Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][C:19]([C:21]([OH:23])=[O:22])=[CH:20][C:15]=3[N:14]=[C:13]2[C:24](=[O:35])NC2CCN(C(C)C)CC2)=[O:10])=[N:6][CH:7]=1.CNCC[OH:40]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][C:19]([C:21]([OH:23])=[O:22])=[CH:20][C:15]=3[N:14]=[C:13]2[C:24]([OH:40])=[O:35])=[O:10])=[N:6][CH:7]=1
Reactant: CC(C)N1CCC(NC(=O)c2nc3cc(C(=O)O)ccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1
Reactant: CNCCO
Product: O=C(Cn1c(C(=O)O)nc2cc(C(=O)O)ccc21)Nc1ccc(Cl)cn1

Procedure:
5-[(2-hydroxy-ethyl)-methyl-amide]2-[(1-isopropyl-piperidin-4-yl)-amide]1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-1H-benzoimidazole-2,5-dicarboxylic acid 5-[(2-hydroxy-ethyl)-methyl-amide]2-[(1-isopropyl-piperidin-4-yl)-amide] was prepared by a procedure according to example 22 starting from 50 mg (0.10 mmol) 1-[(5-chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-5-carboxylic acid and 8.3 mg (0.11 mmol) N-methyl-2-aminoethanol. The title compound was obtained as its formiate in form of a white amorphous solid. Yield: 23 mg MS (ES+): m/e=556, chloro pattern.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:6]=[CH:7][CH2:8]Cl.[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23][C:24]=2[N:25]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][N:21]([CH2:8][CH:7]=[CH:6][C:5]3[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:22][CH2:23][C:24]=2[N:25]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: COc1ccc(C=CCCl)cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COc1ccc(C=CCN2CCc3nc(N)sc3CC2)cc1OC
Yield: 7.7 %

Procedure:
Prepared from 3,4-dimethoxy-cinnamyl chloride (prepared at -5° C. for 10 minutes) and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform. Yield: 7.7% of theory, Melting point: 122°-126° C. (ether).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9]Cl)=[CH:7][CH:6]=[CH:5][C:4]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18].[C-:19]#[N:20].[K+]>CS(C)=O>[CH3:1][O:2][C:3]1[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:5][CH:6]=[CH:7][C:8]=1[CH2:9][C:19]#[N:20]
Reactant: COc1c(CCl)cccc1Oc1ccccc1Cl
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Product: COc1c(CC#N)cccc1Oc1ccccc1Cl
Yield: 98.5 %

Procedure:
A solution of 2-chlorophenyl 2-methoxy-3-chloromethylphenyl ether (6.3 g) in dimethyl sulfoxide (40 ml) and powdered potassium cyanide (1.55 g) were treated in a similar manner to that of Example 3-(7) to give oily 2-[2-methoxy-3-(2-chlorophenoxy)phenyl]acetonitrile (6.0 g).
Reaction SMILES: C[O:2][C:3](=[O:24])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])=[CH:11][C:10]1=[O:23])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+].Cl>O1CCCC1.O>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[O:14][C:12]1[CH2:13][N:9]([C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:24])=[O:2])[C:10](=[O:23])[CH:11]=1
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2ccc(F)cc2F)=CC1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@@H](C(=O)O)N1CC(Oc2ccc(F)cc2F)=CC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.3 %

Procedure:
A mixture of (S)-2-[4-(2,4-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (0.53 g, 1.58 mmol) in tetrahydrofuran (12 mL) and water (4 mL) was treated with lithium hydroxide monohydrate (80 mg, 1.89 mmol). The reaction was stirred at 25° C. for 4 h. At this time, the reaction was diluted with water (75 mL), acidified with a 2N aqueous hydrochloric acid solution and then extracted with 10% methanol/dichloromethane (3×50 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford (S)-2-[4-(2,4-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.50 g, 97%) as a light yellow solid: HR-ES-MS m/z calculated for C16H17NO4F2 [M+Na]+ 348.1018, observed 348.1018; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.86 (d, J=6.4 Hz, 3H), 0.92 (d, J=6.4 Hz, 3H), 1.36-1.52 (m, 1H), 1.53-1.68 (m, 1H), 1.75-1.86 (m, 1H), 4.15 (d, J=18.4 Hz, 1H), 4.26 (d, J=18.4 Hz, 1H), 4.62 (dd, J=11.5, 4.2 Hz, 1H), 4.93 (s, 1H), 7.14-7.25 (m, 1H), 7.49-7.64 (m, 2H), 12.91 (br. s., 1H).
Reaction SMILES: [C:1]([N:4]1[C:8]([CH:9]2[CH2:11][CH2:10]2)=[CH:7][C:6]([NH:12][C:13]2[C:18](Br)=[CH:17][N:16]=[C:15]([C:20]3[S:24][C:23]([S:25]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])(=[O:27])=[O:26])=[CH:22][CH:21]=3)[N:14]=2)=[N:5]1)(=[O:3])[CH3:2].CCN(CC)CC.[C:41]([Si:43]([CH3:46])([CH3:45])[CH3:44])#[CH:42]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[C:1]([N:4]1[C:8]([CH:9]2[CH2:11][CH2:10]2)=[CH:7][C:6]([NH:12][C:13]2[C:18]([C:42]#[C:41][Si:43]([CH3:46])([CH3:45])[CH3:44])=[CH:17][N:16]=[C:15]([C:20]3[S:24][C:23]([S:25]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])(=[O:27])=[O:26])=[CH:22][CH:21]=3)[N:14]=2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)n1nc(Nc2nc(-c3ccc(S(=O)(=O)NCCN(C)C)s3)ncc2Br)cc1C1CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)n1nc(Nc2nc(-c3ccc(S(=O)(=O)NCCN(C)C)s3)ncc2C#C[Si](C)(C)C)cc1C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of crude 5-(4-(1-acetyl-5-cyclopropyl-1H-pyrazol-3-ylamino)-5-bromopyrimidin-2-yl)-N-(2-(dimethylamino)ethyl)thiophene-2-sulfonamide (from step 4), Pd(PPh3)2Cl2 (14 mg, 0.02 mmol, 0.05 eq) and CuI (8 mg, 0.04 mmol, 0.1 eq) was flushed with nitrogen. Anhydrous THF (12 mL) and Et3N (121 mg, 1.2 mmol, 3.0 eq) were added and the reaction mixture was flushed with nitrogen. Ethynyl-trimethylsilane (118 mg, 1.2 mmol, 3.0 eq) was added and the reaction mixture was stirred at rt for 1 h. Then, the reaction mixture was concentrated to about 5 mL, which was taken in EtOAc and was washed with water, brine. The combined organic layers were concentrated to afford crude 5-(4-(1-acetyl-5-cyclopropyl-1H-pyrazol-3-ylamino)-5-((trimethylsilyl)ethynyl)pyrimidin-2-yl)-N-(2-(dimethylamino)ethyl) thiophene-2-sulfonamide, which was used for the next step without further purification). LC-MS (m/z)=572.0 [M+H]+
Reaction SMILES: [CH3:1][N:2]1[CH2:22][CH2:21][C:5]2[N:6]([CH2:14][CH2:15][C:16]([O:18]CC)=O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:23][NH2:24]>>[CH3:1][N:2]1[CH2:22][CH2:21][C:5]2[N:6]([CH2:14][CH2:15][C:16]([NH:24][CH3:23])=[O:18])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CN
Reactant: CCOC(=O)CCn1c2c(c3cc(C)ccc31)CN(C)CC2
Product: CNC(=O)CCn1c2c(c3cc(C)ccc31)CN(C)CC2
Temperature: 110 °C

Procedure:
A mixture of ethyl 3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoate (100 mg, 0.33 mmol) and methyl amine (40% aq, 2.5 ml) was heated at 100-120° C. for 3-4 h. The reaction mixture was evaporated to dryness and the residue was purified by on neutral alumina chromatography eluting with methanol-dichloromethane gradient to obtain 10 mg of 3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-N-methylpropanamide.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:34](=[O:37])[CH2:35][CH3:36])[CH2:32][CH2:33]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(CC)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f48) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [N+]([O-])([O-])=O.[Na+].[BrH:6].N[C:8]1[C:9]([CH3:16])=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][OH:12]>O.[Cu]Br>[Br:6][C:8]1[C:9]([CH3:16])=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][OH:12]
Reactant: Br
Reactant: Cc1c(N)cccc1CO
Agent: [Cu]Br
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1c(Br)cccc1CO
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 40.7 g of sodium nitrate in 300 ml of water is added dropwise to a mixture cooled to 0° C. and consisting of 888 ml of water, 162 ml of 47% strength hydrobromic acid and 81.2 g of 3-amino-2-methylbenzyl alcohol. Stirring is carried out for 30 minutes at 0° C., after which a suspension of 168.7 g of copper(I) bromide in 750 ml of water is added a little at a time at this temperature. The reaction mixture is stirred in succession for 1 hour at 10° C, for 1 hour at room temperature and for 2 hours at 100° C. After cooling, the reaction mixture is extracted several times with ether. The combined organic phases are washed with water, dried and evaporated down. After purification by column chromatography over silica gel using toluene as the mobile phase, 64.2 g of 3-bromo-2-methylbenzyl alcohol of melting point 97°-100 ° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][O:19][C:18]2=[O:27])[CH2:13][CH2:12]1>C(O)(=O)C.O1CCCC1.[Fe]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[CH2:12][CH2:13][CH:14]([N:17]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[CH2:20][O:19][C:18]3=[O:27])[CH2:15][CH2:16]2)=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C1OCc2ccccc2N1C1CCN(c2ccc([N+](=O)[O-])cc2Cl)CC1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Nc1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Iron powder (1.5 g) was added to a solution of the product from step (i) (1.37 g) in acetic acid (50 ml) and tetrahydrofuran (20 ml). After stirring at room temperature for 5 h, the mixture was filtered through celite, the solvent removed under reduced pressure and the residue partitioned between ethyl acetate and aqueous sodium hydrogencarbonate solution. The organic layer was washed with water, dried and evaporated under reduced pressure. Purification was by chromatography eluting with 50% ethyl acetate/isohexane. Yield 1.05 g.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([C:11]2[N:12]=[N:13][C:14](Cl)=[CH:15][CH:16]=2)=[O:10])[CH2:3][CH2:2]1.[N:18]1([C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([F:35])([F:34])[F:33])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH:1]1([CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([C:11]2[N:12]=[N:13][C:14]([N:21]3[CH2:22][CH2:23][N:18]([C:24](=[O:25])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]([F:35])([F:33])[F:34])[CH2:19][CH2:20]3)=[CH:15][CH:16]=2)=[O:10])[CH2:3][CH2:2]1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: O=C(NCCCCC1CC1)c1ccc(Cl)nn1
Product: O=C(NCCCCC1CC1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (4-cyclopropylbutyl)amide in place of 6-chloropyridazine-3-carboxylic acid (3-cyclobutylpropyl)amide to react with piperazin-1-yl-(2-trifluoromethyl-phenyl)methanone, the title compound was obtained as a white powder (21% yield). 1H NMR (300 MHz, CDCl3) δ 8.03, 7.86, 7.72, 7.58, 7.34, 6.98, 4.05, 3.89-3.62, 3.48-3.31, 1.64-1.41, 1.20, 0.60, 0.39-0.30, −0.04. 13C NMR (75 MHz, CDCl3) δ 167.6, 162.9, 160.0, 145.4, 134.3, 132.4, 129.5, 127.2, 126.9, 126.7, 125.4, 121.8, 112.6, 46.4, 44.6, 44.4, 41.2, 39.5, 34.4, 29.4, 27.0, 10.7, 4.4. MS (ES+) m/z 476.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].[OH:11]S(O)(=O)=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]([NH2:6])=[O:11]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc(O)c(Br)c1
Product: NC(=O)c1ccc(O)c(Br)c1
Temperature: 80 °C
Yield: 83 %

Procedure:
3-Bromo-4-hydroxy-benzonitrile (495 mg, 2.5 mmol) is dissolved in H2SO4 98%, heat the solution at 80° C. for 1 hour. Cool the mixture at room temperature and pour it into ice-water. Extract the aqueous layer with EtOAc. Dry the organic layer over Na2SO4. Eliminate the solvent to obtain the title compound (450 mg, 83%). 1H-NMR (metanol-d4, 200 MHz): 8.04 (d, 1H, J=2.0 Hz), 7.70 (dd, 1H, J=2.0 and 8.4 Hz), 6.93 (d, 1H, J=8.6 Hz)
Reaction SMILES: [CH:1]([N-]C(C)C)([CH3:3])[CH3:2].[Li+].O1CCCC1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]#[N:28])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(Br)C=C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24]([CH2:3][CH:1]=[CH2:2])([C:27]#[N:28])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2M lithium diisopropylamide-tetrahydrofuran solution (9.96 ml) in tetrahydrofuran (20 ml) was dropwise added a solution of 4-cyanopiperidine-1-carboxylic acid tert-butyl ester (3.5 g) in tetrahydrofuran (15 ml) at −78° C. and under argon atmosphere, and the mixture was stirred at room temperature for 30 min. Then, allyl bromide (2.15 ml) was added at −78° C., and the mixture was stirred at the same temperature for 30 min and at room temperature for 1 hour. After completion of the reaction, 10% aqueous citric acid was added and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) and dried under reduced pressure to give the title compound (3.5 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Br[CH2:20][CH2:21][CH2:22][CH3:23]>C(#N)C>[C:1]([O:5][C:6]([NH:7][NH:8][CH2:20][CH2:21][CH2:22][CH3:23])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCCCBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCCNNC(=O)OC(C)(C)C
Yield: 39 %

Procedure:
To a magnetically stirred solution of tert-butylcarbazate (47.5 gram, 359 mmol) in anhydrous acetonitrile (300 ml) was successively added DIPEA (Hünig's base) (37.6 ml, 216 mmol) and 1-bromobutane (19.3 ml, 180 mmol). The resulting mixture was reacted at 60° C. for 16 hours. The resulting mixture was allowed to attain room temperature and subsequently concentrated in vacuo and further purified by Sepacore chromatography (eluant: petroleum ether 40-60/ethylacetate=4/1 (v/v)) to give N′-butylhydrazine-carboxylic acid tert-butyl ester (intermediate XIII-1) (13.2 gram, 39%) as a pale yellow oil: 1H-NMR (400 MHz, CDCl3) δ 0.91 (t, J=7, 3H), 1.30-1.49 (m, 13H), 2.81-2.87 (m, 2H), 4.00 (br s, 1H), 6.20 (br s, 1H).
Reaction SMILES: [C:1]([NH:22][C@H:23]([C:36]([OH:38])=[O:37])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][P:32]([OH:35])([OH:34])=[O:33])=[CH:27][CH:26]=1)(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:39](O)(=O)[CH2:40]C/C=C\CC=CCC=CCC=CCC=CCC=CCC>>[C:1]([NH:22][C@H:23]([C:36]([OH:38])=[O:37])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][P:32]([OH:35])([OH:34])=[O:33])=[CH:27][CH:26]=1)(=[O:21])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH:7]=[CH:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:39][CH3:40]
Reactant: CCCCCC=CCC=CCC=CC/C=C\CCCC(=O)N[C@@H](Cc1ccc(OP(=O)(O)O)cc1)C(=O)O
Reactant: CCC=CCC=CCC=CCC=CCC=CC/C=C\CCC(=O)O
Product: CCC=CCC=CCC=CCC=CCC=CC/C=C\CCC(=O)N[C@@H](Cc1ccc(OP(=O)(O)O)cc1)C(=O)O

Procedure:
This compound was prepared as described above for (8) using 0.5 mmol (164 mg) of cis-4,7,10,13,16,19-docosahexaenoic acid; yield 74 mg, (26%); Rf 0.05-0.10 (system B); 1H-NMR (CD3SOCD3, 200 MHz) δ0.9-1.0 (t, 3H, ω-CH3); 2.0-2.1 (t, 2H, CH2CO); 2.2-2.4 (m, 4H, 2CH2CH═CH); 2.7-2.9 (br s, 10H, 5HC═CHCH2CH═CH); 2.9-3.1 (m, 2H, CH2Ar); 4.3-4.4 (m, 1H, NHCHCO); 5.2-5.4 (br s, 12H, 6HC═CH); 7.0-7.2 (q, 4H, Ar); 8.2-8.4 (m, 3H, NH and 2POH)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CO>[Cl:8][C:6]1[CH:7]=[C:2]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:3]=[C:4]([NH2:9])[N:5]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: C1CCNCC1
Solvent: CO
Product: Nc1nc(Cl)cc(N2CCCCC2)n1
Temperature: 50 °C
Reaction time: 4 h
Yield: 87.1 %

Procedure:
In a 25 mL sealable tube under argon were combined 4,6-dichloro-2-pyrimidinamine (0.50 g, 3.05 mmol), piperidine (0.75 mL, 7.62 mmol) and CH3OH (10 mL). The vial was sealed and the reaction mixture was stirred for 4 hours at 50° C. The reaction was cooled to room temperature and concentrated. The resulting solid was partitioned between EtOAc and water. The organic layer was separated, dried (MgSO4), filtered and concentrated to afford the title compound (565 mg, 83%) as a yellow solid. LC-MS (ES) m/z=213 [M+H]+.
Reaction SMILES: [Cl-].[NH2:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:9][C:10]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:22]([O-:24])=[O:23])=[C:17]([CH:21]=1)[C:18](Cl)=[O:19]>C(#N)C>[Cl-:9].[Cl:9][C:10]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:22]([O-:24])=[O:23])=[C:17]([CH:21]=1)[C:18]([NH:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:19]
Reactant: N[n+]1ccccc1
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: [Cl-]
Solvent: CC#N
Product: O=C(N[n+]1ccccc1)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 0.67 h
Yield: 156.1 %

Procedure:
1-Aminopyridinium chloride (2.9 g) was added to 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoyl chloride (7.6 g) in acetonitrile (50 ml). The mixture was stirred and heated to reflux. After 20 minutes a solid precipitated. Reflux was continued for a further 40 minutes. Then the mixture was cooled in ice and the solid filtered off. The solid was washed with cold acetonitrile, then with ether, and was air dried to give 7.4 g of the desired product, mp 234°-237° C.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:20]=[CH:19][C:8]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1.O>C(O)C>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([CH:9]([C:8]2[CH:19]=[CH:20][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[OH:10])=[CH:16][CH:15]=1
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 99.2 %

Procedure:
1.03 g of sodium borohydride was added to 4.84 g of 4,4'-dimethoxybenzophenone in 80 ml of ethanol, followed by stirring for 7 hours at room temperature. Next, after adding water and stirring for 30 minutes, the solution was concentrated to roughly 20 ml. Moreover, ethyl acetate and water were added and after extracting with ethyl acetate (50 ml×3), the product was washed with saturated brine and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 4.84 g of the target compound. Yield: 99%
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH:12][NH2:13])=[O:11].CCN(C(C)C)C(C)C.[Cl:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=O.Cl>C(Cl)Cl>[Cl:23][CH2:24][CH2:25][CH2:26][C:27]1[O:11][C:10]([CH2:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[N:12][N:13]=1
Reactant: NNC(=O)Cc1ccc(F)cc1F
Reactant: O=C(Cl)CCCCl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Fc1ccc(Cc2nnc(CCCCl)o2)c(F)c1
Reaction time: 1 h

Procedure:
A mixture of 2-(2,4-difluorophenyl)acetohydrazide (570 mg, 3.06 mmol) and DIPEA (0.553 ml, 3.2 mmol) in dry DCM (30 ml) was added to 4-chlorobutyryl chloride (0.343 ml, 3.06 mmol) in dry DCM (5 ml) over 15 min. An immediate white precipitate formed. After stirring for 1 h, 2M HCl (20 ml) was added and the solid 2-(3-chloropropyl)-5-[(2,4-difluorophenyl)methyl]-1,3,4-oxadiazole was filtered off, washed with water and dried (726 mg).
Reaction SMILES: [C:1]([C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:31]=[C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]#[N:43])[CH:33]=1)[C:10]([NH:12][C:13]1[N:18]=[CH:17][C:16]([N:19]([CH2:27][CH2:28][O:29][CH3:30])C(=O)OC(C)(C)C)=[CH:15][CH:14]=1)=[O:11])#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:42]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[CH2:35][O:34][C:32]1[CH:31]=[C:9]([CH:8]=[C:7]([O:6][CH2:5][C:4]2[CH:44]=[CH:45][CH:46]=[CH:47][C:3]=2[C:1]#[N:2])[CH:33]=1)[C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][CH2:27][CH2:28][O:29][CH3:30])=[CH:17][N:18]=1)=[O:11])#[N:43]
Reactant: COCCN(C(=O)OC(C)(C)C)c1ccc(NC(=O)c2cc(OCc3ccccc3C#N)cc(OCc3ccccc3C#N)c2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCNc1ccc(NC(=O)c2cc(OCc3ccccc3C#N)cc(OCc3ccccc3C#N)c2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
To a stirred solution of tert-butyl 6-({3,5-di(2-cyanobenzyloxy)benzoyl}amino)pyridin-3-yl(2-methoxyethyl)carbamate (237 mg) in dichloromethane (10 ml) was added trifluoroacetic acid (3 ml). The solution was stirred at ambient temperature for three hours. Volatile material was removed by evaporation. The residue was diluted in DCM (100 ml), washed with 2M sodium Hydroxide (50 ml), brine (50 ml), dried over MgSO4. Volatile material was removed by evaporation to give the title compound (190 mg) as a foam, 1H NMR δ (d6-DMSO): 3.22 (t, 2H), 3.28 (2, 3H), 3.50 (t, 2H), 5.31 (s, 4H), 6.92 (s, 1H), 7.12 (dd, 1H), 7.34 (s, 2H), 7.57 (m, 2H), 7.75 (m, 5H), 7.82 (d, 1H), 7.91 (d, 2H), 10.49 (br s, 1H). MS ES+ 534.41 (M+H)+.