Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[C:3]([C:11]1[CH:12]=[C:13](/[C:17](=[N:23]/[O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[N:35]=[C:36]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[O:37][C:38]=3[CH3:39])=[CH:28][CH:27]=2)/[C:18]([O:20]CC)=[O:19])[CH:14]=[CH:15][CH:16]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CO.Cl>O1CCCC1>[C:3]([C:11]1[CH:12]=[C:13](/[C:17](=[N:23]/[O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[N:35]=[C:36]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[O:37][C:38]=3[CH3:39])=[CH:28][CH:27]=2)/[C:18]([OH:20])=[O:19])[CH:14]=[CH:15][CH:16]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1cccc(C(=O)c2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\C(=O)O)c2cccc(C(=O)c3ccccc3)c2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (7 ml) was added to a solution of ethyl Z-2-(3-benzoylphenyl)2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetate (800 mg) in tetrahydrofuran (14 ml)-methanol (7 ml) and stirred at 40° C. for 1 hour. 1N hydrochloric acid (7.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain Z-2-(3-benzoylphenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetic acid (608 mg, yield 80%) as orange crystals. m.p. 185-186° C. (decomposition)
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH3:7][C:8]1([CH3:47])[CH2:12][CH2:11][CH2:10][N:9]1[CH2:13][CH2:14][NH:15][C:16]([C:18]1[CH:19]=[C:20]([NH:25][C:26]([C:28]2[CH:29]=[N:30][N:31]3[CH:36]=[C:35]([C:37]4[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[C:39]([F:46])[CH:38]=4)[CH:34]=[CH:33][C:32]=23)=[O:27])[C:21]([CH3:24])=[N:22][CH:23]=1)=[O:17].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[CH3:7][C:8]1([CH3:47])[CH2:12][CH2:11][CH2:10][N:9]1[CH2:13][CH2:14][NH:15][C:16]([C:18]1[CH:19]=[C:20]([NH:25][C:26]([C:28]2[CH:29]=[N:30][N:31]3[CH:36]=[C:35]([C:37]4[CH:45]=[CH:44][C:40]([C:41](=[O:42])[NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])=[C:39]([F:46])[CH:38]=4)[CH:34]=[CH:33][C:32]=23)=[O:27])[C:21]([CH3:24])=[N:22][CH:23]=1)=[O:17]
Reactant: CC(C)(N)CO
Reactant: Cc1ncc(C(=O)NCCN2CCCC2(C)C)cc1NC(=O)c1cnn2cc(-c3ccc(C(=O)O)c(F)c3)ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ncc(C(=O)NCCN2CCCC2(C)C)cc1NC(=O)c1cnn2cc(-c3ccc(C(=O)NC(C)(C)CO)c(F)c3)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2-amino-2-methylpropan-1-ol (12.64 mg, 0.142 mmol), 4-(3-(5-(2-(2,2-dimethylpyrrolidin-1-yl)ethylcarbamoyl)-2-methylpyridin-3-ylcarbamoyl)pyrazolo[1,5-a]pyridin-6-yl)-2-fluorobenzoic acid (72 mg, 0.129 mmol) and triethylamine (0.054 ml, 0.387 mmol) in DCM (5 ml) was treated with HATU (53.9 mg, 0.142 mmol) and DMF (1 ml). After stirring at RT for 3 hrs, the reaction mixture was diluted with DCM and washed with sat NaHCO3 and H2O. The organic portion was separated, dried MgSO4 and concentrated in vacuo. The product was purified by flash column chromatography on silica eluting with 0-25% 2M NH3 in MeOH/DCM. The product fractions were combined and concentrated to afford an orange oil which was triturated with EtOAc/hexane to afford a pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:33])=[C:6]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([C@H:24]4[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]4)=[O:23])=[CH:17][CH:16]=3)=[CH:11][N:10]([CH2:30][CH2:31][OH:32])[N:9]=2)[CH:7]=1.[N:34]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])([CH3:46])[C@H:35]([C:43](O)=[O:44])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C1COCC1.C(N=C=NC(C)C)(C)C>O>[C:50]([O:49][C:47](=[O:48])[N:34]([C@@H:35]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:43]([N:25]1[CH2:26][CH2:27][CH2:28][CH2:29][C@@H:24]1[C:22](=[O:23])[NH:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]#[C:13][C:12]2[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[OH:33])=[N:9][N:10]([CH2:30][CH2:31][OH:32])[CH:11]=2)=[CH:20][CH:19]=1)=[O:44])[CH3:46])([CH3:53])([CH3:51])[CH3:52]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1)[C@H]1CCCCN1
Agent: CC(C)N=C=NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)N1CCCC[C@@H]1C(=O)Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
To a mixture of compound 5A (6.50 g, 13.98 mmol) and BOC-N-Me-Phe-OH (6A, 9.76 g, 34.94 mmol) was added anhydrous THF (350 mL) and the resultant mixture was stirred at rt for 10 min. Diisopropylcarbodiimide (DIPC, 5.41 mL, 34.94 mmol) was added slowly at rt. The reaction mixture was stirred at rt overnight. Water (˜10 mL) was added to the above mixture and the reaction mixture was stirred at rt for 3 hour. Solvent was removed and the residua were dissolved in ethyl acetate. It was filtered to remove solid (diisopropylurea). The filtrate was purified by silica column chromatography eluting with hexanes-ethyl acetate (v/v 1/1, 2/3, 1/2) to provide the title compound (7A, 4.3 g) as foam-like powder in 42.3% yield. 1H NMR (CDCl3, 500 MHz) δ 10.63 (s, 1H), 8.67 (s, 1H), 8.62 (s, 1H), 7.76 (s, 1H), 7.63 (m, 1H), 7.52 (d, 2H, J=7.5 Hz), 7.40-7.10 (m, 7H), 6.96 (d, 1H, J=8.0 Hz), 5.35 (br s, 1H), 5.13 (m, 1H), 4.29 (s, 2H), 4.05 (s, 2H), 3.81 (m, 1H), 3.20 (t, 1H, J=8.0 Hz), 3.09 (m, 2H), 2.94 (s, 3H), 2.87 (m, 1H), 2.35 (m, 1H), 1.75-1.10 (m, 12H), 0.74 (m, 1H). LCMS (ESI) m/z 748.26 (MNa+), 726.27 (MH+), 670.21, 626.20, 465.10, 373.18, 317.14 (100). HPLC: tR=5.70 min.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.N1C=CC=CC=1.[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([N+:34]([O-:36])=[O:35])=[C:29]([CH:33]=1)[C:30](Cl)=[O:31]>ClCCl>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([N+:34]([O-:36])=[O:35])=[C:29]([CH:33]=1)[C:30]([NH:15][C:12]1[CH:11]=[N:10][C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:4]=2)=[CH:14][N:13]=1)=[O:31]
Reactant: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Nc1cnc(-c2cccc(C(F)(F)F)c2)cn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cnc(-c2cccc(C(F)(F)F)c2)cn1)c1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 5-(3-(trifluoromethyl)phenyl)pyrazin-2-amine (1.3 g, 5.43 mmol, 1.00 equiv) in dichloromethane (15 mL), and pyridine (2 mL). This was followed by dropwise addition of a solution of 5-chloro-2-nitrobenzoyl chloride (1.2 g, 5.45 mmol, 1.00 equiv) in dichloromethane (5 mL) with stirring. The resulting solution was stirred for 2 h at 25° C. in an oil bath. The resulting solution was diluted with 100 mL of dichloromethane. The resulting mixture was washed with 2×50 mL of hydrogen chloride (aq), dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 2 g (87%) of 5-chloro-2-nitro-N-(5-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)benzamide as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5](=O)[CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].CC(O)=O.[CH2:17]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH2:25]([N:24]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:5]1[CH2:4][CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]([CH3:1])[CH2:6]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1CC(=O)CC1C
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)C1CC(N(Cc2ccccc2)Cc2ccccc2)CC1C
Temperature: 0 °C
Reaction time: 20 h
Yield: 75 %

Procedure:
A round-bottom flask was charged with ethyl 2-methyl-4-oxocyclopentanecarboxylate (10.0 g, 58.8 mmol) and DCE (180 mL). The solution was cooled to about 0° C. and AcOH (5.7 mL, 100 mmol) and dibenzylamine (11.3 mL, 58.8 mmol) were added drop-wise, resulting in formation of a thick suspension. The reaction mixture was warmed to about 10° C. and sodium triacetoxyborohydride (21.2 g, 100 mmol) was added portion-wise and the reaction mixture was stirred at room temperature for about 20 h. The reaction mixture was slowly poured into stirred saturated aqueous NaHCO3 (300 mL) for about 20 min. The layers were separated and the aqueous phase was extracted with DCM (3×100 mL). The combined organic extracts were washed with brine (2×100 mL), dried over anhydrous Na2SO4, and concentrated to dryness under reduced pressure. The crude yellow oil was purified via flash column chromatography eluting with a gradient of 0-30% EtOAc in heptane. The solvent was removed under reduced pressure to give ethyl 4-(dibenzylamino)-2-methylcyclopentanecarboxylate (15.5 g, 75%) as colorless oil: 1H NMR (pyridine-d5) δ 7.53 (dd, J=0.9, 7.9 Hz, 4H), 7.43-7.35 (m, 4H), 7.33-7.25 (m, 2H), 4.22-4.06 (m, 2H), 3.79 (d, J=14.2 Hz, 2H), 3.70 (d, J=14.2 Hz, 2H), 3.34-3.22 (m, 1H), 2.76 (dd, J=7.9, 16.6 Hz, 1H), 2.25-2.13 (m, 1H), 2.09-1.94 (m, 2H), 1.88-1.79 (m, 1H), 1.52 (dd, J=10.5, 22.5 Hz, 1H), 1.16 (t, J=7.1 Hz, 3H), 0.98 (d, J=7.0 Hz, 3H).
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:29][C@@H:30]([C@H:32]4[CH2:36][NH:35][C:34](=[O:37])[CH2:33]4)[CH3:31])=[N:10][C:11]([C:13]4[CH:18]=[CH:17][C:16]([N:19]5[CH2:24][CH2:23][N:22]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:21][CH2:20]5)=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.[CH:38]1(N2C3C(O[C@@H]([C@H]4CNC(=O)C4)C)=NC(C4C=CC(N5CCNCC5)=CC=4)=CC=3N=C2)CC1.C(S(Cl)(=O)=O)C>>[CH:1]1([N:4]2[C:8]3[C:9]([O:29][C@@H:30]([C@H:32]4[CH2:36][NH:35][C:34](=[O:37])[CH2:33]4)[CH3:31])=[N:10][C:11]([C:13]4[CH:18]=[CH:17][C:16]([N:19]5[CH2:24][CH2:23][N:22]([S:25]([CH2:28][CH3:38])(=[O:26])=[O:27])[CH2:21][CH2:20]5)=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCN(S(C)(=O)=O)CC3)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCNCC3)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)N1CCN(c2ccc(-c3cc4ncn(C5CC5)c4c(O[C@H](C)[C@H]4CNC(=O)C4)n3)cc2)CC1

Procedure:
Following the procedure described for intermediate 3.45, starting from (R)-4-((R)-1-((3-cyclopropyl-6-(4-(piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one (100 mg, 0.22 mmol) and ethanesulfonyl chloride (0.02 ml, 0.25 mmol), to provide 49.3 mg of (R)-4-((R)-1-((3-cyclopropyl-6-(4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one.
Reaction SMILES: [CH:1]([CH:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)[C:4]#[N:5])=O.Cl.[NH2:20][NH:21][C:22]([NH2:24])=[O:23].[OH-].[Na+].Cl>O.CO>[NH2:5][C:4]1[N:21]([C:22](=[O:23])[NH2:24])[N:20]=[CH:1][C:3]=1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1
Reactant: NNC(N)=O
Reactant: N#CC(C=O)c1ccc(Cc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC(=O)n1ncc(-c2ccc(Cc3ccccc3)cc2)c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.5 %

Procedure:
A mixture of α-formyl-4-benzylphenylacetonitrile (152.22 g), semicarbazide hydrochloride (72.24 g), methanol (400 ml) and water (80 ml) was stirred at room temperature, and after 18 hours, maintained pH to about 10 with 5N sodium hydroxide aqueous solution. When heat was generated, the reaction mixture was cooled with ice-water. After stirring at room temperature for 1 hour, the reaction mixture was neutralized with 10% hydrochloric acid, and water (1 l) was added. After stirring for 1 hour, the precipitate was separated by filtration, washed with water, and dried to give the title compound (165.52 g).
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)C1C=CC=CC=1.C(N(CC)C(C)C)(C)C.[Cl:33]C(OC(Cl)C)=O.C(=O)(O)[O-].[Na+]>ClCCl.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)(Cl)Cl>[ClH:33].[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:14]1[C:15]2[CH2:16][CH2:17][NH:8][CH2:9][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: CC(Cl)OC(=O)Cl
Reactant: c1ccc(CN2CCc3c(ncnc3-c3ccccn3)C2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cl
Product: c1ccc(-c2ncnc3c2CCNC3)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 52.7 %

Procedure:
Part D: To a solution of 7-benzyl-4-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (2.15 g, 7.1 mmol) and N,N-diisopropylethylamine (2.48 mL, 14.2 mmol) in dichloromethane (30 mL) at 0° C. was added 1-chloroethyl chloroformate (1.15 mL, 10.7 mmol) over several minutes. The resulting solution was stirred at 0° C. for 1.0 h and then at 25° C. for 20 h. To this solution was added a saturated aqueous sodium bicarbonate solution (50 mL), and the resulting two-phase mixture was stirred at 25° C. for 1.0 h. The phases were separated, and the aqueous phase was washed with dichloromethane. The combined organic phases were dried over anhyd. sodium sulfate, filtered, and concentrated. The residue was dissolved in methanol, and the solution was heated at reflux for 1.0 h. After cooling to room temperature the mixture was concentrated under vacuum. The residue was triturated with ethyl acetate, and the resulting solids were recovered by filtration and dried under vacuum to provide a purple solid. These solids were dissolved in a mixture of concentrated aqueous sodium carbonate solution and chloroform. The phases were separated, and the aqueous phase was washed twice with chloroform. The combined organic phases were washed with brine, dried over anhyd. sodium sulfate, filtered, and concentrated. The residue was maintained under high vacuum overnight and then dissolved in methanol. This solution was filtered to remove a dark solid and then concentrated under vacuum. Finally, this residue was dissolved in 1,4-dioxane at 25° C. To this solution was added dropwise an excess (˜1 mL) of 4N HCl in 1,4-dioxane. The resulting precipitate was recovered by filtration and dried under vacuum to furnish 4-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloride (0.93 g, 53%) as a brick-red solid; Mass Spec.: m/e: 213.05 (M+H)+ [calc'd: 213.11]; 1HNMR (500 MHz, DMSO-d6) δ 9.81 (br s, 2H), 9.17 (s, 1H), 8.76 (m, 1H), 8.15 (m, 1H), 7.59 (m, 1H), 4.49 (m, 2H), 3.41 (m, 4H).
Reaction SMILES: [C:1]1([C:7]2(C(O)=O)[CH2:16][CH2:15][C:10]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:22]([CH2:25]C)CC)C.[N-]=[N+]=[N-].C1([O:36]P(=O)(O)OC2C=CC=CC=2)C=CC=CC=1>C1(OC)C=CC=CC=1>[N:22]([C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][C:10]2([O:11][CH2:12][CH2:13][O:14]2)[CH2:15][CH2:16]1)=[C:25]=[O:36]
Reactant: O=P(O)(Oc1ccccc1)Oc1ccccc1
Reactant: O=C(O)C1(c2ccccc2)CCC2(CC1)OCCO2
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=[N-]
Solvent: COc1ccccc1
Product: O=C=NC1(c2ccccc2)CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
8-phenyl-1,4-dioxaspiro[4.5]decane-8-carboxylic acid (3 g, 11.5 mmole) was added to anisole (30 ml). The resultant suspension was cooled to a temperature of 0° C. in an ice-salt bath and triethylamine (2.25 ml, 16 mmole) was added. A clear solution was formed, which was stirred for a further 15 minutes at 0° C. Phosphoric acid diphenyl ester azide (2.5 ml, 11.5 mmole) was then added to the mixture within 5 minutes. The reaction mixture was stirred for 20 minutes at 0° C., left to cool to RT within a further 20 minutes, and was then heated in an oil bath for 2 hours at 100° C. (bath temperature). The reaction mixture was worked up by distilling off the anisole under an oil pump vacuum. The chromatographic purification was carried out on silica gel with toluene. The desired product was obtained as a crystalline solid with a melting point of 38°-41° C. in a yield of 2.7 g (91%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:5][C:6]=1[C:7](O)=[O:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClN1C(=O)CCC1=O.[CH:57]1([CH2:60][N:61]2[C:69]3[N:68]=[C:67]([CH2:70][C:71]4[CH:76]=[CH:75][C:74]([NH:77][CH3:78])=[CH:73][CH:72]=4)[NH:66][C:65]=3[C:64](=[O:79])[N:63]([CH2:80][C:81]3[CH:86]=[CH:85][CH:84]=[CH:83][C:82]=3[F:87])[C:62]2=[O:88])[CH2:59][CH2:58]1>ClCCl>[CH:57]1([CH2:60][N:61]2[C:69]3[N:68]=[C:67]([CH2:70][C:71]4[CH:72]=[CH:73][C:74]([N:77]([CH3:78])[C:7]([C:6]5[S:5][C:4]([NH:10][C:11]([C:24]6[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=6)([C:12]6[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=6)[C:18]6[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=6)=[N:3][C:2]=5[CH3:1])=[O:8])=[CH:75][CH:76]=4)[NH:66][C:65]=3[C:64](=[O:79])[N:63]([CH2:80][C:81]3[CH:86]=[CH:85][CH:84]=[CH:83][C:82]=3[F:87])[C:62]2=[O:88])[CH2:59][CH2:58]1
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reactant: Cc1nc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)sc1C(=O)O
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)sc1C(=O)N(C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
A mixture of 4-methyl-2-(trityl-amino)-thiazole-5-carboxylic acid (46 mg, 0.11 mmol) in dichloromethane (1.0 mL) at 25° C. was treated with triphenylphosphine (36 mg, 0.14 mmol). The reaction was cooled to 0° C. and was treated with N-chlorosuccinimide (18 mg, 0.14 mmol). This mixture was stirred at 0° C. for 30 min and then was warmed to 25° C. for 20 min. At this time, the reaction was treated with 3-cyclopropylmethyl-1-(2-fluoro-benzyl)-8-(4-methylamino-benzyl)-3,7-dihydro-purine-2,6-dione (100 mg, 0.23 mmol) and dichloromethane (2.5 mL). The reaction was stirred at 25° C. for 18 h. At this time, the reaction was treated with another portion of triphenylphosphine (36 mg, 0.14 mmol) and N-chlorosuccinimide (18 mg, 0.14 mmol). The reaction was stirred at 25° C. for 1 h. At this time, the reaction was diluted with dichloromethane (100 mL) and then washed with a saturated aqueous sodium bicarbonate solution (1×25 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 80:20 ethyl acetate/petroleum ether) afforded 4-methyl-2-(trityl-amino)-thiazole-5-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (75.1 mg, 80.0%). The product was used without further purification or characterization.
Reaction SMILES: CCN=C=NCCCN(C)C.[CH3:12][C:13]1[CH2:18][CH2:17][CH2:16][C:15]([CH3:20])([CH3:19])[C:14]=1/[CH:21]=[CH:22]/[C:23](/[CH3:33])=[CH:24]/[CH:25]=[CH:26]/[C:27](/[CH3:32])=[CH:28]/[C:29]([OH:31])=O.[C:34]([O:39][C:40]1[CH:45]=[C:44]([OH:46])[CH:43]=[CH:42][C:41]=1[NH2:47])(=[O:38])[CH2:35][CH2:36][CH3:37]>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:34]([O:39][C:40]1[CH:45]=[C:44]([OH:46])[CH:43]=[CH:42][C:41]=1[NH:47][C:29](=[O:31])/[CH:28]=[C:27](\[CH3:32])/[CH:26]=[CH:25]/[CH:24]=[C:23](\[CH3:33])/[CH:22]=[CH:21]/[C:14]1[C:15]([CH3:19])([CH3:20])[CH2:16][CH2:17][CH2:18][C:13]=1[CH3:12])(=[O:38])[CH2:35][CH2:36][CH3:37]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)C(C)(C)CCC1
Reactant: CCCC(=O)Oc1cc(O)ccc1N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCCC(=O)Oc1cc(O)ccc1NC(=O)/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
To a solution of EDCI (0.023 g, 0.12 mmol) in anhydrous DMF (5 mL) was added a solution of retinoic acid (0.031 g, 0.10 mmol) in anhydrous DMF (5 mL). The mixture was stirred at room temperature for 0.5 h. A solution of 2-amino-5-hydroxy-phenyl butanoate (KCBG05, 0.020 g, 0.12 mmol) and DMAP (cat.) in anhydrous DMF (2 mL) was added to the mixture, and again stirred for 4 h. The reaction was quenched with NH4Cl (aq.), extracted with EtOAc (2×30 mL). The extracts were washed with H2O (2×30 mL), dried over anhydrous Na2SO4, and evaporated. The residue was purified by flash column chromatography over silica gel (EtOAc:hexane=1:6) to give 2-[(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)-nona-2,4,6,8-tetraenoylamino]-5-hydroxyphenyl butanoate (KCBG10, 0.038 g, 78%) as a yellow solid.
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].[C:5]([N:10]=[C:11]=[O:12])(=[O:9])[C:6]([CH3:8])=[CH2:7]>ClCCCl.N1C=CC=CC=1>[C:5]([NH:10][C:11]([NH:4][C:1](=[O:3])[CH3:2])=[O:12])(=[O:9])[C:6]([CH3:8])=[CH2:7]
Reactant: C=C(C)C(=O)N=C=O
Reactant: CC(N)=O
Solvent: ClCCCl
Solvent: c1ccncc1
Product: C=C(C)C(=O)NC(=O)NC(C)=O
Reaction time: 12 h
Yield: 79.9 %

Procedure:
To a solution of acetamide (0.59 g; 10 mmol) in 1,2-dichloroethane (20 ml), a solution of methacryloyl isocyanate (1.11 g; 10 mmol) in 1,2-dichloroethane (10 ml) was dropwise added. After completion of the addition, pyridine (5 drops) was added to the solution, and then stirring was continued at room temperature for 12 hours. 1,2-Dichloroethane was evaporated under reduced pressure to give 1-methacryloyl-3-acetylurea (1.36 g), which was recrystallized from a mixture of benzene and hexane to give colorless needles. M.P., 92°-94° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[C:14]([OH:21])[CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[NH:10])=[CH:4][CH:3]=1.[C:22]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[C:14]([O:21][CH3:22])[CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[NH:10])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: N=C(Nc1ccc(Cl)cc1)c1ccc2cccc(O)c2n1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cccc2ccc(C(=N)Nc3ccc(Cl)cc3)nc12
Yield: 45.7 %

Procedure:
A mixture of 0.10 g (0.33 mmol) of N-(4-chloro-phenyl)-8-hydroxy -quinoline-2-carboxamidine, 0.137 g (1 mmol) of K2CO3 and 0.021 g (0.33 mmol) of iodomethane in 3.5 mL of DMF was heated under microwave (100 W, 5 min). It was diluted with 20 mL of NaHCO3, extracted with three 10 mL portions of ether. The combined organic extracts were washed with 10 mL of brine, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC eluting with 20% ethyl acetate in hexanes to give 0.047 g of N-(4-chloro-phenyl)-8-methoxy -quinoline-2-carboxamidine.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[I:18]N1C(=O)CCC1=O.O>C(O)(=O)C>[I:18][C:11]1[CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:16])([F:17])[F:1])[CH:4]=2)[CH:14]=[CH:13][C:12]=1[OH:15]
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ccc(-c2cccc(C(F)(F)F)c2)cc1
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc(-c2cccc(C(F)(F)F)c2)cc1I
Temperature: 25 °C
Yield: 39.2 %

Procedure:
To a solution of 3′-(trifluoromethyl)biphenyl-4-ol (Preparation 1, 2.17 g, 9.11 mmol) in acetic acid (20 mL) at 0° C. was added N-iodosuccinimide (2.05 g, 9.11 mmol). The reaction was allowed to warm to room temperature and stirred for 48 hours before the addition of water (20 mL). The reaction mixture was extracted with dichloromethane (2×20 mL) and the combined extracts were washed with saturated aqueous sodium thiosulfate solution, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (2%-20% ethyl acetate in heptane gradient elution) to afford the title compound (1.30 g, 39%).