Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:3][CH2:4][S:5][C:6]1[N:7]=[C:8]([CH3:14])[S:9][C:10]=1[C:11]([OH:13])=O.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[F:52][C:53]1[CH:60]=[CH:59][C:56]([CH2:57][NH2:58])=[CH:55][CH:54]=1>CN(C=O)C>[F:22][C:2]([F:1])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:3][CH2:4][S:5][C:6]1[N:7]=[C:8]([CH3:14])[S:9][C:10]=1[C:11]([NH:58][CH2:57][C:56]1[CH:59]=[CH:60][C:53]([F:52])=[CH:54][CH:55]=1)=[O:13]
Reactant: NCc1ccc(F)cc1
Reactant: Cc1nc(SCCC(F)(F)c2ccc(F)cc2)c(C(=O)O)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1nc(SCCC(F)(F)c2ccc(F)cc2)c(C(=O)NCc2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.3 %

Procedure:
To a solution of 4-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-2-methyl-thiazole-5-carboxylic acid (0.25 g, 0.72 mmol) in DMF (4 ml) are added O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (347 mg, 1.08 mmol) and N-methylmorpholine (0.16 ml, 1.44 mmol) at 0° C. followed by the addition of 4-fluorobenzyl amine (0.01 ml, 0.86 mmol). The reaction mixture is stirred at RT for 3 h. After completion of the reaction, the mixture is poured onto ice-water, extracted with EtOAc (3×15 ml). The combined organic layers are washed with brine (20 ml), dried over sodium sulfate and evaporated to dryness to yield the crude product, which is purified by column chromatography (silica gel, 5% acetone/hexane) followed by preparative HPLC affording 4-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-N-[(4-fluorophenyl)-methyl]-2-methyl-thiazole-5-carboxylic acid amide (example 15) (0.2 g, 0.42 mmol, 36%). [M+H]+ 455.1.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:5][CH:4]=1)=O.[CH3:19][CH:20]1[CH2:24][CH2:23][CH2:22][NH:21]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C1COCC1>[CH3:19][CH:20]1[CH2:24][CH2:23][CH2:22][N:21]1[CH2:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(C=O)cc1
Reactant: CC1CCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC1CCCN1Cc1ccc(CCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.1 %

Procedure:
To a solution of tert-butyl 2-(4-formylphenyl)ethylcarbamate (3.0 g, 12.0 mmol), 2-methylpyrrolidine (1.44 ml, 14.4 mmol) and acetic acid (1.4 ml, 24.0 mmol) in THF (100 ml) was added sodium triacetoxyborohydride (5.1 g, 24.0 mmol), and the mixture was stirred at room temperature for 16 hrs. 10% Sodium hydrogencarbonate solution (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 ml). The extract was washed with saturated brine, and dried over magnesium sulfate, and solvent was evaporated under reduced pressure. The residue was purified by alumina column chromatography (developing solvent; hexane:ethyl acetate=4:1) to give the title compound (3.10 g).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:14]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:14][C:11]1[C:10]([NH2:13])=[CH:9][CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(-c2ccccc2)nc1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(-c2ccccc2)nc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.3 %

Procedure:
To a solution of 1B (85 mg, 0.5 mmol) in DMF (1 mL) at RT was added N-bromosuccinimide (89 mg, 0.5 mmol). The reaction was stirred at RT for 16 h. After this time, no starting material was detected by LC-MS. The reaction was diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with saturated NaCl, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel (10 g) column chromatography, eluting with a gradient of EtOAc (0-60%) in hexane to give the title compound as a light brown foam (100 mg, 80%). LC/MS (method A): retention time=2.96 min, (M+H)+=249. 1H NMR (CDCl3, 400 MHz): δ 7.80-7.91(m, 2H), 7.50 (d, J=8.2 Hz, 1H), 7.38-7.44 (m, 2H), 7.31-7.35 (m, 1H), 7.05 (d, J=8.2 Hz, 1H), 4.15 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6](Cl)=[CH:7][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=1[Cl:20].[OH-].[K+]>>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([O:21][C:16]3[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([Cl:13])[CH:15]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Product: Nc1ccc2ccc(Oc3ccc(Cl)c(Cl)c3)nc2n1
Temperature: 125 °C
Yield: 58.8 %

Procedure:
The procedure is similar to that described in Example 24, but starting with 2-amino-7-chloro-1,8-naphthyridine (17.95 g), 3,4-dichlorophenol (65.2 g) and potassium hydroxide pellets (85% pure; 13.2 g), heating to 125° C. for 22 hours. On recrystallization in acetonitrile (1500 cc) of the crude product obtained, 2-amino-7-(3,4-dichlorophenoxy)-1,8-naphthyridine (18 g), m.p. 206° C., is obtained.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[C:5]([C:8](=O)[CH2:9][CH3:10])[C:6]#[N:7])C.Cl.C(N)=[NH:14].C(N(CC)CC)C>C(O)C>[CH2:9]([C:8]1[C:5]([C:6]#[N:7])=[CH:4][N:2]=[CH:1][N:14]=1)[CH3:10]
Reactant: CCC(=O)C(C#N)=CN(C)C
Reactant: N=CN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCc1ncncc1C#N
Yield: 35 %

Procedure:
A mixture of crude 2-((dimethylamino)methylene)-3-oxopentanenitrile (0.98 equiv.), formamidine hydrochloride (2.0 equiv.) and triethyl amine (2.0 equiv.) in ethanol (1.0 M) was refluxed for 36 h. The solvent was removed and the residue was purified by silica column chromatography (20% ethyl acetate in petroleum ether) to afford the title product (35% yield). 1H-NMR (400 MHz, CDCl3) δ (ppm) 9.20 (s, 1H), 8.83 (s 1H), 2.98 (d, J=7.6 Hz, 2H), 1.32 (t, J=7.6 Hz, 3H); MS (ESI) m/z 134.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C[O:10][C:11]([C:13]1[C:18]([CH2:19][CH:20]=O)=[CH:17][C:16]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:15][N:14]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:11](=[O:10])[C:13]3[N:14]=[CH:15][C:16]([CH2:22][O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:17][C:18]=3[CH2:19][CH2:20]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ncc(COc2ccccc2)cc1CC=O
Reactant: Nc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C1c2ncc(COc3ccccc3)cc2CCN1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.2 %

Procedure:
4-Fluoroaniline (0.032 mL, 0.34 mmol) was added to a stirred solution of 3-(2-oxo-ethyl)-5-phenoxymethyl-pyridine-2-carboxylic acid methyl ester (80 mg, 0.28 mmol, from step 7) in DCM (4 mL). The mixture was stirred at RT for 1 h. Sodium triacetoxyborohydride (89 mg, 0.42 mmol) was added and the mixture was stirred at RT for 16 h. Acetic acid (0.040 mL) was added and the mixture was stirred at RT for additional 20 h. The mixture was diluted with DCM and washed with a saturated solution of NaHCO3 and brine. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; 7N solution of ammonia in methanol in DCM 0/100 to 4/96). The desired fractions were collected and the solvents evaporated in vacuo to yield an impure fraction which was re-purified by RP-HPLC on (C18 XBridge, 19×100, 5 μm; 80%/0.1% NH4CO3H/NH4OH pH 9 solution in water, 20% CH3CN to 0%/0.1% NH4CO3H/NH4OH pH 9 solution in water, 100% CH3CN), to yield 7-(4-fluoro-phenyl)-3-phenoxymethyl-6,7-dihydro-[1,7]-naphthyridin-8(5H)-one (14.86 mg, 15% yield) as a white solid: 1H NMR (500 MHz, CDCl3) δ 3.22 (t, J=6.4, 2 H), 4.01 (t, J=6.4, 2 H), 5.17 (s, 2 H), 6.98 (d, J=7.8, 2 H), 7.01 (t, J=7.5, 1 H), 7.07-7.16 (m, 2 H), 7.29-7.35 (m, 2 H), 7.36-7.42 (m, 2 H), 7.76 (br. s, 1 H), 8.78 (d, J=1.7, 1 H); LC-MS (M+H)=349.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[CH:7]=[C:8]([CH2:12][CH3:13])[C:9]([OH:11])=[O:10])([O-:3])=[O:2].Cl.[CH3:18][CH2:19]O>>[CH2:18]([O:10][C:9](=[O:11])[C:8](=[CH:7][C:6]1[CH:14]=[CH:15][CH:16]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH2:12][CH3:13])[CH3:19]
Reactant: CCO
Reactant: CCC(=Cc1cccc([N+](=O)[O-])c1)C(=O)O
Agent: Cl
Product: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)CC

Procedure:
2-(3-Nitro-benzylidene)-butyric acid (500 mg, 2.27 mmol) was esterified by dissolving in EtOH (12.5 ml), adding conc HCl (0.25 ml) and heating to reflux for 8 h. The solvents were evaporated in vacuo to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][C:18]1=[O:23]>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:20]2[CH2:21][CH2:22][NH:17][C:18](=[O:23])[CH2:19]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: O=C1CNCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CN(Cc2ccc(Br)cc2)CCN1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.9 %

Procedure:
A mixture of 4-bromobenzyl bromide (1.0 g, 4.0 mmol), triethylamine (0.84 mL, 6.0 mmol) and piperazin-2-one (0.81 g, 8.0 mmol) in THF (20 mL) was stirred at ambient temperature for 16 h. The solvent was evaporated and the resultant residue diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound (1.0 g, 93%). 1H NMR (CDCl3, 300 MHz): δ 7.49-7.43 (m, 2H); 7.24-7.16 (m, 2H); 6.20 (s, 1H); 3.53 (s, 2H); 3.38-3.32 (m, 2H); 3.15 (s, 2H); 2.66-2.59 (m, 2H).). LCMS (Method G): RT=2.54 min, M−H+=268.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:11](=[N:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:20](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:20][O:1][N:2]=[C:3]([C:11](=[N:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:12])[C:4]([O:6][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:5]
Reactant: CC(=Nc1ccccc1)C(=NO)C(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: CON=C(C(=O)OC(C)(C)C)C(C)=Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
To a solution of tert-butyl 2-hydroxyimino-3-phenyliminobutyrate (1.0 g) in acetone (10 ml) was added potassium carbonate (0.63 g) and dimethyl sulfate (0.43 ml) under ice-cooling. The mixture was stirred at the same temperature for 30 minutes and stirred at ambient temperature for 4 hours. The resulting suspension was poured into ice-water and extracted with diisopropyl ether. The organic layer was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residual oil was subjected to column chromatography on silica gel give tert-butyl 2-methoxyimino-3-phenyliminobutyrate (0.68 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[C:10]([CH:11]([CH3:13])[CH3:12])[C:3]=12.[H-].[Na+].F[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([N+:25]([O-:27])=[O:26])[CH:18]=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([N+:25]([O-:27])=[O:26])[CH:18]=3)[N:9]=[C:10]([CH:11]([CH3:13])[CH3:12])[C:3]=12
Reactant: CC(C)c1n[nH]c2nccc(Cl)c12
Reactant: N#Cc1ccc(F)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1nn(-c2ccc(C#N)c([N+](=O)[O-])c2)c2nccc(Cl)c12
Reaction time: 0.5 h
Yield: 85 %

Procedure:
Compound (6b) (0.335 g) was dissolved in DMF (8.6 mL), and sodium hydride (0.097 g, a 55% dispersion in paraffin liquid) was added to the resulting solution at 0° C., followed by stirring for 30 min. Then, 4-fluoro-2-nitrobenzonitrile was added to the reaction solution, followed by stirring at 60° C. for 30 min. Water was added to the reaction solution, and the precipitate was collected by filtration and washed by sprinkling water to obtain 4-{4-chloro-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-nitrobenzonitrile (0.5 g, 85%). 4-{4-Chloro-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-nitrobenzonitrile (0.35 g) and ammonium chloride (0.35 g) were dissolved in a solvent mixture of THF (3 mL), methanol (3 mL), and water (3 mL). Iron (0.57 g) was added to the resulting solution, followed by stirring at 70° C. for 1 hr. Insoluble matters were filtered by celite, and the solvent was distilled away. The precipitate was washed with water and was collected by filtration to obtain compound (106a) (0.32 g, 95%) as a white solid.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.S(C1C=CC(C)=CC=1)(OC[C@@H]1OC1)(=O)=O.[CH2:42]([NH2:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CS(C)=O>[CH2:42]([NH:49][CH2:11][CH:12]1[O:25][C:16]2=[C:17]3[C:21](=[CH:22][CH:23]=[C:15]2[O:14][CH2:13]1)[NH:20][C:19](=[O:24])[CH2:18]3)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Reactant: NCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Solvent: CS(C)=O
Product: O=C1Cc2c(ccc3c2OC(CNCc2ccccc2)CO3)N1
Temperature: 77.5 °C
Reaction time: 3 h

Procedure:
(S)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (2.0 g, 5.3 mmole), prepared in the same manner as the (R) enantiomer described above with substitution of (S)- for (R)-glycidyl tosylate, and benzylamine (2.9 ml, 26.7 mmole) were placed in 20 ml of fresh DMSO under nitrogen. The mixture was then heated to 75-80° C. with stirring for 3 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and brine. The DMSO layer was extracted with ethyl acetate and the combined ethyl acetate extracts were washed with water to remove trace DMSO, dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant to yield the free base (1.4 g, 4.5 mmole, 83%) of the expected product as a solidified oil under reduced pressure. The free base was dissolved in 20 ml of ethanol, treated with 0.25 M ethanolic fumaric acid (10 ml) and precipitated with diethyl ether to give the title compound as a pale yellow solid fumarate salt, predominantly in the (R)-configuration, m.p. 195-196° C. This sample, from which the pharmacological results reported in this application were obtained, was determined by chiral HPLC to contain 9% of the (S)-enantiomer.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]2[O:19][CH2:18]2)=[N:5][N:6]=1.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]([OH:19])[CH2:18][NH:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:5][N:6]=1
Reactant: Cc1nnc(C=Cc2ccccc2OCC2CO2)s1
Reactant: CC(C)(C)N
Solvent: Cc1ccccc1
Product: Cc1nnc(C=Cc2ccccc2OCC(O)CNC(C)(C)C)s1

Procedure:
7 g (0.025 mole) of 2-methyl-5-[2-(2,3-epoxy-propoxy)styryl]-1,3,4-thiadiazole and 2.1 g (0.028 mole) of tert.butylamine are reacted similarly to the Example relating to compound 3. 3.8 g (44% of theory) of yellow crystals, of melting point 110°-112° C., are obtained from toluene.
Reaction SMILES: C([N:4]1[C:12]2[CH:7]([N:8](C(=O)C)[CH2:9][N:10](C(=O)C)[C:11]=2Cl)[N:6]([C@@H:20]2[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:21]2[OH:22])[CH2:5]1)(=O)C.[CH3:29][NH:30][CH2:31][CH:32]=[CH:33][CH3:34].C(N(CC)CC)C>C(O)(C)C>[CH3:29][N:30]([CH2:31][CH:32]=[CH:33][CH3:34])[C:11]1[C:12]2[N:4]=[CH:5][N:6]([C:7]=2[N:8]=[CH:9][N:10]=1)[C@@H:20]1[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:21]1[OH:22]
Reactant: CC=CCNC
Reactant: CC(=O)N1CN(C(C)=O)C2C(=C1Cl)N(C(C)=O)CN2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC=CCN(C)c1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 8 h
Yield: 70 %

Procedure:
7.3 g. triacetyl-6-chloro-9-(β-D-ribofuranosyl)-purine, 2.1 g. methyl-but-2-enylamine and 2.8 ml. triethylamine were heated under reflux for 2 hours in 100 ml. isopropanol. After cooling, the reaction mixture was mixed with 200 ml. diethyl ether, extracted twice with water and the organic phase evaporated to dryness in a vacuum. The residue was dissolved in 100 ml. 25% methanolic ammonia and then left to stand overnight at ambient temperature. The solution was thereafter evaporated and the residue obtained was recrystallized from water. 4.1 g. (70% of theory) N(6)-methyl-N(6)-but-2-enyl-adenosine were obtained; m.p. 160° - 162° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:25][C@H:26]([CH2:28][OH:29])[CH3:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:25][C@@H:26]([CH3:27])[CH2:28][OH:29])=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)O)cn1
Reactant: C[C@H](N)CO
Product: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)N[C@@H](C)CO)cn1
Yield: 94 %

Procedure:
As described for example 254, 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (100 mg, 0.29 mmol) was converted, using L-alaninol instead of 2-amino-2-methyl-1-propanol, to the title compound (110 mg, 94%) which was obtained as a white solid. MS: m/e=402.3 [M+H]+.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][S:23]([C:26]1[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:27]=1[CH3:34])(=[O:25])=[O:24].[CH3:35]I.O>CN(C)C=O>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]([CH3:35])[S:23]([C:26]1[C:27]([CH3:34])=[CH:28][C:29]([CH3:33])=[CH:30][C:31]=1[CH3:32])(=[O:25])=[O:24]
Reactant: Cc1cc(C)c(S(=O)(=O)Nc2ccccc2CSc2nccn2-c2ccccn2)c(C)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(S(=O)(=O)N(C)c2ccccc2CSc2nccn2-c2ccccn2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
100 mg of 60% sodium hydride are suspended in 2 ml of dimethyl formamide, and a solution of one g of 1-(2-pyridyl)-2-[2-(2,4,6-trimethylphenyl)sulfonylaminobenzylthio]imidazole in 2 ml of dimethyl formamide is added thereto under ice-cooling. The mixture is stirred at room temperature for 30 minutes, and 320 mg of methyl iodide are added thereto. The mixture is stirred for 2 hours. The reaction mixture is poured into water, and the resultant oily product is extracted with ethyl acetate. The extract is dried and evaporated. The residue is purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=3:2), whereby 0.76 g of 1-(2-pyridyl)-2-{2-[N-methyl-N-(2,4,6-trimethylphenyl)sulfonylamino]benzylthio}imidazole is obtained.
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4](\[CH3:17])/[CH2:5][CH2:6]/[CH:7]=[C:8](/[CH3:16])\[CH2:9][CH2:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13].N1C=CC=CC=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(Cl)Cl>[C:24]([O:1][CH2:2]/[CH:3]=[C:4](\[CH3:17])/[CH2:5][CH2:6]/[CH:7]=[C:8](/[CH3:16])\[CH2:9][CH2:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: C=C(C)C(=O)CC/C(C)=C\CC/C(C)=C/CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C(C)C(=O)CC/C(C)=C\CC/C(C)=C/COC(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 0.5 g (0.0021 mol) of (6Z,10E)-12-hydroxy-2,6,10-trimethyl-1,6,10-dodecatrien-3-one dissolved in 5 ml of methylene chloride and 1.3 ml of pyridine is treated with 1 ml of acetic anhydride. The solution is stirred at room temperature for 18 hours under argon. After removing the solvent the residue is taken up three times in toluene and freed from solvent on a rotary evaporator. The residue is chromatographed on silica gel with ether-hexane 1:5. There is obtained (2E,6Z)-3,7,11-trimethyl-10-oxo-2,6,11-dodecatrienyl acetate which has the following bands in the IR spectrum: 1739 cm-1, 1675 cm-1, 1629 cm-1, 1449 cm-1, 1370 cm-1, 948 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[N:22][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:24][CH:25]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=NC(N5CCN(C)CC5)=CC=4)C=3)NC=2)C=N1.Cl[CH2:81][C:82]([NH2:84])=[O:83].C(=O)(O)[O-].[Na+]>C(O)C.CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][N:29]([CH2:81][C:82]([NH2:84])=[O:83])[CH2:28][CH2:27]5)=[N:22][CH:21]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1
Reactant: NC(=O)CCl
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Agent: CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cn2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(CC(N)=O)CC5)nc4)cnc32)cc1
Yield: 73.4 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (step 1 compound of example 137) (100 mg, 0.164 mmol) was alkylated using 2-chloroacetamide (23 mg, 0.247 mmol), sodium bicarbonate (42 mg, 0.494 mmol) and ethanol/acetone (3/3 mL) to get 80 mg (73.0%) of the titled compound after purification by column (Silica gel 60/120) chromatography using 5% methanol in dichloromethane as eluent. 1H NMR (CDCl3, 300 MHz): δ 8.60-8.06 (d, 1H), 8.40-8.39 (d, 1H), 8.11-8.08 (d, 2H), 8.00-7.99 (d, 2H), 7.85 (s, 1H), 7.80 (s, 1H), 7.71-7.67 (m, 2H), 7.37-7.33 (m, 2H), 7.06-6.90 (m, 3H), 7.76-7.73 (d, 1H), 5.45 (s, 1H), 5.37 (s, 2H), 3.65-3.62 (t, 4H), 3.09 (s, 1H), 2.71-2.68 (t, 4H), 2.37 (s, 3H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:33]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:32])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:31])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([O:29][CH3:30])[CH2:16][O:15]2)[N:6]=1.[F:41][C:42]1[C:47]([F:48])=[CH:46][CH:45]=[CH:44][C:43]=1B(O)O>>[NH2:33][C:4]1[S:3][C:2]([C:46]2[CH:45]=[CH:44][CH:43]=[C:42]([F:41])[C:47]=2[F:48])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:31])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([O:29][CH3:30])[CH2:16][O:15]1)=[O:32]
Reactant: OB(O)c1cccc(F)c1F
Reactant: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Product: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(-c4cccc(F)c4F)sc3N)cnn2C)CC[C@H]1N

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-methoxy-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 98), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2,3-difluorophenyl)boronic acid gave 219. 1H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 7.90-7.82 (m, 2H), 7.56-7.42 (m, 3H), 7.38-7.30 (m, 1H), 5.07 (t, J=5.7 Hz, 1H), 3.98-3.90 (m, 1H), 3.88-3.80 (m, 1H), 3.71 (s, 3H), 3.50-3.45 (m, 1H), 3.14 (d, J=1.5 Hz, 3H), 2.36-2.31 (m, 2H), 1.76-1.71 (m, 1H), 1.63-1.58 (m, 4H), 1.50-1.45 (m, 1H). LCMS (ES+) m/z 479 (M+1).