Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]([S:11](=[O:23])(=[O:22])[NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=2)=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:24][CH2:25][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][CH3:28])[CH:3]=1.[C:35]1([CH3:44])[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1.CO>[CH3:44][C:35]1[CH:40]=[CH:39][C:38]([C:2]2[C:10]([S:11](=[O:23])(=[O:22])[NH:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=3)=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:24][CH2:25][CH:26]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:27][CH3:28])[CH:3]=2)=[CH:37][CH:36]=1
Reactant: CCC(CNc1cc(Br)c(S(=O)(=O)NCc2ccc(F)c(Cl)c2)cc1C(=O)O)c1ccccc1
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CO
Product: CCC(CNc1cc(-c2ccc(C)cc2)c(S(=O)(=O)NCc2ccc(F)c(Cl)c2)cc1C(=O)O)c1ccccc1

Procedure:
from reaction of 1 eq. 4-bromo-5-(3-chloro-4-fluorobenzylsulfamoyl)-2-phenylbutylaminobenzoic acid and 1.2 eq. of 4-tolylboronic acid in a solv. mixture of toluene/MeOH 2:1 in the presence of 10 mol % of Pd(OAc)2, 20 mol % of triphenylphosphine and 3 eq. of sodium carbonate under reflux for 3 hours. Aqueous work-up, subsequent preparative HPLC and freeze-drying yields a colorless solid.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH3:10])=[CH:5][CH:4]=1.[CH3:11][Si:12](Cl)([CH3:14])[CH3:13].[NH4+].[Cl-]>C1COCC1>[CH2:9]([C:6]1[CH:7]=[CH:8][C:3]([Si:12]([CH3:14])([CH3:13])[CH3:11])=[CH:4][CH:5]=1)[CH3:10]
Reactant: C[Si](C)(C)Cl
Reactant: CCc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1ccc([Si](C)(C)C)cc1
Temperature: 30 °C
Yield: 93.5 %

Procedure:
Magnesium(9.5 g, 0.39 mole) was suspended in THF (60 mL) at room temperature. A solution of 4-bromo-1-ethylbenzene (49 mL, 0.36 mole) in 300 mL of THF was added dropwise at such a rate as to maintain the temperature between 30° and 60° C. When the addition was complete the reaction mixture was stirred for an additional hour and then cooled to 30° C. Trimethylsilyl chloride (49 mL, 0.39 mole) was added dropwise at such a rate as to maintain the temperature between 30° and 40° C. The thin suspension was stirred overnight at room temperature. Saturated aqueous NH4Cl was added and the reaction mixture partitioned. The aqueous phase was extracted three times with ether, and the combined organic phases were dried (MgSO4) and concentrated. The resultant oil (60 g, 93% yield) was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:11]>C(O)C(C)C>[Br:1][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:11][C:8]1[NH:9][CH2:10][CH2:6][N:7]=1
Reactant: Nc1ccc2nc[nH]c2c1Br
Solvent: CC(C)CO
Product: Brc1c(NC2=NCCN2)ccc2nc[nH]c12
Yield: 171.1 %

Procedure:
A solution of 4-bromo-5-aminobenzimidazole (0.22 g, 0.97 mmol) and ISA (0.34 g, 2.5 mmol) in 5 ml of isobutanol was stirred at reflux for 12 h. Reaction mixture was concentrated in vacuo and subjected to silica gel column chromatography (NH3 saturated 20% MeOH/EtOAc) to yield 0.23 g (0.83 mmol, 84%) of the product. The product obtained was converted to the fumarate salt and recrystallized from MeOH to afford 0.12 g (30%) of the product as a white solid: mp 199-202° C. Anal. Calc. for C10H10N5Br.1.0C4H4O4.0.7H2O requires C, 41.13; H, 3.80; N, 17.13. Found; C, 41.60; H, 3.81; N, 16.97.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:19])=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1.[C-:20]#[N:21].[Na+].O>CS(C)=O>[CH3:19][C:4]1[C:3]([CH2:2][C:20]#[N:21])=[CH:8][CH:7]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:5]=1
Reactant: [C-]#N
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CC#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.8 %

Procedure:
27.2 g of the above prepared 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (95.2 mmol) was dissolved in 100 ml of dimethyl sulfoxide; 5.9 g of sodium cyanide (120 mmol) was added and the mixture was stirred at room temperature for 18 hours. Then, the reaction mixture was poured into a mixture of ice and water, and was subsequently extracted with 3 portions of 400 ml of tert-butyl methyl ether. The combined organic phases were washed with water, then with brine, and dried over anhydrous sodium sulfate. After evaporation of the solvent, 25.2 g of the title compound was obtained as pale yellow solid.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[N:6][S:7][C:8]=2[C:9]([NH2:11])=O)[CH2:3][CH2:2]1.S(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[N:5]=[N:6][S:7][C:8]=2[C:9]#[N:11])[CH2:3][CH2:2]1
Reactant: NC(=O)c1snnc1C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: N#Cc1snnc1C1CC1
Temperature: 25 °C
Yield: 57.9 %

Procedure:
4-Cyclopropyl-1,2,3-thiadiazole-5-carboxamide (4 g; 24 mmols) was dissolved in toluene (15 ml), and thionyl chloride (5 ml) was added thereto, followed by refluxing for 10 hours under heating. After cooling to room temperature, ice was added thereto to stop the reaction, and sodium hydrogen carbonate was added thereto to neutralize, followed by extracting with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to thereby obtain 2.1 g of 4-cyclopropyl-1,2,3-thiadiazole-5-carbonitrile.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[NH:5].C([O:14][C:15]([CH:17]1[C:21](=O)[CH2:20][CH2:19][CH:18]1[CH3:23])=O)C>CCO>[Cl:11][C:8]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([C:4]2[N:6]=[C:15]([OH:14])[C:17]3[CH:18]([CH3:23])[CH2:19][CH2:20][C:21]=3[N:5]=2)[CH:7]=1
Reactant: CCOC(=O)C1C(=O)CCC1C
Reactant: N=C(N)c1cc(Cl)ccc1F
Solvent: CCO
Product: CC1CCc2nc(-c3cc(Cl)ccc3F)nc(O)c21
Temperature: 80 °C
Yield: 35 %

Procedure:
To a solution of 2-fluoro-5-chlorobenzamidine (1.95 g, 11.27 mmol, 1.1 eq) in EtOH (20 ml) was added a solution of 2-methyl-5-oxo cyclopentanecarboxylic acid ethyl ester (prepared according to Wang, C.; Gu, X.; Yu, M. S.; Curran, D. P.: Tetrahedron, 1998, 29, 8355-8370; 1.60 g, 10.26 mmol, 1 eq) in ethanol (5 ml). The reaction mixture was heated to 80° C. overnight. The reaction mixture was cooled to r.t. and the solvent was removed in vacuo to give a crude residue which was purified by recrystallization from hot ethyl acetate to give 2-(5-chloro-2-fluorophenyl)-5-methyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ol (1.0 g, 35%) as a white crystalline solid and the filtrate was further purified by flash column chromatography to give another 850 mg of 2-(5-chloro-2-fluorophenyl)-5-methyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ol.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18](OCC)=[O:19])=[CH:12][CH:11]=1)[CH2:8][CH3:9].C(OCC)(=O)C.N>C1COCC1>[CH2:7]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=1)[CH2:8][CH3:9]
Reactant: CCCc1ccc(CCC(=O)OCC)cc1
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1ccc(CCCO)cc1
Reaction time: 2 h
Yield: 95.7 %

Procedure:
Lithium aluminum hydride (2.9 g) was suspended in THF (200 ml). Ethyl 3-(4-propylphenyl)propionate (s2) (14.2 g) was added dropwise to the suspension in the temperature range of −20° C. to −10° C., and the mixture was stirred at the same temperature range for 2 hours. After the completion of reaction had been confirmed by means of GC analysis, ethyl acetate and a saturated aqueous solution of ammonia were added successively to the reaction mixture under ice-cooling, and the deposits were removed by filtration through Celite. The filtrate was extracted with ethyl acetate. The combined organic layers were washed successively with water and brine, and then dried over anhydrous magnesium sulfate. The products were purified by recrystallization from heptane to give 3-(4-propylphenyl)propanol (s3) (11.0 g). The yield based on the compound (s2) was 95.7%.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH2:13][NH2:14])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.[C:17]1([CH2:23][CH2:24][CH2:25][CH:26]=O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=2)[CH2:13][NH:14][CH2:26][CH2:25][CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][CH:3]=1
Reactant: NCc1cccc(Oc2ccc(F)cc2)c1
Reactant: O=CCCCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Fc1ccc(Oc2cccc(CNCCCCc3ccccc3)c2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 622.1 %

Procedure:
To a mixture of (3-(4-fluorophenoxy)phenyl)methanamine (200 mg, 0.092 mmol, 1.0 eq) in methanol was added 4-phenylbutanal (136 mg, 0.92 mmol, 1.0 eq). The mixture was refluxed for 2 h, then cooled to 0° C., before adding NaBH4 (105 mg, 2.76 mmol, 3.0 eq) portion wise. The mixture was stirred for 15 minutes before being quenched with 10% aq. NaHCO3 solution. The volatiles were evaporated under reduced pressure and the aqueous solution obtained was extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the desired compound (200 mg, 62%); 1H NMR (400 MHz, CD3OD) δ 7.33-6.86 (m, 13H), 3.72-3.50 (s, 2H), 2.63-2.50 (m, 4H), 1.65-1.54 (m, 4H). MS (ESI): 350.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]([OH:18])=O)=[CH:10][C:9]=1[Cl:19].S(Cl)(Cl)=O.[CH:24]1[CH:25]=[CH:26][N:27]2[CH2:33][C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[NH:30][CH2:29][C:28]=12.C(N(CC)CC)C>O1CCCC1.ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([Cl:19])=[CH:10][C:11]([C:16]([N:30]2[C:31]3[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=3[CH2:33][N:27]3[CH:26]=[CH:25][CH:24]=[C:28]3[CH2:29]2)=[O:18])=[C:12]([O:14][CH3:15])[CH:13]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: COc1cc(-c2ccccc2Cl)c(Cl)cc1C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(-c2ccccc2Cl)c(Cl)cc1C(=O)N1Cc2cccn2Cc2ccccc21
Reaction time: 2 h
Yield: 39.8 %

Procedure:
A stirred solution of the 2′-chloro-2-chloro-5-methoxy-[1,1′-biphenyl]-4-carboxylic acid of Step A (3.09 g, 10.46 mmol) in tetrahydrofuran (20 mL) containing a catalytic amount of N,N-dimethylformamide was treated dropwise with thionyl chloride (1.36 g, 11.51 mmol). The reaction mixture was stirred for 2 hours, and then added dropwise to a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (1.92 g 10.46 mmol) in tetrahydrofuran (20 mL) containing triethylamine (2.32 g, 23 mmol). The reaction mixture was stirred for 2 hours, diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. Trituration of the residue with ethyl acetate gave the title compound (1.93 g) which was recrystallized from ethyl acetate/hexanes as white crystals, m.p. 209-211° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=1[NH2:4].[C:11](OC(=O)C)(=[O:13])[CH3:12]>CC(O)=O>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=1[NH:4][C:11](=[O:13])[CH3:12]
Reactant: COc1ccc(Cl)c(N)c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(Cl)c(NC(C)=O)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 10.59 g of 2-chloro-5-methoxyaniline in 50 mL of AcOH were added dropwise at 0° C. 6.8 mL of acetic anhydride. The reaction mixture was allowed to warm up to rt, stirred for 6 h and concentrated in vacuo. The crude product was purified by CC using EtOAc/heptane 1/3 to yield 13.0 g of N-(2-chloro-5-methoxy-phenyl)-acetamide as white solid.
Reaction SMILES: [CH2:1]([N:13]1[CH2:17][C@@H:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=2)[CH2:15][C@H:14]1[C:26](OC)=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[CH2:1]([N:13]1[CH2:17][C@@H:16]([O:18][C:19]2[CH:20]=[CH:21][C:22]([I:25])=[CH:23][CH:24]=2)[CH2:15][C@H:14]1[CH2:26][OH:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN1C[C@@H](Oc2ccc(I)cc2)C[C@H]1C(=O)OC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCN1C[C@@H](Oc2ccc(I)cc2)C[C@H]1CO
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 83.4 %

Procedure:
To a solution of (2S, 4S)-1-N-dodecyl-4-(4-iodophenoxy)pyrrolidine-2-carboxylic acid, methyl ester (2.09 g, 4.06 mmol) in tetrahydrofuran (20 ml) at −78° C. was added dropwise diisobutylaluminum hydride (1.0 M in hexane, 15.0 ml, 15.0 mmol). After stirring at this temperature for 5 min. and at 0° C. for 2.5 h, the reaction was quenched with water at 0° C. After stirring at r.t. for 10 min., the mixture was diluted with ethyl acetate (250 ml), washed with 2N sodium hydroxide (3×100 ml), 35% sodium and potassium tartrate (2×100 ml), brine (100 ml), dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (hexane/ethyl acetate 3:1 to 2:1) to afford the title compound (1.65 g, 79%) as a colorless oil. [a]D=−18.5° (c 0.92, CHCl3).
Reaction SMILES: [CH:1]1([C:5]2[C:10]([O:11][CH2:12][C:13]3[N:17](COCC[Si](C)(C)C)[C:16]4[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=4[N:14]=3)=[N:9][N:8]3[C:30]([C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=4[F:40])=[N:31][N:32]=[C:7]3[CH:6]=2)[CH2:4][CH2:3][CH2:2]1>Cl.C(O)C>[NH:17]1[C:16]2[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=2[N:14]=[C:13]1[CH2:12][O:11][C:10]1[C:5]([CH:1]2[CH2:2][CH2:3][CH2:4]2)=[CH:6][C:7]2[N:8]([C:30]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[F:40])=[N:31][N:32]=2)[N:9]=1
Reactant: C[Si](C)(C)CCOCn1c(COc2nn3c(-c4ccc(F)cc4F)nnc3cc2C2CCC2)nc2ccccc21
Agent: Cl
Solvent: CCO
Product: Fc1ccc(-c2nnc3cc(C4CCC4)c(OCc4nc5ccccc5[nH]4)nn23)c(F)c1
Yield: 41.7 %

Procedure:
A solution of 7-cyclobutyl-3-(2,4-difluorophenyl)-6-[1-(2-trimethylsilanylethoxymethyl)-1H-benzimidazol-2-ylmethoxy]-1,2,4-triazolo[4,3-b]pyridazine (187 mg, 0.333 mmol) in 5M hydrochloric acid (10 ml) and ethanol (4 ml) was heated at 80° C. overnight, then concentrated in vacuo to remove solvents. Saturated potassium carbonate solution was added, then the mixture was diluted with water, filtered and the residual solid washed with water then ether and then dried. The residue was purified by flash chromatography on silica gel using ethyl acetate as eluent to give the title compound (60 mg, 42%). Data for the title compound: 1H NMR (250 MHz, CDCl3) δ 10.62 (1H, br s), 7.85 (2H, m), 7.56 (1H, d, J=1.6 Hz), 7.48 (1H, br s), 7.32 (2H, m), 7.00 (2H, m), 5.65 (2H, s), 3.54 (1H, m), 2.24 (2H, m), 2.01 (3H, m), 1.80 (1H, m); MS (ES+) m/e 433 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH:33]([CH:41]([CH3:43])C)[C:34]2[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=2)[CH:29]=[C:28]([CH2:44][CH3:45])[N:27]=1.[Na].Br[CH2:48][CH2:49][O:50][CH2:51][CH2:52]Br.O>CN(C)C=O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH:33]([CH2:41][CH3:43])[C:34]2[CH:35]=[CH:36][C:37]([O:40][CH2:48][CH2:49][O:50][CH2:51][CH3:52])=[CH:38][CH:39]=2)[CH:29]=[C:28]([CH2:44][CH3:45])[N:27]=1
Reactant: BrCCOCCBr
Reactant: CCc1cc(NC(c2ccc(O)cc2)C(C)C)nc(Cl)n1
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOCCOc1ccc(C(CC)Nc2cc(CC)nc(Cl)n2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
To a solution of 1.2 g of dl-5-chloro-6-ethyl-4-(α-isopropyl-4-hydroxybenzyl)aminopyrimidine. sodium salt dissolved in 30 ml of N,N-dimethylformamide was added 0.6 g of bromoethyl ether, and the mixture was stirred at 80° C. for 8 hours. After completion of the reaction, the reaction mixture was poured into water and the separated oily product was extracted with ethyl acetate. The extract was washed with water, dried with anhydrous sodium sulfate, and then ethyl acetate was distilled off under reduced pressure. The oily product obtained was isolated by column chromatography (Wako Gel C-200, trade name, eluted with toluene:ethyl acetate 32 7:1) to give 0.6 g of the desired product as pale yellow liquid
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH:15]([CH2:17]Br)[CH2:14][C:13]=2[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:34]=[CH:33][C:24]([CH2:25][C:26]2([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH:15]([CH2:17][N:29]3[CH2:30][CH2:31][C:26]([CH2:25][C:24]4[CH:23]=[CH:22][C:21]([CH3:20])=[CH:34][CH:33]=4)([OH:32])[CH2:27][CH2:28]3)[CH2:14][C:13]=2[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCC1Cc2cc(OCc3ccccc3)ccc2O1
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(CC2(O)CCN(CC3Cc4cc(OCc5ccccc5)ccc4O3)CC2)cc1
Temperature: 110 °C
Yield: 88.2 %

Procedure:
(RS)-5-Benzyloxy-2-bromomethyl-2,3-dihydro-benzofuran (840 mg, 2.63 mmol) and 4-(4-methyl-benzyl)-piperidin-4-ol (1.08 g, 5.26 mmol) were suspended in toluene (20 ml) and heated to 110° C. for 17 hr. The mixture was filtered and evaporated to afford an orange oil which was chromatographed over SiO2 (Merck 230-400 mesh) with MeOH—CH2Cl2 (3:97) to afford (RS)-1-(5-benzyloxy-2,3-dihydro-benzofuran-2-ylmethyl)-4-(4-methyl-benzyl)-piperidin-4-ol as a yellow oil (1.03 g, 2.32 mmol, 88%), MS: m/e=444.5 (M+H+).
Reaction SMILES: [CH2:1]([NH:7][C:8](=[O:33])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:34][CH2:35][CH:36]([C:38]1[CH:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=1)[OH:37]>>[CH2:1]([NH:7][C:8]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([S:16]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH2:27][CH2:28][CH:29]([NH:34][CH2:35][CH:36]([OH:37])[C:38]4[CH:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=4)[CH2:30][CH2:31]3)=[CH:24][CH:25]=2)(=[O:18])=[O:17])=[CH:14][CH:15]=1)=[O:33])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: Cc1ccc(C(O)CN)cn1
Product: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NCC(O)c4ccc(C)nc4)CC3)cc2)cc1

Procedure:
The title compound was prepared from 4-(3-hexyl-ureido)-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide (which was obtained in Example 225) and 2-amino-1-(6-methyl-pyridin-3-yl)ethanol according to the procedure of Example 255 as a grey solid; 1H NMR (300 MHz, DMSO-d6) δ 0.86 (t, J=6.8 Hz, 3 H), 1.20–3.30 (m, 19 H), 2.45 (s, 3 H), 3.50–3.75 (m, 2 H), 4.70–4.80 (m, 1 H), 6.41 (t, J=5.5 Hz, 1 H), 6.78 (d, J=9.1 Hz, 2 H), 6.87 (d, J=9.1 Hz, 2 H), 7.21(d, J=8.0 Hz, 1 H), 7.46(d, J=9.2 Hz, 2 H), 7.48(d, J=9.2 Hz, 2 H), 7.64(dd, J=8.0, 2.0 Hz, 1 H), 8.43(d, J=2.0 Hz, 1 H), 9.00 (s, 1 H), 9.50 (brs, 1 H), 11.10 (s, 1 H); MS (ES) m/z: 609.3 (MH+); HRMS Calcd. for C32H45N6O4S (MH+): 609.3223. Found: 609.3235.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]=[C:6]1[O:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[O:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2)=[O:4]>CO>[CH3:1][O:2][C:3]([CH2:5][CH:6]1[O:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[O:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2)=[O:4]
Reactant: COC(=O)C=C1Oc2ccccc2Oc2ccccc21
Solvent: CO
Product: COC(=O)CC1Oc2ccccc2Oc2ccccc21
Reaction time: 10 h
Yield: 47.8 %

Procedure:
27 g of 11-(methoxycarbonyl methylidene) dibenzo (b,e)-1,4-dioxepin (A or B isomer) were dissolved in 150 ml of methanol. The solution was purged with bubbling nitrogen, then 0.5 g of platinum dioxide were added. The mixture was hydrogenated under atmospheric pressure until the end of the absorption. The catalyst was filtered off and the methanol solution was half concentrated. The crystallization was started up, then the crystalline mixture was left at rest for 10 hours in a refrigerator. The crystalline mass was suctioned off and then dried under vacuum in a dessicator over phosphoric acid. There were obtained 13 g of a hydrogenated product (yield: 48%). The pure product, after recrystallization, melts at 72°-74° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.Cl.[N:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[CH2:51][C:52](O)=[O:53].Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:52](=[O:53])[CH:51]=[C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][NH:45]3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)Cc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(C=C1C=CC=CN1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 78.3 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 2-pyridylacetic acid hydrochloride (0.4 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight then was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (3×40 mL) and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: CH3OH/CH2Cl2 3:97) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-pyridinyl-2-yl-acetamide (0.7 g, 74%) as a white solid: mp 146-148° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=0.91 min. (96%); 1H NMR (DMSO-d6) δ 2.02-2.09 (m, 1H), 2.53-2.63 (m, 2H), 2.84-2.96 (m, 1H), 3.74 (s, 2H), 4.75 (d, J=5.9 Hz, 2H), 5.12-5.18 (dd, J=5.2 and 12.7 Hz, 1H), 7.24-7.37 (m, 2H), 7.71-7.85 (m, 4H), 8.50-8.52 (d, J=0.8 and 4.9 Hz, 1H), 8.74 (t, J=5.9 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 21.95, 30.91, 37.94, 44.77, 48.83, 121.81, 123.84, 127.07, 131.48, 133.23, 134.66, 136.52, 139.14, 148.92, 156.09, 166.93, 167.46, 169.65, 169.80, 172.73; Anal. Calcd. for C21H18N4O5: C, 62.07; H, 4.46; N, 13.79. Found: C, 61.74; H, 4.18; N, 13.41.