Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([O:7][C:8]2[CH:9]=[C:10]([C:18]3([C:24]#[N:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].O>CN(C)C=O>[CH2:37]([O:36][C:34](=[O:35])[CH2:33][N:21]1[CH2:20][CH2:19][C:18]([C:10]2[CH:11]=[CH:12][C:13]([O:14][CH:15]([F:17])[F:16])=[C:8]([O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:9]=2)([C:24]#[N:25])[CH2:23][CH2:22]1)[CH3:38]
Reactant: N#CC1(c2ccc(OC(F)F)c(OC3CCCC3)c2)CCNCC1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCC(C#N)(c2ccc(OC(F)F)c(OC3CCCC3)c2)CC1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To a solution of the compound prepared in example 1 (19.8 g) in N,N-dimethylformamide (53 ml) were added potassium carbonate (18.4 g) and ethyl bromoacetate (5.89 ml) and the mixture was stirred for 1.5 hours at 50° C. To the reaction mixture was added water (160 ml) and it was extracted by tert-butyl methyl ether (160 ml). The organic layer was washed by water (80 ml×2) and concentrated to give the title compound (23.4 g) having the following physical data.
Reaction SMILES: Cl[O-].[Na+].[CH3:4][O:5][C:6](=[O:16])[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([OH:15])[CH2:12][CH2:13][OH:14].C(O)(C)C>C(O)(=O)C>[CH3:4][O:5][C:6](=[O:16])[CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:15])[CH2:12][CH2:13][OH:14]
Reactant: COC(=O)CCCCC(O)CCO
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC(=O)O
Solvent: CC(C)O
Product: COC(=O)CCCCC(=O)CCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
100 ml of aqueous sodium hypochlorite solution (10-13% active chlorine) were added dropwise at room temperature, over a period of 45 minutes, to 16.6 g (87 mmol) of 6,8-dihydroxyoctanoic acid methyl ester in 200 ml of glacial acetic acid. After stirring for a further 3 hours at room temperature, 180 ml of isopropanol were added in order to destroy excess sodium hypochlorite, and stirring was carried out for 10 minutes. The reaction mixture was then added to 1200 ml of water and extracted several times with methylene chloride. The combined organic phases were washed with cold-saturated sodium hydrogen carbonate solution. After drying over sodium sulfate, the solvent was distilled off using a rotary evaporator. 13.0 g (80%) of 8-hydroxy-6-oxo-octanoic acid methyl ester were obtained.
Reaction SMILES: [NH4+].[Cl-].[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][CH2:9]2)([O-])=O.COC(C)(C)C>C(O)C.O.C(O)C.[Fe]>[NH2:3][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][CH2:9]2
Reactant: O=C1NCc2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: COC(C)(C)C
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)CNC2=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 48.2 %

Procedure:
To a suspension of Fe (1.1 g, 19.6 mmole), NH4Cl (1.5 g, 28 mmole) in a mixture of ethanol/water (30 ml/7 ml) at 80° C. was added a mixture of 5-Nitro-2,3-dihydro-isoindol-1-one (1 g, 5.6 mmole) in 10 ml ethanol. The reaction mixture was stirred at 80° C. for 2 hours. Mixture was cooled down, filtered off, solid was washed with 50 ml ethanol. The filtrate was concentrated, taken into 50 ml ethylacetate, washed with 20 ml water. Organic layer was dried over Na2SO4, filtered and concentrated to give about 900 mg crude. Trituration with methyl t-butylether gave 400 mg pure product, 48% yield.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].[Cl:21][CH2:22][CH2:23][CH2:24]Cl>CN(C)C=O>[Cl:21][CH2:22][CH2:23][CH2:24][O:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[O:14])[CH3:13]
Reactant: ClCCCCl
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc([N+](=O)[O-])cc1OCCCCl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of 98.1 g (0.5 mol) of N-(2-hydroxy-4-nitrophenyl)acetamide and 69.2 g (0.5 mol) of potassium carbonate in 500 ml of dimethylformamide was heated to 50° C. with stirring, 113.0 g (1 mol) of 1,3-dichloropropane were then added and heating at 50° C. was continued for 1 hour. The reaction mixture was poured into 4 litres of ice-cold water and the crystalline precipitate was filtered off, reimpasted in water and then in isopropyl alcohol and dried under vacuum at 40° C. over phosphorus pentoxide.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:4]=1[NH2:5])[CH3:2].[Br:11][CH2:12][CH2:13][C:14](Cl)=[O:15].O.O.O.C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[Br:11][CH2:12][CH2:13][C:14]([NH:5][C:4]1[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:3]=1[CH2:1][CH3:2])=[O:15]
Reactant: O=C(Cl)CCBr
Reactant: CCc1cccc(C)c1N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCc1cccc(C)c1NC(=O)CCBr
Reaction time: 0.5 h

Procedure:
In a glass-stoppered bottle, a solution of 2-ethyl-6-methylaniline (15.0 g, 0.111 mole) in glacial acetic acid (95 ml) was cooled to 13° C. and 3-bromo-propionyl chloride (21.1 g, 0.122 mole) was added. The mixture was mixed and was combined immediately with a cooled (3° C.) solution of sodium acetate trihydrate (36.9 g) in water (150 ml). The mixture was shaken vigorously for 30 min. The white product that formed was filtered off, washed carefully with water, and dried. This product, i.e., 3-bromo-2'-ethyl-6'-methylpropionanilide (27.4 g, 91%), melted at 149°-150° C. and was sufficiently pure for the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O=[C:23]1[C:31]2[C:26](=[N:27][C:28]([C:32]([OH:34])=[O:33])=[CH:29][CH:30]=2)[CH2:25][O:24]1.Cl>C1COCC1.CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:23]1[C:31]2[C:26](=[N:27][C:28]([C:32]([OH:34])=[O:33])=[CH:29][CH:30]=2)[CH2:25][O:24]1
Reactant: O=C(O)c1ccc2c(n1)COC2=O
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1Nc2ccc(F)cc2C1=C1OCc2nc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 29.3 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (177 mg, 1.17 mmol) in THF (2 mL) is treated with a solution of lithium bis(trimethylsilyl)amide (2.9 mL of a 1M solution in THF, 2.3 mmol) dropwise. The resulting solution is stirred at room temperature for 15 min. A solution 5-oxo-5,7-dihydro-furo[3,4-b]pyridine-2-carboxylic acid (105 mg, 0.59 mmol) in dimethylformamide (2 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 3 h and is then poured into a cold 10% aqueous HCl. solution (30 mL). The reaction mixture is stirred at room temperature for 65 h. The solid which precipitated from solution is collected by filtration, washed with water and purified by chromatography (silica gel, MeOH/EtOAc). The product containing fractions are concentrated to give the title compound as a reddish solid (54 mg, 29%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:13]=[C:12]2[C:7]([C:8](O)=[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=[N:11]2)=[CH:6][CH:5]=1)[CH3:2].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:8]1[C:7]2[C:12](=[N:13][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)[N:11]=[CH:10][C:9]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2nc(OCC)ccc2c1O
Product: CCOC(=O)c1cnc2nc(OCC)ccc2c1Cl

Procedure:
In a similar manner to Example B1, ethyl 7-ethoxy-4-hydroxy-1,8-naphthyridine-3-carboxylate (8.8 g) and phosphorus oxychloride (50 ml) were heated at 80° C. for 25 minutes to give ethyl 4-chloro-7-ethoxy-1,8-naphthyridine-3-carboxylate, m.p. 72°-75° C.
Reaction SMILES: O[C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[C:29]([O-:32])([O-])=O.[K+].[K+].C(Cl)(Cl)Cl>CN(C=O)C>[CH2:13]([O:11][C:6]1[CH:7]=[C:8]([O:10][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13])[CH:9]=[C:2]([O:32][CH2:29][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13])[C:3]=1[CH:4]=[O:5])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: O=C([O-])[O-]
Reactant: O=Cc1c(O)cc(O)cc1O
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOc1cc(OCCCCCCCCCCCCCCCC)c(C=O)c(OCCCCCCCCCCCCCCCC)c1
Temperature: 70 °C
Reaction time: 20 h
Yield: 50 %

Procedure:
2,4,6-Trihydroxybenzaldehyde (435 mg, 2.53 mmol), 1-bromohexadecane (4.58 g, 15.0 mmol), K2CO3 (1.04 g, 4.52 mmol) and KI (70 mg, 0.42 mmol) were mixed in DMF (15 ml), followed by stirring at 70° C. for 20 hours. The resulting reaction product was cooled to 20° C., and chloroform (100 ml) was added thereto to separate into an organic phase and an aqueous phase. The subsequent operations are the same as in Example 1, and therefore are omitted to describe. Thus, white solid 2,4,6-trihexadecyloxybenzaldehyde (2a) was obtained (1.04 g, yield: 50%). It was confirmed by 1H NMR quantitative analysis that 2a is 2,4,6-trihexadecyloxybenzaldehyde.
Reaction SMILES: [C:1]([NH:22][C@H:23]([C:30]([OH:32])=[O:31])[CH2:24][O:25][P:26]([OH:29])([OH:28])=[O:27])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18]CC.[C:33](O)(=O)CCCCCCC/C=C\CC=CCC=CCC.Cl.COC(=O)[C@H]([C@@H](C)O)N>>[C:1]([NH:22][C@H:23]([C:30]([OH:32])=[O:31])[C@@H:24]([CH3:33])[O:25][P:26]([OH:29])([OH:28])=[O:27])(=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH:12]=[CH:13][CH2:14][CH:15]=[CH:16][CH2:17][CH3:18]
Reactant: CCCCCC=CCC=CCC=CC/C=C\CCCC(=O)N[C@@H](COP(=O)(O)O)C(=O)O
Reactant: CCC=CCC=CC/C=C\CCCCCCCC(=O)O
Agent: COC(=O)[C@@H](N)[C@@H](C)O
Agent: Cl
Product: CCC=CCC=CC/C=C\CCCCCCCC(=O)N[C@H](C(=O)O)[C@@H](C)OP(=O)(O)O

Procedure:
This compound was prepared as described above for (6), using 0.5 mmol (139 mg) of cis-9,12,15-octadecatrienoic acid and 1 mmol (1 70 mg) of L-threonine methyl ester hydrochloride; yield 85 mg (37%); Rf 0.05-0.10 (system B); 1H-NMR (CD3SOCD3, 200 MHz) δ0.9-1.0 (t, 3H, ω-CH3); 1.3-1.5 (m, 13H, 5CH2 and CH3CHOP); 2.0-2.2 (m, 6H, CH2CO and 2CH2CH═CH); 2.7-2.9 (br s, 4H, 2HC═CH—CH2—CH═CH); 4.1-4.3 (m, 2H, 2CH); 5.2-5.4 (br s, 6H, 3HC═CH); 8.2-8.4 (m, 3H, NH and 2POH)
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[C:11]([Cl:12])=[N:10][CH:9]=[CH:8][N:7]=2)[CH2:3]1.Cl[C:14]1[N:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:12][C:11]1[C:6]([CH:4]2[CH2:5][N:2]([C:14]3[N:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[CH2:3]2)=[N:7][CH:8]=[CH:9][N:10]=1
Reactant: Clc1ncc2ccccc2n1
Reactant: Clc1nccnc1C1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1nccnc1C1CN(c2ncc3ccccc3n2)C1
Temperature: 110 °C
Reaction time: 17 h
Yield: 47.1 %

Procedure:
2-(Azetidin-3-yl)-3-chloropyrazine hydrochloride (1.50 g, 7.28 mmol), 2-chloroquinazoline (1.20 g, 7.28 mmol, Parkway Scientific), and cesium carbonate (5.22 g, 16.0 mmol, Fluka) were mixed in DMF (30 mL) in a round bottom flask under a nitrogen atmosphere. The mixture was stirred at 110° C. for 17 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (2×). The combined organic extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude mixture was purified via silica gel flash column chromatography eluting with 0% to 100% EtOAc in hexanes to give 1.02 g (47%) of a yellow amorphous solid. 1H NMR (400 MHz, chloroFORM-d) δ ppm 4.41-4.50 (m, 1 H) 4.58-4.63 (m, 2 H) 4.65-4.72 (m, 2 H) 7.22-7.28 (m, 1 H) 7.61-7.72 (m, 3 H) 8.28 (d, J=2.35 Hz, 1 H) 8.51 (d, J=2.35 Hz, 1 H) 9.04 (s, 1 H). m/z=298 (M+1).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:18][C:17]2[C:16]([NH:19][C:20]3[O:21][C:22]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)=[CH:23][N:24]=3)=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].IC.[C:39](OCC)(=O)C>CN(C)C=O>[Si:1]([O:8][CH:9]1[CH2:18][C:17]2[C:16]([N:19]([CH3:39])[C:20]3[O:21][C:22]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][CH:26]=4)=[CH:23][N:24]=3)=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(c1ncc(-c2ccc(C(F)(F)F)cc2)o1)c1cccc2c1CC(O[Si](C)(C)C(C)(C)C)CC2
Reaction time: 0.08 h
Yield: 18 %

Procedure:
The product of Example 18D (300 mg, 0.615 mmol) in 5 mL N,N-dimethylformamide was treated with NaH (60% dispersion, 32 mg, 0.8 mmol) at rt. After stirring for 5 minutes, iodomethane (0.15 mL, 2.4 mmol) was added. The reaction was stirred at rt for 24 h, then it was poured into ethyl acetate and washed several times with water and once with brine. The organic layer was dried over Na2SO4 and was concentrated. The concentrate was purified on silica gel, eluting with 5% ethyl acetate-hexane and afforded the title compound as a brown oil (56 mg, 18%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([O:12][C:13](=[O:16])[CH:14]=[CH2:15])[CH2:9][CH2:10][CH3:11].C(N(C(C)C)C(C)C)C.CN(C=O)C>C(OCC)(=O)C.[Pd]>[C:13]([O:12][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:16])/[CH:14]=[CH:15]/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: C=CC(=O)OCCCC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCOC(=O)/C=C/c1ccccc1
Reaction time: 24 h
Yield: 71 %

Procedure:
The Pd/C monolith (42 mg of a 1% Pd/C monolith, 2 mol % Pd) prepared according to the method described in Example 2 was added to a 1 dram glass vial in air followed by iodobenzene (28 μL, 0.25 mmol), n-butylacrylate (54 μL, 0.375 mmol), ethyldiisopropylamine (1.5 equiv, 0.375 mmol, 65 μL) and 1 mL DMF. The vial was sealed under air with a rubber septum cap and placed in an oil bath preheated to 80° C. for 24 hours. After the allotted time, the reaction mixture was dissolved in ethyl acetate. Gas chromatographic analysis indicated a 71% yield of (E)-n-butyl cinnamate.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][C@@H:16]3[C@@H:20]([OH:21])[C@@H:19]([OH:22])[CH:18]([OH:23])[O:17]3)=[CH:12][CH:11]=[CH:10][C:4]=2[NH:5][S:6](=[O:9])(=[O:8])[N:7]=1.F[C:25](F)(F)C(O)=O>CO>[NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][C@@H:16]3[C@@H:20]([OH:21])[C@@H:19]([OH:22])[CH:18]([O:23][CH3:25])[O:17]3)=[CH:12][CH:11]=[CH:10][C:4]=2[NH:5][S:6](=[O:8])(=[O:9])[N:7]=1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3OC(O)[C@H](O)[C@@H]3O)c21
Reactant: O=C(O)C(F)(F)F
Solvent: CO
Product: COC1O[C@H](COc2cccc3c2C(N)=NS(=O)(=O)N3)[C@@H](O)[C@H]1O
Yield: 100 %

Procedure:
To a solution of 4-Amino-5-(((2R,3S,4R)-3,4,5-trihydroxytetrahydrofuran-2-yl)methoxy)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide (Example 212a) (7 mg, 0.020 mmol) in dry methanol (1 mL) was added trifluoroacetic acid 0.2 mL) and the mixture was refluxed overnight. The resulting solution was evaporated to dryness to provide the title compound as a white powder (7.28 mg, 100%, mixture of diastereomers˜4/1). 1H NMR (400 MHz, DMSO-d6): δ0 [3.17 (s, ¾H)], 3.22 (s, 3H), 3.81 (d, J=4.0 Hz, 1H), [3.93 (m, ½H)], 4.12 (m, 3H), 4.39 (m, 1H), 4.71 (s, 1H), [4.85 (d, J=4.0 Hz, ¼H)], 5.44 (br s, 2H), 6.65 (d, J=8.0 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 7.48 (t, J=8.0 Hz, 1H), 7.95 (s, 1H), 8.41 (s, 1H), 11.00 (s, 1H), [11.01 (s, ¼H)].
Reaction SMILES: [NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]=[C:2]1[NH2:3].[O:12]1[CH:18]2[CH:13]1[CH:14]=[CH:15][CH2:16][CH2:17]2.CO>[Pd].O1CCCC1>[OH:12][CH:13]1[CH2:18][CH2:17][CH:16]([N:6]2[CH:7]=[N:8][C:9]3[C:10](=[O:11])[NH:1][C:2]([NH2:3])=[N:4][C:5]2=3)[CH:15]=[CH:14]1
Reactant: C1=CC2OC2CC1
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc2c(ncn2C2C=CC(O)CC2)c(=O)[nH]1
Yield: 25.1 %

Procedure:
7.56 g (50 mmol) of guanine are reacted with 2 mol % of the palladium(0) catalyst prepared in situ as above and one equivalent of 3,4-epoxycyclohexene in tetrahydrofuran first at 0° C. and then for 8 hours under reflux temperature, and the mixture is then poured into methanol. The reaction mixture is concentrated and the residue is taken up in 2-propanol and filtered off with suction. The residue is recrystallized first from ethanol with active charcoal and then from water. 3.1 g (25.1% of theory) of 9-[(1RS,4SR)-4-hydroxy-cyclohex-2-en-1-yl]guanine of melting point >300° C. are obtained. 1H NMR (270 MHz, d6 -DMSO); δ[ppm]: 10.57 (s, 1H), 7.60 (s, 1H), 6.46 (s, 2H), 6.05 (m, 1H), 5.77 (m, 1H), 4.91 (d, 1H), 4.79 (m, 1H), 4.06 (m, 1H), 1.95-1.75 (m, 3H), 1.53 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=[C:12]([C:15]3[N:16]4[C:20]([C:21]([C:24](O)=[O:25])=[CH:22][CH:23]=3)=[CH:19][CH:18]=[CH:17]4)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:65][CH2:66][CH2:67][C:68]1[CH:69]=[CH:70][C:71]2[C:75]([CH3:77])([CH3:76])[O:74][B:73]([OH:78])[C:72]=2[CH:79]=1>CN(C=O)C.O>[OH:78][B:73]1[C:72]2[CH:79]=[C:68]([CH2:67][CH2:66][NH:65][C:24]([C:21]3[C:20]4[N:16]([CH:17]=[CH:18][CH:19]=4)[C:15]([C:12]4[CH2:11][C:10]([C:4]5[CH:5]=[C:6]([Cl:9])[C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=5)([C:27]([F:30])([F:28])[F:29])[O:14][N:13]=4)=[CH:23][CH:22]=3)=[O:25])[CH:69]=[CH:70][C:71]=2[C:75]([CH3:77])([CH3:76])[O:74]1
Reactant: CC1(C)OB(O)c2cc(CCN)ccc21
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n2cccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OB(O)c2cc(CCNC(=O)c3ccc(C4=NOC(c5cc(Cl)c(Cl)c(Cl)c5)(C(F)(F)F)C4)n4cccc34)ccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (0.37 mmol) and HATU (207 mg, 0.6 mmol) in DMF (5 mL), DIPEA (142 mg, 1.1 mmol) can be added. The reaction mixture can be stirred at rt for 10 min and crude compound 6-(2-aminoethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (0.5 mmol) can be added. The reaction mixture can be stirred overnight. Water can be added and the mixture can be extracted three times with ethyl acetate. The combined organic layers can be washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue can be purified by prep-HPLC to give the final title compound.
Reaction SMILES: [NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:5]([NH:7]N)=[O:6])[CH2:3][OH:4].N(OCCC(C)C)=O.C(N(CC)CC)C.N[C@H:35]([C:38]([O:40][CH3:41])=[O:39])[CH2:36][OH:37].Cl>CN(C)C=O.Cl.O1CCOCC1>[NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:5]([NH:7][C@H:35]([C:38]([O:40][CH3:41])=[O:39])[CH2:36][OH:37])=[O:6])[CH2:3][OH:4]
Reactant: COC(=O)[C@@H](N)CO
Reactant: NNC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Agent: CC(C)CCON=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 0.08 h

Procedure:
5.06 Grams of Z-Ser-NHNH2 was dissolved in 50 ml of dimethylformamide with 6.66 ml of 6N-hydrochloric acid/dioxane, the solution was cooled to -15° C. then 2.68 ml of isoamyl nitrite was added thereto, and the mixture was stirred for 5 minutes. Next, 5.60 ml of triethylamine was added to neutralize the reaction mixture. This reaction mixture was added to 30 ml of dimethylformamide solution containing 3.11 g of H-Ser-OMe.HCl and 2.80 ml of triethylamine, then this mixture was stirred at 4° C. for 20 hours. Dimethylformamide was removed by distillation, the residue obtained was extracted with ethyl acetate, the extract was washed with water and was dried with anhydrous sodium sulfate. After removal of ethyl acetate by distillation, the residue was crystallized by adding ether, reprecipitated from ethyl acetate-ether to obtain 3.75 g of Z-Ser-Ser-OMe.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:38](=[O:37])[CH2:39][OH:40])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:33])[NH:14][C:15]=23)[CH2:31][CH2:32]1
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@@H](NC(=O)CO)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f6) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[S:12][CH:11]=[N:10][CH:9]=1.[OH:13][C:14]([CH3:47])([CH3:46])[CH2:15][C@@:16]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:21][C:20](=[O:22])[N:19]([C@H:23]([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)[CH3:24])[CH2:18][CH2:17]1>CN(C)C=O>[OH:13][C:14]([CH3:46])([CH3:47])[CH2:15][C@@:16]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:21][C:20](=[O:22])[N:19]([C@H:23]([C:25]2[CH:26]=[CH:27][C:28]([C:8]3[S:12][CH:11]=[N:10][CH:9]=3)=[CH:29][CH:30]=2)[CH3:24])[CH2:18][CH2:17]1
Reactant: Brc1cncs1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](c1ccc(-c2cncs2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
2 M aqueous Na2CO3 solution (0.63 mL) was added to a solution of 5-bromothiazole (70 μL) and (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one (0.30 g) in dimethylformamide (3 mL). The resulting mixture was sparged with argon for 10 min, before [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) dichloromethane complex (15 mg) was added. The mixture was heated to 90° C. and stirred at this temperature for 2 h. After cooling to ambient temperature, water was added, and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 50:50->0:100) to afford the title compound as a solid.