Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[F:8][CH:9]([F:36])[C:10]([NH:12][C@H:13]([CH2:34][F:35])[C@H:14]([OH:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[N:23][C:24]([CH2:27][NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:26]=2)=[CH:17][CH:16]=1)=[O:11].C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([O:33][C@H:14]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[N:23][C:24]([CH2:27][NH:28][S:29]([CH3:32])(=[O:30])=[O:31])=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)[C@H:13]([NH:12][C:10](=[O:11])[CH:9]([F:8])[F:36])[CH2:34][F:35])=[O:6]
Reactant: CS(=O)(=O)NCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc2)cn1
Reactant: O=C(Cl)CCCBr
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)NCc1ccc(-c2ccc([C@@H](OC(=O)CCCBr)[C@@H](CF)NC(=O)C(F)F)cc2)cn1
Reaction time: 1 h
Yield: 59.4 %

Procedure:
4-Bromobutanoyl chloride (29.64, 0.255 mmol) is added dropwise to a stirred solution of 2,2-difluoro-N-{(1S,2R)-1-(fluoromethyl)-2-hydroxy -2-[4-(6-{[(methylsulfonyl)amino]methyl}pyridin-3-yl)phenyl]ethyl}acetamide (100.0 mg, 0.232 mmol), N,N-diisopropylethylamine (48.44, 0.278 mmol), and 4-dimethylaminopyridine (11.3 mg, 0.093 mmol) in N,N-dimethylformamide (1.00 mL) at rt. The reaction mixture is stirred for 1 hour before being concentrated. The residue was purified by CombiFlash (4 g column) eluting with 0-100% ethyl acetate to yield the title compound (80.0 mg, 59%) as a yellow foam. MS (ESI+) m/z 581.7 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.C(O)(=O)C.[Br:16]Br>O>[Br:16][CH:9]([CH3:10])[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)=[O:11]
Reactant: BrBr
Reactant: CCC(=O)c1ccc(Br)cc1
Solvent: CC(=O)O
Solvent: O
Product: CC(Br)C(=O)c1ccc(Br)cc1
Temperature: 10 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
Dissolving 5.0 g (23 mmol) of 4′-bromopropiophenon into 50 milliliter of acetic acid, and adding 3.7 g (23 mmol) of bromine while cooling with ice, stirred at the temperature of 10° C. for 3 hours. After the color of bromine disappeared, adding water and an extraction was carried out using dichloro-methane. Washing the organic layer with water, it was dried with the use of sodium sulfate. The solvent was removed by distillation and the resultant crystals were washed with hexane thereby obtaining 4.3 g of 2,4′-dibromopropiophenon (yield: 63%).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)O.[C:11]([O-:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Zn+2:20].C([O-])(=O)C1C=CC=CC=1.C(=O)(O)[O-].[NH4+]>>[CH:6]1[CH:5]=[CH:3][C:2]([C:1]([OH:10])=[O:9])=[CH:8][CH:7]=1.[CH:15]1[CH:16]=[CH:17][C:12]([C:11]([OH:19])=[O:18])=[CH:13][CH:14]=1.[Zn:20]
Reactant: O=C([O-])c1ccccc1
Reactant: O=C(O)c1ccccc1O
Reactant: [Zn+2]
Agent: O=C([O-])O
Agent: [NH4+]
Product: O=C(O)c1ccccc1
Product: [Zn]
Reaction time: 1 h

Procedure:
The weight average molecular weight of the thus-obtained salicylic acid resin was 960. The resin was placed in a separate reactor, to which a mixture of 16.3 g of zinc benzoate and 10 g of ammonium bicarbonate, which had been prepared in advance at 150-160° C, was added little by little over 30 minutes. After the addition, stirring was continued at the same temperature for 1 hour. The contents were taken out of the reactor, cooled and then ground, thereby obtaining 79.5 g of a zinc-benzoate-modified product of the salicylic acid resin. Its softening point was measured by the ring and ball softening point measuring apparatus in accordance with JIS K-2548. It was found to be 82° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([C@H:22]2[CH2:27][CH2:26][C@H:25]([CH3:28])[CH2:24][CH2:23]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19]C#N)=[CH:17][N:18]=2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].SC[C@@H]([C@@H](CS)O)O.[N:37](=[CH:45][CH2:46]Cl)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]Cl>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([C@H:22]2[CH2:27][CH2:26][C@H:25]([CH3:28])[CH2:24][CH2:23]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19][CH2:46][CH2:45][N:37]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:17][N:18]=2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: ClCC=NCCCCCCCl
Reactant: CC(=O)N1CCC(N(C(=O)Nc2ncc(SC#N)s2)[C@H]2CC[C@H](C)CC2)CC1
Agent: O[C@H](CS)[C@@H](O)CS
Product: CC(=O)N1CCC(N(C(=O)Nc2ncc(SCCN3CCCCCC3)s2)[C@H]2CC[C@H](C)CC2)CC1

Procedure:
Prepared as described in general procedures (H) and (I) using 1-(1-acetyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and 2-(hexamethyleneimino)ethylchloride
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10]([CH2:19]O)=[C:11]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[N:12]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:23])=O>C(Cl)Cl>[ClH:23].[ClH:23].[F:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10]([CH2:19][Cl:23])=[C:11]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1[nH]c(-c2cccc(F)c2)nc1-c1cccnc1
Solvent: ClCCl
Product: Cl
Product: Fc1cccc(-c2nc(-c3cccnc3)c(CCl)[nH]2)c1

Procedure:
To a solution of 2-(3-fluorophenyl)-5-hydroxymethyl-4-(3-pyridyl)imidazole (389 mg) in methylene chloride (10 ml) was added thionyl chloride (10 ml), and the mixture was refluxed for one hour. After cooling, the reaction mixture was concentrated under reduced pressure to obtain a crude product of 2-(3-fluorophenyl)-5-chloromethyl-4-(3-pyridyl)imidazole dihydrochloride (508 mg) as colorless powder.
Reaction SMILES: [CH:1]([CH:13]1[CH2:18][C:17](=[O:19])[O:16][C:14]1=O)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11].[C:20]([C:24]1[CH:25]=[C:26]([CH2:35][CH2:36][C:37]([NH:39][NH2:40])=[O:38])[CH:27]=[C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:29]=1[OH:30])([CH3:23])([CH3:22])[CH3:21].C1(C)C=CC=CC=1>O>[C:31]([C:28]1[CH:27]=[C:26]([CH2:35][CH2:36][C:37]([NH:39][N:40]2[C:17](=[O:19])[CH2:18][CH:13]([CH:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([CH3:11])[CH3:12])[C:14]2=[O:16])=[O:38])[CH:25]=[C:24]([C:20]([CH3:21])([CH3:22])[CH3:23])[C:29]=1[OH:30])([CH3:32])([CH3:33])[CH3:34]
Reactant: CC(C)CCCCCCCC=CC1CC(=O)OC1=O
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)CCCCCCCC=CC1CC(=O)N(NC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 102.8 %

Procedure:
A mixture of 2-isododecenylsuccinic anhydride (31.2 g, 111 mmol), 3-(3,5-di-t-butyl-4-hydroxy-phenyl)propanoic acid hydrazide (32.6 g, 111 mmol) and 60 ml of toluene was refluxed for 90 minutes under a nitrogen atmosphere with the azeotropic removal of water (Dean-Stark assembly). The bulk of the solvent was distilled off followed by vacuum stripping of the hot (135° C.) melt for 25 minutes to remove last traces of solvent. After cooling to room temperature, the vacuum was removed. Additional cooling in an acetone/dry ice bath allowed for easy removal of the thermally fractured solid from the vessel. 61.7 g of an amber solid was obtained having a melting range of 62°-68° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]#[C:4][CH2:5][Cl:6].[Cl:7][CH:8]([SiH3:10])[Cl:9]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.C(O)(C)C>[Cl:1][CH2:2][C:3]([SiH2:10][CH:8]([Cl:9])[Cl:7])=[CH:4][CH2:5][Cl:6]
Reactant: ClCC#CCCl
Reactant: [SiH3]C(Cl)Cl
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: ClCC=C(CCl)[SiH2]C(Cl)Cl
Yield: 87.2 %

Procedure:
To a mixture of 10 ml (0.106 mol) of 1,4-dichloro-2-butyne and 11.5 ml (0.11 mol) of dichloromethylsilane (boiling point: 41° C.) was added 0.05 ml (4.8 mmol %) of an isopropanol solution of chloroplatinic acid prepared in the same manner as in Example 1, followed by heating under reflux for 1 hour, thereby obtaining 22 g of 1,4-dichloro-2-(dichloromethyl)silyl-2-butene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][N+:24]([O-:27])=[CH:23][CH:22]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36](O)=[O:37])[CH2:31][CH2:30]1.N1(C2C=CN=CC=2)CCCC1.C1(N=C=NC2CCCCC2)CCCCC1.C(Cl)[Cl:66]>>[ClH:66].[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]([N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2/[CH:19]=[CH:20]/[C:21]2[CH:22]=[CH:23][N+:24]([O-:27])=[CH:25][CH:26]=2)[S:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:11])=[O:10])=[O:37])[CH2:31][CH2:30]1
Reactant: CN1CCN(CC(=O)O)CC1
Reactant: COc1ccc(S(=O)(=O)Nc2ccccc2/C=C/c2cc[n+]([O-])cc2)cc1
Reactant: ClCCl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Product: COc1ccc(S(=O)(=O)N(C(=O)CN2CCN(C)CC2)c2ccccc2/C=C/c2cc[n+]([O-])cc2)cc1
Product: Cl
Temperature: 25 °C

Procedure:
(E) -4-(2-(2-(N-(4-Methoxybenzenesulfonyl)amino)phenyl)ethenyl) pyridine 1-oxide (0.96 g) was dissolved in methylene chloride (25 ml), and 4-methylpiperazin-1-yl acetic acid (0.99 g) prepared in Reference Example 1 and 4-pyrrolidinopyridine (37 mg) were added thereto. To the mixture was added dropwise N,N′-dicyclohexylcarbodiimide (1.29 g) dissolved in methylene chloride (13 ml), and the mixture was stirred over night at room temperature. The reaction solution was filtered and the filtrate was concentrated. The resultant residue was subjected to silica gel column chromatography (eluent: CHCl3/CH3OH=100/1 to 10/1) to obtain fractions. To each fraction was added hydrochloric acid-ether solution followed by concentration. The residue was diluted with water, filtered through membrane filter and lyophilized to yield the objective compound (1.25 g, colorless powder).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].C(Cl)(=O)[C:9](Cl)=[O:10].[C:14]([O:18][C:19]([N:21]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:22]1[N:27]=[CH:26][C:25]([C:28]2[CH:33]=[C:32]([O:34][C:35]3[CH:36]=[N:37][C:38]([NH2:41])=[CH:39][CH:40]=3)[CH:31]=[CH:30][N:29]=2)=[CH:24][CH:23]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>ClCCCl.C(Cl)Cl.[Cl-].[Na+].O>[C:45]([O:44][C:42]([N:21]([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[C:22]1[N:27]=[CH:26][C:25]([C:28]2[CH:33]=[C:32]([O:34][C:35]3[CH:40]=[CH:39][C:38]([NH:41][C:9]([NH:5][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[O:10])=[N:37][CH:36]=3)[CH:31]=[CH:30][N:29]=2)=[CH:24][CH:23]=1)=[O:43])([CH3:48])([CH3:47])[CH3:46]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)C(N)=O
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ccc(-c2cc(Oc3ccc(N)nc3)ccn2)cn1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ccc(-c2cc(Oc3ccc(NC(=O)NC(=O)C(C)(C)C)nc3)ccn2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
A solution of 2,2,2-trimethylacetamide (0.084 g, 0.834 mmol) in DCE (3 mL) was treated with oxalyl chloride (0.073 mL, 0.834 mmol), stirred at RT for 1 h, then heated at 75° C. for 3 h. The mixture was cooled to RT, treated with a solution of 6′-(bis(tert-butoxycarbonyl)amino)-4-((6-aminopyridin-3-yl)oxy)-[2,3′-bipyridine](0.2 g, 0.417 mmol) and TEA (0.174 mL, 1.251 mmol) in DCM (3 mL) and stirred at RT for 2 h. The mixture was treated with brine, extracted with DCM (2×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford N-((5-((6′-(bis(tert-butoxycarbonyl)amino)-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide (230 mg, 91%) as a white amorphous solid. 1H NMR (400 MHz, DMSO-d6): δ 11.22 (s, 1H), 10.45 (br s, 1H), 9.08 (d, J=2.5 Hz, 1H), 8.58 (d, J=5.7 Hz, 1H), 8.49 (dd, J=8.5, 2.5 Hz, 1H), 8.30 (d, J=2.9 Hz, 1H), 8.10 (d, J=9.0 Hz, 1H), 7.78 (dd, J=9.0, 2.9 Hz, 1H), 7.73 (d, J=2.4 Hz, 1H), 7.48 (d, J=8.4 Hz, 1H), 6.94 (dd, J=5.7, 2.4 Hz, 1H), 1.40 (s, 18H), 1.21 (s, 9H); MS (ESI) m/z: 607.3 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:19]=[CH:18][C:8]([C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]2=O)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22](=[O:33])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[NH2:24].O.CO>C1(OC)C=CC=CC=1.[Pd]>[CH3:20][O:21][C:22](=[O:33])[CH:23]([NH:24][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9](=[O:10])[C:8]1[CH:18]=[CH:19][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1)[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1
Reactant: CC(C)(C)c1ccc(C(=O)C2CCCCC2=O)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: [Pd]
Solvent: COc1ccccc1
Solvent: O
Solvent: CO
Product: COC(=O)C(Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1ccc(C(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 41 %

Procedure:
To a mixture of 2-(4-tert-butylbenzoyl)cyclohexanone (116.1 g, 0.45 mol), L-tyrosine methyl ester (78.0 g, 0.40 mol) in anisole (1000 ml) is added 5% palladium on carbon (20 g), then the mixture is heated to reflux for 2 h while the resulting water is removed by a Dean-Stark apparatus. The mixture is cooled to 80° C., and the Pd/C is filtered and washed with anisole (3×60 ml). The mixture is cooled to 40° C., hexane (1000 ml) is added and the mixture kept at −20° C. for 48 h. The solid is filtered and washed with hexane (5×200 ml) to yield the crude 2-[(2-(4-tert-butylbenzoyl)phenyl)-amino]-3-(4-hydroxyphenyl)-propionic acid methyl ester. The crude product is mixed with 250 ml of methanol and is refluxed for 30 min. After cooled to 0° C., the product is filtered, washed with methanol (2×50 ml), and dried under a vacuum to give the title compound (70.7 g, 41.0%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[BH:17]([O-:19])[O-:18].C([O-])(=O)C.[K+].[CH3:25][CH:26]([C:28]1[CH:33]=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)[CH:29]=1)[CH3:27]>O1CCOCC1>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([B:17]3[O:19][C:28]([CH3:33])([CH3:29])[C:26]([CH3:27])([CH3:25])[O:18]3)=[CH:3][CH:4]=2)=[N:9][CH:10]=1)([O-:16])=[O:15]
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Reactant: O=[N+]([O-])c1ccc(-c2ccc(Cl)cc2)nc1
Reactant: [O-]B[O-]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC1(C)OB(c2ccc(-c3ccc([N+](=O)[O-])cn3)cc2)OC1(C)C
Temperature: 115 °C
Yield: 419.6 %

Procedure:
A flask was charged with 2-(4-chlorophenyl)-5-nitropyridine (4.48 g, 14.26 mmol), pinoco boronate (14.48 g, 57.0 mmol), potassium acetate (5.59 g, 57.0 mmol), Pd-(Xphos) (1.404 g, 1.900 mmol), X-phos (1.359 g, 2.85 mmol) and dioxane (50 ml) at room temperature. The flask was sealed, flushed with nitrogen for three times and heated at 115° C. for 72 hours. The mixture was cooled down to room temperature and diluted with dioxane (50 ml) and EtOAc (100 ml), filtered and the filtrate was concentrated. The residue was added dioxane (30 ml) and filtered, the filtrate was purified by flash chromatography (heptanes/acetone 1/2) to afford 5-nitro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridine (3.9 g, 84%) as yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 1.37 (s, 9H) 7.43-8.15 (m, 7H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([OH:21])=[CH:17][N:16]=2)=[C:11]([F:22])[CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].N1C=CC=CC=1.[C:29](Cl)(=[O:38])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:29](=[O:38])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:17][N:16]=2)=[C:11]([F:22])[CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(-c2ncc(O)cn2)c(F)c1
Reactant: CCCCCCCCC(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCC(=O)Oc1cnc(-c2ccc(OCCCCCCC)cc2F)nc1
Reaction time: 12 h

Procedure:
0.1 mol of 2-(4-heptyloxy-2-fluorophenyl)-5-hydroxypyrimidine (prepared from 4-heptyloxy-2-fluorobenzamidine in accordance with Example 1) is dissolved together with 0.12 mol of pyridine in toluene and 0.1 mol of nonanoyl chloride is then added at room temperature. Stirring is then carried out for 12 hours and standard working-up is carried out. 2-(4-Heptyloxy-2-fluorophenyl)-5-nonanoyloxypyrimidine is obtained, C 65 I, Δε=-0.2.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[NH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[CH:21](C1C=C2C(=CC=1)C(NC(=O)C1C=CC=CC=1)=NC=C2)=[O:22]>>[CH:21]([C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[NH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1)=[O:22]
Reactant: O=C(Nc1nccc2ccc(Br)cc12)c1ccccc1
Reactant: O=Cc1ccc2c(NC(=O)c3ccccc3)nccc2c1
Product: O=Cc1ccc2ccnc(NC(=O)c3ccccc3)c2c1

Procedure:
N-(7-Formylisoquinolinyl)benzamide was prepared from 37e using the procedure described for 1f but was not purified using column chromatography. The crude aldehyde was transformed into the title compound using the procedure described for 1g folowed by purification using column chromatography on silica gel (toluene/ethyl acetate: 2/1). M.p. 137.5-139.0° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3]1.CCN(C(C)C)C(C)C.[C:17]([O:21][C:22]([NH:24][C:25]1([CH:29]([OH:33])[C:30](O)=[O:31])[CH2:28][CH2:27][CH2:26]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:33][CH:29]([C:25]1([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:28][CH2:27][CH2:26]1)[C:30]([NH:7][C:4]1[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=1)=[O:31]
Reactant: Cn1ccc(N)n1
Reactant: CC(C)(C)OC(=O)NC1(C(O)C(=O)O)CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccc(NC(=O)C(O)C2(NC(=O)OC(C)(C)C)CCC2)n1
Reaction time: 2 h
Yield: 92.3 %

Procedure:
1-Methyl-1H-pyrazol-3-amine (158 mg, 1.63 mmol) and DIEA (1.08 mL, 6.52 mmol) was added to a solution of 2-(1-(tert-butoxycarbonylamino)cyclobutyl)-2-hydroxyacetic acid (400 mg, 1.63 mmol) dissolved in DMF (20 mL). The solution was cooled to 0° C. and after 10 minutes HATU (620 mg, 1.63 mmol) was added. After approximately 2 hours at RT, LC-MS showed product and no starting material and the solvent was removed by rotary evaporation. The crude product was dissolved in 40 mL EtOAc and washed with 25 mL sat. NaHCO3(aq). The organic phase was dried with Na2SO4, filtered and evaporated to dryness. The crude product was purified on a 25 g silica column on a Biotage Flashmaster, which gave the title product as a white solid (488 mg, 92%). TLC rf: 0.07 in heptane:ethyl acetate 1:1. [M+H]+=325.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[O:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[CH2:11][OH:12].C(N(CC)CC)C>O1CCCC1>[CH3:4][S:1]([O:12][CH2:11][CH:7]1[CH2:8][CH2:9][CH2:10][O:6]1)(=[O:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CCCO1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCCO1
Reaction time: 2 h

Procedure:
Mesyl chloride (6.17 g) was dropwise added to a solution of 5.0 g of (tetrahydro-2furanyl)methanol, 2.18 g of triethylamine and 30 ml of tetrahydrofuran under ice-cooling over 30 minutes, followed by stirring at the same temperature for 2 hours. After the completion of reaction, the insolubles were filtered, and the filtrate was then concentrated under a reduced pressure to obtain (tetrahydro-2-furanyl)methyl methanesulfonate as an oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:43][CH:44](OCC)OCC)[C:9]([CH:11]([NH:24][C:25](=[O:42])[CH2:26][CH:27]([NH:31][C:32]([NH:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH2:28][CH:29]=[CH2:30])[CH2:12][C:13]1[CH:18]=[CH:17]C(OC(C)(C)C)=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:51]([OH:53])=O>>[CH2:35]([NH:34][C:32]([N:31]1[CH:27]([CH2:28][CH:29]=[CH2:30])[CH2:26][C:25](=[O:42])[N:24]2[CH:11]([CH2:12][C:13]3[CH:14]=[CH:15][C:51]([OH:53])=[CH:17][CH:18]=3)[C:9](=[O:10])[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:43][CH:44]12)=[O:33])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=CO
Reactant: C=CCC(CC(=O)NC(Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1ccccc1)CC(OCC)OCC)NC(=O)NCc1ccccc1
Product: C=CCC1CC(=O)N2C(Cc3ccc(O)cc3)C(=O)N(Cc3ccccc3)CC2N1C(=O)NCc1ccccc1
Yield: 38 %

Procedure:
A solution of crude 3-(3-Benzyl-ureido)-hex-5-enoic acid [1-[benzyl-(2,2-diethoxy-ethyl)-carbamoyl]-2-(4-tert-butoxy-phenyl)-ethyl]-amide (2.9 g, 4.95 mmol) in formic acid (100 mL) was stirred at room temperature for 13 h. The solvent was removed under reduced pressure and then diluted with EtOAc, washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo. The residue was purified by chromatography and recrystallized on ethyl acetate and Hexane to give the 2-Allyl-8-benzyl-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[1,2-a]pyrimidine-1-carboxylic acid benzylamide (1.18 g, 3 step yield: 38%). 1H NMR (CDCl3, 300 MHz) δ 7.5˜7.26 (m, 5H), 7.25 (d, J=7.01, 2H), 6.85 (m, 5H), 6.55 (d, J=8.76, 2H), 5.7 (m, 1H), 5.3 (t, J=4.7, 1H), 5.05 (d, J=10.75, 1H), 5.0 (d, J=18.54, 1H), 4.87 (d, J=14.51, 1H), 4.55 (m, 1H), 4.5˜4.25 (m, 4H, OH), 3.5˜3.3 (m, 2H), 3.25-3.1 (m, 2H), 2.6˜2.4 (m, 2H), 2.2 (t, J=7.2, 2H) MS ESI 539 (M+H), 561 (M+Na).
Reaction SMILES: [CH2:1]([C:3]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[C:23]([CH3:30])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]([CH2:18][CH3:19])([OH:17])[CH2:15][CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].Cl.[CH3:32][O:33][C:34](=[O:39])[C:35]([NH2:38])([CH3:37])[CH3:36].O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>>[CH3:32][O:33][C:34](=[O:39])[C:35]([NH:38][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([C:3]([CH2:1][CH3:2])([C:6]2[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]([CH2:18][CH3:19])([OH:17])[CH2:15][CH3:16])=[C:8]([CH3:20])[CH:7]=2)[CH2:4][CH3:5])=[CH:22][C:23]=1[CH3:30])([CH3:37])[CH3:36]
Reactant: COC(=O)C(C)(C)N
Reactant: CCC(O)(C#Cc1ccc(C(CC)(CC)c2ccc(C(=O)O)c(C)c2)cc1C)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(O)(C#Cc1ccc(C(CC)(CC)c2ccc(C(=O)NC(C)(C)C(=O)OC)c(C)c2)cc1C)CC
Yield: 77.4 %

Procedure:
4-{1-Ethyl-1-[4-(3-ethyl-3-hydroxy-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-benzoic acid (437 mg, 1.07 mmol), α-aminoisobutyric acid methyl ester hydrochloride (247 mg, 1.61 mmol), 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (309 mg, 1.61 mmol), 1-hydroxybenzotriazole hydrate (218 mg, 1.61 mmol) and triethylamine (597 μL, 4.28 mmol) are reacted and purified analogous to Example 1J to give the title compound (419 mg, 77%).
Reaction SMILES: C([O:5][C:6](=[O:43])[C@@H:7]([NH:29][S:30]([C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31])[CH2:8][NH:9][C:10](=[O:28])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]2[NH:22][CH2:23][CH2:24][CH2:25][N:26]=2)=[CH:13][CH:12]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:33]1([S:30]([NH:29][C@@H:7]([CH2:8][NH:9][C:10](=[O:28])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]3[NH:26][CH2:25][CH2:24][CH2:23][N:22]=3)=[CH:13][CH:12]=2)[C:6]([OH:43])=[O:5])(=[O:32])=[O:31])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)cc1)NS(=O)(=O)c1cccc2ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2cccc3ccccc23)C(=O)O)cc1)NC1=NCCCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
45 mg (0.074 mmol) of (2S)-2-(naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid tert-butyl ester was dissolved in 2 ml of dichloromethane and 2 ml of trifluoroacetic acid was added. The solution was stirred at room temperature for 3 hours. The solvent was removed in vacuo and toluene was added to the residue and then removed in vacuo. The residue was dissolved in acetonitrile/water (1/1) and lyophilized. Yield 50 mg. MS (ES+): m/e=552 (M+H+).