Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[S:37][C:6]2[N:7]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=3)[C:8](=[O:21])[N:9]([CH2:12][CH2:13][N:14]3[CH:18]=[CH:17][N:16]=[C:15]3[CH2:19][OH:20])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].[C:38]([Si:42](Cl)([CH3:44])[CH3:43])([CH3:41])([CH3:40])[CH3:39].C(N(CC)CC)C>C(Cl)Cl>[Si:42]([O:20][CH2:19][C:15]1[N:14]([CH2:13][CH2:12][N:9]2[C:10](=[O:11])[C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[S:37][C:6]=3[N:7]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=3)[C:8]2=[O:21])[CH:18]=[CH:17][N:16]=1)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:44])[CH3:43]
Reactant: CCc1cc2c(=O)n(CCn3ccnc3CO)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc2c(=O)n(CCn3ccnc3CO[Si](C)(C)C(C)(C)C)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
A mixture of 4′-{[6-ethyl-3-{2-[2-(hydroxymethyl)-1H-imidazol-1-yl]ethyl}-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.5 g), tert-butyl(chloro)dimethylsilane (0.18 g), triethylamine (0.16 mL) and methylene chloride (20 mL) was stirred at room temperature for 4 hr. The reaction mixture was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.61 g, 99%).
Reaction SMILES: O.C([O-])=O.[NH4+].C([N:13]1[C:17]([CH:18]([OH:34])[CH2:19][CH2:20][CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:16][N:15]=[CH:14]1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:34][CH:18]([C:17]1[N:13]=[CH:14][NH:15][CH:16]=1)[CH2:19][CH2:20][CH:21]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OC(CCC(c1ccccc1)c1ccccc1)c1cncn1Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: OC(CCC(c1ccccc1)c1ccccc1)c1c[nH]cn1

Procedure:
A concentrated water solution of ammonium formate (4,0 g) is added dropwise to the boiling mixture of 1-benzyl-5-(1-hydroxy-4,4-diphenylbutyl)-1H-imidazole (4,5 g) and 10% Pd/C (0,5 g) in 50 ml of 50% ethanol. The mixture is refluxed for 2 hours. The catalyst is filtrated and the solvent is evaporated. 2M NaOH is added and the product is extracted into ethyl acetate. The ethyl acetate phase is dried and evaporated to dryness to give the product which is used in the following step b).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15](Cl)(=[O:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:19]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH2:19])(=[O:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: O=S(=O)(Cl)c1ccccc1OCc1ccccc1
Product: NS(=O)(=O)c1ccccc1OCc1ccccc1

Procedure:
To 148 ml of concentrated hydrochloric acid and 45 ml of acetic acid, maintained at <10°, was added 39.2 g of 2-(benzyloxy)aniline [See Berichte, 58, 79 (1925)]. White solid formed. Sufficient additional acetic acid was added to render the mixture stirrable. While temperature was 0° to 3°, a solution of 28 g of sodium nitrite in 75 ml of water was dripped into it. The mixture was kept at 5° to 10° for 15 minutes, then added to a mixture of 5.2 g of cuprous chloride, 37 ml of sulfur dioxide and 211 ml of acetic acid at 3°. Next, 290 ml of butyl chloride was added and the mixture allowed to warm to ambient temperature. After 16 hours, the mixture was diluted with water and the organic layer washed with water and dilute sodium bicarbonate solution until the washings were basic. The mixture was then dried (MgSO4) and evaporated to an oil (A). The effervescing aqueous portion (from which the butyl chloride solution had been removed) was depositing an oil; it was then treated portionwise with sodium bisulfite over several hours. After about 16 hours the oil was extracted into butyl chloride and the butyl chloride solution washed, dried and evaporated, providing an oil (B). Oils A and B are 2-(benzyloxy)benzenesulfonyl chloride. To oils A and B was added an excess of concentrated aqueous ammonia, the mixture was swirled and a white solid was observed. The solid was filtered off and extracted with hot butyl chloride; upon cooling, the extract precipitated 2-(benzyloxy)benzenesulfonamide as a white solid, m.p. 127°-129°.
Reaction SMILES: Br[C:2]1[CH:23]=[C:22]2[C:5]([CH2:6][CH2:7][C@@H:8]3[CH2:13][S:12][C:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:10][C@@:9]32[CH3:24])=[CH:4][CH:3]=1.[NH:25]1[CH:29]=[C:28](B(O)O)[CH:27]=[N:26]1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe].O.O1CCOCC1>[CH3:24][C@@:9]12[C:22]3[C:5](=[CH:4][CH:3]=[C:2]([C:28]4[CH:29]=[N:25][NH:26][CH:27]=4)[CH:23]=3)[CH2:6][CH2:7][C@@H:8]1[CH2:13][S:12][C:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[N:10]2
Reactant: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc(Br)ccc3CC[C@@H]2CS1
Reactant: OB(O)c1cn[nH]c1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])O
Solvent: O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc(-c4cn[nH]c4)ccc3CC[C@@H]2CS1
Temperature: 100 °C

Procedure:
Dioxane (1 mL) and water (0.1 mL) were added to a mixture of tert-butyl rel-((4aS,10bS)-9-bromo-10b-methyl-4a,5,6,10b-tetrahydro-4H-naphtho[1,2-d][1,3]thiazin-2-yl)carbamate from preparation C (10 mg, 0.024 mmol), (1H-pyrazol-4-yl)boronic acid (27.2 mg, 0.243 mmol) and potassium carbonate (33.6 mg, 0.243 mmol). Nitrogen was bubbled through the mixture for 5 min. 1,1′-Bis(diphenylphosphino)ferrocenepalladium (II) dichloride, toluene (10 mg, 0.012 mmol) was added and the resulting mixture was heated at 100° C. for 1 h. The reaction contents were cooled to rt and were transferred to a separatory funnel containing saturated aqueous NaHCO3 solution (10 mL). The aqueous layer was extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The crude product of step 19A was used in the next step without further purification. LCMS (M+H)+=399.08.
Reaction SMILES: Cl[C:2](OC1C=CC=CC=1)=[O:3].[NH2:11][C:12]1[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=1[CH2:14][C:15]1[NH:16][CH:17]=[CH:18][N:19]=1.C(N(CC)CC)C.O>C(#N)C>[N:19]1[CH:18]=[CH:17][N:16]2[C:15]=1[CH2:14][C:13]1[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=1[NH:11][C:2]2=[O:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccccc1Cc1ncc[nH]1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1Nc2ccccc2Cc2nccn21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 32.4 g of phenyl chloroformate in 100 ml of acetonitrile was added dropwise under nitrogen while stirring to a mixture of 34.6 g of 2-(2-aminobenzyl)imidazole and 71 g of triethylamine in 600 ml of acetonitrile at room temperature. After addition was complete, the reaction mixture was heated under reflux for 12 hours, and allowed to cool to room temperature. Water (150 ml) was added, the mixture was stirred at room temperature for 0.5 hour and cooled to 5°. The resulting precipitate was filtered off, washed first twice with 50 ml of water, then 3 times with 33 ml of cold acetone and dried to give 11H-imidazo[1,2-c][1,3]benzodiazepin-5-(6H)-one, m.p. 255°-7°.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CC(C)=O.C(=O)=O.[C:13]([C:15]1(O)[CH2:21][CH:20]2[N:22]([CH2:23][CH:24]([F:26])[F:25])[CH:17]([CH2:18][CH2:19]2)[CH2:16]1)#[N:14].C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1>[C:13]([C:15]1[CH2:16][CH:17]2[N:22]([CH2:23][CH:24]([F:26])[F:25])[CH:20]([CH2:19][CH2:18]2)[CH:21]=1)#[N:14]
Reactant: N#CC1(O)CC2CCC(C1)N2CC(F)F
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(C)=O
Product: N#CC1=CC2CCC(C1)N2CC(F)F
Temperature: 55 °C
Reaction time: 24 h
Yield: 23 %

Procedure:
An oven-dried 50 ml 3-necked round bottom flask was fitted with a reflux condenser, thermometer and magnetic stirrer and an atmosphere of nitrogen was introduced. Phosphorous oxychloride (1.9 ml, 3.16 g, 24 mmol) and pyridine (14.7 ml) were charged and the mixture then cooled to −10° C. in an acetone/Drikold™ bath. 3-Cyano-3-hydroxy-8-(2,2-difluoroethyl)-8-azabicyclo[3.2.1]octane (2 g, assumed 9 mmol, from Step 2) was added in one portion and the resulting exotherm raised the reaction mass temperature to 55° C. The mixture was then heated to 80° C. and held at this temperature for 24 hours. The reaction mass was cooled to ambient, then added to a stirred mixture of ice/water (100 ml). The drowned out mass was made basic by addition of solid sodium carbonate (6 g) and the resulting aquesous solution was then extracted with ethyl acetate (3×100 ml). The combined organics were washed with brine (100 ml), dried (Na2SO4) and concentrated in vacuo to give 3-cyano-8-(2,2-difluoroethyl)-8-azabicyclo[3.2.1]oct-2-ene as a brown oil (0.41 g, 13% yield).
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([NH2:13])[CH:4]=1.C(Cl)Cl.CO>C(O)(=O)C.Br.O.C(OCC)(=O)C>[OH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([NH2:13])[CH:4]=1
Reactant: COc1cc(N)cc2ccccc12
Agent: Br
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cc(O)c2ccccc2c1

Procedure:
A solution of 4-methoxy-2-naphthylamine (230 mg, 1.33 mmol) in glacial acetic acid (9.6 mL) and hydrobromic acid in water (16 mL, 48%) was refluxed under N2 for 4 h. A small amount of sample (0.1 mL) was diluted with ethyl acetate (0.5 mL), and then water (0.5 mL) and TEA (0.1 mL) were added. TLC (20:1 DCM/methanol) of the organic layer showed no starting material and a new much lower spot (Rf=0.1). The solvent was removed under reduced pressure and the product was dried under vacuum to yield the intermediate 4-hydroxy-2-naphthylamine which was used for the next step without any purification. To a solution of 4-hydroxy-2-naphthylamine in dioxane (10 mL) was added TEA (1 mL) and di-tert-butyl dicarbonate (1.149 g, 5.27 mmol). The reaction mixture was refluxed under N2 for 4 h. TLC (4:1 hexane/ethyl acetate) showed no starting material and a new higher spot (Rf=0.55). The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water. The aqueous layer was extracted with ethyl acetate (2×50 mL) and the organics were combined and washed with brine. The organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield N-(tert-butyloxycarbonyl)-4—O—(tert-butyloxycarbonyl)-2-naphthylamine (2, 80% yield) as oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:20]=3[O:19][CH2:18][C:17]2=[O:28])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:31].[Na+]>O.C(OCC)(=O)C.C(OCC)(=O)C.O.[Ru](=O)=O>[C:1]([O:5][C:6](=[O:29])[NH:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:20]=3[O:19][CH2:18][C:17]2=[O:28])[C:12](=[O:31])[CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2c(c1)N(CCN1CCC(NC(=O)OC(C)(C)C)CC1)C(=O)CO2
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2c(c1)N(CCN1CCC(NC(=O)OC(C)(C)C)CC1=O)C(=O)CO2
Temperature: 25 °C
Reaction time: 53 h
Yield: 24.5 %

Procedure:
A mixture of tert-butyl{1-[2-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 47, 1.39 g, 3.4 mmol) in water/ethyl acetate (40 mL, 4:1) was treated with sodium periodate (2.8 g, 21.4 mmol) and ruthenium (IV) oxide hydrate (50 mg, 0.34 mmol) at room temperature. After 53 hours, the reaction was diluted with ethyl acetate, the aqueous phase was extracted with ethyl acetate (6×25 mL), and the combined organic layers were mixed with 2-propanol (20 mL) and stirred for 2 hours at room temperature. The reaction mixture was then filtered through celite, dried over sodium sulfate, and concentrated in vacuo. Chromatography on silica gel with dichloromethane/methanol (95:5) gave 350 mg (25%) of the product as a colorless solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:21]=[CH:20][C:6]2[C:7](=[O:19])[CH2:8][CH2:9][CH2:10][N:11]([C:16]([NH2:18])=[O:17])[C:12](=[O:15])[CH2:13][CH2:14][C:5]=2[CH:4]=1.[CH2:22]([OH:24])[CH3:23]>>[CH2:22]([O:24][C:12](=[O:15])[CH2:13][CH2:14][C:5]1[CH:4]=[C:3]([Cl:2])[CH:21]=[CH:20][C:6]=1[C:7](=[O:19])[CH2:8][CH2:9][CH2:10][NH:11][C:16]([NH2:18])=[O:17])[CH3:23]
Reactant: CCO
Reactant: NC(=O)N1CCCC(=O)c2ccc(Cl)cc2CCC1=O
Agent: Cl
Product: CCOC(=O)CCc1cc(Cl)ccc1C(=O)CCCNC(N)=O
Temperature: 25 °C
Reaction time: 312 h

Procedure:
7 ml of concentrated hydrochloric acid are added to a solution of 6.80 g (0.023 mol) of 11-chloro-2,3,5,6,7,8 -hexahydro-3,8-dioxo-4-benzazecine-4(1H)-carboxamide in 5 1 of ethanol and the mixture is stirred at room temperature for 13 days. The solution is concentrated, extracted with methylene chloride/water, dried with magnesium sulfate and the solvent is distilled in a vacuum. Chromatography on silica gel with methylene chloride/methanol (97:3) and crystallization from ethyl acetate/hexane gives ethyl -5-chloro-2-(4-ureidobutyryl)hydrocinnamate as white crystals with melting point 127-129°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:4]=1[NH:15][C:16]([NH2:18])=[S:17].BrBr>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]2[N:15]=[C:16]([NH2:18])[S:17][C:5]=2[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CCOCC2)cc1NC(N)=S
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: COc1ccc(N2CCOCC2)c2sc(N)nc12

Procedure:
(2-Methoxy-5-morpholin-4-yl-phenyl)-thiourea (5.0 g, 19 mmol) in chloroform (130 ml) are treated with bromine (960 □l) and the mixture refluxed for 18 hours. After removal of the volatile components in vacuo, the product is recrystallized from THF (2.8 g, 57%). MS: m/e=266 (M+).
Reaction SMILES: C[CH2:2][O:3][C:4]([C:6]1[C:15](=O)[N:14](C2C=CC=CC=2)[C:13]2[N:12]=[C:11]([NH:23]C3C=CC=CC=3)[N:10]=[CH:9][C:8]=2[N:7]=1)=O.FC(F)(F)C(O)=[O:33]>Cl.O=[Pt]=O>[NH2:23][C:11]1[NH:10][C:9](=[O:33])[C:8]2[NH:7][CH:6]([CH2:4][O:3][CH3:2])[CH2:15][NH:14][C:13]=2[N:12]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)c1nc2cnc(Nc3ccccc3)nc2n(-c2ccccc2)c1=O
Agent: O=[Pt]=O
Agent: Cl
Product: COCC1CNc2nc(N)[nH]c(=O)c2N1
Yield: 85 %

Procedure:
The pteridinone (0.5 g, 2.4×10-3 mol) previously prepared, vide supra, was hydrogenated under 1 atm of H2 in 30 mL of distilled trifluoroacetic acid over 0.02 g of PtO2 for an hour. The mixture was diluted with 25 mL of 6N HCl, filtered, and evaporated. The crude product, the tetrahydro compound, was recrystallized twice from 6N HCl/acetonitrile to give 2-amino-5,6,7,8-tetrahydro-6-methoxymethyl-4(3H)-pteridinone as a light brown solid (0.6 g, 85%): UV (0.1N HCl) λmax 215.5 nm (19800), 264 nm (19900); IR(KBr) 3300, 1665, 1570, 1540, 1470, 1365, 1300, 1150, 1110, 1005, 955, and 750 cm-1 ; NMR(DMSO-d6) 3.29δ (s, OMe), 3.4 (m, CH's), 3.6 (br s, OCH2), 8.0 (NH); anal. Calcd. for C8H13N5O2.2HCl.1/2H2O: C, 32.78; H, 5.50; N, 23.89; Cl, 24.19. Found: C, 32.75; H, 5.54; N, 23.80; Cl, 24.21.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:15]([CH3:16])[CH2:14][CH2:13][C:12]2=[O:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[Cl:37])[CH:32]=O>C1COCC1.Cl>[Cl:28][C:29]1[CH:30]=[C:31]([CH:32]=[C:13]2[CH2:14][CH:15]([CH3:16])[N:11]([S:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)(=[O:10])=[O:9])[C:12]2=[O:17])[CH:34]=[CH:35][C:36]=1[Cl:37]
Reactant: CC1CCC(=O)N1S(=O)(=O)c1ccc(F)cc1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1CC(=Cc2ccc(Cl)c(Cl)c2)C(=O)N1S(=O)(=O)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 7.3 %

Procedure:
A flame dried flask was charged with 332 mg 1-(4-fluorobenzenesulfonyl)-5-methyl-2-pyrrolidinone (prepared above, 1.29 mmol, 1.0 equiv) and 10 mL THF under N2. The solution was cooled to −78° C. followed by the addition of 1.68 mL of a 1.0 M solution of sodium bis(trimethylsilyl)amide (1.68 mmol, 1.3 equiv). The solution was allowed to stir for an additional 40 min followed by the addition of 271 mg 3,4-dichlorobenzaldehyde (1.54 mmol, 1.2 equiv) in 2 mL THF. After stirring an additional 10 min, the solution was diluted with 10 mL 0.1 N HCl and allowed to warm to rt. The solution was then extracted (3×Et2O), washed with brine, dried (MgSO4), and concentrated under reduced pressure. Purification via flash chromatography (SiO2, 1% MeOH/CH2Cl2) gave the product 3-(3,4-dichlorophenylmethylene)-1-(4-fluorobenzenesulfonyl)-5-methyl-2-pyrrolidinone as a white foam (39 mg, 0.0937 mmol, 7%). 1H NMR (DMSO, 400 MHz) δ 8.28 (m, 2 H), 7.96 (d, J=2 Hz, 1H), 7.85 (d, J=8.4 Hz, 1 H), 7.70-7.63 (m, 3 H), 7.45 (t, J=2.9 Hz, 1 H), 4.86 (m, 1 H), 3.59 (m, 1 H), 2.92 (m, 1 H), 1.56 (d, J=6.0 Hz, 3 H).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][O:8][C:4]=2[N:5]=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.Cl.[CH3:27][O:28][C:29](=[O:36])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH2:35]>CN(C=O)C>[CH3:27][O:28][C:29](=[O:36])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][O:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COC(=O)CCCCCN
Reactant: Clc1ncnc2occ(-c3ccccc3)c12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CCCCCNc1ncnc2occ(-c3ccccc3)c12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Heat 500 mg (2.19 mmol) 4-chloro-5-phenylfuro[2,3-d]pyrimidine, 1.51 ml (8.67 mmol) DIEA and 1 ml DMF to 160° C. and add 787.6 mg (4.34 mmol) 6-aminohexanoic acid methyl ester hydrochloride. After 4 h at 160° C., cool the reaction mixture, add to ice water and extract three times with ethyl acetate. Combine the organic phases and wash with saturated ammonium chloride solution, dry over magnesium sulphate and concentrate under vacuum. Purify the residue by chromatography on silica gel (solvent: cyclohexane/ethyl acetate 10:1→3:1). 470 mg (63.9% of theor.) of the target compound is obtained.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)[OH:8])[CH3:2].[C:20]([O:23][C:24]([CH3:32])([CH3:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br)(=[O:22])[CH3:21].C(=O)(O)[O-].[Na+]>C(#N)C>[CH2:1]([N:3]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:24]([O:23][C:20](=[O:22])[CH3:21])([CH3:31])[CH3:32])[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:13][CH:14]=1)[OH:8])[CH3:2]
Reactant: CCNCCCC(O)c1ccc(NS(C)(=O)=O)cc1
Reactant: CC(=O)OC(C)(C)CCCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCN(CCCCCC(C)(C)OC(C)=O)CCCC(O)c1ccc(NS(C)(=O)=O)cc1
Reaction time: 11 h
Yield: 68.1 %

Procedure:
A stirred mixture of the product from Example 7, Step II (1.5 g, 0.00524 mol), the product from Step V above 1.45 g, 0.00576 mol), sodium bicarbonate (0.88 g, 0.0105 mol) and acetonitrile (45 ml) was warmed at 90°-95°, under nitrogen for 6 hours and kept at ambient temperature for 11 hours. It was then filtered. The filtrate was concentrated and the residue chromatographed on silica gel with 0.5% NH4OH-6% MeOH--CH2Cl2 to give 1.63 g of the titled compound which is a compound of Formula I'. The high resolution mass spectrum had m/z 456 (M+). Theory for C23H40N2O5S: 456.2658; measured: 456.2650.
Reaction SMILES: [CH2:1]([C:3]1[C:27]([O:28][CH3:29])=[CH:26][C:6]([C:7]([N:9]2[CH2:13][CH2:12][C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([CH2:14][CH2:15]S(C)(=O)=O)[CH2:10]2)=[O:8])=[C:5]([O:30][C:31](=[O:33])[CH3:32])[C:4]=1[O:34][CH3:35])[CH3:2].[CH2:36]([O:38][CH2:39][CH2:40][N:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N:43]=[C:42]1[C:50]([CH:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)=[O:51])[CH3:37]>>[CH2:1]([C:3]1[C:27]([O:28][CH3:29])=[CH:26][C:6]([C:7]([N:9]2[CH2:13][CH2:12][C:11]([CH2:14][CH2:15][N:55]3[CH2:56][CH2:57][CH:52]([C:50]([C:42]4[N:41]([CH2:40][CH2:39][O:38][CH2:36][CH3:37])[C:45]5[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=5[N:43]=4)=[O:51])[CH2:53][CH2:54]3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:10]2)=[O:8])=[C:5]([O:30][C:31](=[O:33])[CH3:32])[C:4]=1[O:34][CH3:35])[CH3:2]
Reactant: CCOCCn1c(C(=O)C2CCNCC2)nc2ccccc21
Reactant: CCc1c(OC)cc(C(=O)N2CCC(CCS(C)(=O)=O)(c3ccccc3)C2)c(OC(C)=O)c1OC
Product: CCOCCn1c(C(=O)C2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(CC)c(OC)c4OC(C)=O)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 6.6.2 using 1-(4-ethyl acetoxy-3,5-dimethoxy-benzoyl)-3-phenyl-3-(2-methanesulfonyl-ethyl)-pyrrolidine and 4-[1-(2-ethoxy-ethyl)-1H-benzoimidazole-2-carbonyl]-piperidine to give the title compound.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]([C:24]([O:26]CC)=[O:25])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:38]([CH3:39])[C:37]4[CH:40]=[CH:41][CH:42]=[CH:43][C:36]=4[N:35]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[OH-].[Na+]>C(O)C>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]([C:24]([OH:26])=[O:25])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:38]([CH3:39])[C:37]4[CH:40]=[CH:41][CH:42]=[CH:43][C:36]=4[N:35]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(OC(C(=O)OCC)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(OC(C(=O)O)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 1b from 2-n-propyl-6-(1-methyl-benzimidazol-2-yl)-4-methyl-1-[4-[(α-ethoxycarbonyl)benzyloxy]benzyl]benzimidazole and 1N sodium hydroxide solution in ethanol.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH3:13][C:14]([CH3:58])([CH2:56][CH3:57])[CH2:15][C:16]1[N:17]=[C:18]([CH2:40][CH:41]([C:43]2[CH:48]=[CH:47][C:46]([C:49]3[CH:54]=[CH:53][C:52]([F:55])=[CH:51][N:50]=3)=[CH:45][CH:44]=2)O)[N:19]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=1.[CH3:59][NH:60][S:61]([C:64]1[CH:69]=[CH:68][C:67]([N+:70]([O-:72])=[O:71])=[CH:66][CH:65]=1)(=[O:63])=[O:62].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:13][C:14]([CH3:58])([CH2:56][CH3:57])[CH2:15][C:16]1[N:17]=[C:18]([CH2:40][CH:41]([N:60]([CH3:59])[S:61]([C:64]2[CH:65]=[CH:66][C:67]([N+:70]([O-:72])=[O:71])=[CH:68][CH:69]=2)(=[O:62])=[O:63])[C:43]2[CH:48]=[CH:47][C:46]([C:49]3[CH:54]=[CH:53][C:52]([F:55])=[CH:51][N:50]=3)=[CH:45][CH:44]=2)[N:19]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=1
Reactant: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(O)c2ccc(-c3ccc(F)cn3)cc2)n1
Reactant: CNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(c2ccc(-c3ccc(F)cn3)cc2)N(C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DEAD (1.3 mL, 8.2 mmol) was added to an ambient temperature solution of 2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]ethanol (2.5 g, 4.1 mmol), N-methyl-4-nitrobenzenesulfonamide (1.8 g, 8.2 mmol) and triphenylphosphine (2.7 g, 10.2 mmol) in tetrahydrofuran (20 mL). After stirring at ambient temperature overnight, the reaction mixture was concentrated. Chromatography over silica eluting with 0-60% ethyl acetate/hexane afforded N-{2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]ethyl}-N-methyl-4-nitrobenzenesulfonamide.