Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11]C(=O)C)=[CH:7][C:6]=1[O:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:2][CH2:3][CH3:4].[OH-].[K+]>C(O)C.O.C(Cl)Cl>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[O:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(NC(C)=O)cc1OCCOc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CCCCc1ccc(N)cc1OCCOc1ccccc1
Temperature: 25 °C
Yield: 80 %

Procedure:
N-(4-Butyl-3-(2-phenoxyethoxy)phenyl)acetamide (132 g, 0.41 mol) was dissolved in ethanol (897 mL) and water (104 mL). KOH (312 g, 5.57 mol) was added at 0° C. and the solution was allowed to reflux for 18 hrs. Upon completion the reaction was cooled to room temperature and diluted with 2 L of water and 2 L of DCM. The organic layer was washed with water (×2) and dried over sodium sulfate. The crude compound was purified further via flash chromatography with hexane:ethyl acetate (1:1) to obtain the title compound in 80% yield (92 g) as a pink solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]([Cl:9])=[O:8].[NH2:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[C:13]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[N:12]=1>>[ClH:9].[NH2:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[C:13]([N:25]2[CH2:30][CH2:29][N:28]([C:7]([C:6]3[O:5][CH:4]=[N:3][C:2]=3[CH3:1])=[O:8])[CH2:27][CH2:26]2)[N:12]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: Cc1ncoc1C(=O)Cl
Product: COc1cc2nc(N3CCN(C(=O)c4ocnc4C)CC3)nc(N)c2cc1OC
Product: Cl

Procedure:
The title compound was prepared from 4-methyloxazole-5-carbonyl chloride (0.85 g.) and 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (1.68 g.) following the procedure of Example 1. The product had a m.p. of 283.5°-288° C. with decomposition.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][C:15]=1[C:16]([F:19])([F:18])[F:17])[C:7](N(OC)C)=[O:8])[CH3:2].[CH3:20][Mg]Br.Cl>C1COCC1.CC(OC)(C)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:7](=[O:8])[CH3:20])[CH:13]=[CH:14][C:15]=1[C:16]([F:17])([F:18])[F:19])[CH3:2]
Reactant: CCOc1cc(C(=O)N(C)OC)ccc1C(F)(F)F
Reactant: C[Mg]Br
Agent: Cl
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CCOc1cc(C(C)=O)ccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-ethoxy-N-methoxy-N-methyl-4-trifluoromethyl-benzamide from step 7 (15.96 g, 58 mmol) in THF (182 mL) at −5° C. was added methylmagnesium bromide (3 M in Et2O, 38.37 mL, 115 mmol). The mixture was stirred at 0° C. for 15 min, then warmed up to 23° C., stirring was continued for further 3 h at 23° C. Cooled to 0° C., 1 N HCl (274 mL) was added dropwise, stirring was continued at 23° C. for 15 min, the mixture was diluted with TBME, the phases were separated, the organic layer was washed with water and brine, dried over MgSO4. Removal of the solvent in vacuum left a yellow solid (13.10 g, 98%), which was used without further purification. MS (EI) 232.2 [M].
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]>O.CO>[C:1]([CH2:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:7]=1[C:8]([O:10][CH3:11])=[O:9])#[N:2]
Reactant: [C-]#N
Reactant: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)c1c(CC#N)cccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A solution of KCN (474 mg, 7.2 mmol) in water (1 mL) was slowly added to a solution of methyl 2-(bromomethyl)-6-nitrobenzoate (1 g, 3.6 mmol) in methanol (20 mL). This mixture was allowed to stir for 4 h at 50° C. The reaction mixture was concentrated to remove methanol, diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried (Na2SO4), concentrated and purified by flash column chromatography (25% EtOAc in hexanes) to give the title compound as 0.5 g of an oily liquid (62%). 1H NMR (CDCl3, 600 MHz): δ 3.9 (s, 2H), 3.97 (s, 3H), 7.65 (t, J=7.8 Hz, 1H), 7.85 (d, J=7.8 Hz, 1H), 8.09 (d, J=7.8 Hz, 1H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+]([O-])=O)[C:5](O)=[O:6].CC[N:16]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.Cl[Sn]Cl>CCO.CN(C=O)C>[C:5]([NH2:16])(=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Cl[Sn]Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCO
Product: NC(=O)c1ccccc1

Procedure:
In one embodiment, intermediate [1C] is prepared according to Scheme 5A. In this route, 3-fluoro-4-nitro benzoic acid [Q1] is converted to corresponding amide [R1] using R7R8NH, EDCI.HCl, HOBt, TEA, and DMF at about rt for about 10 h. Amide [R1] is then reduced using SnCl2 in EtOH at reflux for about 3-4 h to provide benzamide [S1]. Benzamide [S1] is then converted to urea [T1] using 4-bromophenylisocyanate in the presence of TEA and DCM at about rt. Conversion of urea [T1] to intermediate [1C] is accomplished using Pd(dppf)Cl2.DCM, bis(pinacolato)diboron, KOAc, and 1,4-dioxane, at about 110° C. for about 10 h.
Reaction SMILES: [N:1]#[C:2]Cl.[CH2:4]([N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(#N)C>[C:5]1([CH2:4][N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[C:2]#[N:1])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: c1ccc(Cn2ccnc2)cc1
Reactant: N#CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1nccn1Cc1ccccc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
In a 50 ml 4-neck flask with stirring bar, nitrogen bubbler, gas inlet tube, thermometer, septum and acetonitrile (20 ml) was bubbled cyanogen chloride (3.1 g, 50 mmol) (ice bath was used to avoid mild heat of solution). The reaction was cooled in an ice bath and a solution of 1-benzylimidazole (3.16 g, 20 mmol) in acetonitrile (ca. 5 ml) was added via syringe. The colorless solution turned yellow-orange and within a few minutes a yellow-orange crystalline solid started to form. After 1 hour, the thick slurry was cooled to -20° C. and triethylamine (7 ml, 50 mmol) was added at such a rate to prevent the temperature from rising above 0° C. The mixture was stirred 1 hour while warming to room temperature, poured into saturated aq NaHCO3 (100 ml) and extracted with ether (3×75 ml). The combined organic layers were dried (MgSO4), evaporated and purified by Kugelrohr distillation. After a forerun of diethylcyanamide, the desired product was collected at 130° C. (0.4 mm) (3.05 g, 83%) as a colorless liquid which crystallized on standing, mp 51°-52° C. (cyclohexane).
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([CH3:13])[C:5]2[N:6]=[C:7]([NH2:10])[N:8]=[N:9][C:4]=2[CH:3]=1.[CH3:14][S:15]([NH:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)(=[O:17])=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:10][C:7]1[N:8]=[N:9][C:4]2[CH:3]=[C:2]([C:23]3[CH:24]=[C:19]([NH:18][S:15]([CH3:14])(=[O:16])=[O:17])[CH:20]=[CH:21][CH:22]=3)[CH:12]=[C:11]([CH3:13])[C:5]=2[N:6]=1
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Reactant: Cc1cc(Br)cc2nnc(N)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(-c2cccc(NS(C)(=O)=O)c2)cc2nnc(N)nc12
Yield: 81.6 %

Procedure:
An oven dried 25 mL round bottom flask was charged with 7-bromo-5-methyl-benzo[1,2,4]triazin-3-ylamine (0.889 g, 3.72 mmol, 1 equiv), 3-(methylsulfonylamino) phenyl boronic acid (1.12 g, 5.21 mmol, 1.4 equiv), sodium carbonate (1.57 g, 14.9 mmol, 4 equiv) and tetrakis(triphenylphosphine)palladium(0) (0.43 g, 0.372 mmol, 0.1 equiv). The reactants were flushed with argon and diluted with ethylene glycol dimethyl ether (20 mL), ethanol (5 mL) and DI water (5 mL). The reaction vessel was outfitted with condenser and refluxed for 4 hours. The reaction was filtered hot and diluted with ethyl acetate. The Organic layer was isolated and concentrated to a dark residue. This was dissolved in DMF (6 mL) and slowly diluted with water so as to precipitate out the product. Solids were filtered off and dried to yield an orange solid (1 g, 82% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[C:15]([C@@:17]1([C:37]2([OH:41])[CH2:40][CH2:39][CH2:38]2)[CH2:21][CH2:20][C@@H:19]([N:22](C(=O)C(F)(F)F)[C@@H:23]2[C@H:28]([O:29][CH3:30])[CH2:27][O:26][CH2:25][CH2:24]2)[CH2:18]1)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[C:15]([C@@:17]1([C:37]2([OH:41])[CH2:40][CH2:39][CH2:38]2)[CH2:21][CH2:20][C@@H:19]([NH:22][C@@H:23]2[C@H:28]([O:29][CH3:30])[CH2:27][O:26][CH2:25][CH2:24]2)[CH2:18]1)=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CO[C@@H]1COCC[C@@H]1N(C(=O)C(F)(F)F)[C@@H]1CC[C@@](C(=O)N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)(C2(O)CCC2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1CC[C@@](C(=O)N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)(C2(O)CCC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.1 %

Procedure:
A mixture of 1.31 g (2.23 mmol) of 1,5-anhydro-3-{[(1R,3S)-3-{[(1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-(1-hydroxycyclobutyl)cyclopentyl](trifluoroacetyl)amino}-2,3-dideoxy-4-O-methyl-D-erythro-pentitol and 860 mg (23 mmol) of sodium borohydride 6.3 mL of ethanol was stirred at ambient temperature for 18 h, then partitioned between water and dichloromethane. The aqueous phase was extracted with additional dichloromethane, and the combined organic phase dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography on silica using 6-15% methanol in dichloromethane afforded 1.08 g (98%) of the title compound as a white foam. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.42-1.47 (m, 9H) 1.56-2.35 (m, 14H) 2.72 (br. s., 1H) 3.11-3.68 (m, 10H) 3.90-3.98 (m, 1H) 4.08 (dd, J=12.6, 2.7 Hz, 1H) 4.38-4.58 (m, 1H) 4.84-5.16 (m, 1H). LC-MS ES+ 494.3. HRMS calculated for C26H43N3O6: 494.3230. found: 494.3260.
Reaction SMILES: C(OC1C=C(C=C([N+]([O-])=O)C=1C1C=CC=CC=1)C(O)=O)C1C=CC=CC=1.[N+:27]([C:30]1[C:31]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[C:32]([O:39][CH2:40][C:41]2[CH:45]=[CH:44][S:43][CH:42]=2)[CH:33]=[C:34]([CH:38]=1)[C:35]([OH:37])=[O:36])([O-])=O>>[NH2:27][C:30]1[C:31]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[C:32]([O:39][CH2:40][C:41]2[CH:45]=[CH:44][S:43][CH:42]=2)[CH:33]=[C:34]([CH:38]=1)[C:35]([OH:37])=[O:36]
Reactant: O=C(O)c1cc(OCc2ccsc2)c(-c2ccccc2)c([N+](=O)[O-])c1
Agent: O=C(O)c1cc(OCc2ccccc2)c(-c2ccccc2)c([N+](=O)[O-])c1
Product: Nc1cc(C(=O)O)cc(OCc2ccsc2)c1-c1ccccc1

Procedure:
By replacing in Example 2, step D, 3-benzyloxy-5-nitro-4-phenylbenzoic acid with 5-nitro-4-phenyl-3-(3-thenyloxy)benzoic acid, and following the procedure described, 5-amino-4-phenyl-3-(3-thenyloxy)benzoic acid is obtained as a hemihydrate with a melting point of 139°-140° C.
Reaction SMILES: Cl.O1CCOCC1.[CH2:8]([O:15][C:16]([NH:18][C@H:19]1[C@@H:24]([F:25])[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH2:8]([O:15][C:16](=[O:17])[NH:18][C@H:19]1[C@@H:24]([F:25])[CH2:23][CH2:22][NH:21][CH2:20]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](F)[C@H](NC(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(N[C@@H]1CNCC[C@@H]1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
4N HCl in dioxane (3.29 mL, 13.2 mmol) was added to a solution of cis-tert-butyl 3-(benzyloxycarbonylamino)-4-fluoropiperidine-1-carboxylate (0.58 g, 1.65 mmol) in DCM (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo. The resulting solid was dissolved in water (5 mL) and extracted with ether (10 mL). The resulting aqueous layer was basified with 30% potassium carbonate to a pH of about 10 and extracted with DCM (2×30 mL). The combined organic layer was dried (sodium sulfate) and concentrated in vacuo to give benzyl-cis-4-fluoropiperidin-3-ylcarbamate (0.39 g, 94%) as a solid.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@@H:27]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[C@H:26]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@@H:25]([CH2:44][OH:45])[O:24][C@H:11]1[S:12][C:13]1[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[CH:15][C:14]=1[CH3:23])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:46]1[CH:51]=[CH:50][C:49]([CH2:52]Br)=[CH:48][CH:47]=1.[H-].[Na+]>C1COCC1.CN(C=O)C>[C:1]([O:9][C@@H:10]1[C@@H:27]([O:28][Si:29]([C:32]([CH3:33])([CH3:34])[CH3:35])([CH3:30])[CH3:31])[C@H:26]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@@H:25]([CH2:44][O:45][CH2:52][C:49]2[CH:50]=[CH:51][CH:46]=[CH:47][CH:48]=2)[O:24][C@H:11]1[S:12][C:13]1[CH:18]=[C:17]([C:19]([CH3:20])([CH3:21])[CH3:22])[CH:16]=[CH:15][C:14]=1[CH3:23])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(C)(C)C)cc1S[C@@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1OC(=O)c1ccccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc(C(C)(C)C)cc1S[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
To a solution of crude 28 (approx. 1.23 mmol) in THF/DMF (9:1, 10 ml) at 0° C., BnBr (0.18 ml, 1.50 mmol) and NaH (36 mg, 1.50 mmol) were added. The solution was warmed to room temperature over 2 h, then cooled to 0° C. again and further BnBr (0.18 ml, 1.50 mmol) was added. The reaction was warmed to room temperature over 30 min, cooled to 0° C. and quenched by the addition of water. After dilution with Et2O the phases were separated and the aqueous layer extracted with Et2O. The organic phase was then dried over MgSO4, filtered and concentrated. Column chromatography on silica gel (hexanes/ethyl acetate) afforded 29 (797 mg, 1.08 mmol, 88%). 1H-NMR (400 MHz, CDCl3) δ 8.14-7.00 (m, 18H, Ar—H), 5.31 (dd, 1H, J1=10.1 Hz, J2=8.9 Hz, 2-H), 4.83 (app. d, 1H, J=11.3 Hz, benzyl-Ha), 4.72 (d, 1H, J=10.2 Hz, 1-H), 4.63 (app. d, 1H, J=11.0 Hz, benzyl-Hb), 4.58 (app. d, 2H, J=3.1 Hz, benzyl-H), 3.95 (app. t, 1H, J=8.7 Hz, 3-H), 3.78-3.51 (m, 4H, 4-H, 5-H, 6-H), 2.15 (s, 3H, S—CH3), 1.25 (s, 9H, S-tBu), 0.79 (s, 9H, TBS-tBu), 0.00 (s, 3H, TBS-CH3), −0.16 (s, 3H, TBS-CH3); 13C-NMR (100 MHz, CDCl3) δ 165.6, 149.7, 138.2, 136.5, 133.2, 130.5, 130.1, 129.8, 129.2, 128.5, 128.4, 128.0, 127.72, 127.68, 127.6, 124.7, 88.0 (C-1), 79.5 (C-5), 78.9 (C-4), 77.0 (C-3), 75.1, 73.6 (C-2), 73.5, 69.0 (C-6), 31.4, 25.8, 20.3, −3.9, −4.1; HRMS (ESI): Calcd for C44H56O6SSiNa+ [M+Na]+ 763.3459. found: 763.3500
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]([NH:8][CH:9]1[C:18]2[C:13](=[N:14][C:15]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[Cl:33])=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH:17]=2)[O:12][C:11]([CH3:35])([CH3:34])[CH2:10]1)=[O:7])=[O:4].[H-].[Na+]>CS(C)=O.CCOC(C)=O>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([C:16]2[CH:17]=[C:18]3[CH:9]([N:8]4[CH2:2][C:3](=[O:4])[NH:5][C:6]4=[O:7])[CH2:10][C:11]([CH3:34])([CH3:35])[O:12][C:13]3=[N:14][C:15]=2[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])=[CH:24][CH:23]=1
Reactant: CC1(C)CC(NC(=O)NC(=O)CCl)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC1(C)CC(N2CC(=O)NC2=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product obtained in Step A (127 mg, 0.23 mmol) was dissolved in DMSO (2 mL). NaH (20 mg, 0.51 mmol) was added and the reaction was stirred at rt for 1 h. The reaction was diluted with EtOAc and washed with a saturated NaHCO3 solution, 10% NaHSO4, brine, dried (Na2SO4), filtered and concentrated The residue was purified by flash chromatography on silica gel gradient eluted with 0-70% EtOAc in hexane to afford Example 113. Further purification on an AD column, eluting with 12% IPA/heptane provided the two pure enantiomers indicated below:
Reaction SMILES: [CH:1]1[C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=[C:3]([OH:12])[CH:2]=1.[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][O:12][C:3]2[CH:4]=[CH:5][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:1][CH:2]=2)=[CH:16][CH:15]=1
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Reactant: Fc1ccc(CBr)cc1
Product: O=C(O)C=Cc1ccc(OCc2ccc(F)cc2)cc1
Yield: 56 %

Procedure:
The title compound is prepared in analogy to example 12 a) from p-cumaric acid and 4-fluorobenzyl bromide. Yield=56%. Colorless solid. MS: m/e=271.0 (M−H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[N+:12]([C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][CH2:20][NH:21]2)=[CH:17][CH:16]=1)([O-:14])=[O:13]>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[N:21]2[C:22]3[C:18](=[CH:17][CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:23]=3)[CH2:19][CH2:20]2)=[CH:4][N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Solvent: CCCCO
Product: O=[N+]([O-])c1ccc2c(c1)N(n1cnc3cnc(Cl)nc31)CC2
Reaction time: 72 h
Yield: 90.6 %

Procedure:
378 mg of 2,6-dichloropurine, 7 ml of butanol and 328 mg of 6-nitroindoline are mixed and brought to a temperature of 90° C. for approximately 3 days. The mixture is allowed to return to ambient temperature. Partial drying, washing with ethyl ether and drying under vacuum at 50° C. are carried out, and 573 mg of expected product are obtained, in the form of beige crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[CH3:21][N:22]1[C:26]([CH3:27])=[C:25]([CH:28]=O)[C:24]([CH3:30])=[N:23]1.C([O-])(=O)C.[NH4+]>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:28]([C:25]3[C:24]([CH3:30])=[N:23][N:22]([CH3:21])[C:26]=3[CH3:27])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: Cc1nn(C)c(C)c1C=O
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: Cc1nn(C)c(C)c1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Br)cnc2[nH]1
Yield: 63.4 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (75 mg, 0.22 mmol), 1,3,5-Trimethyl-1H-pyrazole-4-carbaldehyde (33.7 mg, 0.244 mmol), and Ammonium acetate (34.2 mg, 0.444 mmol) were reacted to produce 63.66 mg (64%) of the title compound. (300 MHz, DMSO-d6) 12.46 (s, 1H), 7.99 (s, 1H), 7.70 (s, 1H), 7.19 (s, 1H), 7.93 (d, J=9 Hz, 1H), 6.32 (m, 1H), 6.25 (m, 1H), 5.23 (t, J=17 Hz, 9 Hz, 1H), 3.76 (s, 3H), 2.85 (s, 1H), 2.75 (s, 1H), 2.57 (d, J=9 Hz, 1H), 2.47 (s, 3H), 2.35 (s, 3H), 2.25 (d, J=8 Hz, 1H), 1.39 (d, J=8 Hz, 1H). MS=458 (M+H), HPLC: 2.0 min. (G Method)
Reaction SMILES: [CH3:1][C:2]1([C:21]([OH:23])=O)[CH2:17][C:10]2([N+:18]([O-:20])=[O:19])[C:11]3[C:16]([CH:3]1[C:4]1[C:9]2=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.CCN=C=NCCCN(C)C.[C:54]1([C:64]2[NH:68][N:67]=[C:66]([NH2:69])[N:65]=2)[C:63]2[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=2)[CH:57]=[CH:56][CH:55]=1>C(#N)C>[CH3:1][C:2]1([C:21]([N:67]2[C:66]([NH2:69])=[N:65][C:64]([C:54]3[C:63]4[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=4)[CH:57]=[CH:56][CH:55]=3)=[N:68]2)=[O:23])[CH2:17][C:10]2([N+:18]([O-:20])=[O:19])[C:11]3[C:16]([CH:3]1[C:4]1[C:9]2=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3
Reactant: CC1(C(=O)O)CC2([N+](=O)[O-])c3ccccc3C1c1ccccc12
Reactant: Nc1n[nH]c(-c2cccc3ccccc23)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C(=O)n2nc(-c3cccc4ccccc34)nc2N)CC2([N+](=O)[O-])c3ccccc3C1c1ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
To a stirred solution of 15-methyl-8-nitrotetracyclo[6.6.2.02,7.09,14]hexadeca-2,4,6,9,11,13-hexaene-15-carboxylic acid (22 mg, 0.07 mmol, prepared according to WO04009017), 1-hydroxybenzotriazole (14 mg, 0.11 mmol), and N-ethyl-N,N-diisopropylamine (0.25 mL) in anhydrous acetonitrile (2 mL) was added EDCI (34 mg, 0.18 mmol) at RT under argon. After the mixture was stirred at RT for 10 min, 5-(naphthalen-1-yl)-1H-1,2,4-triazol-3-amine (22 mg, 0.1 mmol) was added. The reaction mixture was stirred at RT overnight and at 80° C. for 1 h. After the solvents were removed, the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The aqueous solution was extracted with methylene chloride. The combined organic solutions were dried (Na2SO4), concentrated and purified by silica gel chromatography to give 33 mg (94% yield) of the title compound as a white solid. (M+H)+=502.26.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[C:5]1[O:6][C:7]2[CH:13]=[C:12]([C:14]([O:16]C)=[O:15])[CH:11]=[CH:10][C:8]=2[CH:9]=1)[CH3:2].[OH-].[Na+]>CO.O>[CH2:19]([O:18][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[O:6][C:7]2[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[CH:11]=[CH:10][C:8]=2[CH:9]=1)[CH3:20]
Reactant: CCOC(OCC)c1cc2ccc(C(=O)OC)cc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOC(OCC)c1cc2ccc(C(=O)O)cc2o1
Reaction time: 96 h
Yield: 103.4 %

Procedure:
Methyl 2-(diethoxymethyl)-1-benzofuran-6-carboxylate (417 mg, 1.5 mmol) is dissolved in MeOH (8 ml) and H2O (2 ml). 2N NaOH (0.9 ml, 1.8 mmol) is added drop-wise, and the reaction is stirred for 4 days. The volatiles are removed in vacuo and the residue is dissolved in H2O (2 ml). Concentrated HCl is used to adjust the pH to 3, and the resulting precipitate is isolated via filtration and dried overnight to afford 410 mg (>100%, water present) of 2-(diethoxymethyl)-1-benzofuran-6-carboxylic acid as a brown solid. 1H NMR (400 MHz, CDCl3): δ 1.29, 3.72, 6.9, 7.66, 8.04, 8.29 ppm.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17]CC)=[O:16])[CH2:10]1)=[O:8].[OH-].[Na+].Cl>C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([OH:17])=[O:16])[CH2:10]1)=[O:8]
Reactant: CCOC(=O)C1CCCN(C(=O)Cc2cccs2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CCCN(C(=O)Cc2cccs2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
Ethyl 1-(2-thiopheneacetyl)-3-piperidinecarboxylate (256.4 mg; 0.91 mmol) was dissolved in absolute ethanol (5 ml). 1 N sodium hydroxide (10 ml) was added and the mixture was allowed to stir at ambient temperature for approximately 1 hour. It was then poured into 1 N HCl and extracted with dichloromethane. The dichloromethane was dried with magnesium sulfate and then evaporated at ambient temperature under reduced pressure, giving 1-(2-thiopheneacetyl)-3-piperidine carboxylic acid (210.1 mg) as a thick, yellow oil which solidified without further purification. MS m/z (positive ion) 254 (MH+; 100).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([C:9]1[CH:30]=[CH:29][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([N:20](C)[C:21](=O)OC(C)(C)C)[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].FC(F)(F)C(O)=O>ClCCl>[F:32][C:2]([F:1])([F:31])[C:3]([C:9]1[CH:30]=[CH:29][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][CH3:21])[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reaction time: 20 h
Yield: 93.1 %

Procedure:
A mixture of tert-butyl 1-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)-piperidin-4-yl(methyl)carbamate (3.19 mmol, 1.5 g), dichloromethane (5 mL) and trifluoroacetic acid (5 mL) was stirred for 20 hours. Purification by SCX chromatography gave the title compound (1.1 g). MS (ESI) m/z 371.4 [M+H]+