Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][N:20]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)[C:19](=[O:36])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][N:20]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:25][CH2:24]2)[C:19](=[O:36])[C:18]=1[I:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ccc(OCc3ccccc3)cc2=O)CC1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(n2ccc(OCc3ccccc3)c(I)c2=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
N-Iodosuccinimide (2.85 g) was added at room temperature to an acetic acid (57.6 mL) solution of tert-butyl 4-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)piperidine-1-carboxylate (4.43 g), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was rendered basic by the addition of a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate twice. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (4.83 g).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]3[S:17][CH:18]=[CH:19][C:11]2=3)=[O:9])=[CH:6][CH:5]=1)([O-])=O>C(O)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]3[S:17][CH:18]=[CH:19][C:11]2=3)=[O:9])=[CH:20][CH:21]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCCCc2sccc21
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1ccc(C(=O)N2CCCCc3sccc32)cc1
Reaction time: 4.5 h
Yield: 44.5 %

Procedure:
A solution of 9.97 g of 4-(4-nitrobenzoyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine in 110 ml of glacial acetic acid and 0.997 g of 10% palladium-on-carbon is hydrogenated in a Parr hydrogenator under 30-50 lb. of pressure for 4.5 hours. The mixture is filtered through a pad of diatomaceous earth and the filtrate concentrated to dryness under vacuum. The gummy residue (8.1 g) is purified by HPLC on a Waters-Prep-500 instrument with silica gel and ethyl acetate-hexane (1:1) as solvent. Fractions containing product are combined and the solvent removed. The residue is crystallized to give 4.0 g of crystals, m.p. 168°-172° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[C:15]=2[OH:18])[CH2:10]1.C([O-])(=O)C.[Na+]>O>[C:1]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[C:15]=2[OH:18])[CH2:10]1)(=[O:3])[CH3:2]
Reactant: NC1Cc2ccc(O)c(O)c2C1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)NC1Cc2ccc(O)c(O)c2C1
Reaction time: 4 h

Procedure:
Acetic anhydride is added to a mixture of 2-amino-4,5-dihydroxyindane Cannon, J. G., et al., J. Med. Chem.,27, 922(1984)! in water containing sodium acetate. The mixture is chilled and stirred in ice for 4 hours followed by filtration to give N-acetyl-2-amino-4,5-dihydroxyindane. Benzylbromide, powdered potassium carbonate and acetone is added to the isolated N-acetyl-2-amino-4,5-dihydroxyindane and the mixture is stirred for 18 hours. The reaction mixture is poured into water, extracted and evaporated in vacuo to give N-acetyl-2-amino-4,5-dibenzyloxyindane. Hydrolysis with ethanolic sodium hydroxide gives 2-amino-4,5-dibenzyloxyindane.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH2:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:15][C:16](=O)[CH2:17][CH3:18].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[CH2:17]([C:16]1[N:13]=[C:11]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[O:12][CH:15]=1)[CH3:18]
Reactant: CCC(=O)CBr
Reactant: NC(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1coc(Cc2ccc([N+](=O)[O-])cc2)n1
Temperature: 140 °C
Reaction time: 2 h
Yield: 14.1 %

Procedure:
A mixture of 2-(4-nitrophenyl)acetamide (14.6 g), 1-bromo-2-butanone (20.46 g) and N,N-dimethylformamide (2 mL) was stirred at 140° C. for 2 hrs. Water, potassium carbonate and ethyl acetate were added to basify the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 4-ethyl-2-(4-nitrobenzyl)-1,3-oxazole as brown crystals (2.65 g, yield 14%) from a fraction eluted with hexane-ethyl acetate (2:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave brown prism crystals. melting point: 58-59° C.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.CCCCCC.[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[C:16](=[O:22])[CH2:15]2.CO>O1CCCC1>[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[C:16](=[O:22])[CH2:15][CH2:1]2
Reactant: O=C1CN2CCC1CC2
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CO
Product: O=C1CCN2CCC1CC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
An ice-cooled solution (5° C.) of (trimethylsilyl)diazomethane/hexane (2 N, 30 mL, 60 mmol; Aldrich) under nitrogen was treated dropwise with a solution of quinuclidin-3-one (7500 mg, 60 mmol) in dry tetrahydrofuran (40 mL). Methanol (20 mL) was added, and the yellow solution was warmed to room temperature, stirred for 24 hours, and quenched to colorless by addition of acetic acid. After a few minutes, saturated aqueous sodium carbonate (15 mL) was added. The organic layer was separated, and the aqueous solution was extracted with methylene chloride (3×50 mL). The combined organic layer and extracts were dried over magnesium sulfate, and concentrated in vacuo to give the titled compound. The material was used directly for next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]=[O:18])=[C:12]([F:19])[C:11]=2[F:20])=[C:6]([F:21])[C:5]=1[F:22])[CH3:2].CC(C)=[O:25].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:25])=[O:18])=[C:12]([F:19])[C:11]=2[F:20])=[C:6]([F:21])[C:5]=1[F:22])[CH3:2]
Reactant: CCOc1ccc(-c2ccc(CC=O)c(F)c2F)c(F)c1F
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CCOc1ccc(-c2ccc(CC(=O)O)c(F)c2F)c(F)c1F
Reaction time: 2 h
Yield: 75.2 %

Procedure:
2-(4′-Ethoxy-2,2′,3,3′-tetrafluorobiphenyl-4-yl)acetoaldehyde (9) (17.2 g) prepared in the seventh step was dissolved in acetone (150 ml) and the solution was cooled on an ice bath. The Jones reagent (2.67M; 35 ml) was added to the solution. After 2 hours of stirring, isopropyl alcohol (10 ml) was added, and the stirring was continued for 30 minutes. The reaction mixture was filtered through Celite, and water (200 ml) and ethyl acetate (100 ml) were added to filtrate to give two layers. The water layer was extracted with ethyl acetate (50 ml) three times, and the combined organic layer was washed with water. The solution was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of back-extraction to give 2-(4′-ethoxy-2,2′,3,3′-tetrafluorobiphenyl-4-yl)acetic acid (10) (13.6 g) in 75.2% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:15])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH2:14])[CH:7]=1.[CH:16](OC)(OC)OC.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:15])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH3:16])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1-c1ccncc1N
Reactant: COC(OC)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Product: CNc1cnccc1-c1cc(Cl)ccc1C

Procedure:
To a solution of 4-(5-chloro-2-methyl-phenyl)-pyridin-3-ylamine (500 mg, 2.29 mmol) in trimethyl orthoformate (1.94 g, 2.00 mL, 18.3 mmol, CAS RN 149-73-5) was added 2-3 drops of TFA. The reaction mixture was stirred at reflux for 2 hours and then concentrated under vacuum. The residue was dissolved in 5 ml toluene and evaporated (repeated 3 times). The residue was dissolved in THF (10 mL) and LiAlH4 (260 mg, 6.86 mmol) was added in portions at 0° C. The cooling bath was removed, the reaction mixture stirred at room temperature for 1 hour and then poured on 30 mL 10% aqueous NH4Cl solution and 30 mL EtOAc. The layers were separated and the aqueous layer extracted a second time with 30 mL EtOAc. The combined organic layers were washed with 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light yellow solid (331 mg, 62%). MS (ESI): m/z=233.084 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24](O)=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:60][CH2:61][CH2:62][CH2:63][NH:64][C:65](=[O:71])[O:66][C:67]([CH3:70])([CH3:69])[CH3:68]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([NH:60][CH2:61][CH2:62][CH2:63][NH:64][C:65](=[O:71])[O:66][C:67]([CH3:69])([CH3:68])[CH3:70])=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NCCCNC(=O)OC(C)(C)C)c2n1
Reaction time: 3 h
Yield: 86.9 %

Procedure:
To a mixture of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation K, 200 mg, 0.560 mmol) and HATU (255 mg, 0.672 mmol) in DMF (2 mL) was added DIEA (292 μL, 1.68 mmol), followed by dropwise addition of tert-butyl 3-aminopropylcarbamate (117 mg, 0.672 mmol) at ambient temperature. After stirring for 3 hours, the reaction was directly purified by reverse-phase chromatography (5 to 70% acetonitrile/water) to yield the final product as white solid (250 mg, 87%). LCMS (apci) m/z=414.1 (M+H-Boc).
Reaction SMILES: C([C:3]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1)(C([O-])=O)[C:4]([O:6][C:7](C)(C)[CH3:8])=[O:5])C.Cl>C(OCC)(=O)C>[CH2:7]([O:6][C:4](=[O:5])[CH2:3][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1)[CH3:8]
Reactant: CCC(C(=O)[O-])(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])cn1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To tert-butyl ethyl(5-nitropyridin-2-yl)malonate (10 g) obtained in Step A of Example 153 was added a solution of 4 M hydrogen chloride in ethyl acetate (40 mL), and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and diethyl ether (150 mL) and saturated aqueous sodium hydrogen carbonate solution were added thereto. To the reaction mixture was added sodium hydrogen carbonate until bubble generation stopped, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (5.6 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:14][C:15]1[CH:24]=[CH:23][C:18]2[O:19][CH2:20][CH2:21][O:22][C:17]=2[CH:16]=1)[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[O:26]=[C:27]1[CH:36]=[N:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]1[CH2:37][CH:38]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:14][C:15]1[CH:24]=[CH:23][C:18]2[O:19][CH2:20][CH2:21][O:22][C:17]=2[CH:16]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:38][CH2:37][N:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:35]=[CH:36][C:27]2=[O:26])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=CCn1c(=O)cnc2ccccc21
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cnc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
To 3 mL of dichloromethane solution containing 0.19 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 0.10 g of (2-oxoquinoxalin-1(2H)-yl)acetaldehyde and 30 μl of acetic acid were added and stirred at room temperature for 2 hours. To the reaction mixture, 0.17 g of sodium triacetoxyborohydride was added and stirred at the same temperature for 30 min. Chloroform and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; ethyl acetate] to give 0.22 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a light brown oil.
Reaction SMILES: [SiH:1]([C:4]([C:7]([C:10]([C:13]([C:16]([C:19]([C:22]([C:25](F)(F)F)(F)F)(F)F)(F)F)(F)F)(F)F)(F)F)(F)F)([CH3:3])[CH3:2].C(I)(C(C(C(C(C(C(C(F)(F)F)(F)F)(F)F)(F)F)(F)F)(F)F)(F)F)(F)F>>[SiH:1]([CH2:4][CH2:7][CH2:10][CH2:13][CH2:16][CH2:19][CH2:22][CH3:25])([CH3:2])[CH3:3]
Reactant: C[SiH](C)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Product: CCCCCCCC[SiH](C)C

Procedure:
A 10.14 g fraction of HSi(CH3)2C8F17 with a boiling point of 57-59° C. under a pressure of 11 mbar and which comprises, according to 19F NMR, approximately 5% of C8F17I is obtained (yield: 44%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]([CH3:22])=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.[CH:27](=O)[CH3:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCl.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]([CH3:22])=[C:6]([N:8]([CH2:27][CH3:28])[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1
Reactant: CC=O
Reactant: COC(=O)c1cc(Cl)cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCN(c1cc(Cl)cc(C(=O)OC)c1C)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
To a stirred solution of tert-butyl 4-{[5-chloro-3-(methoxycarbonyl)-2-methylphenyl]amino}piperidine-1-carboxylate (2.40 g, 6.28 mmol) in dichloromethane (50 mL) and acetic acid (1.8 mL) was added acetaldehyde (830 ul, 12.6 mmol) and sodium triacetoxyborohydride (4.00 g, 18.8 mmol). The reaction mixture was stirred at rt for 18 hours. Then aq. NaHCO3 was added and the mixture was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO2 heptane/ethylacetate=10/1) to give the titled compound as oil (2.40 g, 89% yield). 1H-NMR (400 MHz, CDCl3) δppm; 7.56 (s, 1H), 7.21 (d, J=1.6 Hz, 1H), 4.04 (m, 2H), 3.89 (s, 3H), 3.02 (q, J=7.0 Hz, 2H), 2.88 (m, 1H), 2.68 (m, 2H), 2.44 (s, 3H), 1.71 (m, 2H), 1.48-1.61 (m, 2H), 1.45 (s, 9H), 0.83-0.89 (t, J=7.0 Hz, 3H); MS (ES) [M+Na] 433.0.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([CH3:28])[CH:19]=1>C(O)C.Cl>[CH3:15][N:14]([CH3:16])[CH2:13][CH2:12][NH:11][S:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[C:20]([CH3:28])[CH:19]=2)[CH:3]=1)(=[O:10])=[O:9]
Reactant: Cc1cc(Cl)c2ccccc2n1
Reactant: CN(C)CCNS(=O)(=O)c1cccc(N)c1
Agent: Cl
Solvent: CCO
Product: Cc1cc(Nc2cccc(S(=O)(=O)NCCN(C)C)c2)c2ccccc2n1
Yield: 3.2 %

Procedure:
To a solution of 4 (0.3 g, 1.23 mmol) and 4-chloroquinaldine (5, 0.26 mL, 1.29 mmol) in ethanol (10 mL) were added 2 drops of conc. HCl. The resulting mixture was heated under reflux overnight before ethanol was removed under reduced pressure. The residue was basified with saturated NaHCO3 (aq. 20 mL) and the basic solution was extracted with EtOAc (2×20 mL). The combined organic layers were dried over MgSO4, the solids were filtered and the filtrate was concentrated on a rotavap. The residue was purified on Florisil® to give the title compound as an orange solid (15 mg).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:18]1[C:23]([I:24])=[C:22]([CH:25]([Cl:27])[CH3:26])[N:21]=[CH:20][N:19]=1>C1(C)C=CC=CC=1>[Cl:27][CH:25]([C:22]1[N:21]=[CH:20][N:19]=[C:18]([NH:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:23]=1[I:24])[CH3:26]
Reactant: NCCc1ccccc1
Reactant: CC(Cl)c1ncnc(Cl)c1I
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(Cl)c1ncnc(NCCc2ccccc2)c1I
Temperature: 60 °C

Procedure:
In 20 ml of toluene were dissolved 2-phenylethylamine (0.6 g) and triethylamine (0.6 g), then, 4-chloro-6-(1-chloro-ethyl)-5-iodopyrimidine (1.5 g) was added to the solution, and the mixture was heated at about 60° C. for 3 hours while stirring.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH2:6][C:7]([OH:9])=[O:8])[C:3](O)=[O:4]>C(OC(=O)C)(=O)C>[CH3:1][C:2]1([CH3:10])[CH2:6][C:7](=[O:9])[O:8][C:3]1=[O:4]
Reactant: CC(C)(CC(=O)O)C(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC1(C)CC(=O)OC1=O
Yield: 84.4 %

Procedure:
50 g of 2,2-dimethylsuccinic acid and 70 ml of acetic anhydride were reacted at 140° C. for 3 hours and, after removing acetic acid and acetic anhydride under reduced pressure, the residue was subjected to vacuum distillation to obtain 37 g of 2,2-dimethylsuccinic anhydride.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:23](Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[CH2:23]([NH:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: ClCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: c1ccc(CNCC(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
To a solution of 2,2-diphenyl ethyl amine (10.0 g, 0.051 mol) and triethyl amine (20.5 g, 0.203 mol) in 200 mL tetrahydrofuran was added a solution of benzyl chloride (7.1 g, 0.056 mol) in 100 mL tetrahydrofuran. The reaction mixture was heated to reflux for 48 hours, then cooled to room temperature and concentrated in vacuo. The residue was taken up in 300 mL chloroform and washed with 3×100 mL water. The organic layer was then stirred with 100 mL 2N NaOH solution for 30 minutes. The layers were separated and the aqueous layer was extracted further with 2×100 mL chloroform. The chloroform layers were combined, dried over sodium sulfate, filtered, and concentrated under vacuum. The resulting oil was further purified by chromatography, eluting with hexane/ethyl acetate. 5.8 g of a clear oil was isolated which was characterized by analytical and spectroscopic properties as the hydrochloride salt, mp 250-253° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[OH:12][CH:13]([CH2:16][OH:17])[CH2:14][NH2:15].C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:15][CH2:14][CH:13]([OH:12])[CH2:16][OH:17])=[C:3]([CH3:11])[CH:4]=1)([O-:10])=[O:9]
Reactant: NCC(O)CO
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1cc([N+](=O)[O-])ccc1NCC(O)CO
Temperature: 60 °C
Yield: 68.6 %

Procedure:
2 g of 2-fluoro-5-nitrotoluene were added to a solution of 20 ml of N-methylpyrrolidinone, 1.4 g of 2,3-dihydroxy-1-propylamine, and 2.14 g of K2CO3. The reaction medium was heated at 60° C. for 15 hours and, after cooling to room temperature, was poured into a water/ice mixture. A yellow precipitate formed, which was filtered off, reslurried in water and then dried over P2O5. 2 g of 3-(4-nitro-2-methylphenylamino)propane-1,2-diol (7) were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][C@@H:8]([C:24]([O:26]C)=[O:25])[NH:9][C:10](=[O:23])[CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[CH:5][CH:4]=1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][C@@H:8]([C:24]([OH:26])=[O:25])[NH:9][C:10](=[O:23])[CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:21])([F:20])[F:22])=[CH:5][CH:4]=1
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1ccccc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C[C@H](NC(=O)C=Cc2ccccc2C(F)(F)F)C(=O)O)cc1
Yield: 83.4 %

Procedure:
The same procedures as in Example 64 were carried out from the compound obtained in Example 43 (4.1 g), 1 mol/L of an aqueous sodium hydroxide solution (15 mL), and methanol (150 mL), to give the captioned compound (3.3 g, 83%) as crystals.
Reaction SMILES: C([O:3][C:4](=[O:37])[C@@H:5]([NH:13][C:14]1[S:15][C:16](=[CH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:36][CH2:35][C:30]4(OCCO4)[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)[C:17](=[O:19])[N:18]=1)[CH2:6][CH2:7][C:8]([O:10]CC)=[O:9])C.[OH:38][C@@H:39]([CH2:52][NH2:53])[CH2:40][O:41][C:42]1[C:50]2[NH:49][C:48](=[O:51])[NH:47][C:46]=2[CH:45]=[CH:44][CH:43]=1.CNC1SC(=CC2C=CC(N3CCC(=O)CC3)=CC=2)C(=O)N=1.NCC(C1C=CC(O)=C(NS(C)(=O)=O)C=1)O>>[OH:38][C@H:39]([CH2:40][O:41][C:42]1[C:50]2[NH:49][C:48](=[O:51])[NH:47][C:46]=2[CH:45]=[CH:44][CH:43]=1)[CH2:52][NH:53][CH:30]1[CH2:29][CH2:28][N:27]([C:24]2[CH:25]=[CH:26][C:21]([CH:20]=[C:16]3[S:15][C:14]([NH:13][C@@H:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[C:4]([OH:3])=[O:37])=[N:18][C:17]3=[O:19])=[CH:22][CH:23]=2)[CH2:36][CH2:35]1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: CCOC(=O)CC[C@H](NC1=NC(=O)C(=Cc2ccc(N3CCC4(CC3)OCCO4)cc2)S1)C(=O)OCC
Agent: CNC1=NC(=O)C(=Cc2ccc(N3CCC(=O)CC3)cc2)S1
Agent: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Product: O=C(O)CC[C@H](NC1=NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)S1)C(=O)O

Procedure:
The title compound was prepared from (2S)-2-{5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-pentanedioic acid diethyl ester (which was obtained in Intermediate 34) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (Jesudason, C. D., et al., EP 0 764 640) according to the procedures of Intermediate 18, Example 1 and Example 9 as a yellowish solid; mp>270° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.40-1.70 (m, 2 H), 1.80-4.30 (m, 17 H), 6.50-6.80(m, 2 H), 6.80-7.10(m, 3 H), 7.23(d, J=8.4 Hz, 2 H), 7.37 (s, 1 H), 10.61(brs, 1 H), 11.01 (brs, 1 H); MS (ES) m/z: 320.3 ((M+2H)2+, 100%); 639.4 (MH+, 60%); HRMS Calcd. for C30H35N6O8S (MH+): 639.2231. Found: 639.2233.