Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[C:17]([CH2:19][O:20][C:21]4[CH:34]=[CH:33][C:24]([CH2:25][CH:26]5[S:30][C:29](=[O:31])[NH:28][C:27]5=[O:32])=[CH:23][CH:22]=4)[N:16]([CH3:35])[C:15]=3[CH:36]=2)=[CH:4][CH:3]=1.[F:37][C:38]([F:49])([F:48])[C:39]1[CH:44]=[CH:43][C:42]([N:45]=[C:46]=[O:47])=[CH:41][CH:40]=1>CN(C)C=O>[O:31]=[C:29]1[NH:28][C:27](=[O:32])[CH:26]([CH2:25][C:24]2[CH:33]=[CH:34][C:21]([O:20][CH2:19][C:17]3[N:16]([CH3:35])[C:15]4[CH:36]=[C:11]([O:10][CH2:9][CH2:8][C:5]5[CH:6]=[CH:7][C:2]([NH:1][C:46]([NH:45][C:42]6[CH:41]=[CH:40][C:39]([C:38]([F:37])([F:48])[F:49])=[CH:44][CH:43]=6)=[O:47])=[CH:3][CH:4]=5)[CH:12]=[CH:13][C:14]=4[N:18]=3)=[CH:22][CH:23]=2)[S:30]1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(OCCc3ccc(N)cc3)cc21
Solvent: CN(C)C=O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(OCCc3ccc(NC(=O)Nc4ccc(C(F)(F)F)cc4)cc3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
To a mixture of 5-[4-[6-[2-(4-aminophenyl)ethoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione (0.4 g) and N,N-dimethylformamide (10 ml) was added α,α,α-trifluoro-p-tolyl isocyanate (0.17 g) and the mixture was stirred at room temperature for 2 hours and allowed to stand overnight. The reaction mixture was partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. To the residue was added a mixture of ethyl acetate and diethyl ether (1:1). The precipitate was isolated by filtration and washed with diethyl ether to afford the title compound (0.4 g, mp 145-147° C.).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][C:23]([O:25]C)=[O:24])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:27](=[O:29])[NH2:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].Cl>C1COCC1.CO>[CH:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][C:23]([OH:25])=[O:24])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:27](=[O:29])[NH2:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2CC1CCCCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(OCC(=O)O)cccc1n2CC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A slurry of [9-[(cyclohexyl)methyl]-5-carbamoylcarbazol-4-yl]oxyacetic acid, methyl ester (20 mg, 0.051 mmol) in 0.3 mL of THF and 0.1 mL of MeOH was treated with 0.1 mL of 1 N aq LiOH (0.1 mmol), and the mixture stirred at room temperature for 2 h. The reaction was acidified with 0.2 N HCl, and the organics were removed in vacuo. The white precipitate was filtered away from the aqueous layer and rinsed with Et2O to afford 16 mg (0.042 mmol; 83%) the title acid as a white powder. MS (ES) m/e 381 (M+1), 364 (M+H—NH3), 379 (M−1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[C:16]1([C@H:26]([N:28]([CH2:36][C@@H:37]2[C@@H:41]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:40][NH:39][CH2:38]2)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH3:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.CS(C)=O>C(OCC)(=O)C>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([N:39]2[CH2:40][C@H:41]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C@@H:37]([CH2:36][N:28]([C@@H:26]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)[CH3:27])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:38]2)=[CH:9][CH:10]=1)#[N:13]
Reactant: N#Cc1ccc(F)cc1
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CNC[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(c2ccc(C#N)cc2)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 110 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
A 650 mg portion of potassium carbonate and 339 mg of 4-fluorobenzonitrile were added to a mixture of 1.0 g of tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[(3R,4S)-4-phenylpyrrolidin-3-yl]methyl}carbamate and 10 ml of DMSO and stirred overnight at 110° C. After cooling down to room temperature, the reaction solution was mixed with ethyl acetate, washed with water and saturated brine in that order and dried with anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography (hexane-ethyl acetate) to obtain 723 mg of tert-butyl {[(3R,4S)-1-(4-cyanophenyl)-4-phenylpyrrolidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate as a colorless amorphous substance. EP: 532.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@@H:8]([C:20](=[O:37])[N:21]([CH3:36])[C@@H:22]([CH2:29][N:30]([CH3:35])[S:31]([CH3:34])(=[O:33])=[O:32])[CH2:23][C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].O>ClCCl>[CH3:6][NH:7][C@H:8]([CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[C:20]([N:21]([CH3:36])[C@@H:22]([CH2:29][N:30]([CH3:35])[S:31]([CH3:34])(=[O:32])=[O:33])[CH2:23][C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)=[O:37]
Reactant: CN(C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C)[C@H](Cc1cccs1)CN(C)S(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1cccs1)CN(C)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 106.5 %

Procedure:
A solution of of N-Methyl-N-((1R)-1-(N-methyl-N-((1R)-1-((N-methyl-N-(methylsufonyl)amino)methyl)-2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamic acid tert-butyl ester (1.94 g, 3.37 mmol) in dichloromethane (7 ml) was cooled to 0° C. Trifluoroacetic acid (7 ml) was added. The reaction mixture was stirred for 45 min at 0° C. A saturated aqueous solution of sodium hydrogen carbonate (30 ml) was added. Solid sodium hydrogen carbonate was added until pH 7. Water (100 ml) was added, until a clear solution was obtained. The phases were separated. The aqueous solution was extracted with dichloromethane (2×50 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (200 g), using dichloromethane/methanol/25% aqueous ammonia as eluent, to give 1.70 g of (2R)-2-Methylamino-N-methyl-N-((1R)-1-((N-methyl-N-(methylsulfonyl)amino)methyl)-2-(2-thienyl)ethyl)-3-(2-naphthyl)propionamide.
Reaction SMILES: [CH3:1][Li].[CH3:3][C:4]1[C:9]([CH:10]=[O:11])=[CH:8][C:7]2[O:12][CH2:13][O:14][C:6]=2[CH:5]=1.O>C(OCC)C.O1CCCC1>[CH3:3][C:4]1[C:9]([CH:10]([OH:11])[CH3:1])=[CH:8][C:7]2[O:12][CH2:13][O:14][C:6]=2[CH:5]=1
Reactant: [Li]C
Reactant: Cc1cc2c(cc1C=O)OCO2
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: Cc1cc2c(cc1C(C)O)OCO2
Temperature: -40 °C

Procedure:
32 ml of a 1.4M solution of methyllithium in diethyl ether was dissolved in 50 ml of anhydrous tetrahydrofuran. The obtained solution was cooled to -40° C. in a nitrogen atmosphere, followed by the addition of 5.0 g of solid (6-methyl-1,3-benzodioxol-5-yl)carboxaldehyde. The mixture was heated to a room temperature over a period of one hour, followed by the addition of water. The obtained mixture was extracted with ether and the obtained organic layer was washed with an aqueous solution of common salt, dried over magnesium sulfate and distilled to remove the solvent. The obtained white solid was recrystallized from diisopropyl ether/n-hexane to obtain 2.8 g of the title compound as a colorless crystal.
Reaction SMILES: [CH3:1][CH:2](O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]CC.CCC([OH:34])CCCCCCCCCCCCC.CCCC(O)CCCCCCCCCCCC>>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([OH:34])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCC(C)O
Reactant: CCCCCCCCCCCCCC(O)CC
Agent: CCCCCCCCCCCCC(O)CCC
Product: CCCCCCCC(O)CCCCCC

Procedure:
2-hexadecanol; 3-hexadecanol; 4-hexadecanol;
Reaction SMILES: [I-:1].[Na+].Br[C:4]1[CH:5]=[CH:6][C:7]([C:12]([F:15])([F:14])[F:13])=[C:8]([CH:11]=1)[C:9]#[N:10]>O1CCOCC1.[Cu]I>[I:1][C:4]1[CH:5]=[CH:6][C:7]([C:12]([F:15])([F:14])[F:13])=[C:8]([CH:11]=1)[C:9]#[N:10]
Reactant: [I-]
Reactant: N#Cc1cc(Br)ccc1C(F)(F)F
Agent: [Cu]I
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1cc(I)ccc1C(F)(F)F
Reaction time: 0.17 h

Procedure:
In a microwave vial 2.24 g 5-bromo-2-(trifluoromethyl)benzonitrile are dissolved in 10 ml 1,4-dioxane. 90 mg copper-(I)-iodide and 2.7 g sodium iodide are added and the mixture is purged for 5 minutes with argon. 142 μl trans-N,N′-dimet6hylcyclohexane-1,2-diamine and 1.9 ml hexamethyldisilazane are added and the mixture is heated for 6 hours to 110° C. The mixture is diluted in 100 ml 4 M hydrochloric acid and stirred for 10 minutes. This aqueous phase is three times extracted with dichloromethane. The combined organic phases are washed with brine and dried with magnesium sulphate. The solvents are evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethylacetate 85:15).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].C([O-])([O-])=O.[K+].[K+].[CH2:18](I)[CH2:19][CH3:20]>CC(C)=O.CCOC(C)=O.C(Cl)(Cl)Cl>[OH:11][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:18][CH2:19][CH3:20])=[CH:9][C:4]=1[C:2](=[O:3])[CH3:1]
Reactant: CC(=O)c1cc(O)ccc1O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCCOc1ccc(O)c(C(C)=O)c1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
10 g of 2,5-dihydroxyacetophenone suspended in 100 ml of acetone are placed in a 500 ml round-bottomed flask and 9.14 g of anhydrous K2CO3 are added, followed by addition of 12.4 g of propyl iodide. The reaction medium is refluxed for 30 hours. After cooling to room temperature, the medium is filtered through Celite® and then concentrated. The brown oil obtained is taken up in EtOAc, filtered, washed with water, with 2M HCl solution and then with saturated NaCl solution. The organic phase is evaporated to give a black paste. The paste is taken up in chloroform and filtered. The medium is concentrated to give 11.4 g of a black solid. This solid is taken up in absolute ethanol. The solution is placed in a freezer for 10 minutes; a solid precipitates out, and is collected by filtration. The filtrate is concentrated, taken up in ethanol, cooled in a freezer and then filtered again. This operation is repeated four more times to give 8.35 g of the expected compound in the form of a powder.
Reaction SMILES: N1C=CC=C(CCCN)C=1.C1(=O)CCCCC1.[BH3-]C#N.[Na+].[CH:22]1([NH:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[N:38]1[C:46]2[C:41]3[C:42](=[CH:47][CH:48]=[CH:49][C:40]=3[C:39]=1S)[CH:43]=[CH:44][CH:45]=2>CO.C(O)C>[CH:22]1([N:28]([CH2:29][CH2:30][CH2:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[C:39]2[C:40]3[CH:49]=[CH:48][CH:47]=[C:42]4[C:41]=3[C:46](=[CH:45][CH:44]=[CH:43]4)[N:38]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: SC1=Nc2cccc3cccc1c23
Reactant: c1cncc(CCCNC2CCCCC2)c1
Agent: NCCCc1cccnc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: O=C1CCCCC1
Product: c1cncc(CCCN(C2=Nc3cccc4cccc2c34)C2CCCCC2)c1

Procedure:
The reaction of 3-(3-pyridinyl)propanamine and cyclohexanone in methanol in the presence of NaBH3CN leads to the preparation of N-cyclohexyl-3-(3-pyridinyl)propanamine. The latter compound, upon reaction with molar equivalents of benz(cd)indol-2-thiol and mercuric acetate in refluxing ethanol under the conditions of Example 55 leads to the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[NH2:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=1)=[O:6].[CH3:20][C:21]1[CH:28]=[C:27]([O:29][CH2:30][CH2:31][N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:26]=[C:25]([CH3:37])[C:22]=1[CH:23]=O>CO>[CH3:15][C:10]1[CH:9]=[C:8]([NH:7][C:5]([C:4]2[CH:16]=[CH:17][C:18]3[N:19]=[C:23]([C:22]4[C:21]([CH3:20])=[CH:28][C:27]([O:29][CH2:30][CH2:31][N:32]5[CH2:36][CH2:35][CH2:34][CH2:33]5)=[CH:26][C:25]=4[CH3:37])[NH:1][C:2]=3[CH:3]=2)=[O:6])[CH:13]=[CH:12][C:11]=1[CH3:14]
Reactant: Cc1cc(OCCN2CCCC2)cc(C)c1C=O
Reactant: Cc1ccc(NC(=O)c2ccc(N)c(N)c2)cc1C
Solvent: CO
Product: Cc1ccc(NC(=O)c2ccc3nc(-c4c(C)cc(OCCN5CCCC5)cc4C)[nH]c3c2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3,4-diamino-N-(3,4-dimethyl-phenyl)-benzamide (0.1 mL in 0.2 M DMSO solution), 2,6-dimethyl-4-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde (0.1 mL in 0.2 M toluene solution) and FeCl3 (0.05 mL in 0.02M THF solution) was stirred in open air at ambient temperature overnight. The mixture was then diluted by MeOH and the whole was loaded onto a solid phase extraction (SPE) cartridge that contained strong cation exchange (SCX) (1 g media in 6 mL cartridge, United Chemical Technology). Wash-to-waste (5 mL MeOH) was followed by elute-to-collect (5 mL 20:2:1 ethyl acetate-MeOH-Et3N) and, after evaporation of volatiles, the crude was further purified by silica gel column chromatography to give 2-[2,6-dimethyl-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3H-benzoimidazole-5-carboxylic acid (3,4-dimethyl-phenyl)-amide: MS (m/z) 483 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=[N:29][CH:28]=[CH:27]2)=O)C=1.[O:31]1C[CH2:34][CH2:33][CH:32]1N>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH:29][CH2:28][CH:27]1[CH2:34][CH2:33][CH2:32][O:31]1)=[O:16])[CH2:6][CH2:5]2
Reactant: NC1CCCO1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCC1CCCO1)O2
Yield: 61.8 %

Procedure:
Following the amide coupling procedure described in protocol A, 496 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (1.98 mmol), 376 mg CDI (2.32 mmol) and 404 mg tetrahydrofuranylamine (4.0 mmol) produced 408.0 mg of crude 6-hydroxy-2,5,7,8-tetramethyl-N-((tetrahydrofuran-2-yl)methyl)chroman-2-carboxamide, which was oxidized following protocol B, with 335 mg CAN (0.612 mmol) to yield 74.7 mg of 2-hydroxy-2-methyl-N-((tetrahydrofuran-2-yl)methyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow oil.
Reaction SMILES: [C:1]([C:4]1([CH2:10][CH2:11][C:12]([OH:14])=O)[NH:8][C:7](=[O:9])[CH2:6][NH:5]1)([OH:3])=[O:2].C[Si](C)(C)N[Si](C)(C)C.C[Si](C)(C)Cl>C(#N)C>[O:9]=[C:7]1[CH2:6][N:5]2[C:12](=[O:14])[CH2:11][CH2:10][C:4]2([C:1]([OH:3])=[O:2])[NH:8]1
Reactant: O=C(O)CCC1(C(=O)O)NCC(=O)N1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CC#N
Product: O=C1CN2C(=O)CCC2(C(=O)O)N1
Reaction time: 0.17 h
Yield: 49.4 %

Procedure:
A mixture of 2-carboxy-4-oxo-2-imidazolidinepropanoic acid (2 g, 9.89 mmol), hexamethyldisilazane (20 mol) and trimethylchlorosilane (10 ml) in dry acetonitrile (50 ml) was refluxed under nitrogen for 4 hours. After cooling, the precipitate was filtered off and the filtrate was evaporated under vacuum. The residue was dissolved in methanol (20 ml) containing some drops of concentrated hydrochloric acid and stirred for 10 minutes. The insoluble material was filtered off and the filtrate was evaporated to dryness. The residue was triturated with acetonitrile and crystallized with tetrahydrofuran (250 ml) to yield 0.9 g (50%) of the title compound, m.p. 207° C. (with decomposition). NMR (DMSO-d6): deltaH : 9.20 (b.s., 1H, NH); 3.82 and 3.46 (ABq, J=16.8 Hz, 2H, NCH2CO); 2.90-1.80 (c.a., 4H, CH2 --CH2). MS (E.I., 70 eV, 1.5 mA) m/z=184 (M+ ), 139 (M-COOH)+, 83 (C3H3N2O)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>[OH-].[Na+]>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: NCCCCCCC(=O)O
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCNS(=O)(=O)c1ccc(Cl)cc1

Procedure:
A solution of 7-aminoheptanoic acid in 10% sodium hydroxide solution was treated with 4-chlorobenzenesulphonyl chloride in the manner of Example 1 to give the title compound which, after recrystallisation from aqueous ethanol, had a melting point of 128°-129° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[C:10](=[O:26])[O:11][C:12]([CH3:25])([CH3:24])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[N:6][CH:7]=1.[Cl:27]C1C(=O)NC=C(Cl)C=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH3:25][C:12]1([CH3:24])[O:11][C:10](=[O:26])[C:9]([O:8][C:5]2[C:4]([Cl:27])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[C:13]1[C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][CH:19]=1
Reactant: O=c1[nH]cc(Cl)cc1Cl
Reactant: CC1(C)OC(=O)C(Oc2ccc(Cl)cn2)=C1c1ccc(S(C)(=O)=O)cc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)OC(=O)C(Oc2ncc(Cl)cc2Cl)=C1c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C

Procedure:
To a R.T. solution of 2-chloroacetic acid 2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one ester (954 mg, 3 mmol, example 25) in acetonitrile (15 mL) was added 3,5-dichloro-2-pyridone (656 mg, 4.0 mmol) followed by DBU (2.28 g, 15 mmol) and the mixture was slowly warmed up to gentle reflux for 2 hours. The mixture was cooled to 25° C. the volatiles were removed in vacuo. The residue was purified on silica gel chromatography (1/1, EtOAc/Hexanes then 100% EtOAc)) to provide the title compound.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1.[C:13]([O:17][CH3:18])(=[O:16])[CH2:14][OH:15]>O1CCOCC1>[CH3:18][O:17][C:13]([CH2:14][O:15][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:16]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)COc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
First, 0.4 g of sodium hydride was added to a mixture of 1.59 g of 2-chloro-3-nitropyridine, 0.95 g of methyl glycolate, and 10 ml of 1,4-dioxane at 10° C. After stirring at room temperature for 2 hours, the reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 1.5 g of 2-(methoxycarbonyl)methoxy-3-nitropyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([OH:8])[CH:7]=1.Br[CH2:12][CH2:13][CH2:14][CH3:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([O:8][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1
Reactant: OCc1ccc(Cl)cc1O
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1cc(Cl)ccc1CO
Temperature: 100 °C
Yield: 45.9 %

Procedure:
Charged 5-chloro-2-(hydroxymethyl)phenol (965 mg, 6.09 mmol, PREPARATION 7), bromobutane (918 mmol, 6.70 mmol), K2CO3 (1.68 g, 12.19 mmol) and DMF (6 mL) to a sealed tube, and the mixture was heated to 100° C. overnight. After cooling to room temperature, the reaction mixture was poured into ice water, extracted with ethyl acetate twice, and the organic extract was washed with water, brine and dried with anhydrous Na2SO4. Solvent removed and the residue was purified by flash column chromatograph to give 600 mg of the title compound (46%). 1H NMR (300 MHz, CDCl3): δ 0.98 (3H, t, J=7.2 Hz), 1.46-1.56 (2H, m), 1.75-1.84 (2H, m), 2.23 (1H, t, J=6.0 Hz), 4.00 (2H, t, J=6.3 Hz), 4.64 (2H, d, J=6.3 Hz), 6.85 (1H, d, J=1.8 Hz), 6.91 (1H, dd, J=1.8 Hz, 8.1 Hz), 7.19 (1H, d, J=7.8 Hz).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[O:30]1[CH2:35][CH2:34][CH:33]([CH:36]2[CH2:39][NH:38][CH2:37]2)[CH2:32][CH2:31]1.COC(OC)OC.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:38]4[CH2:39][CH:36]([CH:33]5[CH2:34][CH2:35][O:30][CH2:31][CH2:32]5)[CH2:37]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: C1CC(C2CNC2)CCO1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: COC(OC)OC
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(C4CCOCC4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.6 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.10 g, 0.26 mmol), 3-(tetrahydropyran-4-yl)azetidine (0.050 g, 0.28 mmol) in DCE (2 mL), trimethoxymethane (0.277 mL, 2.6 mmol) and acetic acid (0.015 mL, 0.26 mmol) was stirred for 2 h at room temperature. Sodium triacetoxyborohydride (0.090 g, 0.43 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The reaction mixture was partitioned between DCM and water, the organic phase was separated, washed with brine, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography (Si—PPC, MeOH:EtOAc gradient 0:100 to 10:90) to give 325 as a yellow solid (0.072 g, 56%). LCMS (Method G): RT=6.14 min, [M+H]+ 517.2. 1H NMR (CDCl3, 400 MHz) δ 8.02-7.98 (m, 1 H); 7.78-7.73 (m, 1 H); 7.35-7.25 (m, 2 H); 4.40-4.32 (m, 4 H); 3.98 (dd, J=11.7, 4.3 Hz, 2 H); 3.89-3.86 (m, 9 H); 3.42-3.30 (m, 5 H); 1.67-1.64 (m, 4 H); 1.55 (d, J=11.7 Hz, 2 H); 1.48-1.39 (t, J=7.5 Hz, 3 H); 1.29-1.16 (m, 3 H)
Reaction SMILES: C[C:2]1([CH3:18])[O:7][C:6](=[O:8])[CH:5]([C:9](=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]C)[C:4](=[O:17])O1.OCC[C:22]#[N:23]>C1(C)C=CC=CC=1>[O:17]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH:5]([C:6]([O:7][CH2:2][CH2:18][C:22]#[N:23])=[O:8])[CH2:4]1
Reactant: N#CCCO
Reactant: CCCCCCC(=O)C1C(=O)OC(C)(C)OC1=O
Solvent: Cc1ccccc1
Product: N#CCCOC(=O)C1CCCCCCOC1

Procedure:
A mixture of 2,2-dimethyl-5-(1-oxoheptyl)-1,3-dioxane-4,6-dione (29.4 mmol) and 3-hydroxypropionitrile (4.48 g, 63.0 mmol) in 25 mL of dry toluene were heated at reflux temperature for 1 hour. The solvent was removed in vacuo, and the residue was chromatographed on silica gel to give the title compound as a viscous oil, which was used in the next step after spectral characterization.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[CH:17]=[C:16]([CH3:24])[C:4]=1[C:5]([C:7]1[C:8]([F:15])=[N:9][CH:10]=[C:11]([CH3:14])[C:12]=1I)=[O:6].[C:25](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[CH:17]=[C:16]([CH3:24])[C:4]=1[C:5]([C:7]1[C:8]([F:15])=[N:9][CH:10]=[C:11]([CH3:14])[C:12]=1[CH3:25])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C)c(C(=O)c2c(F)ncc(C)c2I)c(OC)c1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc(C)c(C(=O)c2c(F)ncc(C)c2C)c(OC)c1OC
Temperature: 25 °C
Yield: 70.3 %

Procedure:
1.50 g (3.37 mmol) of 3-(2,3,4-trimethoxy-6-methylbenzoyl)-2-fluoro-4-iodo-5-methylpyridine obtained in Step (c), 1.40 g (10.1 mmol) of potassium carbonate, 0.39 g (0.34 mmol) of tetrakis(triphenylphosphine)palladium, 15 ml of dioxane and 0.42 g (1.67 mmol) of 50% trimethylboroxin were mixed, followed by reflux with heating for 6 hours. After cooling to room temperature, filtration on the pad of celite and washing with ethyl acetate and tetrahydrofuran were carried out, the solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel chromatography to obtain 0.79 g (yield: 70%) of 3-(2,3,4-trimethoxy-6-methylbenzoyl)-2-fluoro-4,5-dimethylpyridine (Compound No. 19).