Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([CH:26]=3)[C:23](O)=[O:24])[CH:16]=2)[NH:11][N:10]=1.C1[CH:32]=[CH:31][C:30]([CH2:33][NH:34]S(C2C=CC3N=NN(O)C=3C=2)(=O)=O)=CC=1.Cl.CCN=C=NCCCN(C)C.N1CCCC1>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:26]=[C:22]([C:23]([N:34]4[CH2:33][CH2:30][CH2:31][CH2:32]4)=[O:24])[CH:21]=[N:20][CH:19]=3)[CH:16]=2)[NH:11][N:10]=1
Reactant: O=S(=O)(NCc1ccccc1)c1ccc2nnn(O)c2c1
Reactant: COc1ccccc1-c1n[nH]c2ncc(-c3cncc(C(=O)O)c3)cc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cncc(C(=O)N4CCCC4)c3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 1 %

Procedure:
(5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-nicotinic acid (350 mg, 62% pure, 0.63 mmol) was dissolved in anhydrous DMF (20 mL) at 50-60° C. and the solution was cooled to room temperature when PS-HOBt resin (Argonaut Technologies) (0.9 mmol·g−1 loading, 2.20 g, 1.98 mmol), DMAP (32 mg, 0.26 mmol) and EDCI (375 mg, 1.95 mmol) were added. The mixture was shaken at room temperature for 16 h. The resin was filtered off, washing six times with DMF and subsequently three times with ether and dried. The resin and (5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-nicotinate) (460 mg, theoretical loading 105 μmol) were suspended in anhydrous DMF (3 mL) containing pyrrolidine (110 μl, 1.3 mmol) and shaken for 22 h. The resin is filtered off, washing with dichloromethane, ether and DMF. The filtrate and washings were combined and concentrated. The resulting residue is purified by mass-triggered reverse phase HPLC using a gradient of acetonitrile in water containing 0.1% of formic acid to afford {5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-pyridin-3-yl}-pyrrolidin-1-yl-methanone (2.4 mg, 6 μmol, 6% yield) as a light brown solid. 1H-NMR (500 MHz, d6-MeOH) δ 68.98 (d, 1H), 8.87 (d, 1H), 8.74 (d, 1H), 8.50 (d, 1H), 8.31 (t, 1H), 7.67 (dd, 1H), 7.48 (ddd, 1H), 7.21 (d, 1H), 7.11 (dt, 1H), 3.89 (s, 3H), 3.65 (t, 2H), 3.58 (t, 2H), 2.02 (m, 2H), 1.96 (m, 2H). MS: m/z 400 [MH+].
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:9])=[C:4](Cl)[CH:5]=[CH:6][CH:7]=1.[CH3:10][O-:11].[Na+]>CC(N(C)C)=O.CO>[Cl:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[O:11][CH3:10]
Reactant: Clc1cccc(Cl)c1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CO
Product: COc1cccc(Cl)c1Cl
Reaction time: 0.5 h

Procedure:
Trichlorobenzene (363 g, 2 moles) was dissolved in 600 ml of dimethyl acetamide and 650 ml of 25% sodium methoxide in methanol solution added all at once. The solution was stirred and heated to 166° as the methanol slowly distilled out. The solution was held at 166° for 30 minutes, * cooled and quenched with 5 times its volume of water and extracted with toluene (2 × 1000 ml). The toluene extracts were washed with water (1 L) and dried over sodium sulfate. The toluene was removed by distillation under reduced pressure and the residue fractionated to yield the pure 2,3-dichloroanisole, bp 140°/28 mm. Yield 212 g (60%). Considerable material remains in the aqueous DMAC layer and can be recovered by repeated extractions with methylene chloride.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:26])=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13]OS(C)(=O)=O)=[O:5])[CH3:2].C(OCC)(=O)C.CO.[N:35]1([CH2:40][CH2:41][NH2:42])[CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:26])=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13][NH:42][CH2:41][CH2:40][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CCCOS(C)(=O)=O)[nH]c(C(=O)OC(C)(C)C)c1C
Reactant: NCCN1CCCC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)c1c(CCCNCCN2CCCC2)[nH]c(C(=O)OC(C)(C)C)c1C
Yield: 63.5 %

Procedure:
5-(3-Methanesulfonyloxy-propyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1 g (8.462 g, 21.75 mmol) was dissolved in 2-pyrrolidin-1-yl-ethylamine (6.3 ml, 49.79) under stirring, the resulting solution was stirred at room temperature overnight. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was added with ethyl acetate (200 ml) and a little methanol until a clear solution was obtained. The mixture was washed with water (30 ml×3), saturated brine (40 ml×2) and concentrated under reduced pressure to obtain light brown oil. The oil was purified by silica gel column chromatography to obtain the title compound 3-methyl-5-[3-(2-pyrrolidin-1-yl-ethylamino)-propyl]-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 28a (4.488 g, yield 63.5%) as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:22][CH2:21][CH:20]([N:23]([CH3:32])[CH2:24][C:25]([N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)=[O:26])[CH2:19][CH2:18]4)[C:6]=3[C:5]1=2.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>CN(C=O)C>[CH3:33][S:34]([O:1][CH2:2][CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:18][CH2:19][CH:20]([N:23]([CH3:32])[CH2:24][C:25](=[O:26])[N:27]5[CH2:28][CH2:29][CH2:30][CH2:31]5)[CH2:21][CH2:22]4)[C:6]=3[C:5]1=2)(=[O:36])=[O:35]
Reactant: CN(CC(=O)N1CCCC1)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CCO)CC4)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(CC(=O)N1CCCC1)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CCOS(C)(=O)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
For the preparation of the starting material Compound I-90, please refer to Example 107. A 25-mL round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was charged with a solution of 2-[(4-[[(3R)-3-(2-hydroxyethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)(methyl)amino]-1-(pyrrolidin-1-yl)ethan-1-one (100 mg, 0.22 mmol, 1.00 equiv) in 5 mL of distilled DMF. MsCl (38 mg, 0.33 mmol, 1.50 equiv) and triethylamine (66.7 mg, 0.66 mmol, 3.00 equiv) were added at 0° C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched with water, extracted with DCM. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel with DCM/MeOH (20:1 to 10:1) to give 2-[(3R)-12-[(4-[methyl[2-oxo-2-(pyrrolidin-1-yl)ethyl]amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]ethyl methanesulfonate (107 mg) as a white solid. MS (ES): m/z 537 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[N:3]=1.C(N(CC)CC)C.[CH2:20]([NH:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:21]>C(O)C>[Cl:11][C:6]1[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][CH2:25][CH3:26])[N:3]=[C:4]([CH3:12])[N:5]=1
Reactant: CCCCNCC
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCN(CC)c1nc(C)nc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 92 %

Procedure:
Part A. A solution of 4,6-dichloro-2-methyl-5-nitropyrimidine (prepared using the methods of Albert, et al., J. Chem. Soc. 1954, p. 3832) (2.77 g, 13.3 mmol) in absolute ethanol (25 mL) was cooled to 0° C., and treated with triethylamine (2.00 mL, 14.3 mmol). Then, a solution of ethylbutylamine (1.80 mL, 13.2 mmol) in ethanol (3 mL) was added dropwise with stirring. The mixture was allowed to stir and warm to ambient temperature overnight, then was partitioned between water and ethyl acetate (100 mL each). The organic phase was seperated, washed with satd. aq. brine (100 mL), dried over anhydrous sodium sulfate, filtered and evaporated. The residue was separated by column chromatography (silica gel, dichloromethane) to afford 4-chloro-6-(ethylbutylamino)-2-methyl-5-nitropyrimidine as an oil (3.34 g, 12.2 mmol, 92%). Spectral data: TLC RF 0.59 (dichloromethane). 1H NMR (300 MHz, CDCl3): δ3.45 (2H, q, J=7.0 Hz), 3.38 (2H, t, J=7.7 Hz), 2.50 (3H, s), 1.62-1.52 (2H, m), 1.38-1.26 (2H, m), 1.20 (3H, t, J=7.0 Hz), 0.94 (3H, t, J=7.3 Hz). MS (NH3—CI): m/e 276 (4), 275 (40), 274 (16), 273 (100).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[OH:9].[H-].[Na+].B(OCC)(OCC)OCC.[S:22](Cl)([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>CN(C)C=O.C(OCC)(=O)C>[CH3:29][C:28]1[CH:30]=[CH:31][C:25]([S:22]([O:8][C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([OH:9])[CH:4]=2)(=[O:24])=[O:23])=[CH:26][CH:27]=1
Reactant: Oc1ccc(O)c(O)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CCOB(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)Oc2ccc(O)c(O)c2)cc1
Reaction time: 1 h
Yield: 50.2 %

Procedure:
1.37 g of 1,2,4-trihydroxy benzene and 40 ml of anhydrous dimethylformamide were mixed together under an inert gas atmosphere and then 0.984 g of sodium hydride in suspension at 53% in oil were added slowly at 15°-20° C. The mixture was stirred for one hour and then 1.906 ml of triethyl borate were added, followed by stirring for one hour. Then, a solution of 2.072 g of tosyl chloride in 15 ml of dimethylformamide were added over 2 hours and the mixture was stirred for 4 hours at ambient temperature. The mixture was poured into a water-ice-hydrochloric acid mixture and extraction took place with ethyl acetate followed by evaporating to dryness. The crude residue was washed with petroleum ether and after chromatography on silica and eluting with a cyclohexane-ethyl acetate (1-1) mixture, 1.53 g of the expected product were obtained which was crystallized from a flugene-isopropyl ether mixture.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH2:21][CH2:22][C:23]([OH:25])=O)[N:20]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:26]1([CH2:31][CH2:32][NH2:33])[CH2:30][CH2:29][CH2:28][CH2:27]1.O.N1(O)C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>>[CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH2:21][CH2:22][C:23]([NH:33][CH2:32][CH2:31][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:25])[N:20]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCN1CCCC1
Reactant: O=C(O)CCc1csc(Nc2ncccc2OCc2ccccc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Product: O=C(CCc1csc(Nc2ncccc2OCc2ccccc2)n1)NCCN1CCCC1
Temperature: 0 °C

Procedure:
3-(2-(3-(Benzyloxy)pyridin-2-ylamino)thiazol-4-yl)propanoic acid (40 mg, 0.113 mmol), 2-(pyrrolidin-1-yl)ethanamine (0.0171 mL, 0.135 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (22.4 mg, 0.146 mmol) and 4-methylmorpholine (0.0173 ml, 0.158 mmol) were placed in an 8.5 mL screw-cap vial. The reaction mixture was cooled to 0° C. in an ice bath, and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (33.0 mg, 0.172 mmol) was added as a solid. The mixture was stirred at 0° C. and then allowed to warm to room temp overnight. The reaction mixture was concentrated under high vacuum to remove DMF, and the residue was partitioned between dichloromethane and saturated aqueous NaHCO3 diluted with an equal part of water. The organic phase was washed with once with water, then with brine, and dried by passing through a plug of anhydrous sodium sulfate. The solution was concentrated in vacuo and dried under high vacuum to provide the title compound as a colorless oil. 1H NMR (CDCl3) δ 1.76 (s, 4H), 2.56 (m, 4H), 2.59 (dd, J=5.6, 12.9 Hz, 4H), 3.01-2.94 (m, 4H), 3.37 (dd, J=11.3, 5.5 Hz, 2H), 5.13 (s, 2H), 6.75 (bs, 1H), 6.47 (s, 1H), 6.82 (dd, J=8.2, 5.1 Hz, 2H), 7.10 (dd, J=1.2, 7.9, Hz, 1H), 7.42 (br s, 4H), 7.94 (dd, J=1.2, 5 Hz, 1H), 8.59 (bs, 1H); Mass spectrum (apci) m/z=452.2 (M+H).
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[O:8])=[C:5]([CH3:17])[CH:4]=1)=O.Cl.[OH:19][NH2:20].C([O-])(=O)C.[Na+]>C(O)C.O>[OH:19][N:20]=[CH:1][C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[O:8])=[C:5]([CH3:17])[CH:4]=1
Reactant: Cc1cc(C=O)ccc1C(=O)NCC(F)(F)F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C=NO)ccc1C(=O)NCC(F)(F)F
Temperature: 25 °C
Yield: 58.9 %

Procedure:
In a solution of 0.8 g of 4-formyl-2-methyl-N-(2,2,2-trifluoroethyl)benzoic acid amide in 10 ml of ethanol and 5 ml of water, 0.3 g of hydroxyamine hydrochloride and 0.4 g of anhydrous sodium acetate were added with stirring at room temperature, and stirred at the same temperature for 30 minutes. After the completion of the reaction, the solvent was distilled off under reduced pressure, and precipitated crystal was filtered off, washed with water and dried to obtain 0.5 g of the aimed product as white crystal.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:28][C:29]([CH3:35])([CH3:34])[CH2:30][C:31](Cl)=[O:32].C(N(CC)CC)C>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:13]=[CH:14][N:15]=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([C:31](=[O:32])[CH2:30][C:29]([CH3:35])([CH3:34])[CH3:28])[CH2:24][CH2:23]3)[C:17]=2[N+:18]([O-:20])=[O:19])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)CC(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])CC1
Yield: 78 %

Procedure:
Compound A2 (0.12 mmol, 50 mg), 3,3-dimethyl-butyryl chloride (0.18 mmol, 24 mg) and triethylamine (0.63 mmol, 88 L) were dissolved in DMF and microwaved at 80° C. for 5 minutes. The reaction mixture was quenched with water and extracted with ethyl acetate. Removal of organic solvents in vacuo provided Compound A3 as a yellow solid (46 mg, 78%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.98 (s, 1H), 8.20 (s, 1H), 7.77 (d, 2H), 7.64 (d, 2H), 5.44 (heptet, 1H), 3.71 (m, 1H), 3.48 (m, 3H), 2.75 (s, 3H), 2.11 (quartet, 2H), 1.76 (m, 4H), 0.85 (s, 9H). LCMS (ESI), m/z 492.4 (M+H+, 100%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C@@H:19]1[C:14](=[CH:15][C:16](=[O:23])[CH2:17][CH2:18]1)[CH2:13][C@H:12]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])(=[O:3])[CH3:2].[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C@@H:19]1[C:14](=[CH:15][C:16](=[O:23])[CH2:17][CH2:18]1)[CH2:13][C@H:12]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:32])[CH3:31])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3[C@H](CCCCCO)CC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]12C
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCCCC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)[C@@H](OC(C)=O)CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 37.7 g of 17β-acetoxy-7α-(5-hydroxypentyl)-estr-4-en-3-one in 160 ml of pyridine is slowly mixed with 80 ml of acetic anhydride and stirred for 16 hours at 25° C. Then, it is diluted with ethyl acetate, and the organic phase, after washing with sodium bicarbonate solution, is dried and concentrated by evaporation. The residue is chromatographed on silica gel, and 26.6 g of 17β-acetoxy-7α-(5-acetoxypentyl)-estr-4-en-3-one is obtained as oil. [α]D22 =+20.0°(c=0.51% in chloroform)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C@@H:4](C(CCC)=O)[CH2:5][C@H:6]([C:14]([O:16]C)=[O:15])[N:7]2N.[OH-:23].[Li+]>O1CCCC1.O>[C:14]([C@H:6]1[CH2:5][C@H:4]([NH:7][C:6]([CH2:5][CH2:4][CH3:3])=[O:23])[C:3]2[C:8](=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=2[Cl:1])[NH:7]1)([OH:16])=[O:15]
Reactant: [OH-]
Reactant: CCCC(=O)[C@H]1C[C@H](C(=O)OC)N(N)c2cc(Cl)cc(Cl)c21
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC(=O)N[C@H]1C[C@H](C(=O)O)Nc2cc(Cl)cc(Cl)c21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of trans-5,7-dichloro-2-methoxycarbonyl-4-n-propylcarbonyl-amino-1,2,3,4-tetrahydroquinoline (0.70 g, 0.493 mmol) in a mixture of tetrahydrofuran (15 ml) and water (5 ml) was added aqueous lithium hydroxide (1.1 ml of a 0.50M solution, 0.55 mmol) and the resulting mixture was stirred at room temperature for 20 h. The organic solvent was then removed under vacuum and the aqueous residue was diluted with dilute sodium bicarbonate solution (50 ml) then washed with ethyl acetate (1×30 ml). The aqueous phase was separated, acidified with dilute hydrochloric acid and extracted with ethylacetate (2×50 ml). The combined extracts were washed with brine (1×50 ml), dried (MgSO4) and evaporated to give a solid which was triturated with diethyl ether to give the title compound as colourless crystals (0.123 g) m.p. 174°-176° C. (dec). δ (DMSO, 360 MHz) δ 0.85 (3H, t, J=7.4 Hz, COCH2CH2CH3), 1.48-1.64 (3H, m, CHACHBHCCHD) and COCH2CH2CH3), 2.04 (2H, t, J=7.2 Hz, COCH2CH2CH3), 2.16 (1H, dm, J=13.1 Hz, CHACHBHCCHD), 3.82 (1H, dd, J=12.6 and 2.8 Hz, CHACHBHCCHD), 5.01 (1H, m, CHACHBHcCHDNHCO) 6.64 (1H, d, J=2.1 Hz, 6-H or 8-H), 6.76 (1H, s, ArNH), 6.87 (1H, d, J=2.1 Hz, 6-H or 8-H), 8.10 (1H, d, J=7.2 Hz, --CHDNHCO--); m/e 330 (M+), 198 (100%, M-NHCOCH2CH2CH3, CO2H and H); Found C, 50.09; H, 4.78; N, 8.41; C14H16Cl2N2 03.0.2H2O requires C, 50.22; H, 4.94; N, 8.37%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1Cl)([O-])=O.[C:14](N)(=[S:16])[CH3:15].O>S1(CCCC1)(=O)=O>[CH3:15][C:14]1[S:16][C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N:1]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(N)=S
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: Cc1nc2cc([N+](=O)[O-])ccc2s1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A suspension of 10.13 g of 2,4-dinitrochlorobenzene and 15 g of thioacetamide in 50 ml of sulpholane was heated to 100° C. and stirred at this temperature for 1 hour. After cooling, the mixture was clarified. 200 ml of water were added to the filtrate. The solid was filtered off with suction, washed with water and dried.
Reaction SMILES: Br[C:2]1[C:7]2[N:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:9]([C@@H:11]([NH:13][C:14]3[N:22]=[CH:21][N:20]=[C:19]4[C:15]=3[N:16]=[CH:17][N:18]4[CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:35].[CH:36]1(B(O)O)[CH2:38][CH2:37]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[CH:36]1([C:2]2[C:7]3[N:8]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:9]([C@@H:11]([NH:13][C:14]4[N:22]=[CH:21][N:20]=[C:19]5[C:15]=4[N:16]=[CH:17][N:18]5[CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][O:24]4)[CH3:12])=[N:10][C:6]=3[CH:5]=[CH:4][C:3]=2[F:35])[CH2:38][CH2:37]1
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(Br)c2n1-c1ccccc1
Reactant: OB(O)C1CC1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(C3CC3)c2n1-c1ccccc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 44.7 %

Procedure:
A mixture of [(S)-1-(7-bromo-6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]-[9-(tetrahydropyran-2-yl)-9H-purin-6-yl]amine (50 mg, 0.09 mmol), cyclopropylboronic acid (10 mg, 0.12 mmol) and Cs2CO3 (46 mg, 0.14 mmol) in a 4:1 mixture dioxane:water (2.5 mL) was degassed with a stream of argon prior to addition of Pd(PPh3)4 (5 mg) and was heated at 100° C. for 18 h in a sealed vial. Additional cyclopropylboronic acid (10 mg, 0.12 mmol) and Pd(PPh3)4 (5 mg) in dioxane (0.25 mL) were added and stirring at 100° C. in a sealed vial was continued for 3 h. The reaction mixture was diluted with water and extracted with EtOAc (×3). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a 25 min gradient 10-90%, 0.1% HCO2H in acetonitrile/water) to afford the title compound (20 mg, 43%). LCMS (Method C): RT 3.32 min [M+H]+ 498.1.
Reaction SMILES: [Na].CC1C(C[S:23]([C:25]2[NH:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[N:26]=2)=O)=NC=CC=1OCC1(C)OCC2(OCCO2)CO1.CC1(C)OCC(COC2C(C)=CN=[C:45]([CH2:50][OH:51])C=2C)CO1.O.CC1(C)OCC(COC2C(C)=CN=C(CO)C=2C)C[O:57]1>C1(C)C=CC=CC=1>[NH:29]1[C:28]2[CH:30]=[C:31]3[O:51][CH2:50][CH2:45][O:57][C:32]3=[CH:33][C:27]=2[N:26]=[C:25]1[SH:23]
Reactant: Cc1cnc(CO)c(C)c1OCC1COC(C)(C)OC1
Reactant: Cc1c(OCC2(C)OCC3(CO2)OCCO3)ccnc1CS(=O)c1nc2ccccc2[nH]1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O
Product: Sc1nc2cc3c(cc2[nH]1)OCCO3

Procedure:
The same procedure as in the steps (5f) to (5h) was repeated using the (4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-3,5-dimethylpyridin-2-yl)methanol, which was obtained by subjecting (4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-3,5-dimethylpyridin-2-yl)methanol monohydrate obtained in the same manner as in Example 96(5) to azeotropic distillation with toluene, and 6,7-dihydro-1H-[1,4]dioxino[2′,3′:4,5]benzo[d]imidazole-2-thiol, to obtain the title compound (395 mg, total 61.7% yield) as a white solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[CH3:11][C:12]1[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=1>>[CH3:11][C:12]1[CH:13]=[CH:14][C:15](=[O:18])[N:16]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=2)[CH:17]=1
Reactant: Cc1ccc(=O)[nH]c1
Reactant: O=[N+]([O-])c1cccc(I)c1
Product: Cc1ccc(=O)n(-c2cccc([N+](=O)[O-])c2)c1
Yield: 75 %

Procedure:
The reaction of 24.9 g of 1iodo-3-nitrobenzene (Aldrich Chemical Co.) with 10.9 of 5-methyl-2-(1H)-pyridone by the procedure described in Example 1 affords 16.2g (75%) of 5-methyl-1-(3-nitrophenyl) pyridone.
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]([C:12]([NH:14][CH2:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)=[O:13])[CH2:10][OH:11])=O)(C)(C)C.[F:21][C:22]([F:27])([F:26])C(O)=O.FC(F)(F)C(OCC)=O>C(N(CC)CC)C>[F:21][C:22]([F:27])([F:26])[C:6]([NH:8][C@H:9]([C:12]([NH:14][CH2:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)=[O:13])[CH2:10][OH:11])=[O:5]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)NCc1nccs1
Agent: CCOC(=O)C(F)(F)F
Solvent: CCN(CC)CC
Product: O=C(NCc1nccs1)[C@H](CO)NC(=O)C(F)(F)F
Reaction time: 0.5 h

Procedure:
A 1.540 g portion of 2-[(N-tert-butoxycarbonyl-L-seryl)amino]methylthiazole and 15 ml of trifluoroacetic acid were added, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated to dryness under reduced pressure. To the solution of (L-seryl)aminomethylthiazole trifluoroacetatate salt thus obtained in 50 ml of methylene chloride were added with stirring 2.73 g of triethylamine and 3.84 g of ethyl trifluoroacetate. The mixture was stirred at room temperature for 3 hours, concentrated under reduced pressure and subjected to flash column chromatography on silica gel (eluted with ethyl acetate) to give 1.519 g of 2-[(N-trifluoroacetyl-L-seryl)amino]methylthiazole. Quantitative yield. NMR (CDCl3) δ: 1.5-1.75 (1H, br), 3.69 (1H, dd, J=11.5 Hz, 6.7 Hz), 4.18 (1H, dd, J=11.5 Hz, 3.5 Hz), 4.58 (1H, td, J=11.5 Hz, 3.5 Hz), 4.75 (1H, dd, J=16.7 Hz, 5.5 Hz), 4.96 (1H, dd, J=16.7 Hz, 6.9 Hz), 7.01-7.07 (1H, br), 7.31 (1H, d, J=3.3 Hz), 7.60-7.70 (1H, br), 7.68 (1H, d, J=3.3 Hz).