Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([O:5][CH2:6][CH2:7][CH2:8][C:9]1([OH:12])[CH2:11][CH2:10]1)(=O)=O.O[C:14]1[CH:23]=[C:22]2[C:17]([C:18]([O:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:32]([C:34]4([C:37]([NH2:39])=[O:38])[CH2:36][CH2:35]4)=[O:33])=[CH:27][C:26]=3[F:46])=[CH:19][CH:20]=[N:21]2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[OH:12][C:9]1([CH2:8][CH2:7][CH2:6][O:5][C:14]2[CH:23]=[C:22]3[C:17]([C:18]([O:24][C:25]4[CH:30]=[CH:29][C:28]([N:31]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)[C:32]([C:34]5([C:37]([NH2:39])=[O:38])[CH2:35][CH2:36]5)=[O:33])=[CH:27][C:26]=4[F:46])=[CH:19][CH:20]=[N:21]3)=[CH:16][CH:15]=2)[CH2:11][CH2:10]1
Reactant: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(O)ccc34)c(F)c2)CC1
Reactant: CS(=O)(=O)OCCCC1(O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(OCCCC5(O)CC5)ccc34)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 36 h
Yield: 99.9 %

Procedure:
To a mixture of 3-(1-hydroxycyclopropyl)propyl methanesulfonate (170.7 mg, 0.877 mmol, from example 9) and N-(4-(7-hydroxyquinolin-4-yloxy)-3-fluorophenyl)-N-phenylcyclopropane-1,1-dicarboxamide (300 mg, 0.656 mmol) in 5 mL of N,N-dimethylacetamide was added cesium carbonate (893 mg, 2.74 mmol). After stirring at room temperature for 36 hrs, then the reaction mixture was warmed to 40° C. for 8 hrs. The reaction mixture was concentrated in vacuo and the residue was chromatographed with a silica gel column (4:1 (v/v) EtOAc/n-hexane) to afford the title compound as a white solid (364.1 mg, 74%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[S:16][C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=2)/[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O.O.[Cl-].[Ca+2].[Cl-]>C(O)C.[Zn]>[NH2:20][C:17]1[S:16][C:15](/[CH:14]=[C:11](/[C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)\[C:12]#[N:13])=[CH:19][CH:18]=1
Reactant: COc1ccc(/C(C#N)=C/c2ccc([N+](=O)[O-])s2)cc1OC
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: COc1ccc(/C(C#N)=C/c2ccc(N)s2)cc1OC
Reaction time: 2 h
Yield: 12.2 %

Procedure:
Compound 1 (316 mg) was dissolved in ethanol (25 mL), and calcium chloride dihydrate (132 mg) and zinc powder (2.55 g) were added to the solution, followed by stirring for 2 hours under reflux. The reaction mixture was subjected to filtration by use of a celite pad, to thereby remove zinc powder, and the solvent was evaporated to dryness. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), to thereby yield the target product (yield: 35 mg, 12%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.[CH:18]([O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)([CH3:20])[CH3:19]>>[CH2:12]([NH:11][C:9](=[O:10])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([O:21][CH:18]([CH3:20])[CH3:19])[CH:27]=2)=[CH:3][CH:4]=1)([CH3:17])[CH3:16])[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(Br)cc1
Reactant: CC(C)Oc1cccc(B(O)O)c1
Product: CC(C)CNC(=O)C(C)(C)c1ccc(-c2cccc(OC(C)C)c2)cc1
Yield: 60 %

Procedure:
Prepared in a similar manner to Example 8 from 2-(4-Bromophenyl)-N-isobutyl-2-methylpropanamide (Example 1a) and 3-isopropoxyphenylboronic acid. Yield: 60%. 1H NMR (400 MHz, CDCl3): δ 0.8 (d, 6H), 1.35 (d, 6H), 1.65 (s, 6H), 1.67-1.70 (m,1H), 3 (m, 2H), 4.6 (m, 1H), 6.9 (dd, 1H), 7.1 (t, 1H), 7.15 (d, 1H), 7.35 (t, 1H), 7.45 (d, 2H), 7.6 (d, 2H). MS (M+H, 354).
Reaction SMILES: [OH:1][CH:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][NH:8][CH2:7][C@@H:6]1[C:11]([O:13][CH3:14])=[O:12].[C:27]([S:31][CH2:32][CH2:33]Cl)([CH3:30])([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C.CO>[OH:1][CH:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:33][CH2:32][S:31][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:7][C@@H:6]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: CC(C)(C)SCCCl
Reactant: COC(=O)[C@H]1CNCC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: COC(=O)[C@H]1CN(CCSC(C)(C)C)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Temperature: 20 °C
Yield: 27.9 %

Procedure:
0.717 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate in 15 cm3 of acetonitrile and 15 cm3 of methanol was heated for 16 hours at a temperature in the region of the reflux temperature, with stirring and under an inert atmosphere, with 0.43 g of 2-chloroethyl tert-butyl sulfide in the presence of 0.33 g of potassium carbonate and 0.4 g of potassium iodide. After cooling the reaction mixture to a temperature in the region of 20° C., the insoluble material was filtered off. The filtrate was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under a nitrogen pressure of 100 kPa on a column of silica gel (particle size 40-63 μm; diameter 3.5 cm; height 35 cm), elution being was out with a dichloromethane/methanol (97/3 by volume) mixture, and 35-cm3 fractions were collected. Fractions 54 to 70 were combined and then evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 0.265 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(tert-butylthio)ethyl]piperidine-3-carboxylate was obtained in the form of a lacquer with a brown color.
Reaction SMILES: O[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[Br:15][C:16]1[C:17]([CH3:25])=[C:18](O)[CH:19]=[C:20]([CH3:23])[C:21]=1[CH3:22].S(=O)(=O)(O)O>O>[Br:15][C:16]1[C:21]([CH3:22])=[C:20]([CH3:23])[C:19]2[CH:2]([C:6]3[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=3)[C:3](=[O:4])[O:5][C:18]=2[C:17]=1[CH3:25]
Reactant: CC(C)c1ccc(C(O)C(=O)O)cc1
Reactant: Cc1cc(O)c(C)c(Br)c1C
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(C)c2c(c(C)c1Br)OC(=O)C2c1ccc(C(C)C)cc1
Temperature: 115 °C
Reaction time: 4 h

Procedure:
To a mixture of hydroxy(4-isopropylphenyl)acetic acid (10.0 g, 46.5 mmol) synthesized in Reference Example 1 and 3-bromo-2,4,5-trimethylphenol synthesized in Reference Example 68 (8.2 g, 42.2 mmol) was added 70% sulfuric acid (10 mL) at room temperature, and the mixture was stirred at 115° C. for 4 hours. The mixture was added to water, which was extracted with diisopropyl ether. The extract was washed with water and a saturated sodium hydrogen carbonate solution, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the residue, which was purified by silica gel column chromatography (ethyl acetate:hexane=1:8) to obtain 6-bromo-3-(4-isopropylphenyl)-4,5,7-trimethyl-1-benzofuran-2 (3H)-one. To a solution of the compound in THF (80 mL) was added lithium aluminum hydride (2.40 g, 63.3 mmol) at 0° C., and the mixture was heated under reflux for 1 hour. Water was added to the reaction solution, and the product was extracted with ethyl acetate. The combined extract was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was crystallized from hexane-ethyl acetate to obtain 15.5 g (yield 97%) of the title compound. Melting point: 96-97° C.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([CH:8]=O)=[CH:5][CH:4]=1)#[N:2].C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13]>N1C=CC=CC=1.N1CCCCC1>[C:1]([C:3]1[S:7][C:6]([CH:8]=[CH:11][C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)s1
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: N#Cc1ccc(C=CC(=O)O)s1

Procedure:
A stirred solution of 5-cyano-2-thiophene carboxaldehyde (3.3 g) and malonic acid (2.5 g) in pyridine (35 ml) and piperidine (0.7 ml) was heated under reflux for 2 hours adding further malonic acid (1.3 g) after 1 hour. The solution was evaporated and the residue was stirred with M hydrochloric acid solution (100 ml) to give a pale solid which was washed with water and dried, m.p. ca 260° C. (subliming).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:15]([NH:30][C:31](=[O:36])[CH2:32][C:33](=[O:35])[CH3:34])([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.[N:37]([O-])=[O:38].[Na+]>C(O)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([C@:15]([NH:30][C:31](=[O:36])[C:32](=[N:37][OH:38])[C:33](=[O:35])[CH3:34])([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1
Reactant: CC(=O)CC(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)C(=NO)C(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.6 %

Procedure:
To a solution of (R)—N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-oxobutanamide (Example 251, 62 mg, 0.12 mmol), in acetic acid (0.5 mL) was added dropwise a solution of NaNO2 (25 mg, 0.36 mmol) in H2O (0.5 mL). The reaction mixture was stirred at rt for 10 min and diluted with H2O (10 mL). The aqueous portion was extracted with EtOAc (3×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to yield (R)—N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-(hydroxyimino)-3-oxobutanamide (Example 331) as a yellow solid (65 mg, 100% yield). LCMS: RT=1.99 min [M+H] 539.4 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 10.07 (1H, s), 7.15-7.21 (2H, m), 7.07-7.14 (7H, m), 7.00-7.05 (4H, m), 6.84-6.96 (6H, m), 6.55-6.60 (2H, m), 5.88 (1H, t, J=2.78 Hz), 3.91 (1H, d, J=13.14 Hz), 3.72-3.80 (1H, m), 2.52 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C:10](=[CH:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[Br:28]N1C(=O)CCC1=O>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([Br:28])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2cc3n(c2n1)[C@H](C)CN(C(=O)OC(C)(C)C)C3
Solvent: C1CCOC1
Product: Cc1nc2c(cc1Br)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Reaction time: 1.5 h

Procedure:
To a stirred solution of 0.20 g (0.66 mmol) (R)-4,6-dimethyl-3,4-dihydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (example 5, intermediate b)) in 2 mL tetrahydrofuran 0.12 g (0.69 mmol) was added N-bromosuccinimide; the reaction was stirred for 1.5 h. The solvent was evaporated and the residue was purified by column chromatography on silica gel (0.032–0.063 mm) with ethyl acetate:dichloromethane (1:19) as eluant.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>O1CCOCC1>[ClH:23].[ClH:23].[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][N:16]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C#N)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(NC2CCNCC2)nc1

Procedure:
A solution of 4-(5-cyano-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (2.6 g, 8.60 mmol) in 4 M HCl in dioxane (20 mL) was stirred at rt for 1 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 203.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][C:24]([OH:26])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH2:31][C:32]([NH2:34])=[O:33].S(=O)(=O)(O)O>C1C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][C:24]([NH:31][C:32]([NH2:34])=[O:33])=[O:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(=O)O)N(C(=O)OCc2ccccc2)C1
Reactant: NC(N)=O
Agent: O=S(=O)(O)O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(=O)NC(N)=O)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Yield: 43.9 %

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-2-carboxymethyloxymethyl-4-methanesulfonyloxypyrrolidine (3.80 g) in benzene (19 ml) was added thionyl chloride (0.90 ml) with stirring at ambient temperature and the mixture was stirred at the same temperature for one hour. To the mixture were added urea (1.80 g) and concentrated sulfuric acid (0.05 ml) successively. The mixture was heated under reflux for 5 hours. The reaction mixture was poured into ice-water (100 ml) and extracted with ethyl acetate (100 ml). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (100 g) and eluted with a mixture of methanol and chloroform (1:99 V/V) to give (2S,4R)-1-benzyloxycarbonyl-4-methanesulfonyloxy-2-[(ureidocarbonylmethyl)oxymethyl]pyrrolidine (1.85 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].C(S[C:15](=[O:32])[CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=1[Cl:31])[C:17](=[O:19])[CH3:18])(C)(C)C>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([OH:9])=[CH:3][C:2]=1[NH:1][C:15](=[O:32])[CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=1[Cl:31])[C:17](=[O:19])[CH3:18]
Reactant: Nc1cc(O)ccc1Cl
Reactant: CC(=O)C(Cc1ccc(S(C)(=O)=O)cc1Cl)C(=O)SC(C)(C)C
Product: CC(=O)C(Cc1ccc(S(C)(=O)=O)cc1Cl)C(=O)Nc1cc(O)ccc1Cl

Procedure:
The title compound was prepared by the method of Preparation 34b using 3-amino-4-chlorophenol and 2-(2-chloro-4-methanesulfonylbenzyl)-3-oxothiobutyric acid S-tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:16]1[CH:17]=[CH:18][C:19]([CH2:23][OH:24])=[N+:20]([CH3:22])[CH:21]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][C:12]([CH3:13])([CH3:14])[CH3:15])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:16]1[CH2:17][CH2:18][CH:19]([CH2:23][OH:24])[N:20]([CH3:22])[CH:21]=1
Reactant: C[n+]1cc(-c2ccc3c(nnn3CC(C)(C)C)c2Br)ccc1CO
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1C=C(c2ccc3c(nnn3CC(C)(C)C)c2Br)CCC1CO
Reaction time: 16 h

Procedure:
To a solution of 5-[4-bromo-1-(2,2-dimethylpropyl)-1H-benzotriazol-5-yl]-2-(hydroxymethyl)-1-methylpyridinium (36 mg, 0.092 mmol) in methanol (1 ml) was added sodium borohydride (28.0 mg, 0.74 mmol) in 4 portions over 4 hours. After stirring for 16 hours, the mixture was purified via silica gel chromatography (methanol/dichloromethane gradient), providing the titled compound: 1H NMR (500 MHz, d6-DMSO) δ 7.91 (1H, d, J=8.50 Hz), 7.40 (1H, d, J=8.46 Hz), 5.76 (1H, s), 4.56 (1H, m), 4.52 (2H, s), 3.67-3.61 (1H, m), 3.55-3.49 (1H, m), 2.64 (1H, s), 2.42 (3H, s), 2.30-2.19 (2H, m), 1.24 (1H, s), 0.96 (9H, s) ppm. LRMS m/z (M+H) 393.0 and 395.0 found, 393.1 and 395.1 required.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.[NH2:65][CH:66]1[CH2:71][CH2:70][N:69]([CH3:72])[CH2:68][CH2:67]1>C(OCC)(=O)C.CN(C)C=O>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:65][CH:66]5[CH2:71][CH2:70][N:69]([CH3:72])[CH2:68][CH2:67]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.25 h
Yield: 76.1 %

Procedure:
A mixture of 0.15 g (0.33 mmole) of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-246), 0.133 g (1.32 mmole) of triethylamine, 0.186 g (0.49 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 5 mL of dimethylformamide was stirred for 15 minutes and then 0.056 g (0.49 mmole) of 4-amino-1-methyl-piperidine was added. The mixture was stirred for 3 hours, then taken up in 100 mL of ethyl acetate and washed twice with 100 mL of water and then 100 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol-ammonium hydroxide (gradient 100:0:0-92:8:0.3) to give 0.140 g of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-247).
Reaction SMILES: [OH:1][CH:2]1[O:10][C@H:9]([C:11](=[O:13])[OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[NH2:14][C@H:15]([C:20]([NH:22][C@H:23]([C:31]([O:33]CC1C=CC=CC=1)=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21])[C@H:16]([CH2:18][CH3:19])[CH3:17]>CN(C=O)C.O.[Pd]>[OH:1][CH:2]1[O:10][C@H:9]([C:11](=[O:12])[OH:13])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[NH2:14][C@H:15]([C:20]([NH:22][C@H:23]([C:31]([OH:33])=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21])[C@H:16]([CH2:18][CH3:19])[CH3:17]
Reactant: CC[C@H](C)[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=C(O)[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@H](C)[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 5 h
Yield: 98 %

Procedure:
GlcA-Ile-Phe-OBzl (1.04 g, 1.9 mmol) was hydrogenolyzed in presence of palladium/activated charcoal (10% Pd) (200 mg) in DMF-water (9:1, v/v) solution for 5 h. After removal of the catalyst by filtration the solution was evaporated to dryness and the product was recovered by lyophilization from water with 98% yield (0.85 g); mp 173°-174° C.; [α]54625 =+3,36 (c=1, MeOH); Rf(A) =0.15.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[Cl:10])(=O)[CH3:2].[C:11]([NH:16][NH2:17])(=[O:15])[CH2:12][CH2:13][CH3:14]>C(O)C>[Cl:10][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:4]=1[C:1](=[N:17][NH:16][C:11](=[O:15])[CH2:12][CH2:13][CH3:14])[CH3:2]
Reactant: CCCC(=O)NN
Reactant: CC(=O)c1ccncc1Cl
Solvent: CCO
Product: CCCC(=O)NN=C(C)c1ccncc1Cl
Yield: 25 %

Procedure:
A mixture of 5.20 gm (0.0335 mole) of 4-acetyl-3-chloropyridine, 3.43 gm (0.0336 mole) of butyric acid hydrazide and 100 ml of ethanol was refluxed 18 hr. The mixture was chilled in the freezer. The solid which separated was collected to give 2.01 gm (25%) of white solid having a melting point of 103.8° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[C:25](/[CH:27]=[CH:28]/[C:29]4[CH:30]=[C:31]([CH:36]=[CH:37][N:38]=4)[C:32]([O:34][CH3:35])=[O:33])[C:24]([C:39]([F:42])([F:41])[F:40])=[CH:23][N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[C:25]([CH2:27][CH2:28][C:29]4[CH:30]=[C:31]([CH:36]=[CH:37][N:38]=4)[C:32]([O:34][CH3:35])=[O:33])[C:24]([C:39]([F:40])([F:41])[F:42])=[CH:23][N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccnc(/C=C/c2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccnc(CCc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)c1
Reaction time: 16 h
Yield: 63.6 %

Procedure:
A suspension of (E)-methyl 2-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)vinyl)isonicotinate (I128) (110 mg, 0.188 mmol), and 10% Pd/C (20 mg) in MeOH (10 mL) was stirred under an atmosphere of hydrogen at atmospheric pressure for 16 hours. The resulting mixture was filtered and the filtrate evaporated under reduced pressure to give the title compound (I129) (70 mg, 63%) as a yellow liquid; 1H NMR (400 MHz, CDCl3) δ 8.68 (dd, J=5.1, 0.7 Hz, 1H), 8.51 (s, 1H), 7.76 (s, 1H), 7.66 (dd, J=5.1, 1.5 Hz, 1H), 7.54-7.47 (m, 3H), 7.18 (t, J=5.5 Hz, 2H), 4.22 (s, 2H), 3.93 (d, J=3.9 Hz, 3H), 3.43-3.35 (m, 2H), 3.34-3.26 (m, 2H), 2.80 (t, J=12.1 Hz, 2H), 2.63 (d, J=3.5 Hz, 1H), 1.82 (d, J=12.3 Hz, 2H), 1.67-1.54 (m, 2H), 1.48 (d, J=7.1 Hz, 3H). LCMS Method C: rt 6.75 min; m/z 586.1 [M+1]+, 584.2 [M−H]−.
Reaction SMILES: Cl.[CH:2]1([NH:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)([O-])O.[Na+].O.[CH3:16][C:17]1[O:18][C:19]([CH3:26])=[C:20]([CH3:25])[C:21]=1[C:22](Cl)=[O:23]>ClCCl>[CH:2]1([N:8]([C:22]([C:21]2[C:20]([CH3:25])=[C:19]([CH3:26])[O:18][C:17]=2[CH3:16])=[O:23])[OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: ONC1CCCCC1
Reactant: Cc1oc(C)c(C(=O)Cl)c1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1oc(C)c(C(=O)N(O)C2CCCCC2)c1C

Procedure:
49 Parts of N-cyclohexylhydroxylamine hydrochloride is dissolved in 400 parts of dichloromethane; at room temperature a solution of 50.4 parts of sodium hydrogen carbonate in 500 parts of water and subsequently 51.6 parts of 2,4,5-trimethylfuran- 3-carboxylic chloride are added to the mixture. After the mixture has been stirred for 2 hours the dichloromethane phase is separated, dried over anhydrous sodium sulfate and evaporated. There is obtained 75 parts of N-cyclohexyl-2,4,5-trimethylfuran-3-hydroxamic acid in the form of an oil. This oil is dissolved in 300 parts of dichloromethane. To this solution there is added 36 parts of sodium hydroxide in 200 parts of water and 75.6 parts of dimethyl sulfate and the whole is stirred for 2 hours. The dichloromethane phase is then separated, washed with water until neutral, dried over anhydrous sodium sulfate and evaporated. Upon distillation of the residue there is obtained 52 parts of O-methyl-N-cyclohexyl-2,4,5-trimethylfuran-3-hydroxamic acid having a boiling point at 0.3 mm Hg of 128° to 130° C and the refractive index nD25 : 1.5021. ##SPC11##
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][CH2:12]/[CH:13]=[CH:14]/[P:15]([O:21][CH:22]([CH3:24])[CH3:23])([O:17][CH:18]([CH3:20])[CH3:19])=[O:16].[NH3:25]>>[CH:18]([O:17][P:15](/[CH:14]=[CH:13]/[CH2:12][CH2:11][N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[NH2:25])([O:21][CH:22]([CH3:24])[CH3:23])=[O:16])([CH3:20])[CH3:19]
Reactant: CC(C)OP(=O)(/C=C/CCn1cnc2c(Cl)ncnc21)OC(C)C
Reactant: N
Product: CC(C)OP(=O)(/C=C/CCn1cnc2c(N)ncnc21)OC(C)C
Yield: 70 %

Procedure:
A solution of (E)-6-chloro-9-[4-(diisopropoxy-phosphoryl)but-3-enyl]purine (309 mg, 829mmol) in saturated ethanolic ammonia (35 ml) was heated at 80° C. in a stainless steel autoclave for 5 hr. The solvent was removed and the residue purified by column chromatography on silica gel eluting with ethyl acetate-methanol (3:1) to give (E)-9-[4-(diisopropoxyphosphoryl)but-3-enyl]adenine as a white solid (205 mg, 70%), m.p. 121°-122° C.; λmax (EtOH) 262 (11,855)nm; υmax (KBr) 3320, 3175, 2935, 1650. 1600, 1575, 1475 and 1240 cm-1 ; δH (CDCl3) 1.25 (12H, dd, J 6 Hz and 19 Hz, CH(CH3)2), 2.84 (2H, m, CH2), 4.35 (2H, t, J 7 Hz, CH2N), 4.55 (2H, m, CH(CH3)2), 5.69 (1H, dd, J 17 Hz and 19 Hz, PCH=CH), 5.76 (2H, s, NH2), 6.70 (1H, ddt, J 7 Hz, 17 Hz and 22 Hz, PCH=CH ), 7.79 (1H, s, H-2/H-8), 8.37 (1H, s, H-2/H-8) (Found: MH+ 354.1695. C15C24N5O3P requires MH+ 354. 1695).