Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:5][N:4]=1.[SH:13][C:14]1[NH:18][C:17]2[CH:19]=[C:20]3[C:24](=[CH:25][C:16]=2[N:15]=1)[C:23]([CH3:27])([CH3:26])[C:22](=[O:28])[C:21]3([CH3:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:29][C:21]1([CH3:30])[C:20]2[C:24](=[CH:25][C:16]3[NH:15][C:14]([S:13][CH2:2][C:3]4[C:8]([CH3:9])=[C:7]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:5][N:4]=4)=[N:18][C:17]=3[CH:19]=2)[C:23]([CH3:27])([CH3:26])[C:22]1=[O:28]
Reactant: Cc1c([N+](=O)[O-])ccnc1CCl
Reactant: CC1(C)C(=O)C(C)(C)c2cc3[nH]c(S)nc3cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c([N+](=O)[O-])ccnc1CSc1nc2cc3c(cc2[nH]1)C(C)(C)C(=O)C3(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 11.5 g of 2-chloromethyl-3-methyl-4-nitropyridine and 16 g of 5,7-dihydro-2-mercapto-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(lH)-one in 200 ml of absolute acetone was treated with 13 g of finely ground potassium carbonate and the mixture was stirred at room temperature under argon for 18 hours. 100 ml of acetone were distilled off in vacuo, whereupon the residue was poured on to ice. The product which crystallized out was filtered off and dissolved in methylene chloride; the solution obtained was washed with water, dried and concentrated. By recrystallization from ethyl acetate/ether there was obtained 5,7-dihydro-5,5,7,7-tetramethyl-2-[[(3-methyl-4-nitro-2 -pyridyl)methyl]thio]indeno[5,6-d]imidazol-6(lH)-one of melting point 181-183° (decomposition).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:27]=[C:28]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:29]=[N:30][CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:27]=[C:28]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:29]=[N:30][CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: NS(=O)(=O)c1cncc(Br)c1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1cncc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2)(340 mg, 1.0 mmol) and 5-Bromo-pyridine-3-sulfonic acid amide (example B.1) (215 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (330 mg, 66%). MS (ISP) 494.3 [(M+H)+]; mp 238° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[CH:7]([CH:10]1[CH2:12][CH2:11]1)[CH2:8][NH2:9])([CH3:4])([CH3:3])[CH3:2].C[O:15][C:16]([C:18]1[N:19]=[C:20]([C:37]#[N:38])[C:21]2[C:26]([C:27]=1[OH:28])=[CH:25][CH:24]=[C:23]([O:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[CH:22]=2)=O.C1CCN2C(=NCCC2)CC1>CC(N(C)C)=O>[C:1]([O:5][C:6](=[O:13])[CH:7]([CH:10]1[CH2:12][CH2:11]1)[CH2:8][NH:9][C:16]([C:18]1[N:19]=[C:20]([C:37]#[N:38])[C:21]2[C:26]([C:27]=1[OH:28])=[CH:25][CH:24]=[C:23]([O:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[CH:22]=2)=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(CN)C1CC1
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccc(F)cc3)ccc2c1O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)C(CNC(=O)c1nc(C#N)c2cc(Oc3ccc(F)cc3)ccc2c1O)C1CC1
Temperature: 150 °C
Yield: 45.9 %

Procedure:
A mixture of 3-amino-2-cyclopropyl-propionic acid tert-butyl ester (20 mg), 1-cyano-7-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester (15 mg) and DBU (10 mg) in DMA (0.3 mL) was heated in an oil bath (150° C.) for 1 h. The reaction mixture was then partitioned between EtOAc and diluted HCl solution, EtOAc phase was separated and washed with water, diluted NaCl solution and dried over anhydrous sodium sulfate solution, filtered, concentrated and silica gel column purified to give desired product as brown solid (10 mg). LC-MS ESI+: 492 (M+1)+.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH:7]1[NH:10][C:9](=[O:11])[CH:8]1[CH2:12][CH3:13])(=O)C.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CO>[CH2:12]([CH:8]1[CH:7]([CH2:6][CH2:5][OH:4])[NH:10][C:9]1=[O:11])[CH3:13]
Reactant: CCC1C(=O)NC1CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: CCC1C(=O)NC1CCO

Procedure:
The crude 4-[2-(acetyloxy)ethyl]-3-ethyl-2-azetidinone is stirred with 9.7 g of potassium carbonate in 880 ml of absolute methanol at room temperature for 30 minutes. The mixture is neutralized with acetic acid and then evaporated to dryness at 50° C. under vacuum. The residue is suspended in a saturated aqueous solution of sodium chloride and the mixture is extracted with four 150-ml portions of ethyl acetate. The combined organic layers are dried over MgSO4 and then evaporated to dryness yielding 34 g of 3-ethyl-4-[2-(hydroxy)ethyl]-2-azetidinone which contains 80% of the trans isomer (estimated by N.M.R.). The I.R. and N.M.R. data confirm the assigned structure.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:8][CH:9]=1)([O-])=O.[H][H]>C(O)C.O1CCCC1.[Pd]>[F:19][C:16]([F:17])([F:18])[C:13]1[CH:12]=[CH:11][C:10]([C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)=[CH:15][CH:14]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.2 %

Procedure:
To a solution of 5-nitro-2-(4-(trifluoromethyl)phenyl)pyridine (260 mg, 0.97 mmol) in ethanol (10 mL) and tetrahydrofuran (5 mL) was added 10 wt % palladium on carbon (100 mg). The reaction was pressurized to 50 psi hydrogen and stirred at room temperature for 4 hours. The reaction was filtered through Celite and concentrated to give 6-(4-(trifluoromethyl)phenyl)pyridin-3-amine (220 mg, 95%). 1H NMR (400 MHz, CD3OD, δ): 7.98 (s, 1H), 7.88 (d, 2H), 7.60 (d2, H), 7.54 (d, 1H), 7.09 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH2:27][CH3:28])[CH2:24][CH2:25][OH:26])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:32].O>CN(C)C=O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH2:27][CH3:28])[CH2:24][CH2:25][O:26][CH3:32])=[CH:4][CH:3]=1
Reactant: CI
Reactant: CCC(CCO)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CCOC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
To a solution of 3-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]pentan-1-ol (148 mg, 0.34 mmol) in N,N-dimethylformamide (5.0 mL) was added sodium hydride (60% dispersion in mineral oil, 27 mg, 0.675 mmol) at 0° C. After the mixture was stirred at 0° C. for 0.5 hr, iodomethane (0.064 mL, 1.03 mmol) was added to the reaction mixture at 0° C. The mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture and recrystallization from 2-propanol/n-hexane to give the title compound (81.1 mg, 0.179 mmol, 53%) as colorless crystals.
Reaction SMILES: C(O)(C)(C)C.[Li].[CH3:7][C:8]1([CH3:17])[C@@H:10]([C:11](Cl)=[O:12])[C@@H:9]1[C:14](=[O:16])[CH3:15].[Cl-].[Na+]>O1CCCC1>[CH3:7][C:8]1([CH3:17])[C@@H:10]([CH:11]=[O:12])[C@@H:9]1[C:14](=[O:16])[CH3:15]
Reactant: CC(=O)[C@H]1[C@H](C(=O)Cl)C1(C)C
Agent: [Cl-]
Agent: [Li]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CC(=O)[C@H]1[C@H](C=O)C1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
36.6 g (0.495 mol) of tert.-butanol were added dropwise to a mixture of 6.3 g (0.165 mol) of lithium alanate and 100 ml of tetrahydrofuran at 20°-30° C. in the course of 1 hour. The mixture was subsequently stirred at room temperature for 2 hours and was then added dropwise to a solution of 26.1 g (0.15 mol) of trans-3,3-dimethyl-2-acetyl-cyclopropane-carboxylic acid chloride in 75 ml of tetrahydrofuran at -50° to -60° C. When the addition had ended, the mixture was subsequently stirred for 1 hour, without cooling, poured onto a mixture of 30 ml of concentrated sodium chloride and 300 g of ice and extracted twice by shaking with 400 ml of ether each time. The organic phases were first washed with 50 ml of saturated sodium bicarbonate solution and then with 100 ml of water, dried over sodium sulphate and evaporated in vacuo. Distillation of the residue in vacuo gave 12.7 g (62% of theory) of trans-3,3-dimethyl-2-acetyl-cyclopropane-carbaldehyde in the form of a colorless oil with a boiling point of 80°-86° C./10 mbars.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:14][CH2:15][C@H:16]2[CH2:20][CH2:19][CH2:18][NH:17]2)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].CCN(CC)CC.[CH3:28][C:29](OC(C)=O)=[O:30]>C(Cl)Cl>[C:29]([N:17]1[CH2:18][CH2:19][CH2:20][C@@H:16]1[CH2:15][O:14][C:6]1[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:30])[CH3:28]
Reactant: O=[N+]([O-])c1cc(OC[C@H]2CCCN2)cc(C(F)(F)F)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC[C@@H]1COc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(2R)-2-(((3-nitro-5-(trifluoromethyl)phenyl)oxy)methyl)pyrrolidine (3.46 g, 11.9 mmols, 1 eq) was dissolved in 100 mL of CH2Cl2. Et3N (5 mL, 35.7 mmols, 3 eq) was added followed by Ac2O (1.2 mL, 13.1 mmols, 1.1 eq). The reaction was stirred at RT for 1.5 h. The solvent was removed in vacuo and the residue dissolved in EtOAc. The solution was washed once each with saturated NH4Cl, 1 N HCl, and twice with brine. The organic layer was dried over Na2SO4 filtered and concentrated in vacuo. The crude material was purified on a Biotage chromatography system eluting with a gradient of 10% to 75% EtOAc:hexane to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.N1C=CN=C1.[CH3:21][Si:22](Cl)([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C>[C:8]([C:6]1[CH:5]=[C:4]([CH2:12][O:13][Si:22]([CH3:24])([CH3:23])[CH3:21])[C:3]([O:14][CH3:15])=[C:2]([NH2:1])[CH:7]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: COc1c(N)cc(C(C)(C)C)cc1CO
Reactant: C[Si](C)(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1c(N)cc(C(C)(C)C)cc1CO[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.03 g (3-amino-5-tert-butyl-2-methoxy-phenyl)-methanol and 2.4 g imidazole are dissolved in 20 ml of tetrahydrofuran and 2.75 ml trimethylsilyl chloride are added dropwise thereto. The mixture is stirred for 2 hours at ambient temperature, the solvents are eliminated in vacuo and the residue is divided between 10% aqueous potassium carbonate solution and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution. After drying with magnesium sulphate the solvents are eliminated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 95:5 to 50:50).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[C:13]([NH:15][CH:16]2[CH2:18][CH2:17]2)[N:12]2[N:19]=[CH:20][C:21]([CH:22]=[C:23]3[NH:27][C:26](=[O:28])[NH:25][C:24]3=[O:29])=[C:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.FC(F)(F)C(O)=O>[CH2:1]([S:8][C:9]1[CH:14]=[C:13]([NH:15][CH:16]2[CH2:18][CH2:17]2)[N:12]2[N:19]=[CH:20][C:21](/[CH:22]=[C:23]3/[C:24](=[O:29])[NH:25][C:26](=[O:28])[NH:27]/3)=[C:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)C(=Cc2cnn3c(NC4CC4)cc(SCc4ccccc4)nc23)N1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NC(=O)/C(=C/c2cnn3c(NC4CC4)cc(SCc4ccccc4)nc23)N1
Reaction time: 1 h
Yield: 96.8 %

Procedure:
5-((5-(Benzylthio)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (60 mg, 0.15 mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL). After 1 h, the solution was concentrated under a stream of air. The residue was triturated with Et2O (3 mL) and the precipitate was collected to provide (Z)-5-((5-(benzylthio)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (59 mg, 98%). LCMS (ES): >95% pure, m/z 407 [M+1]+.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C:11]1[CH:12]=[C:13]([CH3:33])[C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=3[F:32])=[O:24])[CH2:19][CH2:18]2)=[N:15][CH:16]=1.ClC(Cl)(Cl)C[O:37][C:38](=O)[NH:39][C:40]1[N:41]([C:50]2[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=2)[N:42]=[C:43]([C:45]([CH3:49])([CH3:48])[CH2:46][F:47])[CH:44]=1>C(#N)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[C:23]([N:20]1[CH2:19][CH2:18][N:17]([C:14]2[N:15]=[CH:16][C:11]([NH:10][C:38]([NH:39][C:40]3[N:41]([C:50]4[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=4)[N:42]=[C:43]([C:45]([CH3:49])([CH3:48])[CH2:46][F:47])[CH:44]=3)=[O:37])=[CH:12][C:13]=2[CH3:33])[CH2:22][CH2:21]1)=[O:24]
Reactant: Cc1cc(N)cnc1N1CCN(C(=O)c2c(F)cccc2F)CC1
Reactant: Cc1ccc(-n2nc(C(C)(C)CF)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)CF)cc2NC(=O)Nc2cnc(N3CCN(C(=O)c4c(F)cccc4F)CC3)c(C)c2)cc1
Temperature: 80 °C
Reaction time: 96 h
Yield: 48 %

Procedure:
Add DIEA (2 equiv.) to a solution of [4-(5-amino-3-methyl-pyridin-2-yl)-piperazin-1-yl]-(2,6-difluoro-phenyl)-methanone (400 mg, 1.205 mmol) and [5-(2-fluoro-1,1-dimethyl-ethyl)-2-p-tolyl-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester (1 equiv) in acetonitrile (12 mL). Stir the mixture at 80° C. in a sealed tube. After 4 days, remove solvent. Dilute crude with DCM, extract with water, and dry over Na2SO4. Filter and remove solvent under reduced pressure. Subject solid to silica gel chromatography, eluting with hexane/acetone 3:1 to obtain 352 mg of 1-{6-[4-(2,6-difluoro-benzoyl)-piperazin-1-yl]-5-methyl-pyridin-3-yl}-3-[5-(2-fluoro-1,1-dimethyl-ethyl)-2-p-tolyl-2H-pyrazol-3-yl]-urea as a white solid (48% yield). ES+(m/z): 606 [M+1]
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH:7]=[CH:6][C@@H:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:3]1=[O:22].[F:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32]([NH:34][C@H:35]([C:37](O)=[O:38])[CH3:36])=[O:33])[CH:27]=[C:28]([F:30])[CH:29]=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>C(Cl)Cl>[CH2:15]([N:4]1[C@H:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH2:8][C@H:2]([NH:1][C:37](=[O:38])[C@H:35]([CH3:36])[NH:34][C:32](=[O:33])[CH2:31][C:26]2[CH:27]=[C:28]([F:30])[CH:29]=[C:24]([F:23])[CH:25]=2)[C:3]1=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: N[C@H]1CC=C[C@@H](c2ccccc2)N(Cc2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@H]1CC=C[C@@H](c2ccccc2)N(Cc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 71.2 %

Procedure:
To a solution of (3S,7S)-3-amino-1-benzyl-7-phenyl-1,3,4,7-tetrahydro-2H-azepin-2-one (5d) (40 mg) in DCM (2 mL) at 0° C. under N2 was added N-[(3,5-difluorophenyl)acetyl]-L-alanine (33 mg), HOBt-hydrate (46 mg), EDAC.HCl (39 mg) and N-methyl morpholine (22 mg). The reaction mixture was stirred 1 h at 0° C. and 3 h at RT, then diluted with 30% hexanes/EtOAc (100 mL). The organic phase was consecutively washed with H2O, 0.2 N HCl, saturated NaHCO3, and brine, dried (Na2SO4), filtered and evaporated. The crude product was purified by flash chromatography (1%-2% MeOH/DCM) to afford a white solid (50 mg, 71%). Sample contains approx. 20% 5A.
Reaction SMILES: [Na].[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH2:12][C:13]([OH:15])=[O:14])=[C:5](Cl)[N:4]=1.[OH-].[Na+].[CH2:19]([OH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH2:12][C:13]([OH:15])=[O:14])=[C:5]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:4]=1
Reactant: Nc1nc(Cl)c2ncn(CC(=O)O)c2n1
Reactant: OCc1ccccc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Nc1nc(OCc2ccccc2)c2ncn(CC(=O)O)c2n1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
Sodium (2 g 87 mmol) was dissolved in benzyl alcohol (20 mL) and heated to 130° C. for 2 h. After cooling to 0° C., a solution of 2-amino-6-chloro-9-carboxymethylpurine (4.05 g, 18 mmol) in DMF (85 mL) was slowly added, and the resulting suspension stirred overnight at 20° C. Sodium hydroxide solution (1N, 100 mL) was added and the clear solution was washed with ethyl acetate (3×100 mL). The water phase was then acidified to a pH of 3 with 4N hydrochloric acid. The precipitate was taken up in ethyl acetate (200 mL,), and the water phase was extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with saturated sodium chloride solution (2×75 mL), dried with anhydrous sodium sulfate, and evaporated to dryness, in vacuo. The residue was recrystallized from ethanol (300 mL). Yield, after drying in vacuo, over sicapent: 2.76 g (52%). M.p. 159°-65° C. Anal. (calc.; found): C(56.18; 55.97), H(4.38; 4.32), N(23.4; 23.10). 1H-NMR (DMSO-d6) δ:4.82 (s, 2H); 5.51 (s, 2H); 6.45 (s, 2H); 7.45 (m, 5H); 7.82 (s, 1H).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[O:11]=[C:12]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13]1.Cl.CN(C)CCCN=C=NCC.Cl.[CH3:33][NH:34][O:35][CH3:36].C(N(CC)CC)C>C(Cl)Cl>[CH3:36][O:35][N:34]([CH3:33])[C:17]([CH:14]1[CH2:15][CH2:16][C:12](=[O:11])[CH2:13]1)=[O:19]
Reactant: O=C1CCC(C(=O)O)C1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C1CCC(=O)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a slurry of 1-hydroxybenzotriazole (7.91 g, 58.5 mmol), 3-oxo-1-cyclopentanecarboxylic acid (5.00 g, 39.0 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (11.22 g, 58.5 mmol) in 44 mL DCM under nitrogen was added N,O-dimethylhydroxylamine hydrochloride (5.71 g, 58.5 mmol) followed by triethylamine (8.16 mL, 58.5 mmol) in portions. The reaction mixture became warm and was cooled with an ice bath for the remainder of TEA addition, then stirred at ambient temp under nitrogen for 2 d. The reaction mixture was concentrated in vacuo, and taken up in EA (300 mL), washed with water, sat'd aq. Sodium bicarbonate, brine, and the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo, to give (rac)-N-methoxy-N-methyl-3-oxocyclopentanecarboxamide as a yellow oil which was used without further purification. 1H NMR (400 MHz, CDCl3-d) δ ppm 3.74 (s, 3 H), 3.41-3.61 (m, 1 H), 3.23 (s, 3 H), 2.52-2.64 (m, 1 H), 2.34-2.50 (m, 2 H), 2.08-2.31 (m, 3 H).
Reaction SMILES: [CH3:1][N:2]([CH2:6][CH2:7][CH2:8][N:9]1[C:18]2[C:13](=[CH:14][C:15]([N+:19]([O-])=O)=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1)[CH2:3][CH2:4][OH:5]>C(O)C.O1CCCC1.[Pd]>[NH2:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:9]([CH2:8][CH2:7][CH2:6][N:2]([CH3:1])[CH2:3][CH2:4][OH:5])[CH2:10][CH2:11][CH2:12]2
Reactant: CN(CCO)CCCN1CCCc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(CCO)CCCN1CCCc2cc(N)ccc21
Reaction time: 2 h

Procedure:
To a stirred solution of 2-(methyl(3-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)propyl)amino)ethanol (76 mg, 0.259 mmol) in ethanol (2 mL) and tetrahydrofuran (2.0 mL) was added palladium, 10 wt % on activated carbon (27.6 mg, 0.026 mmol). The reaction mixture was stirred under an atmosphere of hydrogen (balloon pressure) for 2 h. The reaction mixture was then filtered through a pad of celite (washed with methanol) and concentrated to give a dark oil. The crude product was used directly in the subsequent reaction.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:20]([CH2:34][CH2:35][O:36][CH3:37])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:45]C1C=CC2C3N(CC(C)C)C(C)=NC=3C=NC=2C=1)C1C=CC=CC=1.C1C=C(Cl)C=C(C(OO)=O)C=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:30])[CH3:31])[C:20]([CH2:34][CH2:35][O:36][CH3:37])=[N:19][C:14]=3[CH:15]=[N+:16]([O-:45])[C:17]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)C
Reactant: COCCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Agent: O=C(OO)c1cccc(Cl)c1
Product: COCCc1nc2c[n+]([O-])c3cc(OCc4ccccc4)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Reaction time: 28 h

Procedure:
A modification of the general method described in Part B of Example 3 was followed using tert-butyl {4-[7-benzyloxy-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}carbamate (9.08 g, 17.9 mmol) in lieu of 7-benzyloxy-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline. Over a period of 28 hours, three equivalents of mCPBA were added. Following the work-up procedure, 8.07 g of tert-butyl {4-[7-benzyloxy-2-(2-methoxyethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]butyl}carbamate were obtained.
Reaction SMILES: [C:1]1([C:7]([OH:9])=[O:8])([C:4]([OH:6])=[O:5])[CH2:3][CH2:2]1.[C:10]1(=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(OC(=O)C)(=O)C>S(=O)(=O)(O)O>[CH2:3]1[C:1]2([C:7](=[O:9])[O:8][C:10]3([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[O:5][C:4]2=[O:6])[CH2:2]1
Reactant: O=C1CCCCC1
Reactant: O=C(O)C1(C(=O)O)CC1
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC2(CCCCC2)OC(=O)C12CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12843.3 %

Procedure:
A mixture of cyclopropane-1,1-dicarboxylic acid (13.0 g, 0.10 mmol), cyclohexanone (10.8 g, 0.11 mol), acetic anhydride (11.2 g, 0.11 mol) and concentrated sulphuric acid (5 drops) was stirred at room temperature 0.5 h. The mixture soon became a wine-red solution which later darkened to purple. The reaction mixture was partitioned between water (100 ml) and ether (2×100 ml). The combined organic extracts were washed with brine (50 ml), dried (MgSO4), filtered and evaporated to leave a purple oil plus some solid material. This mixture was purified by column chromatography on silica [eluent=ether/hexane (4:1)] to give the title compound as colourless crystals (2.70 g, 13%), m.p. 134.5°-135° C.
Reaction SMILES: [C:1]([N:4]([CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](O)=[O:11])(=[O:3])[CH3:2].[NH2:26][C@H:27]([C:30]([O:32]CC)=[O:31])[CH2:28][OH:29].[OH-].[K+]>C(O)C>[C:1]([N:4]([CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:26][C@H:27]([C:30]([OH:32])=[O:31])[CH2:28][OH:29])=[O:11])(=[O:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](N)CO
Reactant: CC(=O)N(CCCCCC(=O)O)C(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)N(CCCCCC(=O)N[C@@H](CO)C(=O)O)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-acetyl-6-benzhydrylaminocaproic acid and ethyl L-serinate and suitable processing, dissolving the evaporation residue in ethanol, adding an ethanolic solution of potassium hydroxide, stirring for 12 hours at room temperature and further processing yields N-(N-acetyl-6-benzhydrylaminohexanoyl)-L-serine.