Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH:7](=O)[CH3:8].S(=O)(=O)(O)O.[BrH:15]>>[Br:15][CH2:3][C:2](=[CH:7][CH3:8])[C:1]([O:5][CH3:6])=[O:4]
Reactant: CC=O
Reactant: C=CC(=O)OC
Reactant: Br
Agent: O=S(=O)(O)O
Product: CC=C(CBr)C(=O)OC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
In a manner to that of S. E. Drews, D. Emsley, et al., in J. Chem. Soc., Perkin Transaction I, pp. 2079 and 2079 (1982), an ice cooled solution of methyl acrylate (IV) (8.6 g) in conc. HBr (16.5 ml) is mixed dropwise with acetaldehyde (V) (4.4 g) and then conc. sulfuric acid (15 ml). After stirring overnight, the reaction mixture is extracted thrice with ether. The extract is washed with saturated saline, dried over MgSO4, and concentrated. The resulting residue is distilled under reduced pressure to give methyl 2-bromomethyl-2-butenoate (III) (8.59 g). 83°~85° C./10 mmHg.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([N:7]1[CH:11]=[C:10]([C:12](O)=[O:13])[C:9]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[N:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:30][C:31]=3[CH3:32])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[N:8]1)[CH3:6]>CN(C=O)C.C(Cl)Cl>[CH2:5]([N:7]1[CH:11]=[C:10]([C:12]([Cl:3])=[O:13])[C:9]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[N:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:30][C:31]=3[CH3:32])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[N:8]1)[CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CCn1cc(C(=O)O)c(NS(=O)(=O)c2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCn1cc(C(=O)Cl)c(NS(=O)(=O)c2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)n1
Reaction time: 16 h

Procedure:
To a solution of thionyl chloride (2.0 mL) and 2 drops of DMF in DCM stirring under nitrogen at RT is added the title compound of Example 3, 1-ethyl-3-{4-[5-methyl-2-phenyl-oxazol-4-ylmethoxy]-benzenesulfonylamino}-1H-pyrazole-4-carboxylic acid (0.8 g, 1.65 mmol) in one portion. The resulting suspension is stirred for 16 h. The solution is concentrated and the resulting residue is azeotrophed twice with toluene. It is used as such without any additional purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[C:9]1([C:15]#[CH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O1CCCC1.Cl>[Cu]I.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.C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]#[C:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Brc1ccc(C#Cc2ccccc2)cc1

Procedure:
In a 500 mL three-necked flask were placed 14 g (51 mmol) of p-bromoiodobenzene, 5.2 g (52 mmol) of phenylacetylene, and 98 mg (0.50 mmol) of copper(I) iodide. After the atmosphere in the flask was replaced with nitrogen, 200 mL of tetrahydrofuran and 9.0 mL of triethylamine were added to the flask, and the mixture was degassed by being stirred under reduced pressure. To this mixture was added 0.34 mg (0.50 mmol) of bis(triphenylphosphine)palladium(II) dichloride, and the mixture was stirred under a stream of nitrogen at room temperature for 20 hours. After a predetermined time, a 3% aqueous hydrochloric acid solution was added to the mixture, and an organic substance was extracted with ethyl acetate from the aqueous layer. The obtained extract was washed with a saturated aqueous sodium chloride solution together with the organic layer and then dried over magnesium sulfate. The mixture was subjected to suction filtration through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135), and alumina, and the filtrate was condensed to obtain a solid. The obtained solid was recrystallized with hexane; thus, 7.41 g of target light-brown powder was obtained with a yield of 55%.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].C(OCC)(=O)C>C(O)CCC.CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:14]([C:13]([F:12])([F:21])[F:22])[CH:15]=2)[N:3]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCOC(C)=O
Solvent: CCCCO
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(Nc2nc(Cl)nc3nc[nH]c23)c1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
1.9 g (10 mmol) of 2,6-dichloro-purine and 8.05 g (50 mmol) of 3-trifluoromethyl-aniline (Fluka, Buchs, Switzerland) in 60 ml of n-butanol and 3 ml of DMF are stirred at 60° C. for 6 h. 50 ml of ethyl acetate are added to the cooled reaction solution and the precipitate is filtered off and further stirred in 40 ml of isopropanol at 40° C. for 60 min. After filtration with suction and drying, 2-chloro-6-(3-trifluoromethyl-phenyl-amino)-purine is obtained; m.p. 248–250° C.; FAB-MS: (M+H)+=314; Rf=0.45 (methylene chloride:methanol=95:5).
Reaction SMILES: C(OC(=O)[CH:7]([C:11](=[O:24])[C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[C:13]=1[Cl:23])[C:8]([CH3:10])=[O:9])(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:23][C:13]1[C:14]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C:11]([CH2:7][C:8](=[O:9])[CH3:10])=[O:24]
Reactant: COC(=O)c1ccc(Cl)c(C(=O)C(C(C)=O)C(=O)OC(C)(C)C)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(Cl)c(C(=O)CC(C)=O)c1Cl

Procedure:
A suspension of 1.65 g of magnesium ethylate in 30 ml of toluene was kept at 60-70° C. and 2.28 g of acetoacetic tert-butyl ester was added dropwise thereto. After the dropwise addition was completed, the resultant mixture was refluxed for two hours. Then, the reaction solution was cooled to room temperature and 3.85 g of 2,6-dichloro-3-methoxycarbonyl benzoic acid chloride was added dropwise thereto. The reaction mixture was stirred at room temperature for two hours and at 50-100° C. for three hours, then cooled to room temperature, treated with dilute hydrochloric acid, and extracted from ethyl acetate. Then, the organic layer was alkali extracted from an aqueous 5% sodium carbonate solution. The water layer was mixed with chloroform, educed with dilute hydrochloric acid, and extracted again. The organic layer was washed with saturated saline solution and dried over magnesium sulfate. The solution was distilled under a reduced pressure to expel the solvent and obtain 2.80 g of 2-(2,6-dichloro-3-methoxycarbonyl benzoyl) acetoacetic tert-butyl ester. A solution of this ester in 45 ml of toluene and 0.2 g of p-toluene sulfonic acid hydrate added thereto were refluxed together for six hours. The reaction solution was cooled, mixed with 200 ml of ethyl acetate, washed twice with 200 ml of water, further washed with saturated saline solution, and dried over magnesium sulfate. The solution was distilled under a reduced pressure to expel the solvent and obtain 2.10 g of 2,6-dichloro-3-methoxycarbonyl benzoyl acetone. nD22 1.5759.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:22])[CH:19]([OH:21])[CH3:20])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][C:40]3[C:45]([CH:46]=2)=[CH:44][CH:43]=[CH:42][CH:41]=3)O1>>[OH:21][C@@H:19]([CH3:20])[C:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([C:37]4[CH:38]=[N:39][C:40]5[C:45]([CH:46]=4)=[CH:44][CH:43]=[CH:42][CH:41]=5)[N:3]=[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:5]=3[N:10]=2)[CH2:13][CH2:14]1)=[O:22]
Reactant: CC(O)C(=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: CC1(C)OB(c2cnc3ccccc3c2)OC1(C)C
Product: C[C@H](O)C(=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(-c4cnc5ccccc5c4)nc3s2)CC1
Yield: 35.7 %

Procedure:
1-[4-(5-Chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-ylmethyl)-piperazin-1-yl]-2-hydroxy-propan-1-one (100 mg) was reacted with 72 mg of 3-(4,4,5,5-tetramethyl-1,3,2,-dioxaborolan-2-yl)quinoline via General Procedure A. The product was purified by reverse phase HPLC to yield 43.5 mg of 106. MS (Q1) 520.3 (M)+.
Reaction SMILES: Cl[C:2]1[C:11](C=O)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([CH3:15])=[C:7]([CH3:14])[CH:8]=2)[N:3]=1.Cl.[NH2:17]O.[CH:19]([O-:21])=O.[Na+].C(O)=O>O>[C:2]([C:11]1[C:19](=[O:21])[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:14])=[C:6]([CH3:15])[CH:5]=2)#[N:17]
Reactant: O=C[O-]
Reactant: Cc1cc2cc(C=O)c(Cl)nc2cc1C
Reactant: NO
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: Cc1cc2cc(C#N)c(=O)[nH]c2cc1C

Procedure:
A mixture was prepared from 15 g of 2-chloro-6,7-dimethyl-3-quinolinecarboxaldehyde, 5.4 g of hydroxylamine hydrochloride, 8.5 g of sodium formate and 155 ml of 97% formic acid and this was heated at reflux for 3 hours. Initially, the mixture became a heavy yellow paste but a homogeneous brown solution formed later. However, by the end of the 3-hour reflux period, the mixture was again heterogeneous and it was cooled and poured into 300 ml of water. The solid which formed was separated by filtration and dried to give 3-cyano-6,7-dimethyl-2(1H)-quinolinone melting at about 300° C. The indicated product contained 1/4 molecule of water of hydration.
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]=[C:10]=[O:11])=[N:6][N:5]=2)[CH2:3][CH2:2]1.[CH2:12]([NH:15][CH2:16][CH2:17][CH:18]=[O:19])[C:13]#[CH:14]>C1C=CC=CC=1>[CH2:12]([N:15]([CH2:16][CH2:17][CH:18]=[O:19])[C:10]([NH:9][C:7]1[S:8][C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][N:6]=1)=[O:11])[C:13]#[CH:14]
Reactant: O=C=Nc1nnc(C2CC2)s1
Reactant: C#CCNCCC=O
Solvent: c1ccccc1
Product: C#CCN(CCC=O)C(=O)Nc1nnc(C2CC2)s1

Procedure:
A mixture of 5-cyclopropyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 3-propargylaminopropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 3-[1-propargyl-3-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)C=CC1.[C:11](CC(OCC)=O)(=[O:15])[CH2:12][CH2:13]C.[C:22]1([CH:30]=[C:28]([OH:29])[CH:27]=[C:25]([OH:26])[CH:24]=1)[OH:23].S(=O)(=O)(O)O.C(Cl)(=O)CC>C(=S)=S.[N+](C1C=CC=CC=1)([O-])=O>[OH:23][C:22]1[CH:30]=[C:28]([OH:29])[C:27]([C:11](=[O:15])[CH2:12][CH3:13])=[C:25]2[C:24]=1[C:8]([CH2:7][CH2:6][CH3:5])=[CH:9][C:10](=[O:1])[O:26]2
Reactant: CCCC(=O)CC(=O)OCC
Reactant: C1=Cc2ccccc2OC1
Reactant: Oc1cc(O)cc(O)c1
Agent: CCC(=O)Cl
Agent: O=S(=O)(O)O
Solvent: S=C=S
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCc1cc(=O)oc2c(C(=O)CC)c(O)cc(O)c12
Yield: 78 %

Procedure:
The key intermediate in the inventive method of preparation is chromene 4, which is synthesized by the sequence depicted in Scheme I. Thus, 5,7-dihydroxy-4-propylcoumafin, 2,5 was prepared quantitatively from ethyl butyrylacetate and phloroglucinol under Pechman conditions.6Product yield and purity was dependent on the amount of sulfuric acid used. The 8-position of 5,7-dihydroxy-4-propylcoumafin, 2, was then selectively acylated at 8°-10° C. by propionyl chloride and A1Cl3 in a mixture of carbon disulfide and nitrobenzene to afford 5,7-dihydroxy-8-propionyl-4-propylcoumarin, 3. A route developed for synthesis of Mammea coumarins7 was initially attempted for preparation of compound 3, but it proved too awkward and low-yielding. The chromene ring was introduced upon treatment of compound 3 with 4,4-dimethoxy-2-methylbutan-2-ol,8 providing 4 in 78% yield. ##STR2##
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][C:6]=1[C:12]([F:15])([F:14])[F:13])(=[O:4])=[O:3].[N+:16]([O-])([O-])=O.[Na+].O.O.[Sn](Cl)[Cl:24].[OH-].[Na+]>Cl.O>[ClH:24].[CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH:9][NH2:16])=[CH:7][C:6]=1[C:12]([F:13])([F:14])[F:15])(=[O:4])=[O:3]
Reactant: Cl[Sn]Cl
Reactant: CS(=O)(=O)c1ccc(N)cc1C(F)(F)F
Reactant: O=[N+]([O-])[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)c1ccc(NN)cc1C(F)(F)F
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
To a stirred suspension of 4-(methylsulfonyl)-3-(trifluoromethyl)aniline (1.04 g, 4.35 mmol) in conc. HCl (10 mL) was added dropwise a solution of sodium nitrate (0.315 g, 4.57 mmol) in water (10 mL) at −20° C. After stirring for 30 minutes, the resulting suspension was added Tin(II) chloride dihydrate (4.92 g, 21.8 mmol) in conc.HCl (10 mL) at −10° C. After stirring for 1 hour at −5° C., the mixture was stirred further 1 hour at room temperature. The reaction mixture was made alkaline with aqueous NaOH at 0-5° C. The mixture was filtered through Celite, the filterate was extracted with THF (30 mL×3), the combined organic layer washed with brine, dried over MgSO4 and concentration in vacuo to give the subtitle compound (1 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][C:28]=1[Cl:36].C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=C(F)C=2)=O)C=CC=1)(C)(C)C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:13]2[CH:14]=[CH:15][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:27]4[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][C:28]=4[Cl:36])[CH2:21][CH2:20]3)=[CH:17][CH:18]=2)=[O:25])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc(Br)c(Cl)c1
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(C3CCNCC3)cc2)c1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(C3CCN(c4ccc(C(=O)O)cc4Cl)CC3)cc2)c1

Procedure:
4-{4-[4-(3-tert-Butyl-phenylcarbamoyl)-phenyl]-piperidin-1-yl}-3-chloro-benzoic acid was synthesized from N-(3-tert-butyl-phenyl)-4-piperidin-4-yl-benzamide and 4-bromo-3-chloro-benzoic acid in a manner similar to the one described in the synthesis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid above. LCMS calcd for C29H31ClN2O3 (m/e) 490, obsd 491 (M+H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][N:30]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[O:22])=[CH:17][CH:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:6].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH:25]1([CH2:24][NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:11]([CH3:14])=[CH:12][CH:13]=[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:28]=[CH:29][N:30]=[C:2]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[CH:3]=4)[CH:9]=3)=[CH:16][CH:17]=2)=[O:22])[CH2:27][CH2:26]1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: C1COCCN1
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-morpholin-4- ylisonicotinamide was prepared from 2-chloro-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isonicotinamide and morpholine using method A. NMR; δH [2H6]—DMSO 10.32,(1H, s), 8.62,(1H, t), 8.27,(1H, d), 7.93,(2H, d), 7.70,(1H, dd), 7.64,(1H, d), 7.44,(2H, d), 7.30,(1H, d), 7.24,(1H, s), 7.11,(1H, d), 3.71,(4H, m), 3.51,(4H, m), 3.16,(2H, t), 2.20,(3H, s), 1.05,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.31 min, MH+471.
Reaction SMILES: CN.C1COCC1.[Cl:8][C:9]1[C:10]([CH3:38])=[C:11]([C:29]2[CH:30]=[C:31]([C:35]([OH:37])=O)[N:32]([CH3:34])[CH:33]=2)[C:12]([O:27][CH3:28])=[C:13]([CH:15]([NH:17][C:18]2[N:26]=[CH:25][N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][NH:22]3)[CH3:16])[CH:14]=1.F[P-](F)(F)(F)(F)F.[N:46]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:50]2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[Cl:8][C:9]1[C:10]([CH3:38])=[C:11]([C:29]2[CH:30]=[C:31]([C:35]([NH:46][CH3:50])=[O:37])[N:32]([CH3:34])[CH:33]=2)[C:12]([O:27][CH3:28])=[C:13]([CH:15]([NH:17][C:18]2[N:26]=[CH:25][N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][NH:22]3)[CH3:16])[CH:14]=1
Reactant: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1-c1cc(C(=O)O)n(C)c1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)c1cc(-c2c(C)c(Cl)cc(C(C)Nc3ncnc4[nH]cnc34)c2OC)cn1C
Reaction time: 2 h

Procedure:
2.0 M Methylamine in THF (0.2 mL, 0.4 mmol) was added to a solution of 4-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-1-methyl-1H-pyrrole-2-carboxylic acid (10.0 mg, 0.02 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (24 mg, 0.054 mmol) in DMF (0.8 mL) at room temperature followed by addition of triethylamine (33 μL, 0.24 mmol). The reaction was stirred for 2 hours. The mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C22H25ClN7O2 (M+H)+: m/z=454.2. found: 454.2.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:5][C:4]=1[C:19]([OH:21])=[O:20].O[N:23]1[C:27](=[O:28])[CH2:26][CH2:25][C:24]1=[O:29].CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C1COCC1.C(OCC)(=O)C>[O:29]=[C:24]1[CH2:25][CH2:26][C:27](=[O:28])[N:23]1[O:20][C:19]([C:4]1[CH:5]=[CH:6][C:7]([C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:8][C:3]=1[NH2:2])=[O:21]
Reactant: Nc1nc(-c2ncccc2C(F)(F)F)ccc1C(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1nc(-c2ncccc2C(F)(F)F)ccc1C(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve 6-Amino-3′-trifluoromethyl-[2,2′]bipyridinyl-5-carboxylic acid hydrochloride (11.33 g, 35.44 mmol), N-hydroxy-succinimide (8.15 g, 70.9 mmol), and EDCI (10.19 g, 53.16 mmol) in a solution of dry THF (100 mL) and Hunig's base (16.12 g, 125 mmol). Stir the reaction mixture overnight at room temperature. Add ethyl acetate (200 mL) was and extract the organic phase with water (3×100 mL) and brine (100 mL). Dry the organic extract over Na2SO4 and remove the solvent under reduced pressure to yield the title compound as a brown foam.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:12][C:13]([C@H:15]([CH2:22][CH:23]([CH3:25])[CH3:24])[C@H:16]([OH:21])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[CH:10]=[CH2:11].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)C.[Ag-]=O>[CH2:9]([O:12][C:13]([C@H:15]([CH2:22][CH:23]([CH3:25])[CH3:24])[C@H:16]([O:21][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:17]([O:19][CH3:20])=[O:18])=[O:14])[CH:10]=[CH2:11]
Reactant: BrCc1ccccc1
Reactant: C=CCOC(=O)[C@H](CC(C)C)[C@H](O)C(=O)OC
Agent: O=[Ag-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CCOC(=O)[C@H](CC(C)C)[C@H](OCc1ccccc1)C(=O)OC
Reaction time: 24 h

Procedure:
0.51 g of silver(I) oxide and 0.33 ml of benzyl bromide were added to a solution of 0.27 g of methyl 3(R)-(allyloxycarbonyl)-2(S)-hydroxy-5-methylhexanoate in 5 ml of dimethylformamide. After stirring the mixture for 24 hours, 0.36 g of cesium carbonate were added and stirring was continued for 3 hours. The mixture was diluted with diethyl ether and filtered. The filtrate was then washed in succession with 5% aqueous citric acid, water, 5% aqueous sodium hydrogen carbonate, water and brine. The diethyl ether phase was dried over anhydrous magnesium sulphate and the solvent was evaporated. The residue was purified by flash column chromatography on silica gel using ethyl acetate/hexane (1:19) for the elution. There was obtained 0.16 g of methyl 3(R)-(allyloxycarbonyl)-2(S)-benzyloxy-5-methylhexanoate in the form of a clear oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([CH2:11][N:12](CC2C=CC=CC=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[OH:10])=[CH:4][C:3]=1[Cl:38].Cl.C(O)C.[H][H].C(O)(=O)/C=C/C(O)=O>C(O)C.ClCCl.CO.[Pd]=O>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[OH:10])=[CH:4][C:3]=1[Cl:38]
Reactant: [H][H]
Reactant: Nc1c(Cl)cc(C(O)CN(CCCCCCOCCOCCc2ccccn2)Cc2ccccc2)cc1Cl
Agent: O=[Pd]
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: Nc1c(Cl)cc(C(O)CNCCCCCCOCCOCCc2ccccn2)cc1Cl
Yield: 65 %

Procedure:
A solution of 4-amino-3,5-dichloro-α-[[(phenylmethyl)[6-[2-[2(2-pyridinyl)ethoxy]ethoxy]hexyl]amino]methyl]benzenemethanol (1.1 g,) in ethanol (25 ml) was hydrogenated over pre-reduced 10% palladium oxide on charcoal catalyst (50% aqueous paste, 600 mg) in ethanol (10 ml) containing 1:9 conc. hydrochloric acid/ethanol, (1.78 ml,) until the uptake of hydrogen ceased (1 h). The mixture was filtered and evaporated in vacuo to give an oil which was dissolved in dichloromethane (100 ml) and washed with 8% sodium bicarbonate (50 ml). The aqueous phase was re-extracted with dichloromethane (50 ml) and the combined organic phases dried and evaporated in vacuo to give an oil. Purification by FCC eluting with System G (95:5:1) gave a colourless oil, which was dissolved in methanol (10 ml) and treated with fumaric acid (0.09 g), evaporated in vacuo and triturated with diethyl ether to give a white solid (0.75 g,). The solid was dissolved in dichloromethane (150 ml) and washed with 8% sodium bicarbonate (100 ml). The aqueous layer was re-extracted with dichloromethane (100 ml) and the combined organic fractions dried and evaporated in vacuo to give an oil. Trituration with System F (ca. 10:1) gave the title compound (0.60 g,) as a white solid m.p. 45.5°-46.5°. T.l.c. (System E 40:10:1) Rf 0.49.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:13])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10].OS(O)(=O)=O.[CH3:19]O>>[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:13])=[C:8]([CH:12]=1)[C:9]([O:11][CH3:19])=[O:10]
Reactant: CO
Reactant: NCc1ccc(Cl)c(C(=O)O)c1
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(CN)ccc1Cl

Procedure:
To a solution of 5-(aminomethyl)-2-chlorobenzoic acid hydrochloride (17.0 g, 76.5 mmol) in methanol (200 mL) was added conc.H2SO4 (15 mL). The reaction mixture was refluxed for 15 h. The reaction mixture was concentrated and water was added. The aq. solution was basified with sodium bicarbonate. The reaction mixture was extracted with 10% MeOH:DCM and concentrated to afford 15.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 2.1 (br s, 2H), 3.73 (s, 2H), 3.85 (s, 3H), 7.50 (s, 2H), 7.77 (s, 1H); MS (m/z): 200.05 (M+H)+.
Reaction SMILES: Br[CH:2]([C:6]([CH3:26])([CH3:25])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:24])([CH3:23])[CH:18](Br)[C:19]([OH:21])=[O:20])[C:3]([OH:5])=[O:4].[CH3:27][OH:28].[CH3:29][O-:30].[Na+]>O>[CH3:27][O:28][CH:2]([C:6]([CH3:26])([CH3:25])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:24])([CH3:23])[CH:18]([O:30][CH3:29])[C:19]([OH:21])=[O:20])[C:3]([OH:5])=[O:4]
Reactant: CC(C)(CCCCCCCCCCC(C)(C)C(Br)C(=O)O)C(Br)C(=O)O
Reactant: C[O-]
Reactant: CO
Agent: [Na+]
Solvent: O
Product: COC(C(=O)O)C(C)(C)CCCCCCCCCCC(C)(C)C(OC)C(=O)O
Temperature: 60 °C

Procedure:
1.21 g. 2,15-Dibromo-3,3,14-,14-tetramethylhexadecane-1,16-dioic acid, prepared according to Example 9 of EP-OS No. 0 081 930, was dissolved in 50 ml. methanol, in which are contained 0.58 g. sodium methylate. Thereafter, 64 ml. water were added thereto and the mixture heated to 60° C. for 4 days. The solvent was evaporated to dryness and the crude product dissolved in water, washed with ether, acidified with HCl and extracted with ether. The ether extract was dried over anhydrous magnesium sulphate and evaporated to dryness.