Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C@@H:12]3[CH2:16][C@H:5]([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[C:3]=1[C:17](O)=O.[CH3:20][N:21]([CH3:40])[S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[CH2:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)(=[O:24])=[O:23]>>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C@@H:12]3[CH2:16][C@@:5]([CH2:4][N:37]4[CH2:38][CH2:39][CH:34]([CH2:33][C:26]5[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:25]=5[S:22](=[O:24])(=[O:23])[N:21]([CH3:20])[CH3:40])[CH2:35][CH2:36]4)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:17]=2[CH:3]=1
Reactant: O=C(O)c1c(Cl)ccc2c1[C@@H]1C[C@@H]2c2ccccc21
Reactant: COc1ccc(S(=O)(=O)N(C)C)c(CC2CCNCC2)c1
Product: COc1ccc(S(=O)(=O)N(C)C)c(CC2CCN(C[C@]34C[C@H](c5ccccc53)c3ccc(Cl)cc34)CC2)c1

Procedure:
Using a procedure similar to that described in Example 55a, except starting with (9R,10R)-2-chloro-9,10-dihydro-9,10-methanoanthracenecarboxylic acid, prepared as described in Example 2a, and 4-(2-dimethylsulfamoyl-5-methoxyphenylmethyl) piperidine, prepared as described in Example 58e, the title compound was obtained as a white solid (617 mg, 1.09 mmol, 57%)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13].[CH2:14](Cl)[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)(=O)C.CCCCCC>[CH3:12][C:4]1[C:3]([CH3:13])=[C:2]([O:1][CH2:14]/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[NH:9][CH:10]=[O:11]
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Reactant: ClCC=Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(OC/C=C/c2ccccc2)c(C)c(C)c1NC=O
Yield: 44 %

Procedure:
By using N-(4-hydroxy-2,3,6-trimethylphenyl)formamide and cinnamyl chloride, the title compound was synthesized according to Reference Example 17b. Yield: 44%. Melting point: 197-199° C. (Ethyl acetate-hexane).
Reaction SMILES: [CH3:1][CH:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[C:9]([NH2:22])[N:8]=1)[CH2:3][O:4][CH3:5].C1C(=O)N([Br:30])C(=O)C1>ClCCl>[Br:30][C:12]1[N:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:14]2[C:10]([N:11]=1)=[C:9]([NH2:22])[N:8]=[C:7]([O:6][CH:2]([CH3:1])[CH2:3][O:4][CH3:5])[N:15]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: COCC(C)Oc1nc(N)c2ncn(C3CCCCO3)c2n1
Solvent: ClCCl
Product: COCC(C)Oc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Reaction time: 4 h
Yield: 80.8 %

Procedure:
To a stirred solution of 2-{[1-methyl-2-(methoxy)ethyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (7.2 g, 23.4 mmol) in dichloromethane (100 ml) was added NBS (4.6 g, 25.8 mmol). After 4 h, the solvent was removed. The product was purified on a silica column using petroleum ether: ethyl acetate 2:1 as eluent. This gave the product (7.3 g, 81.1%).
Reaction SMILES: [ClH:1].Br[C:3]1[CH:25]=[CH:24][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH2:15][CH:14]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH2:13][CH2:12]3)=[CH:5][CH:4]=1.[C:26]1([CH3:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].B(O)(O)O.CC1C=CC=CC=1>O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C>[ClH:1].[CH3:22][N:21]([CH2:20][CH2:19][CH:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:7][C:6]3[CH:24]=[CH:25][C:3]([C:29]4[CH:30]=[CH:31][C:26]([CH3:32])=[CH:27][CH:28]=4)=[CH:4][CH:5]=3)[CH:10]=2)[CH2:15]1)[CH3:23]
Reactant: CN(C)CCC1CCc2cc(OCc3ccc(Br)cc3)ccc2C1
Reactant: Cc1ccccc1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2ccc(COc3ccc4c(c3)CCC(CCN(C)C)C4)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of (+)-6-(4-bromobenzyl)oxy-2-[2-(N,N-dimethylamino)ethyl]tetralin hydrochloride (1 g), toluene (20 ml), ethanol (2.5 ml), and 2 M aqueous sodium carbonate (2.5 ml) was stirred at room temperature for 10 min. 4-Methylbenzeneboric acid (416 mg) and tetrakis(triphenylphosphine) palladium (82 mg) were added and the reaction mixture was heated under reflux for 5 hr under argon. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by alumina column chromatography (eluent:ethyl acetate hexane=1:40 to 1:4) and converted into its hydrochloride, which was then recrystallized from methanol-diisopropyl ether to obtain the titled compound (660 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:5][CH:4]=1
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(OC)cc1
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
To a solution of 4-methoxyphenol (5.0 g, 40 mmol) in N,N-dimethylformamide (50 mL) was added 60% sodium hydride (1.6 g, 40 mmol) under ice-cooling, and the mixture was stirred for 30 min. Ethyl bromoacetate (7.4 g, 44 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=7:1) to give the title compound (8.0 g, yield 94%). oil.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:4][N:3]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[S:11][C:10]([NH:12][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:9][C:8]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:4][N:3]=1
Reactant: Cc1noc(-c2sc(N)nc2-c2ccccc2)n1
Reactant: O=C(Cl)c1ccccc1
Product: Cc1noc(-c2sc(NC(=O)c3ccccc3)nc2-c2ccccc2)n1

Procedure:
Prepared from 5-(3-methyl-[1,2,4]oxadiazol-5-yl)-4-phenyl-thiazol-2-ylamine and benzoyl chloride.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH2:19][CH2:20][OH:21])([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd].CO>[N:14]1([C:11]2([CH2:19][CH2:20][OH:21])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: OCCC1(N2CCCC2)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: OCCC1(N2CCCC2)CCNCC1
Reaction time: 72 h
Yield: 98.7 %

Procedure:
A mixture of 2-(1-benzyl-4-pyrrolidine-1-ylpiperidine-4-yl)ethanol (9.28 g), 10% Pd/C (1.86 g) and methanol (100 mL) was stirred under hydrogen (4 atm) for 3 days. The insoluble material was filtrated and the filtrate was concentrated to give the title compound (6.30 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[Zn][C:10]1[O:11][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:14]=1>CCOC(C)=O.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>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:10]1[O:11][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1ccc([Zn]Br)o1
Reactant: Brc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(-c2ccccn2)o1
Temperature: 70 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
A mixture of 2-bromopyridine (1.4 mL, 15 mmol) and bromo[5-(ethoxycarbonyl)-2-furyl]zinc (0.5 M in THF, 30 mL) was degassed. To this mixture was added tetrakis(triphenylphosphine)palladium(0) (0.9 g, 0.8 mmol). The reaction mixture was allowed to stir at 70° C. overnight and then to cool to rt. The mixture was diluted with EtOAc and washed with aq. Sat. NaHCO3. A precipitate formed and was filtered. The filtrate was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give ethyl 5-pyridin-2-yl-2-furoate (2.02 g, 62%). LCMS: (FA) ES+ 218.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH3:28])[CH2:14][C:15]2[O:16][C:17]([C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[O:21])=[N:18][N:19]=2)(=[O:12])=[O:11])=[C:5]([CH3:29])[CH:4]=1.[Cl:30][C:31]1[N:36]=[CH:35][C:34]([CH:37]=O)=[CH:33][CH:32]=1.ClCCCl>>[Cl:30][C:31]1[N:36]=[CH:35][C:34]([CH2:37][N:25]2[CH2:24][CH2:23][N:22]([C:20]([C:17]3[O:16][C:15]([CH2:14][N:13]([CH3:28])[S:10]([C:6]4[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[CH3:29])(=[O:11])=[O:12])=[N:19][N:18]=3)=[O:21])[CH2:27][CH2:26]2)=[CH:33][CH:32]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N3CCNCC3)o2)c(C)c1
Reactant: O=Cc1ccc(Cl)nc1
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N3CCN(Cc4ccc(Cl)nc4)CC3)o2)c(C)c1

Procedure:
The title compound was prepared according to general procedure CD using 4-methoxy-N,2,6-trimethyl-N-{[5-(piperazin-1-ylcarbonyl)-1,3,4-oxadiazol-2-yl]methyl}benzenesulfonamide (210 mg, 0.50 mmol), 6-chloropyridine-3-carbaldehyde (84 mg, 0.60 mmol), STAB (210 mg, 0.99 mmol) DCE (4.0 mL) and a few 4 Å molecular sieves. The crude product recrystallised from IPA/MeOH/DCM.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[NH2:15][C:16]1[CH:35]=[CH:34][C:19]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:22]=2)=[CH:18][CH:17]=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:15][C:16]2[CH:35]=[CH:34][C:19]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH:22]=3)=[CH:18][CH:17]=2)=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
At room temperature, 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (656 mg, 2.96 mmol, 1.05 eq) was disolved in dichloromethane (5 mL). To the resulted solution, a solution of tert-butyl 4-(4-aminophenoxy)picolinate (805 mg, 2.81 mmol, 1 eq) in dichloromethane (5 mL) was slowly added dropwise. The mixture was stirred for 16 hours at room temperature. The solvent was removed under reduced pressure, and the resulted solid was purified by column chromatography (dichoromethane:methanol=30:1) to give the title compound (1.4 g, putity 95%, yield 85%) as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([NH2:10])[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1.Br[C:12]1[C:13](=[O:20])[N:14]([CH3:19])[CH:15]=[C:16]([Br:18])[CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:18][C:16]1[CH:17]=[C:12]([NH:10][C:8]2[CH:7]=[CH:6][N:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[N:9]=2)[C:13](=[O:20])[N:14]([CH3:19])[CH:15]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: Nc1ccnc(C2CC2)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cn1cc(Br)cc(Nc2ccnc(C3CC3)n2)c1=O
Temperature: 25 °C
Yield: 58.9 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 196a (300 mg, 2.22 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (593 mg, 2.22 mmol), and cesium carbonate (1.45 g, 4.44 mmol). After bubbling nitrogen through the suspension for 30 minutes, Xantphos (127 mg, 0.22 mmol) and tris(dibenzyl-ideneacetone)dipalladium(0) (100 mg, 0.11 mmol) were added. The system was subject to three cycles of vacuum/argon flush and heated at reflux for 5 h. It was then cooled to room temperature and filtered. The solid was washed with dichloromethane (2×50 mL). The combined filtrate was concentrated under reduced pressure and the residue was washed with acetonitrile (5 mL) to afford 196b (420 mg, 59%) as a yellow solid. MS-ESI: [M+H]− 321
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([NH:30][C:31]([NH:33][C:34]5[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][O:43][CH3:44])=[CH:36][CH:35]=5)=[O:32])=[N:28][CH:29]=4)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=3)[N:10]=2)=CC=1.FC(F)(F)S(O)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].CC(O)C>C(O)(C(F)(F)F)=O.C(Cl)(Cl)Cl>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[C:17]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([NH:30][C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][O:43][CH3:44])=[CH:36][CH:35]=4)=[O:32])=[N:28][CH:29]=3)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=2)[N:10]=1
Reactant: COCCOc1ccc(NC(=O)Nc2ccc(Nc3ncc(Cl)cc3-c3nc(C)nc(N(Cc4ccc(OC)cc4)Cc4ccc(OC)cc4)n3)cn2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: COCCOc1ccc(NC(=O)Nc2ccc(Nc3ncc(Cl)cc3-c3nc(C)nc(N)n3)cn2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
A solution of 1-(5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-chloropyridin-2-ylamino)pyridin-2-yl)-3-(4-(2-methoxyethoxy)phenyl)urea (0.176 g, 0.231 mmol) and trifluoromethanesulfonic acid (0.020 mL, 0.231 mmol) in TFA (2 mL) was stirred at rt for 30 min then warmed up to 60° C. and stirred overnight. After cooling to rt, solid sodium carbonate was added in portions until effervescence subsided. 25% iPrOH in CHCl3 (+1% NH4OH) was added to the residue, and the organic phase was washed with sodium bicarbonate. The material was not fully soluble in the organic layer so the organic layer containing solid was directly dried under vacuum (no drying agent was added). The crude product was purified by preparative HPLC using Phenomenex, Gemni 5 micron C18 100×30 mm column (1%-90% CH3CN w/0.1% TFA/H2O w/0.1% TFA in 15 min). The fractions containing product were collected and concentrated in vacuo. Sodium bicarbonate was added and the resulting solid was collected to give 1-(5-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-chloropyridin-2-ylamino)pyridin-2-yl)-3-(4-(2-methoxyethoxy)phenyl)urea (0.0834 g, 69% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 11.82 (br. s., 1H); 10.10 (br. s., 1H); 9.30 (br. s., 1H); 8.62-8.86 (m, 2H); 8.36 (d, J=2.54 Hz, 1H); 8.13 (br. s., 7.96 (br. s., 1H); 7.84 (br. s., 1H); 7.51 (br. s., 1H); 7.33-7.46 (m, 2H); 6.90 (d, J=8.41 Hz, 2H); 4.04 (br. s., 2H); 3.64 (d, J=3.72 Hz, 2H); 3.30 (d, J=5.87 Hz, 3H); 2.44 (d, J=5.48 Hz, 3H). m/z (ESI, +ve ion) 521.9 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([NH:13][C:14](=S)[NH2:15])=[C:11]([C:17]([NH2:19])=[O:18])[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OO.O.Cl>[OH-].[Na+].[O-][W]([O-])(=O)=O.[Na+].[Na+]>[CH2:1]([N:8]1[CH:9]=[N:10][C:11]2[C:17](=[O:18])[NH:19][C:14]([NH2:15])=[N:13][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ncn(Cc2ccccc2)c1NC(N)=S
Agent: O=[W](=O)([O-])[O-]
Agent: Cl
Agent: OO
Solvent: O
Product: Nc1nc2c(ncn2Cc2ccccc2)c(=O)[nH]1
Reaction time: 1 h
Yield: 54 %

Procedure:
1-Benzyl-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide (2.75 g, 10.0 mM) and sodium tungstate (0.1 g) were suspended in 6N sodium hydroxide (20 ml) at 5° C. 35% hydrogen peroxide (4.0 ml, 44 mM) was added dropwise at 5°-15° C. over 30 minutes. Water (60 ml) was added to the resulting reaction mixture. After stirring for 1 hour in an ice bath pH was adjusted to 5 with hydrochloric acid. The formed product was filtered off, washed with water and dried. Hereby was isolated 1.30 g (54%) of the title compound as a white powder. HPLC indicated about 98% purity. The product had the same physical data as the product of example 4.
Reaction SMILES: FC(F)(F)C(O)=O.ClC1C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)=C2N=C(C3C=CC(CN4CCOCC4)=CC=3)NC2=NC=1.[NH2:42][C:43]1[C:48]([NH2:49])=[C:47]([NH:50][C@H:51]2[C@H:56]3[CH2:57][C@H:53]([CH:54]=[CH:55]3)[C@H:52]2[C:58]([NH2:60])=[O:59])[C:46]([Cl:61])=[CH:45][N:44]=1.[CH3:62][O:63][C:64]1[CH:71]=[C:70]([N:72]2[CH2:77][CH2:76][CH:75]([N:78]3[CH2:83][CH2:82][O:81][CH2:80][CH2:79]3)[CH2:74][CH2:73]2)[CH:69]=[CH:68][C:65]=1[CH:66]=O>>[Cl:61][C:46]1[C:47]([NH:50][C@H:51]2[C@H:56]3[CH2:57][C@H:53]([CH:54]=[CH:55]3)[C@H:52]2[C:58]([NH2:60])=[O:59])=[C:48]2[N:49]=[C:66]([C:65]3[CH:68]=[CH:69][C:70]([N:72]4[CH2:73][CH2:74][CH:75]([N:78]5[CH2:83][CH2:82][O:81][CH2:80][CH2:79]5)[CH2:76][CH2:77]4)=[CH:71][C:64]=3[O:63][CH3:62])[NH:42][C:43]2=[N:44][CH:45]=1
Reactant: NC(=O)[C@H]1[C@@H](Nc2c(Cl)cnc(N)c2N)[C@@H]2C=C[C@H]1C2
Reactant: COc1cc(N2CCC(N3CCOCC3)CC2)ccc1C=O
Agent: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N2CCC(N3CCOCC3)CC2)ccc1-c1nc2c(N[C@@H]3[C@H](C(N)=O)[C@H]4C=C[C@@H]3C4)c(Cl)cnc2[nH]1
Yield: 8 %

Procedure:
In the same fashion as for Compound III, (1R,2R,3S,4S)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 2-Methoxy-4-(4-morpholin-4-yl-piperidin-1-yl)-benzaldehyde were reacted to produce the title compound (8%). 1H NMR (d-6 DMSO): 12.26 (br s, 1H), 9.70 (br s, 1H), 8.02 (m, 1H), 7.79 (s, 1H), 7.42 (br s, 1H), 7.26 (s, 1H), 6.78 (d, J=9 Hz, 1H), 6.66 (s, 1H), 6.38 (s, 2H), 5.17 (m, 1H), 4.11 (m, 2H), 4.03 (m, 2H), 4.00 (s, 3H), 3.68 (m, 2H), 3.48 (m, 4H), 3.12 (m, 2H), 2.92-2.77 (m, 3H), 2.63 (d, J=8 Hz, 1H), 2.24 (m, 1H), 2.13 (m, 2H), 1.68 (m, 2H), 1.40 (d, J=9 Hz, 1H). MS: 578.20 (M+H). HPLC retention time: 1.92 minutes (G Method).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=1)[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:6]
Reactant: NCC(c1ccc(F)cc1)N1CCOCC1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(c1ccc(F)cc1)N1CCOCC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(4-fluoro-phenyl)-2-morpholin-4-yl-ethylamine.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[N:35][C:34]2=[CH:38][C:31]3=[N:32][N:33]2[C:13]=1[N:14]1[CH2:41][CH2:40][C:17]([CH3:42])([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:39]=[C:27]([CH2:28][O:29][CH2:30]3)[CH:26]=[CH:25][CH:24]=2)[CH2:16][CH2:15]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO>[C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[N:35][C:34]2=[CH:38][C:31]3=[N:32][N:33]2[C:13]=1[N:14]1[CH2:15][CH2:16][C:17]([CH3:42])([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:39]=[C:27]([CH2:28][O:29][CH2:30]3)[CH:26]=[CH:25][CH:24]=2)[CH2:40][CH2:41]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCCc1cccc(c1)COC3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCCCCc1cccc(c1)COC3
Temperature: 25 °C
Yield: 88.6 %

Procedure:
A mixture of ethyl (2S)-2-(tert-butoxy)-2-{4,23-dimethyl-11,22-dioxa-1,5,7,8-tetraazapentacyclo[21.2.2.16,9.113,17.02,7]nonacosa-2,4,6(29),8,13(28),14,16-heptaen-3-yl}acetate (20 mg, 0.035 mmol) and NaOH (0.035 mL, 0.035 mmol) in EtOH (2 mL) was refluxed for 2 h. It was then cooled to rt, filtered and purified by preparative HPLC to obtain (2S)-2-(tert-butoxy)-2-{4,23-dimethyl-11,22-dioxa-1,5,7,8-tetraazapentacyclo[21.2.2.16,9.113,17.02,7]nonacosa-2,4,6(29),8,13(28),14,16-heptaen-3-yl}acetic acid (17 mg, 0.031 mmol, 89% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 7.41 (s, 1H), 7.33-7.24 (m, 1H), 7.16 (d, J=7.0 Hz, 2H), 6.51 (s, 1H), 5.64 (s, 1H), 4.50-4.29 (m, 5H), 3.65-3.58 (m, 1H), 3.57-3.38 (m, 3H), 2.76 (d, J=11.4 Hz, 1H), 2.51 (s, 3H), 2.66 (t, J=8.1 Hz, 2H), 1.97 (d, J=13.6 Hz, 1H), 1.89-1.51 (m, 7H), 1.22 (s, 3H), 1.15 (s, 9H). LCMS (M+1)=551.6.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([O:8][CH3:9])[CH:7]=1.OS(O)(=O)=O.N([O-])=O.[Na+].NC(N)=O.[I-:24].[K+]>O>[I:24][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(N)ccc1C
Reactant: [I-]
Agent: NC(N)=O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1cc(I)ccc1C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
5-amino-2-methylanisole (8.05 g, 58.7 mmol) was dissolved in 244 mL water and 8.1 mL concentrated H2SO4 and cooled to 0° C. NaNO2 (4.86 g, 70.4 mmol) in 61 mL water was added dropwise with stirring. Reaction was stirred 30 minutes at 0° C. Urea (0.70 g, 11.7 mmol) was added and stirring continued for an additional 30 minutes. The pale yellow solution was transferred to a dropping funnel and added slowly to a stirred solution of potassium iodide (19.48 g, 117.4 mmol) in 122 mL water. The solution was stirred at ambient temperature for 1 h after completion of the addition. The reaction was extracted with diethyl ether (3×300 mL). The organic extracts were combined and washed with 1M Na2S2O3 (2×200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield 9.60 g (66%) of 5-iodo-2-methyl anisole as a brown oil.
Reaction SMILES: [C:1]([CH:6]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:7]#[N:8])([O:3][CH2:4][CH3:5])=[O:2].[C:20]([O:23][CH:24](OCC)[O:25][CH2:26][CH3:27])(=O)[CH3:21]>>[C:1]([C:6]([CH:24]([O:25][CH2:26][CH3:27])[O:23][CH2:20][CH3:21])([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:7]#[N:8])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)C(C#N)Cc1ccc(OC)c(OC)c1
Reactant: CCOC(OCC)OC(C)=O
Product: CCOC(=O)C(C#N)(Cc1ccc(OC)c(OC)c1)C(OCC)OCC
Temperature: 95 °C

Procedure:
A mixture of α-Carbethoxy-β-[3,4-dimethoxyphenyl]propionitrile (10 g) and diethoxymethyl acetate (30 g) was heated at 95° C. for 20 hours. The volatiles were removed under vacuum pump pressure leaving 13.4 g (94%) of a nearly colorless oil which solidified on standing at -5° C. to a white solid, m.p. 62°-65° C.
Reaction SMILES: [CH2:1]([CH:8]1[O:12][C:11](=[O:13])[CH:10]=[C:9]1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][CH2:25][NH:26][C:27](=[O:29])[CH3:28])=[CH:16]1>>[CH2:1]([CH:8]1[O:12][C:11](=[O:13])[C:10]([CH:8]([C:16]2[NH:15][C:23]3[C:18]([C:17]=2[CH2:24][CH2:25][NH:26][C:27](=[O:29])[CH3:28])=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:1][CH:2]([CH3:7])[CH3:3])=[C:9]1[OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=C(O)C(Cc2ccccc2)O1
Reactant: CC(=O)NCCc1c[nH]c2ccccc12
Product: CC(=O)NCCc1c(C(CC(C)C)C2=C(O)C(Cc3ccccc3)OC2=O)[nH]c2ccccc12

Procedure:
Using general procedure C, 5-benzyl-4-hydroxy-5H-furan-2-one (Lit. 13) was reacted with 3-methyl-butyraldehydeand and N-[2-(1H-indol-3-yl)-ethyl]-acetamide) to give the title compound as a yellow solid. MS: 459.1 ([M−H ]−).