° C. Iodine (18.7 g, 73.6 mmol) was added in portions, then the mixture was stirred for 4 h. The reaction mixture was diluted with ether (1 L), washed with saturated Na2S2O3 (3×300 mL), aqueous CuSO4 (2×300 mL), and brine (2×300 mL), dried over Na2SO4, filtered, and concentrated to a volume of 200 mL. The precipitate of triphenylphosphineoxide was removed by filtration and the filtrate was triturated with ether/hexanes (2:1, 300 mL). Additional triphenylphosphine-oxide was removed by filtration, and the filtrate was concentrated to dryness to provide 1-(2-iodoethyl)-3-trifluoromethylbenzene as a yellow oil (16.5 g, quantitative): 1H NMR (300 MHz, CDCl3) δ 7.54–7.35 (m, 4H), 3.37 (t, J=8.3 Hz, 2H), 3.24 (t, J=8.3 Hz, 2H); 19F NMR (282 MHz, CDCl3) δ −63.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([OH:14])=[CH:9][CH:8]=2)=[O:4].Cl[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=1)=[CH:9][CH:8]=2)=[O:4]
Reactant: COC(=O)c1cc2cc(O)ccc2[nH]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(Oc3ccc([N+](=O)[O-])cn3)ccc2[nH]1
Temperature: 80 °C
Reaction time: 18 h
Yield: 54.4 %

Procedure:
5-Hydroxy-1H-indole-2-carboxylic acid methyl ester (0.845 g, 4.42 mmol) and 2-chloro-5-nitropyridine (0.771 g, 4.86 mmol) were dissolved in DMF (5 mL). To the solution was added anhydrous potassium carbonate (0.611 g, 4.42 mmol) and the resulting solution was stirred for 18 hours at 80° C. Water (80 mL) was added to the reaction solution and the mixture was extracted with ethyl acetate (80 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was removed by evaporation. The residue was purified by silica gel column chromatography (AcOEt:n-hexane=1:3), then the obtained solid was recrystallized from ethyl acetate and n-hexane to yield 0.753 g of the title compound as a yellow powder.
Reaction SMILES: [C:1]([S:5][CH2:6][C:7](=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:15][C:16]1[CH:34]=[CH:33][C:19]([CH2:20][N:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH:31]=[CH2:32])=[CH:25][CH:24]=2)N)=[CH:18][CH:17]=1.CC([O-])=O.[Na+]>C1(C)C=CC=CC=1.CC(O)=O>[Cl:15][C:16]1[CH:34]=[CH:33][C:19]([CH2:20][N:21]2[C:23]3[C:24](=[CH:25][C:26]([O:29][CH2:30][CH:31]=[CH2:32])=[CH:27][CH:28]=3)[C:6]([S:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[C:7]2[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:18][CH:17]=1
Reactant: CCOC(=O)C(=O)CSC(C)(C)C
Reactant: C=CCOc1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: C=CCOc1ccc2c(c1)c(SC(C)(C)C)c(C(=O)OCC)n2Cc1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
A solution of 18.6 g ethyl 3-t-butylthio-2-oxopropanoate, 26.3 g 1-(4-chlorobenzyl)-1-(4-allyloxyphenyl)hydrazine hydrochloride and 15 g NaOAc in 300 mL toluene and 150 mL HOAc was stirred at room temperature under nitrogen for 16 hours then at 70° C. for 2 hour. The mixture was cooled, poured onto H2O, extracted (3×) EtOAc and the organic layers then washed successively with sat. NaHCO3 and brine. After drying over MgSO4 the solution was filtered, evaporated and the residue chromatographed (silica gel; hexane/EtOAc 4:1) to afford the title compound.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[Cl:24][C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27]>>[Cl:24][C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH:27][C:1]([C:4]12[CH2:5][CH2:6][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:10][CH2:11]2)=[O:2]
Reactant: Nc1ccccc1Cl
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccccc3Cl)(CC1)CC2

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-chloroaniline (35.8 μL) were used to obtain (2S,4S)-1-[[N-[4-[N-(2-chlorophenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (17.4 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:10]=O>CN(C)C=O>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH:9]=[O:10]
Reactant: CN(C)c1ccccc1
Reactant: O=O
Solvent: CN(C)C=O
Product: CN(C=O)c1ccccc1
Yield: 15.4 %

Procedure:
By essentially the procedure of Example 1, a tube was charged with 20 g of dimethylaniline, 20 g of dimethylformamide, and 1.0 g of cupric chloride dihydrate. The reaction was run at 114°-115° C. for one hour while oxygen was injected incrementally at 200-400 psi. The oxygen absorption was about 0.12 mole. Analysis of the reaction mixture by GC/MS showed a 94.5% conversion of dimethylaniline and a 15.4% yield of N-methyl-N-phenylformamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[Br:21][C:22]1[CH:23]=[C:24]([C:28](O)=[O:29])[CH:25]=[N:26][CH:27]=1>>[Br:21][C:22]1[CH:27]=[N:26][CH:25]=[C:24]([CH:23]=1)[C:28]([NH:20][C:10]1[CH:11]=[N:12][C:13]([O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:9]=1)=[O:29]
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: O=C(O)c1cncc(Br)c1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1cncc(Br)c1

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and 5-bromo-3-pyridinecarboxylic acid (CAN 20826-04-4) as starting materials; LC-MS (UV peak area/ESI) 92.7%, 485.9662 (M−H)−.
Reaction SMILES: [NH2:1][C@@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].Cl(O)(=O)(=O)=O.C(O[C:20]([CH3:23])([CH3:22])[CH3:21])(=O)C>>[C:20]([O:9][C:8](=[O:10])[C@@H:2]([CH2:3][CH2:4][C:5]([O:7][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:6])[NH2:1])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(=O)OC(C)(C)C
Reactant: N[C@H](CCC(=O)O)C(=O)O
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(C)(C)OC(=O)CC[C@@H](N)C(=O)OC(C)(C)C

Procedure:
D-Glutamic acid (5.88 g), tert-butyl acetate (100 ml) and 70% aqueous perchloric acid (6.3 g) were stirred at laboratory temperature for 4 days. The mixture was then cooled in an ice-water bath and extracted with 0.5 N hydrochloric acid (3×100 ml). The combined aqueous extracts were immediately neutralised with solid sodium bicarbonate. The aqueous solution was extracted with diethyl ether (3×100 ml), the ether extracts pooled, dried over anhydrous sodium sulphate and the ether evaporated in vacuo to give di-tert-butyl-D-glutamate (0.855 g).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[Na+].[OH:27][CH:28]([CH3:37])[CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]/B(O)O.OO>O1CCCC1>[CH2:1]([O:11][C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21](/[CH:33]=[CH:32]/[CH2:31][CH2:30][CH2:29][CH:28]([OH:27])[CH3:37])=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(Br)cc2)nc1
Reactant: CC(O)CCC/C=C/B(O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1cnc(-c2ccc(/C=C/CCCC(C)O)cc2)nc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.7 %

Procedure:
Apart from the above, inner atmosphere of a four-necked flask equipped with a stirring device, a reflux condenser and a thermometer was replaced with nitrogen gas, and then the flask was charged with 6.6 g (17 mmol) of 5-decyloxy-2-(4-bromophenyl)-pyrimidine, 0.23 g (0.2 mmol) of tetrakis-triphenylphosphine-palladium, 2.4 g (60 mmol) of sodium hydroxide and 60 ml of tetrahydrofuran. Subsequently, 50 ml of a solution prepared by dissolving 20 mmol of the above-obtained E-6-hydroxy-1-heptenyldihydroxyborane in tetrahydrofuran was dropwise added thereto at room temperature. Then, the whole mixture was heated under reflux with stirring for 6 hours. After cooling the reaction mixture to room temperature, 5 ml of 10% aqueous solution of sodium hydroxide and 2 ml of 30% aqueous solution of hydrogen peroxide were added, and the resulting mixture was stirred for one hour. The mixture was extracted with ether, and the organic layer was twice washed with each 20 ml portion of saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 5.9 g (yield 82%) of 5-decyloxy-2-{4-(6-hydroxy-1-trans-heptenyl)-phenyl}-pyrimidine.
Reaction SMILES: C(O)(=O)C1C=CC=CC=1.[CH:10]([NH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[CH2:16][CH2:15]1)([CH3:12])[CH3:11].[CH3:29][O:30][CH:31]([O:39][CH3:40])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:40][O:39][CH:31]([O:30][CH3:29])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][N:13]([CH:10]([CH3:12])[CH3:11])[CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[CH2:18][CH2:19]1
Reactant: COC(CCCCCC=O)OC
Reactant: COc1ccncc1CN1CCC(NC(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)c1ccccc1
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccncc1CN1CCC(N(CCCCCCC(OC)OC)C(C)C)CC1
Reaction time: 1 h

Procedure:
To a reactor containing dichloromethane (4 L) was added 4-isopropylamino-1-(4-methoxypyrid-3-ylmethyl)piperidine monobenzoic acid salt (1.5 kg, 3.89 mol) while maintaining the temperature of the mixture at −5° C. to 5° C. The container used to add the salt was rinsed with dichloromethane (1.5 L) and the rinse was added to the reaction mixture. The temperature of the reaction mixture was then adjusted to 0° C. to 5° C. and 7,7-dimethoxyheptanal (790 g, 4.25 mol, 93.8% purity by GC) was added while maintaining the temperature of the reaction mixture between 0° C. to 5° C. The container used to add the 7,7-dimethoxyheptanal was rinsed with dichloromethane (0.8 L) and the rinse was added to the reactor. The resulting reaction mixture was then stirred at 0° C. to 5° C. for 1 hour. Sodium triacetoxyborohydride (1.07 kg, 5.05 mol) was then added in 7 equal portions over a period of 1 hour while maintaining the temperature of the reaction mixture between −5° C. to 5° C. The container used to add the sodium triacetoxyborohydride was rinsed with dichloromethane (0.8 L) and the rinse was added to the reaction mixture. The reaction mixture was then stirred at 0° C. to 5° C. for 21 hours. An aqueous solution of potassium carbonate (500 g) in deionized water (8.6 L) was then added to the reaction mixture while maintaining the temperature of the mixture between to 0° C. to 25° C. The resulting mixture was stirred for 2 hours at a temperature between 15° C. to 25° C. The layers were then allowed to separate over a period of 30 minutes and the organic layer was collected. The washing procedure with aqueous potassium carbonate solution was repeated 2 times. To the organic layer was then added an aqueous solution of sodium chloride (5.7 kg) in deionized water (15 L) while maintaining the temperature between to 15° C. to 25° C. The resulting mixture was stirred for 30 minutes at a temperature between 15° C. to 25° C. and then the layers were allowed to separate over a period of 30 minutes. The organic layer was collected and to this layer was added dichloromethane (1.5 L). The resulting solution containing the title compound was stored under a nitrogen atmosphere, protected from light, at 0° C. to 5° C. until used in the subsequent reaction.
Reaction SMILES: [Na].[OH:2][C:3]1[C:4](=[O:11])[CH:5]=[C:6]([CH2:9][OH:10])[O:7][CH:8]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[OH:10][CH2:9][C:6]1[O:7][CH:8]=[C:3]([O:2][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4](=[O:11])[CH:5]=1
Reactant: O=c1cc(CO)occ1O
Reactant: BrCc1ccccc1
Agent: [Na]
Solvent: CO
Product: O=c1cc(CO)occ1OCc1ccccc1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
69 g (3 mmol) of sodium were dissolved in 5 l of methanol. Subsequently 425.3 g (3 mol) of 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one was added and stirred at 30° C. until a clear solution was obtained. 595 g (3.5 mol) of benzyl bromide was then added and stirred for 1 hour under reflux. The warm, dark colored solution was poured into 15 l of ice water. The product crystallized immediately. The crystals were collected and washed first with 8 l of water and then twice with 2.5 l of ether. The product was left to stand overnight and finally dried at 50° C. for 16 hours. Yield: 646 g.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH2:34][CH:35]1[CH2:38][CH2:37][CH2:36]1>CN(C)C=O>[CH:35]1([CH2:34][N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:30])[CH2:3][CH2:4]2)=[O:9])[CH2:38][CH2:37][CH2:36]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: BrCC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3CC2CCC2)CC1
Yield: 69 %

Procedure:
The title compound was synthesized in analogy to example 51, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), sodium hydride and (bromomethyl)cyclobutane in N,N-dimethylformamide, to give the desired product as a colorless foam (69%).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:22])=[C:4]([C:9](=O)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(N(C(C)C)CC)(C)C.[NH:32]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([NH2:40])=[NH:39])=[CH:36][CH:35]=1)[NH2:33]>CCO>[Br:1][C:2]1[C:3]([OH:22])=[C:4]([C:9](=[N:33][NH:32][C:34]2[CH:35]=[CH:36][C:37]([C:38]([NH2:40])=[NH:39])=[CH:41][CH:42]=2)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: N=C(N)c1ccc(NN)cc1
Reactant: Cc1cc(Br)c(O)c(C(=O)CCc2ccc([N+](=O)[O-])cc2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1cc(Br)c(O)c(C(CCc2ccc([N+](=O)[O-])cc2)=NNc2ccc(C(=N)N)cc2)c1
Temperature: 25 °C
Yield: 90 %

Procedure:
For example, a solution of 1-(3-bromo-2-hydroxy-5-methyl-phenyl)-3-(4-nitro-phenyl)-propan-1-one 201 (1.48 g, 0.004 mol), EtOH (30 mL), diisopropylethylamine (Hunigs base)(3 mL), and 4-Hydrazino-benzamidine 200 (0.93 g, 0.004 mol) is heated at reflux for 4 hr. (reaction times can vary between 2 h to 18 h). The solution is cooled to ambient temperature, filtered, washed with 6N HCl (2×25 mL), and dried for 12-18 h in a vacuum oven to give a 90% yield of 4-{N′-[1-(3-bromo-2-hydroxy-5-methyl-phenyl)-3-(4-nitro-phenyl)-propylidene]-hydrazino}-benzamidine 202 as an off-white solid (1.78 g, 0.0036 mol).