Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[Cl:11][C:12]1[N:17]2[N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=3)[CH:20]=[C:16]2[CH:15]=[CH:14][CH:13]=1.O>ClCCl>[Cl:11][C:12]1[N:17]2[N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=3)[C:20]([CH:3]=[O:4])=[C:16]2[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cccc(-c2cc3cccc(Cl)n3n2)c1
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1cccc(-c2nn3c(Cl)cccc3c2C=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
N,N-Dimethylformamide (150 mL) was cooled to 0° C. and treated with phosphorous oxychloride (8.8 mL, 94 mmol). After the addition was complete, the mixture was warmed to room temperature and stirred for 1 hour. To this was added 7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridine (16.3 g, 67 mmol) and the resultant solution was stirred overnight. Water was added, followed by dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was recrystallized from diethyl ether and hexanes to give 7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (14.3 g, 79%) as a pale yellow solid. 1H NMR (CDCl3): δ 10.11 (s, 1 H), 8.41 (dd, 1H), 7.63 (s, 1H), 7.58 (d, 1H), 7.49 (dd, 1H), 7.42 (t, 1H), 7.33 (d, 1H), 7.20 (dd, 1H), 2.45 (s, 3H); MS m/z 271 (M+1).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:9][C:8]=1[CH3:20].[B:21](OC)([O:24]C)[O:22]C.Cl>O1CCCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:9]=[C:8]([CH3:20])[C:7]([B:21]([OH:24])[OH:22])=[CH:12][CH:11]=2)=[CH:14][CH:15]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)ccc1Br
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(Cl)cc2)ccc1B(O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
A solution of n-butyl lithium in hexanes (1.6 M, 37.5 ml, 0.060 mol) is added dropwise to a solution of 4-bromo-4′-chloro-3-methylbiphenyl (11.5 g, 0.041 mol) in tetrahydrofuran (120 ml) at −78° C., under an atmosphere of nitrogen, and the mixture is stirred at −78° C. for 30 minutes. Trimethyl borate (27.4 ml, 0.245 mol) is added slowly at −78° C. and the mixture is stirred for 1 hr. The reaction mixture is allowed to warm to room temperature over 2-3 hrs and then stirred at room temperature for 1 hr. 0.1N aqueous hydrochloric acid (320 ml) is added and the mixture is stirred at room temperature overnight. The reaction mixture is extracted with ethyl acetate (3×300 ml) and the organic extracts are combined, dried with anhydrous sodium sulfate, filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4′-chloro-3-methylbiphen-4-ylboronic acid (6.0 g) as white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:16]=[CH:17][CH:18]=1)[O:9][CH2:10][C:11]([O:13]CC)=[O:12])[CH:2]([CH3:4])[CH3:3].CCO.[OH-].[K+].Cl>O>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:16]=[CH:17][CH:18]=1)[O:9][CH2:10][C:11]([OH:13])=[O:12])[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)COc1cccc(OCC(C)C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)COc1cccc(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
A 250 mL flask fitted with a stir-bar was charged with ethyl 3-isobutoxyphenoxyacetate (9.11 g, 36.1 mmol, 71% purity) and EtOH (100 mL). To the resultant solution was added KOH (4.05 g, 72.2 mmol) in H2O (15 mL). The mixture stirred 30 min at rt. 1M HCl was then added until a pH of 2.5 was reached. The mixture was concentrated in vacuo to 75 mL. NaOH (4 g) was added, and the solution was washed with CH2Cl2 (3×50 mL). 3M HCl was then added until a pH of 3 was attained, and the mixture was extracted with EtOAc (75 mL). The organic phase was washed with brine (50 mL), filtered through phase separation paper, and concentrated in vacuo to give 5.2 g of 72 as an off-white solid (64% from 71). 1H NMR (60 MHz, CDCl3): δ 11.4 (s, 1H), 7.3-7.0 (m, 1H), 6.7-6.3 (m, 3H), 4.6 (s, 2H), 3.7 (d, 2H), 2.0 (nonet, 1H), 1.0 (d, 6H) ppm. HPLC analysis (5:10:85 H2O:A1:MeOH) showed a purity of 95% with a retention time of 3.5 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1>O>[N:1]1([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(Cl)cc1
Reactant: C1COCCN1
Solvent: O
Product: N#Cc1ccc(N2CCOCC2)cc1
Temperature: 120 °C
Yield: 52.2 %

Procedure:
A mixture of morpholine (3 g, 34 mmol) and 4-chlorobenzonitrile (1.55 g, 11.2 mmol) is heated at 120° C. The conversion of the 4-chlorobenzonitrile is complete after 12 hours. Water (10 ml) is then added into the reaction mixture. The precipitate is filtered off, washed with water and dried under vacuum (30° C.). Recrystallisation (50% aqueous ethanol) of the dried crude product gives 1.1 g of the title-compound. Yield: 52%, m.p. 82-83° C.; MS 188 (100, M+); H1 NMR (CDCl3): δ 7.46 (dd, 2H), 6.81 (dd, 2H), 3.79 (t, 4H), 3.22 (t, 4H); C13 NMR (CDCl3): δ 153.69, 133.71, 120.07, 114.26, 101.16, 66.65, 47.49.
Reaction SMILES: [CH3:1][C@@:2]1([C:18]([F:21])([F:20])[F:19])[CH2:17][N:5]2[C:6](=[O:16])[CH:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:9]=[C:4]2[NH:3]1.Br[CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:1][C@@:2]1([C:18]([F:21])([F:19])[F:20])[CH2:17][N:5]2[C:6](=[O:16])[CH:7]=[C:8]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)[N:9]=[C:4]2[N:3]1[CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCCOc1ccccc1
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1CCOc1ccccc1

Procedure:
The product is prepared according to the procedure described in Example 1, using 100 mg of (S)-2-methyl-7-morpholin-4-yl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one (Example 1j) and 143 mg of (2-bromoethyl)phenyl ether, replacing the sodium hydride with caesium carbonate. After purification by silica column chromatography (eluent: dichloromethane/methanol 97/03), 124 mg of (S)-2-methyl-7-morpholin-4-yl-1-(2-phenoxyethyl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one are obtained, the characteristics of which are the following:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9](B3OC(C)(C)C(C)(C)O3)=[CH:10][C:5]=2[S:4][C:3]1=[O:20].Br[C:22]1[CH:23]=[C:24]([NH2:28])[CH:25]=[N:26][CH:27]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:28][C:24]1[CH:23]=[C:22]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3](=[O:20])[S:4][C:5]=3[CH:10]=2)[CH:27]=[N:26][CH:25]=1
Reactant: Cn1c(=O)sc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: Nc1cncc(Br)c1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cn1c(=O)sc2cc(-c3cncc(N)c3)ccc21
Temperature: 95 °C
Yield: 49.2 %

Procedure:
A mixture of 3-Methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-benzothiazol-2-one (873.5 mg, 3 mmol), 5-Bromo-pyridin-3-ylamine (519 mg, 3 mmol), Pd2(dba)3 (24.7 mg, 0.06 mmol), S—PHOS (62 mg, 0.15 mmol), K3PO4 (1.27 g, 6 mmol) in toluene (15 mL) was heated to 95° C. for overnight. After filtration, concentration, the residue was purified by flash column (MeOH/CH2Cl2, v/v, 1.5-3%) and yielded yellow solid (380 mg). MS (ESI) m/z 258.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 3.49 (s, 3H), 3.78 (brs, 2H), 7.10-7.12 (m, 1H), 7.12 (s, 1H), 7.51 (dd, J=8, 2 Hz, 1H), 7.60 (d, J=2 Hz, 1H), 8.08 (d, J=2.6 Hz, 1H), 8.23 (d. J=2 Hz, 1H).
Reaction SMILES: C([O:5][C:6](=[O:27])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C@H:14]([OH:26])/[CH:15]=[CH:16]/[C@H:17]([OH:25])[C@@H:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(C)(C)C.[OH-].[K+].Cl>C(O)C.O>[CH3:23][CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]([OH:24])[C@@H:17]([OH:25])/[CH:16]=[CH:15]/[C@@H:14]([OH:26])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:27])=[O:5]
Reactant: CCCCC[C@H](O)[C@@H](O)/C=C/[C@@H](O)CCCCCCCC(=O)OC(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCC[C@H](O)[C@@H](O)/C=C/[C@@H](O)CCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 46 h

Procedure:
(9S,12S,13S)-(E)-9,12,13-trihydroxy-10-octadecaenoic acid t-butyl ester (13) (6.5 mg, 0.0168 mmol) was added to an ethanol-water (4:1) solution (500 μL) of 2.0 N potassium hydroxide at room temperature, and the mixture was stirred at room temperature for 46 hours. The reaction solution was cooled to 0° C., 1.0 N hydrochloric acid solution (500 μL) was added to the reaction solution to make it weakly acidic, and the mixture was extracted with chloroform (5 mL) three times. The organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution (5 mL), dried over sodium sulfate, and concentrated. The resulting colorless oily crude product (10 mg) was separated and purified by silica gel column chromatography (chloroform:methanol=10:1) to obtain 9S,12S,13S-trihydroxy-10E-octadecenoic acid (14) as a while solid (4.5 mg, 82%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]([CH:4]1[CH2:8][CH:7]([O:9][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])=[O:17]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C1CC(OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OC(C)(C)C
Yield: 100.1 %

Procedure:
To a solution of trans-N-Boc-4-hydroxy-L-proline methyl ester (45 g, 0.183 mol) in pyridine (140 ml) and dry DCM (140 ml) at 0° C. was added dropwise 4-methyl-benzenesulfonyl chloride (41.9 g, 0.22 mol). After adding, the mixture was refluxed overnight. The solvent was evaporated and then the residue was dissolved in CH2Cl2 (140 ml). The organic phase was washed with water (150 ml), brine (140 mL), and dried over sodium sulphate. After removal of solvent, the crude 4-(toluene-4-sulfonyloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester 73.2 g (92%) was obtained as yellow oil, which was used in the following reaction without further purification.
Reaction SMILES: [CH3:1]C1(C)OC(=O)CC(=O)O1.ClCCl.N1C=CC=CC=1.Cl[C:21](=[O:39])[CH2:22][CH2:23][CH:24]([C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1>O>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH:24]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH2:23][CH2:22][C:21](=[O:39])[CH3:1])=[CH:26][CH:27]=1
Reactant: O=C(Cl)CCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)CCC(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
To a stirred solution of 17.3 parts of 2,2-dimethyl-1,3-dioxane-4,6-dione in 130 parts of dichloromethane were added 18 parts of pyridine under nitrogen atmosphere. Then there were added dropwise, during a 20 minutes-period a solution of 35.4 parts of 1-chloro-4,4-bis(4-fluorophenyl)-1-butanone in 65 parts of dichloromethane at about 0° C. while nitrogen gas was still introduced. Upon completion, stirring was continued first for 1 hour at about 0° C. and further for 1 hour at room temperature. Dichloromethane and water were added and the layers were separated. The organic phase was washed with water, dried, filtered and evaporated. The residue was boiled in 750 parts of a mixture of acetic acid and water (1:2 by volume) for 5 hours. Methylbenzene was added. The organic phase was separated, washed with water, with a sodium hydrogen carbonate solution and again with water, dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated, yielding 18.5 parts of 5,5-bis(4-fluorophenyl)-2-pentanone as a residue (intermediate 31).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:10](Br)=[CH:9][C:8]([F:12])=[C:7]([N+:13]([O-])=O)[C:6]=1Br>C(O)C.[Pd]>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([F:12])=[C:7]([NH2:13])[CH:6]=1
Reactant: O=[N+]([O-])c1c(F)cc(Br)c(OCCCl)c1Br
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(OCCCl)ccc1F
Reaction time: 120 h
Yield: 90.2 %

Procedure:
A solution of 1-(2-chloroethoxy)-2,6-dibromo-4-fluoro-3-nitrobenzene (73.2 g, 0.19 mol) in ethanol (1.1 L) containing 7.3 g of 10% palladium on carbon was hydrogenated at 40 psi for 5 days. The catalyst was filtered and the solvent was removed. The residue was dissolved in diethyl ether (300 mL) and washed with saturated aqueous sodium carbonate (200 mL). The organic layer separated and washed with water, dried over anhydrous magnesium sulfate, filtered, and the solvent removed to afford an oil which solidies to afford 32.5 g (90.0%) a dark solid: mp 42°-43° C.; MS EI m/e 189/191 (M+); 1H NMR (CDCl3) δ 3.40-3.60 (2H, bs, NH2), 3.77 (2H, d, J=6 Hz), 4.14 (2H, d, J=6 Hz), 6.19-6.23 (1H, m), 6.36 (1H, dd, J=7, 3 Hz), 6.88 (1H, dd, J=11, 9 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17](=[O:31])[C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=2[O:27]C(=O)C)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.O[Li].O>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17](=[O:31])[C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=2[OH:27])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1
Reactant: CC(=O)Oc1ccc([N+](=O)[O-])cc1C(=O)Nc1ccc(Nc2ccc(Cl)cc2)c(Cl)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(Nc2ccc(Cl)cc2)c(Cl)c1)c1cc([N+](=O)[O-])ccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-[3-Chloro-4-(4-chloro-phenylamino)-phenyl]-2-acetoxy-5-nitro-benzamide (155 mg) was dissolved in a 1:1 mixture of THF and water (12 ml) and LiOH.H2O (64 mg) was added. After stirring at room temperature for 2 hours the solvents were evaporated and water was added to the residue. Filtration, acidification of the filtrate and filtration of the precipitate gave a residue which was flash-chromatographed (EtOAc; 1:3) to provide N-[3-Chloro-4-(4-chloro-phenylamino)-phenyl]-2-hydroxy-5-nitro-benzamide as a curry coloured powder (70 mg). Mp. >219° C. (dec.).
Reaction SMILES: [C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[Na+].COC1C=CC(O)=CC=1.[CH:17]([O:19][CH2:20][CH2:21]Cl)=[CH2:18].[OH-].[Na+]>CS(C)=O.O.C(Cl)(Cl)Cl>[C:1]([O:6][CH2:21][CH2:20][O:19][CH:17]=[CH2:18])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)[O-]
Reactant: C=COCCCl
Agent: COc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: C=COCCOC(=O)C(=C)C
Temperature: 80 °C

Procedure:
40 g of sodium methacrylate was suspended in 300 g of dimethylsulfoxide (DMSO) in a 2 L flask equipped with a mechanical stirrer, cold water condenser and heating mantle. 0.35 g of 4-methoxyphenol was added. The mixture was heated to 80° C. with stirring under a nitrogen blanket. During heating, 36 g of 2-chloroethyl vinyl ether was added over 30 minutes. The reaction was then maintained at 80° C. for 20 hr. After the reaction solution was cooled to room temperature, 0.45 g of sodium hydroxide dissolved in 300 ml of water was added and the mixture was stirred for 20 minutes. About 500 g of chloroform was then added and the resulting mixture was stirred for 30 minutes. The mixture was then transferred into a separatory funnel. The bottom layer was separated and discarded. The chloroform layer was washed thoroughly with deionized (Dl) water and dried with sodium sulfate. The filtrate was then subjected to rotary evaporation at room temperature to remove most of the volatile materials. The lightly colored liquid was consistent with 2-vinyloxyethyl methacrylate (VEMA) by proton NMR: (in CDCl3): 1.98 ppm (3H CH3), 3.8 ppm (2H C(O)CH2CH2-O), 4.3 ppm (2 H C(O)CH2CH2-O), 4.0 ppm and 4.2 ppm (2H OCHCH2), 5.5 ppm and 6.2 ppm (2H CH2=C(CH3)), 6.5 ppm (1H OCHCH2).
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[N:8](CC=C)[CH:7]=[N:6][C:5]=2[N:4]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]1=[O:20].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:31][N:32](C=O)C>C1COCC1>[CH3:1][N:2]1[C:10](=[O:11])[C:9]2[NH:8][C:7]([C:31]#[N:32])=[N:6][C:5]=2[N:4]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]1=[O:20]
Reactant: CN(C)C=O
Reactant: C=CCn1cnc2c1c(=O)n(C)c(=O)n2CCCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCn1c(=O)n(C)c(=O)c2[nH]c(C#N)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To 1-methyl-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (1.05 g, 3.6 mmol) in THF (15 ml) at −78° C. was added LiHMDS (4 ml, 1M in hexane, 4 mmol) over 10 min and the solution stirred for 0.5 h. DMF (0.5 ml) was added and the solution stirred at −78° C. for a further 0.5 h then allowed to warm to ambient temperature with the cooling bath over 2 h. The reaction was quenched with 2N hydrochloric acid (3 ml) and partioned between ethyl acetate and brine. The organics were isolated, dried and concentrated. The crude product was chromatographed over silica (gradient elution dichloromethane to 5:1 dichloromethane/ethyl acetate) to afford the title compound as a white solid (0.35 g, 30%). m/z 305 [MH+]
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8](OC(N1C=CN=C1)=S)[C:9]([F:12])([F:11])[F:10].C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([F:10])([F:11])[F:12]
Reactant: FC(F)(F)C(OC(=S)n1ccnc1)c1ccccc1Br
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: FC(F)(F)Cc1ccccc1Br
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
A solution of imidazole-1-carbothioic acid O-[1-(2-bromophenyl)-2,2,2-trifluoroethyl]-ester (Preparation 56, 27.0 g, 73.8 mmol) in toluene (400 ml) was heated at reflux and treated with tri-n-butyltin hydride in three portions: 22 g (75.6 mmol) at first, an additional 10 g (34.4 mmol) after 30 min, and finally 11 g (37.8 mmol) 30 min later. After the addition, the mixture was heated at reflux for another 30 min. The reaction mixture was cooled then the product was distilled at 25 Pa, 60-100° C. to afford the title compound as a colourless oil (17.0 g, 59%).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][CH:5]([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:4][O:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH3:44][O:45][C:46]1[CH:51]=[CH:50][C:49](O)=[CH:48][CH:47]=1>O1CCCC1>[CH3:1][C:2]1([CH3:12])[O:6][CH:5]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:49]2[CH:50]=[CH:51][C:46]([O:45][CH3:44])=[CH:47][CH:48]=2)[CH2:4][O:3]1
Reactant: CC1(C)OCC(CCCCO)O1
Reactant: COc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(OCCCCC2COC(C)(C)O2)cc1

Procedure:
1.74 g (10 mmol) of 2,2-dimethyl-4-hydroxybutyl-1,3-dioxolane from Example 1a, 3.41 g (13 mmol) of triphenylphosphine, 2.26 g (13 mmol) of diethyl azodicarboxylate and 3.72 g (30 mmol) of 4-methoxyphenol were dissolved in 30 ml of absolute tetrahydrofuran (THF) and boiled under reflux for 1 h. The solvent was removed by distillation, and the residue was chromatographed on silica gel using ethyl acetate (EA)/n-heptane (1:4).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH2:6][C@H:5]([NH:14]C(=O)OC(C)(C)C)[C:4]1=[O:22])[CH3:2].[ClH:23]>O1CCOCC1>[ClH:23].[NH2:14][C@@H:5]1[C:4](=[O:22])[N:3]([CH2:1][CH3:2])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: CCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)COc2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: CCN1C(=O)[C@@H](N)COc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.286 g of 19 (0.934 mmol) is taken up in a 50 mL round-bottomed flask and 7 mL of dioxane and 7 mL of a solution of hydrochloric acid in dioxane (4M) are added. The medium is stirred overnight at RT under argon. After evaporation of the solvent, the residue is taken up in 1 mL of CH2Cl2 and 10 mL of isopropyl ether. The solid formed is drained and dried under vacuum. 185 mg of expected product 20 (white solid) are thus recovered.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1.C([O-])(=O)C.[Na+]>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[N+:24]([C:23]1[C:18]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][NH:13]2)=[N:19][CH:20]=[CH:21][CH:22]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1ccc2[nH]cc(C[C@H]3CCCN3)c2c1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: CC(=O)[O-]
Agent: [Na+]
Product: O=[N+]([O-])c1cccnc1Nc1ccc2[nH]cc(C[C@H]3CCCN3)c2c1
Temperature: 116 °C
Yield: 23 %

Procedure:
(R)-5-Amino-3-(pyrrolidin-2-ylmethyl)indole and 2-chloro-3-nitropyridine. Sodium acetate was used as base, acetic was used as solvent, and the reaction was heated at reflux (116° C.) for 2 hours. Column chromatography afforded the title compound (23%) as a dark red foam: 1H NMR (CDCl3) δ10.05 (br s, 1H), 9.23 (br s, 1H), 8.49 (dd, J=1.8 and 8.3 Hz, 1H), 8.39 (1.8 and 4.5 Hz, 1H), 7.70 (d, J=1.7 Hz, 1H) 7.33-7.22 (m, 2H), 6.98 (s, 1H), 6.73 (dd, J=4.5 and 8.3 Hz, 1H), 3.46-3.34 (m, 1H), 310-2.97 (m, 1H), 2.97-2.78 (m, 3H), 1.99-1.64 (m, 3H), 1.56-1.42 (m, 1H); 13C NMR (CDCl3) δ155.7, 151.5, 135.5, 134.5, 129.2, 128.1, 127.8, 123.8, 119.4, 114.3, 113.0, 111.6, 59.5, 45.7, 31.3, 30.6, 24.7; FAB LRMS (m/z, relative intensity) 338 (6,[MH+ ]), 309 (12), 155 (49), 135 (38), 119 (100). Anal. calcd. for C18H19N5O2. 0.67 C2H4O2 [acetic acid]: C, 61.53; H, 5.79; N, 18.56. Found: C, 61.57; H, 5.74; N, 18.82.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>CN(C=O)C>[O:5]=[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][NH:2][S:13]([CH3:12])(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: NCC(=O)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Product: CS(=O)(=O)NCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.5 %

Procedure:
To a solution of 2-amino-1-phenylethanonehydrochloride (1a) (1715 mg, 10 mmol) in DMF (20 mL) was added TEA (2.8 mL, 20 mmol). Upon cooling under ice-water bath, methylsulfonyl chloride (0.77 mL, 10 mmol) was added slowly and the reaction mixture stirred at RT for 12 h. The mixture was partitioned between dichloromethane and brine, dried over sodium sulfate and then concentrated in vacuo to give the title compound (2100 mg, 98%) as an off white solid. MS APCI, m/z=214 (M+1). LCMS: 1.19 min.