Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N+:11]([O-])=O)=[CH:4][N:3]=1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[H][H].C1CCCCC=1>C(O)C.[Pd]>[ClH:1].[ClH:1].[NH2:8][C:7]1[C:2]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:3][CH:4]=[C:5]([NH2:11])[CH:6]=1
Reactant: C1CCNCC1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: Cl
Product: Nc1cnc(N2CCCCC2)c(N)c1

Procedure:
2 g of (1-piperidyl)-3,5-dinitropyridine, obtained according to Protocol A from 2-chloro-3,5-dinitropyridine and piperidine, were reduced by hydrogen transfer in 50 ml of ethanol in the presence of palladium-on-charcoal and 5 ml of cyclohexene. 930 mg of N-(3,5-diaminopyrid-2-yl)piperidine dihydrochloride were thus obtained.
Reaction SMILES: [CH:1]([CH:4]1[C:12]2[C:7](=[CH:8][C:9](C)=[C:10]([CH3:13])[CH:11]=2)[C:6]([CH3:16])([CH3:15])[CH:5]1[CH3:17])([CH3:3])[CH3:2].C[O:19][CH:20](Cl)Cl.[CH2:23](Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl>[CH:20]([C:9]1[C:8]([CH3:23])=[C:7]2[C:12](=[CH:11][C:10]=1[CH3:13])[CH:4]([CH:1]([CH3:2])[CH3:3])[CH:5]([CH3:17])[C:6]2([CH3:16])[CH3:15])=[O:19]
Reactant: COC(Cl)Cl
Reactant: Cc1cc2c(cc1C)C(C)(C)C(C)C2C(C)C
Reactant: ClCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Product: Cc1cc2c(c(C)c1C=O)C(C)(C)C(C)C2C(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The compound 1-isopropyl-2,3,3,4,6-pentamethylindane is then treated as follows to yield 5-formyl-1-isopropyl-2,3,3,4,6-pentamethylindane. Specifically, 1-isopropyl-2,3,3,5,6-pentamethylindane (12.96 g) is placed in a 1 liter three-necked round bottom flask equipped with a reflux condenser, a stirrer and a dropping funnel. In accordance with the general procedures described in Organic Syntheses, Collective Vol. 5, pp. 49-50, by A. Rieche, H. Gross, and E. Hoft, edited by H. E. Baumgarten, John Wiley and Sons (New York, N.Y. 1973), methylene chloride (37.5 ml) is added to the flask. The solution is then cooled in an ice bath, and titanium tetrachloride (19.0 g) is added over a period of about 3 minutes. While the solution is stirred and cooled, α,α-dichloromethyl methyl ether (5.75 g) is added dropwise over a 25 minute period. After the addition is complete, the mixture is stirred for about 5 minutes in the ice bath, for about 30 minutes without cooling, and for about 15 minutes at about 35° C. The reaction mixture is then poured into a separatory funnel containing about 50 g of crushed ice and is shaken thoroughly. The organic layer is separated, and the aqueous solution is extracted with two 10 ml portions of methylene chloride. The combined organic solution is washed three times with 10 ml portions of water. A crystal of hydroquinone is added to the methylene chloride solution, which is then dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue is distilled to yield, as a crude product, 5-formyl-1-isopropyl-2,3,3,4,6-pentamethylindane. The 5-formyl-1-isopropyl-2,3,3,4,6-pentamethylindane is then further purified using standard fractional distillation techniques.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:8][CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1.O.O>[CH2:16]([O:23][C:24](=[O:25])[NH:1][C:2]1[C:3]([O:8][CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1ncccc1N
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ncccc1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 3-amino-2-methoxypyridine (3.93 g, 31.7 mmol) in THF/H2O (1:1) (120 mL) was added Cs2CO3 (12.4 g, 38.0 mmol) and benzylchloroformate (5.33 mL, 37.9 mmol) and the reaction stirred at room temperature for 5 hours. The mixture was diluted with water, extracted with EtOAc, dried over MgSO4, filtered, and the solvent was removed. The crude product was purified by chromatography (silica gel, 25% EtOAc/hexanes). MS 259 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[N:4][C:3]=1[NH:31][C@@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1.[C:37]1(B(O)O)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CN1CCCC1=O.C(=O)([O-])[O-].[Na+].[Na+]>O.C(Cl)(Cl)Cl>[CH3:30][N:27]1[CH2:28][CH2:29][N:24]([CH:21]2[CH2:22][CH2:23][N:18]([C:15]3[CH:16]=[CH:17][C:12]([NH:11][C:5]4[C:6]([C:8]([NH2:10])=[O:9])=[N:7][C:2]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)=[C:3]([NH:31][C@@H:32]5[CH2:36][CH2:35][NH:34][CH2:33]5)[N:4]=4)=[CH:13][CH:14]=3)[CH2:19][CH2:20]2)[CH2:25][CH2:26]1
Reactant: CN1CCN(C2CCN(c3ccc(Nc4nc(N[C@@H]5CCNC5)c(Br)nc4C(N)=O)cc3)CC2)CC1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN1CCN(C2CCN(c3ccc(Nc4nc(N[C@@H]5CCNC5)c(-c5ccccc5)nc4C(N)=O)cc3)CC2)CC1
Temperature: 120 °C
Reaction time: 4 h
Yield: 95.4 %

Procedure:
Under an argon atmosphere, to a mixture of 6-bromo-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-[(3R)-pyrrolidin-3-ylamino]pyrazine-2-carboxamide (257 mg), phenylboronic acid (196 mg), and N-methylpyrrolidone (5.14 mL) were added tetrakistriphenylphosphine palladium (0) (80 mg) and a 2 M aqueous sodium carbonate solution (805 μL), followed by stirring at 120° C. for 4 hours. After leaving to be cooled, chloroform and water were added thereto, followed by stirring, and the insoluble matter was separated by filtration. The filtrate was subjected to liquid separation, and the organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform:methanol:28% aqueous ammonia=1:0:0-150:10:1) to obtain 3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-6-phenyl-5-[(3R)-pyrrolidin-3-ylamino]pyrazine-2-carboxamide (244 mg) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:19])=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:19])=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCCc1ccc(-c2ccc(OC)c(Cl)c2F)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCCc1ccc(-c2ccc(O)c(Cl)c2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
22.0 g of the compound (b66) was dissolved in 200 mL of methylene chloride. 23.7 g of boron tribromide was added dropwise to the resulting solution in a temperature range of −27 to −20° C., and the temperature of the solution was gradually increased to room temperature, followed by stirring overnight. The resulting reaction mixture was poured slowly to 300 mL of iced water, and the mixture was left at rest to separate into an organic layer and an aqueous layer, followed by extracting to the organic layer. The resulting organic layer was washed with a sodium chloride aqueous solution in three times, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was a yellowish solid. 19.7 g of the residue was purified by recrystallization from a mixed solvent of heptane and toluene (heptane/toluene=2/1 by volume) to obtain 18.0 g of 3-chloro-2-fluoro-4′-propylbiphenyl-4-ol (b67). The resulting compound (b67) was a white solid.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:20][C:6]2[C:7]3[NH:8][C:9](=[O:19])[C:10](=[O:18])[NH:11][C:12]=3[CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:5]=2[CH2:4]1.[C:21](OC(=O)C)(=[O:23])[CH3:22].C(N(CC)CC)C>O>[CH3:1][N:2]([CH:3]1[CH2:20][C:6]2[C:7]3[NH:8][C:9](=[O:19])[C:10](=[O:18])[NH:11][C:12]=3[CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:5]=2[CH2:4]1)[C:21](=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CNC1Cc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N(C)C1Cc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 8-methylamino-6-nitro-4,7,8,9-tetrahydro-1H-cyclopenta[f]quinoxaline-2,3-dione (0.5 g. 1.6 mmol), acetic anhydride (0.5 g, 5 mmol), triethylamine (0.5 g, 5 mmol) in water (5 mL) was stirred for 15 min at room temperature. The solid was collected by filtration, washed with 2N HCl, then washed with diethyl ether and dried (0.5 g). Calc'd for C14 H14N4O5 : C, 52.83; H, 4.43; N, 17.60; found: C, 48.62; H, 4.26; N, 15.50.
Reaction SMILES: CS(C)=O.[C:5]([Si:9]([CH3:27])([CH3:26])[O:10][C@H:11]1[CH2:20][CH2:19][CH2:18][C@@:17]2([CH3:21])[C@H:12]1[CH2:13][CH2:14][CH:15]=[C:16]2[C@H:22]([CH3:25])[CH2:23][OH:24])([CH3:8])([CH3:7])[CH3:6].CCN(CC)CC>C(Cl)Cl.C(Cl)(=O)C(Cl)=O>[C:5]([Si:9]([CH3:27])([CH3:26])[O:10][C@H:11]1[CH2:20][CH2:19][CH2:18][C@@:17]2([CH3:21])[C@H:12]1[CH2:13][CH2:14][CH:15]=[C:16]2[C@H:22]([CH3:25])[CH:23]=[O:24])([CH3:7])([CH3:8])[CH3:6]
Reactant: C[C@H](CO)C1=CCC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](C=O)C1=CCC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Reaction time: 0.3 h

Procedure:
Swern reagent was prepared at -78° C. by adding slowly 1.6 ml of abs. DMSO, dissolved in 4 ml of CH2Cl2, to 0.908 ml of oxalylchloride in 26 ml of CH2Cl2.15 minutes later, 3.27 g of (S)-2-[(4aR,5S,8aS)-5-(tert-butyldimethyl-silanyloxy)-8a-methyl-3,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl]-propan-1-ol (synthesis described in ref. Ex. 12) dissolved in 11 ml of CH2Cl2, were slowly added. After 0.3 h, 4.6 ml of NEt3 were added dropwise and the temperature allowed to reach -15° C. The reaction was quenched by pouring onto crushed ice/NH4Cl, extracted with ether, washed with water and brine, dried over magnesium sulfate and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=97/3) yielded (S)-2-[(4aR,5S,8aS)-5-(tert-butyldimethyl-silanyloxy)-8a-methyl-3,4,4a,5,6,7,8,8a-octa-hydro-naphthalen-1-yl]-propionaldehyde in nearly quantitative yield.
Reaction SMILES: [OH:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:3].C(O)(=O)CCCCCCCCCCC.[Ag:27].[N+]([O-])([O-])=O.[Ag+].[BrH:33]>C(OCCCC)(=O)C>[O-:3][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:1].[Ag+:27].[Ag:27][Br:33]
Reactant: CCCCCCCCCC(=O)O
Reactant: [Ag]
Reactant: Br
Agent: [Ag+]
Agent: CCCCCCCCCCCC(=O)O
Agent: O=[N+]([O-])[O-]
Solvent: CCCCOC(C)=O
Product: Br[Ag]
Product: CCCCCCCCCC(=O)[O-]

Procedure:
A solution of 8.5 g of capric acid dissolved in 100 ml of butyl acetate was kept to 5° C, and 0.7 g of an N-halo compound of the invention (Compound 2) was emulsified in the solution with stirring. To the emulsion, 50 ml of an aqueous solution of silver ammine complex salt containing 8.5 g of silver nitrate (5° C) was added dropwise over a period of 30 seconds to react the capric acid, hydrogen bromide and silver ion and to form silver caprate and silver bromide, simultaneously. After removing the water layer, the butyl acetate layer containing the silver caprate and silver bromide was dispersed in 120 g of a 15 wt% isopropanol solution of polyvinyl butyral using a mixer to provide a polymer dispersion of the silver salt. To the polymer dispersion of the silver salt, the following components were added at intervals of 5 minutes at 40° C to provide a coating solution which was then coated on a coated paper in a silver amount of 0.7 g/m2 to obtain a heat developable light-sensitive material (Sample 3).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@@H:7]([NH2:10])[CH2:8][OH:9])=[CH:3][CH:2]=1.Cl[CH2:12]/[CH:13]=[CH:14]\[CH2:15]Cl>>[C:4]1([C@@H:7]([N:10]2[CH2:15][CH:14]=[CH:13][CH2:12]2)[CH2:8][OH:9])[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: ClC/C=C\CCl
Product: OC[C@@H](c1ccccc1)N1CC=CC1
Yield: 58 %

Procedure:
This was prepared from R-(−)-2-phenylglycinol and cis-1,4-dichloro-2-butene in 58% yield according to the procedures similar to those described in Preparation 1.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[CH2:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:57][N:58]1[CH2:63][CH2:62][CH:61]([NH2:64])[CH2:60][CH2:59]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:64][CH:61]5[CH2:62][CH2:63][N:58]([CH3:57])[CH2:59][CH2:60]5)=[O:28])=[CH:24][C:23]=4[CH2:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCC(N)CC1
Reactant: CCc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CCc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethylbenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (t, J=8.0 Hz, 3H) 1.23-1.69 (m, 11H) 1.77 (m, 4H) 1.99 (m, 2H) 2.20 (s, 3H) 2.69 (q, J=7.3 Hz, 2H) 3.75 (s, 1H) 3.97 (t, J=14.2 Hz, 2H) 4.54 (t, J=8.1 Hz, 1H) 7.57-7.81 (m, 3H) 8.12 (d, J=7.8 Hz, 1H) 8.17 (s, 1H) 8.61 (s, 1H). [M+H] calc'd for C28H37F2N7O2, 542. found 542.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]([F:17])([F:16])[S:11]([O:14]C)(=[O:13])=[O:12].[CH3:18]CCCCC>C(Cl)Cl>[F:9][C:10]([F:17])([F:16])[S:11]([O-:14])(=[O:13])=[O:12].[CH3:8][S+:7]([CH3:18])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCC
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: CSc1ccccc1
Solvent: ClCCl
Product: C[S+](C)c1ccccc1
Product: O=S(=O)([O-])C(F)(F)F

Procedure:
To a solution of thioanisole (2.48 g, 20 mmole) in methylene chloride (20 ml), methyl trifluoromethanesulfonate (3.28 g, 20 mmole) was added dropwise at 10° C. or below, and the mixture was refluxed for 2 hours with stirring. After cooling, the reaction solution was poured into n-hexane (75 ml), and the precipitate was filtered, washed with n-hexane and dried. The resultant crude solid (5.35 g) was recrystallized from iso-propanol to give 4.8 g of dimethylphenylsulfonium trifluoromethanesulfonate as white leaflets. m.p. 106.0°-107.2° C.
Reaction SMILES: [H-].[Na+].CCCCC.[C:8]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH2:19](Br)[CH:20]=[C:21]([CH3:23])[CH3:22]>O1CCCC1.CN(C)C=O>[CH3:22][C:21]([CH3:23])=[CH:20][CH2:19][CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:8]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC=C(C)C)C(=O)OCC
Reaction time: 0.67 h
Yield: 89.4 %

Procedure:
422 mg (14.1 mmol, 80% mineral oil dispersion) sodium hydride was washed 3 ×, each with 5 mL pentane, and suspended in a mixture of 10 mL tetrahydrofuran and 5 mL dimethylformamide. 2.04 g (13.4 mmol) diethyl malonate was added, and the mixture stirred for 40 mins to form a clear light brown solution. Prenyl bromide (2.00 g, 13.4 mmol) was then added, and the solution refluxed for 1 hr. The reaction was quenched with water, acidified to pH 2 with 1N HCl, and extracted 2 ×, each with 10 mL diethyl ether. The organic phases were dried over MgSO4, filtered, and concentrated. Chromatography on a 2×18 cm column, packed with hexane and eluted with 50 mL each of 2%, 4%, 7%, 10%, and 15% diethyl ether/hexane, furnished 2.734 g of a clear colorless oil in 12 mL fractions 4-16.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[C:9]([O:13][C:14]([NH:16][C:17]([CH3:22])([C:19](O)=[O:20])[CH3:18])=[O:15])([CH3:12])([CH3:11])[CH3:10].CN(C)CCCN=C=NCC>ClCCl>[O:8]=[C:3]1[CH2:4][CH2:5][C:6](=[O:7])[N:2]1[O:1][C:19](=[O:20])[C:17]([NH:16][C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])([CH3:22])[CH3:18]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)ON1C(=O)CCC1=O

Procedure:
A stirred solution of N-hydroxysuccinimide (112 g, 0.973 mol), N-t-butoxycarbonyl-α-methylalanine (197 g, 0.969 mol), and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (186 g, 0.970 mol) in anhydrous dichloromethane (1.4 L) was stirred at room temperature for about 18 hours under nitrogen atmosphere. The reaction mixture was washed three times each with saturated sodium bicarbonate solution and then brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound of part 1-D as a white solid (256 g, 88%): PBMS (M+18)+ 318; 1H NMR=250 MHz (CDCl3) δ: 4.91 (NH, br s, 1H), 2.84 (—CO(CH2)2CO—, s, 4H), 1.67 (Me, s, 6H), 1.48 (BOC, s, 9H).
Reaction SMILES: [C:1]([O:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([CH3:14])[C:8]([CH3:16])([CH3:15])[CH2:7]1)(=[O:4])[NH:2][NH2:3].[CH3:17][C:18]1([CH3:34])[CH2:23][CH:22]([NH:24][C:25](=[O:31])[C:26](OCC)=[O:27])[CH2:21][C:20]([CH3:33])([CH3:32])[NH:19]1>CO>[CH3:17][C:18]1([CH3:34])[CH2:23][CH:22]([NH:24][C:25](=[O:31])[C:26]([NH:3][NH:2][C:1]([O:5][CH:6]2[CH2:11][C:10]([CH3:12])([CH3:13])[N:9]([CH3:14])[C:8]([CH3:16])([CH3:15])[CH2:7]2)=[O:4])=[O:27])[CH2:21][C:20]([CH3:33])([CH3:32])[NH:19]1
Reactant: CCOC(=O)C(=O)NC1CC(C)(C)NC(C)(C)C1
Reactant: CN1C(C)(C)CC(OC(=O)NN)CC1(C)C
Solvent: CO
Product: CN1C(C)(C)CC(OC(=O)NNC(=O)C(=O)NC2CC(C)(C)NC(C)(C)C2)CC1(C)C
Temperature: 50 °C

Procedure:
Into a 100 ml 3-neck flask was added 7.3 grams (0.0318 mole) of 1,2,2,6,6-pentamethyl-4-piperidinyl carbazate, 12.9 grams (0,032 mole) of a 60% solution of ethyl N-(2,2,6,6-tetramethyl-4-piperidinyl)oxamate in methanol and 15 ml of methanol. The flask was equipped with a magnetic stirrer, thermometer and a Dean Stark trap with reflux condenser. The flask was placed in a hot oil bath and heated to reflux. The methanol was distilled off through the Dean Stark trap and the residue was heated for 4 hours at 75°-80° C. Liquid chromatography of the residue indicated that the reaction had proceeded to 85-90% of completion. The reaction was cooled to 50° C. and 50 ml of methanol was added to dissolve the product. The methanol solution was cooled in the freezer (-10° C.) overnight and the next day the crystals that formed were filtered off and air dried. The dry crystals weighed 3.1 grams and melted at 165°-170° C. A liquid chromatography scan indicated the presence of only one component. The infrared spectrum of the product contained a weak carbonyl peak at 1740 cm-1 and strong, sharp carbonyl peaks at 1600 and 1685 cm-1. A second crop of 4.5 grams was obtained by concentrating the filtrate to about 25 ml, cooling and filtering off the solids that formed. The filtrate was stripped to dryness, leaving 7.0 grams of product which was contaminated with small amounts of the starting materials.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[CH3:2].Cl[CH2:26][C:27]1[N:35]([CH2:36][CH2:37][O:38][CH2:39][CH3:40])[C:30]2=[N:31][CH:32]=[CH:33][CH:34]=[C:29]2[N:28]=1.[C:41](=[O:44])([O-:43])[O-].[Na+].[Na+]>CN(C)C(=O)C>[C:4]([OH:3])(=[O:38])[C:41]([OH:43])=[O:44].[CH2:39]([O:38][CH2:37][CH2:36][N:35]1[C:30]2=[N:31][CH:32]=[CH:33][CH:34]=[C:29]2[N:28]=[C:27]1[CH2:26][N:22]1[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][CH2:16][CH2:15][C:7]2[N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)[CH2:24][CH2:23]1)[CH3:40]
Reactant: CCOCCn1c(CCl)nc2cccnc21
Reactant: CCOCCn1c(CCCCN2CCNCC2)nc2cccnc21
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOCCn1c(CCCCN2CCN(Cc3nc4cccnc4n3CCOCC)CC2)nc2cccnc21
Product: O=C(O)C(=O)O
Temperature: 70 °C
Reaction time: 6 h
Yield: 6.8 %

Procedure:
A mixture of 3.3 parts of 3-(2-ethoxyethyl)-2-[4-(1-piperazinyl)butyl]-3H-imidazo[4,5-b]pyridine, 2.9 parts of 2-(chloromethyl)-3-(2-ethoxyethyl) -3H-imidazo[4,5-b]pyridine, 1.2 parts of sodium carbonate and 22.5 parts of N,N-dimethylacetamide was stirred for 6 hours at 70° C. The reaction mixture was evaporated and the residue was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was converted into the ethanedioate salt in 2-propanol. The salt was filtered off and crystallized from 2-propanol. The product was filtered off and dried, yielding 0.7 parts (6.8%) of 3-(2-ethoxyethyl)-2-[[4-[4-[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]butyl]-1-piperazinyl]methyl]-3H-imidazo[4,5-b]pyridine ethanedioate(1:6); mp. 121.9° C. (compound 24).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:11]([N:18]([C:29]1[C:41]2[CH:40]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]=2[CH:32]=[CH:31][CH:30]=1)[C@H:19]([C:25]([O:27][CH3:28])=[O:26])[CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:48](OS(C(F)(F)F)(=O)=O)[CH3:49]>C1COCC1>[CH2:48]([CH:20]([C:21]([O:23][CH3:24])=[O:22])[C@@H:19]([C:25]([O:27][CH3:28])=[O:26])[N:18]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:29]1[C:41]2[CH:40]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]=2[CH:32]=[CH:31][CH:30]=1)[CH3:49]
Reactant: CCOS(=O)(=O)C(F)(F)F
Reactant: COC(=O)C[C@@H](C(=O)OC)N(Cc1ccccc1)c1cccc2c1C(c1ccccc1)c1ccccc1-2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCC(C(=O)OC)[C@@H](C(=O)OC)N(Cc1ccccc1)c1cccc2c1C(c1ccccc1)c1ccccc1-2
Temperature: -74 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of 8.65 ml (5.2 mmol) KHMDS (0.6M solution in toluene) in 50 ml dry THF was added 1.96 g (4.0 mmol) of dimethyl N-benzyl-N-(9-phenylfluorenyl)-aspartate of Example 3 dissolved in 8 ml THF drop by drop at -74° C. under N2. The pale yellow solution was stirred at -74° C. for 45 minutes then 568 μl (4.4 mmol) EtOTf were added neat at once at -76° C. After 10 minutes the reaction was quenched with 3 ml MeOH and partitioned between 40 ml 1M H3PO4 and 50 ml Et2O. The water layer was extracted with 40 ml Et2O and the combined organic layers were dried (MgSO4) and evaporated. The residue was purified by flash-chromatography (Kieselgel, Hexane/EtAc 8:1) to yield a mixture of dimethyl 3-ethyl N-benzyl-N-(9-phenylfluorenyl)-aspartate (20:1 mixture of diastereomers). The diastereomers were separated by MPLC (Kieselgel, Hexane/EtOAc 15:1) to yield the desired compound.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[CH:20]1[CH:25]=[CH:24][C:23]([C@@H:26]([NH2:30])[C:27]([OH:29])=[O:28])=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C>>[O:8]=[C:6]1[N:7]=[C:3]([NH:30][C@H:26]([C:23]2[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=2)[C:27]([OH:29])=[O:28])[S:4]/[C:5]/1=[CH:9]\[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[CH:13]2
Reactant: N[C@@H](C(=O)O)c1ccccc1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(N[C@@H](C(=O)O)c2ccccc2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, D-phenylglycine and DIEA to give (R)-{4-oxo-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-4,5-dihydro-thiazol-2-ylamino}-phenyl-acetic acid. LC-MS m/e 390 (MH+).