Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]([O:17]CC)=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11](=[CH:14][C:15]([OH:17])=[O:16])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=C1CCN(Cc2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C=C1CCN(Cc2ccccc2)CC1
Temperature: 45 °C
Reaction time: 1 h
Yield: 114.4 %

Procedure:
To a solution of ester 203 (8.06 g, 31.1 mmol) in THF (100 mL) was added an aqueous solution of LiOH (1.96 g, 46.6 mmol) in water (30 mL) and the reaction mixture was allowed to stir at 45° C. for 60 min. Then more LiOH (0.5 g, 11.9 mmol) was added to the heating solution. After further heating for 8 h, the reaction mixture was concentrated, extracted with AcOEt. The extract was concentrated and the residue was combined with the white solid which was collected by filtration from the aqueous phase. The combined solid materials were dissolved in DCM, treated with 2N HCl in diethyl ether (10 mL) and the mixture was diluted with benzene, evaporated and dried under vacuum to give (presumably) mono-hydrochloride salt of the acid 204 (8.23 g, 99% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([OH:15])[CH:11]=[CH:12][C:13]=2[CH3:14])[CH:5]=[C:4]([Cl:16])[N:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])(=O)=O>ClCCl>[Si:31]([O:15][C:10]1[CH:11]=[CH:12][C:13]([CH3:14])=[C:8]([C:6]2[CH:5]=[C:4]([Cl:16])[N:3]=[C:2]([NH2:1])[N:7]=2)[CH:9]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: Cc1ccc(O)cc1-c1cc(Cl)nc(N)n1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1-c1cc(Cl)nc(N)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
3-(2-amino-6-chloropyrimidin-4-yl)-4-methylphenol (2.12 g, 9.00 mmol) obtained in Step 4 above was placed in a reaction vessel, and then dichloromethane (60 ml) was added thereto. The mixture was cooled to 0° C. 2,6-Lutidine (1.25 ml, 10.7 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (2.27 ml, 9.88 mmol) were sequentially added to the solution. The mixture was stirred at 0° C. for 1 hour and then at room temperature for 30 minutes. The resulting reaction solution was diluted with dichloromethane (150 ml), and sequentially washed with a saturated aqueous sodium bicarbonate solution (150 ml), water (150 ml), and a saturated aqueous sodium chloride solution (150 ml). The dichloromethane solution was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=9:1 to 6:1) to yield 4-[5-(tert-butyldimethylsilanyloxy)-2-methylphenyl]-6-chloropyrimidin-2-ylamine (Compound 1-5) (2.41 g, 77%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:21][C:22]1[C:27]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)=[O:29])=[C:26](Cl)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>C(O)(C)(C)C>[NH2:21][C:22]1[C:27]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)=[O:29])=[C:26]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:25]=[CH:24][N:23]=1
Reactant: COc1ccc(COC(=O)c2c(N)ncnc2Cl)cc1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Agent: [Cs+]
Agent: [F-]
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(COC(=O)c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc1
Temperature: 80 °C
Yield: 323.5 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (515 mg, 0.27 mmol), 4-methoxybenzyl 4-amino-6-chloropyrimidine-5-carboxylate (691 mg, 1.86 mmol), DIEA (1.77 ml, 10.16 mmol) and cesium fluoride (770 mg, 5.07 mmol) were suspended in tert-butanol (50 ml) and the mixture was heated at 80° C. in a sealed tube for 24 h. The solvent was evaporated under reduced pressure and the reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution and brine. After evaporation of the solvent, the residue was purified by flash chromatography (0 to 50%, hexane-ethyl acetate) using SP1® Purification System to give 459 mg (51% yield) of the title compound as a solid. Purity 99%.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5].[CH3:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH:21]2[OH:26])=[CH:17][CH:16]=1>>[OH:13][C:10]1[CH:11]=[CH:12][C:7]([S:4]([CH2:3][CH2:2][N:23]2[CH2:24][CH2:25][CH:20]([CH2:19][C:18]3[CH:27]=[CH:28][C:15]([CH3:14])=[CH:16][CH:17]=3)[CH:21]([OH:26])[CH2:22]2)(=[O:6])=[O:5])=[CH:8][CH:9]=1
Reactant: Cc1ccc(CC2CCNCC2O)cc1
Reactant: O=S(=O)(CCCl)c1ccc(O)cc1
Product: Cc1ccc(CC2CCN(CCS(=O)(=O)c3ccc(O)cc3)CC2O)cc1
Yield: 30 %

Procedure:
The title compound was prepared from 4-(2-chloro-ethanesulfonyl)-phenol and (3SR,4SR)-4-(4-methyl-benzyl)-piperidin-3-ol in 30% yield as a white solid.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[C:12]([O:16][C:17](=[O:22])[NH:18][CH2:19][CH2:20][OH:21])([CH3:15])([CH3:14])[CH3:13].CCN(CC)CC>C(Cl)Cl>[C:12]([O:16][C:17]([NH:18][CH2:19][CH2:20][O:21][S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2])=[O:22])([CH3:15])([CH3:13])[CH3:14]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 78.7 %

Procedure:
Tosyl chloride (1.50 g, 7.87 mmol) was added to a solution of (2-hydroxy-ethyl)-carbamic acid tert-butyl ester (0.84 g, 5.2 mmol) and Et3N (1.23 mL, 8.82 mmol) in CH2Cl2 (26 mL), and the solution was stirred at room temperature for 17 h. The solution was washed with H2O (15 mL), and the aqueous phase was extracted with CH2Cl2 (10 mL). The combined organic phases were dried (MgSO4) and concentrated in vacuo. Purification of the crude material by column chromatography on silica gel (20% EtOAc/hexanes) gave yellow crystals (1.29 g, 79%). 1H NMR (CDCl3) δ 1.41 (s, 9H), 2.45 (s, 3H), 3.38 (m, 2H), 4.07 (m, 2H), 4.82 (br s, 1H), 7.35 (d, 2H, J=8.1 Hz), 7.79 (d, 2H, J=8.1 Hz).
Reaction SMILES: [CH:1]([CH:4]1[C:9](CO)([C:10](OCC)=[O:11])[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]#[CH:24])=[C:7]([CH:25]=[CH:26][CH2:27][CH2:28][CH3:29])[C:6]([CH:30]([CH3:32])[CH3:31])=[N:5]1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH:23]=[CH2:24])[C:7]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[C:6]([CH:30]([CH3:31])[CH3:32])[N:5]=1)([CH3:3])[CH3:2]
Reactant: C#Cc1ccccc1C1=C(C=CCCC)C(C(C)C)=NC(C(C)C)C1(CO)C(=O)OCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=Cc1ccccc1-c1c(CO)c(C(C)C)nc(C(C)C)c1CCCCC

Procedure:
The title compound was prepared from ethyl 2,6-diisopropyl-3-hydroxymethyl-4-(2-ethynylphenyl)-5-(pent-1-enyl)pyridine-3-carboxylate by the procedure described in Example 125, Step F. 1H NMR (300 MHz, CDCl3) (reported as a mixture of olefin isomers): δ 0.60-0.90 (m, 3 H), 1.0-1.40 (m, 15 H), 1.60-1.90 (m, 2 H), 3.20-3.50 (m, 2 H), 4.20-4.40 (m, 2 H), 5.14 (dt, J=11.0, 1.0 Hz, 1 H), 5.40 (m, 1 H), 5.90 (m, 1 H), 6.30 (m, 1 H), 7.0-7.70 (m, 4 H). FAB-MS: calculated for C25H33NO 363.5; found 364 (M+H, 100%). Rf 0.28 (10% ethyl acetate/n-hexane).
Reaction SMILES: [H-].[Na+].C1(C)C=CC=CC=1.C(OP([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])(OCC)=O)C.[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[C:31](=O)[CH2:30][CH2:29]2>O>[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)/[C:31](=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])/[CH2:30][CH2:29]2
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C1\CCc2cc(OC)ccc21
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed sodium hydride (1 g, 46.00 mmol, 2.50 equiv), toluene (150 mL), ethyl 2-(diethoxyphosphoryl)acetate (7 g, 31.22 mmol, 1.69 equiv). This was followed by the addition of 5-methoxy-2,3-dihydro-1H-inden-1-one (3 g, 18.50 mmol, 1.00 equiv) at 30° C. The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting solution was diluted with 10 mL of water. The resulting solution was extracted with 3×100 mL of toluene and the organic layers combined. The resulting mixture was washed with 2×20 mL of sodium chloride. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (30:70). This resulted in 2 g (47%) of ethyl 2-[(1E)-5-methoxy-2,3-dihydro-1H-inden-1-ylidene]acetate as yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH3:18][C:19]([CH3:39])([CH3:38])[CH2:20][C:21]([NH:23][C:24]1[C:25]([CH3:37])=[C:26]([CH3:36])[C:27]2[O:31][C:30]([CH3:33])([CH3:32])[C:29](=[O:34])[C:28]=2[CH:35]=1)=[O:22].O>C1COCC1>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:4]1[CH:3]=[C:2]([C:29]2([OH:34])[C:28]3[CH:35]=[C:24]([NH:23][C:21](=[O:22])[CH2:20][C:19]([CH3:18])([CH3:38])[CH3:39])[C:25]([CH3:37])=[C:26]([CH3:36])[C:27]=3[O:31][C:30]2([CH3:33])[CH3:32])[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2=O
Reactant: Brc1cccc(C2OCCO2)c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2(O)c1cccc(C2OCCO2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
To a solution of 2-(3-bromophenyl)-1,3-dioxolane (1.65 mL, 10.9 mmol) in THF (20 mL) was added dropwise at −78° C. under an argon atmosphere n-butyllithium (1.59 M hexane solution, 6.4 mL, 10.2 mmol), and the resulting mixture was stirred for 30 minutes. To the reaction solution was added dropwise at −78° C. a solution of 3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamide (1.0 g, 3.30 mmol) obtained in Reference Example 65 in THF (10 mL), and the resulting mixture was stirred for 30 minutes. The reaction solution was warmed to room temperature and stirred for 1 hour, and water was added to the reaction solution and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:3) to obtain 1.38 g (yield: 92%) of N-(3-(3-(1,3-dioxolan-2-yl)phenyl)-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide as an amorphous powder. To a mixed solution of the obtained N-(3-(3-(1,3-dioxolan-2-yl)phenyl)-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (300 mg, 0.66 mmol) in acetone (4 mL)-water (0.3 mL) was added pyridinium p-toluenesulfonate (5 mg, 0.03 mmol), and the mixture was stirred for 30 minutes. The reaction solution was cooled to room temperature, and water was added to the reaction solution and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from THF-diisopropyl ether to obtain 194 mg (yield: 72%) of the title compound. Melting point: 189-190° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:30])[CH:20]=[C:21]([C:22]4[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[Cl:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([Cl:28])[C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=[C:19]([F:30])[CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4c(Cl)cccc4Cl)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(F)cc(-c3c(Cl)cccc3Cl)c2O1

Procedure:
The title compound was prepared (0.081 g, 52%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.2 g, 0.43 mmol) and methylamine (0.133 g, 4.3 mmol). mp 196-198° C.
Reaction SMILES: [C:1]1([CH:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([NH2:23])[C:18]([NH:21][CH3:22])=[CH:19][CH:20]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1.[N+](C1C=CC=CC=1)([O-])=O.Cl>O>[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]2[N:21]([CH3:22])[C:18]3[CH:19]=[CH:20][C:15]([CH2:14][N:11]4[CH2:12][CH2:13][N:8]([CH:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:9][CH2:10]4)=[CH:16][C:17]=3[N:23]=2)=[CH:33][CH:32]=1
Reactant: CNc1ccc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1N
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: Cn1c(-c2ccc(Cl)cc2)nc2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc21
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3.9 parts of 4-[4-(diphenylmethyl)-1-piperazinylmethyl]-N1 -methyl-1,2-benzenediamine, 2.5 parts of 4-chlorobenzaldehyde and 18 parts of nitrobenzene is stirred in an oil-bath first for 1 hour at 50° C. and further for 1.50 hours at 120° C. The reaction mixture is cooled and allowed to stand overnight at room temperature. About 100 parts of water are added and the whole is acidified with a hydrochloric acid solution 10 N. The product is extracted with 2,2'-oxybispropane. The aqueous phase is treated with activated charcoal. The latter is filtered off and the filtrate is alkalized with a sodium hydroxide solution 50%. The product is extracted with dichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is crystallized from 35 parts of 1,1'-oxybisethane. The product is filtered off, washed with 1,1'-oxybisethane and dried, yielding 1.3 parts of 2-(4-chlorophenyl)-5-[4-(diphenylmethyl)-1-piperazinylmethyl]- 1-methyl-1H-benzimidazole; mp. 198.3° C.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH:40]([CH3:49])[C:41]([N:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH:40]([CH3:49])[CH2:41][N:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CC(Cl)C(=O)N1CCCCC1
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OC(C)CN2CCCCC2)c(F)c1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 63.4 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (21 mg) and 2-chloro-1-piperidin-1-ylpropan-1-one (16 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (14 mg) was obtained.
Reaction SMILES: [Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[Cl:19][C:20]1[CH:21]=[C:22]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[NH:42][C:43](=[O:49])[CH2:44][CH2:45][C:46](O)=[O:47])[CH:23]=[CH:24][C:25]=1[C:26](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33].[NH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][OH:57].Cl>C1COCC1>[Cl:19][C:20]1[CH:21]=[C:22]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[NH:42][C:43](=[O:49])[CH2:44][CH2:45][C:46]([NH:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][OH:57])=[O:47])[CH:23]=[CH:24][C:25]=1[C:26](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: NCCCCCCO
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2NC(=O)CCC(=O)O)cc1Cl
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2NC(=O)CCC(=O)NCCCCCCO)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (DMT-MM) (138 mg, 0.50 mmol) was added to a solution of N-(2-{[3-chloro-4-(2-methylbenzoyl)phenyl]amino}phenyl)-succinamic acid (200 mg, 0.46 mmol) (disclosed in WO 01/05746) and 6-aminohexanol (60 mg, 0.51 mmol) in THF (4.0 mL). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was poured into 1 N HCl (aq.) and was extracted with EtOAc (×2). The combined organic phases were washed with water, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using DCM/MeOH/NH3(aq.) 95:5:0.5 as the eluent to afford the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][N:7]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(OCc2ccccc2)cn1
Temperature: 15 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 6-bromo-3-pyridinol (10 g, Commercial eg Apollo Scientific Ltd.) in DMF (100 ml) was added potassium carbonate (17.8 g). The reaction mixture was stirred for 15 min at 25-30 C before cooling to 15° C. To this was added slowly benzyl bromide (7.5 ml) and this was stirred at 25-30° C. for 48 h. The reaction mixture was poured into cold water and the solid was collected by filtration to give the title compound, 14.5 g
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[O:20][CH3:21]>CS(O)(=O)=O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([C:17]1[C:16]([CH3:19])=[CH:15][C:14]([O:20][CH3:21])=[C:13]([O:12][CH3:11])[CH:18]=1)=[O:6]
Reactant: COc1ccc(C)cc1OC
Reactant: O=C(O)c1ccccc1Br
Agent: CS(=O)(=O)O
Product: COc1cc(C)c(C(=O)c2ccccc2Br)cc1OC
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A solution of 20 g of bisphosphorus pentoxide in 200 ml of methanesulfonic acid is poured over 20.7 g (0.1 mol) of 2-bromobenzoic acid and 15.2 g (0.1 mol) of 1,2-dimethoxy-4-methylbenzene, and the mixture is heated, with stirring, for 30 minutes at 70° C. The mixture is then poured into ice-water and extracted with ether. After concentration by evaporation, the ether extracts yield (2-bromophenyl)-(3,4-dimethoxy-6-methylphenyl)-methanone as a brown product of honey-like consistency.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[N:11]3[C:12](=[N:17][C:18]([CH3:19])=[C:10]3[C:9]1=[O:20])[CH:13]=[CH:14][CH:15]=2.C(N(CC)CC)C.[F:28][C:29]([F:36])([F:35])[CH2:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:19][C:18]1[N:17]=[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[N:11]2[C:10]=1[C:9](=[O:20])[N:8]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:31]([CH2:30][C:29]([F:36])([F:35])[F:28])(=[O:33])=[O:32]
Reactant: Cc1nc2cccc3n(CCCCCCN)c(=O)c1n23
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2cccc3n(CCCCCCNS(=O)(=O)CC(F)(F)F)c(=O)c1n23
Yield: 77.3 %

Procedure:
To a solution of 676 mg (2.48 mmol) of 1-[6-(amino)hexyl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one and 0.52 ml (3.73 mmol) of triethylamine in 30 ml of methylene chloride was added, while stirring under ice-cooling, 0.55 g (3.01 mmol) of 2,2,2-trifluoroethanesulfonylchloride, and the mixture was stirred for 30 minutes at the same temperature range. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to give 802 mg of the desired compound (77.2%, pale brown solid).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)/[CH:4]=[C:5](/[CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])\[CH3:6].[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>>[CH2:3]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)/[CH:4]=[C:5](/[CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])\[CH3:6]
Reactant: c1c[nH]cn1
Reactant: CC(C)=CCC/C(C)=C/COCCCCBr
Agent: [H-]
Agent: [Na+]
Product: CC(C)=CCC/C(C)=C/COCCCCn1ccnc1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
Sodium hydride (1.1 g 60% dispersion in oil, 0.66 g, 27.5 mmol) was weighed out in a 100 mL round bottom flask. The sodium hydride was washed with hexane (3×5 mL) to remove the mineral oils. DMF (anhydrous, 20 mL) was added, followed by geranyloxybutyl bromide (1.51 g, 5.47 mmol). The reaction mixture was stirred at room temperature under N2 for a couple of minutes. Imidazole (1.84 g, 103 mmol, 27.1 equiv) was added slowly in small portions while cooling in an ice bath. The addition of imidazole was exothermic and the reaction mixture bubbled vigorously becoming initially a milky off-white and then clear brown in colour. This was left stirring at room temperature overnight. The reaction mixture was diluted with chloroform (50 mL) and then it was washed with brine (3×50 mL), and dried (Na2SO4). The solvent was removed under reduced pressure followed by high vacuum to give the product as a brown oil (1.37 g, 90%).
Reaction SMILES: C1COCC1.[C:6]([NH:10][S:11]([C:14]1[S:15][C:16]([Cl:19])=[CH:17][CH:18]=1)(=[O:13])=[O:12])([CH3:9])([CH3:8])[CH3:7].C([Li])CCC.C1(S(N(S(C2C=CC=CC=2)(=O)=O)[F:35])(=O)=O)C=CC=CC=1>CCCCCC>[C:6]([NH:10][S:11]([C:14]1[S:15][C:16]([Cl:19])=[CH:17][C:18]=1[F:35])(=[O:12])=[O:13])([CH3:9])([CH3:7])[CH3:8]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Cl)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)NS(=O)(=O)c1sc(Cl)cc1F
Temperature: 23 °C
Reaction time: 1 h
Yield: 108.2 %

Procedure:
A THF solution (1.5 mL) of 128 mg (0.50 mmol) of (tert-butyl)[(5-chloro(2-thienyl))sulfonyl]amine was cooled to −78° C. and treated with 954 μL (1.5 mmol) of a 1.6. M solution of butyl lithium in hexane. After 1 h, 159 mg (0.5 mmol) of bis(phenylsulfonyl)fluoroamine was added and the solution was allowed to warm to 23° C. The reaction was quenched with 1 mL of sat. NH4Cl, extracted 3 times with diethyl ether, dried (MgSO4), concentrated in vacuo to afford a quantitative yield (147 mg) of the desire product. 19F-NMR (CDCl3) δ (ppm): −113.4.