Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCCCCCCCCCCC.C(=O)(O)[O-:22].[Na+].OO>O.S([O-])([O-])(=O)=O.[Mn+2]>[CH2:1]1[O:22][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: O=C([O-])O
Agent: [Mn+2]
Agent: O=S(=O)([O-])[O-]
Agent: OO
Solvent: CCCCCCCCCCCC
Solvent: O
Product: c1ccc(C2CO2)cc1

Procedure:
To a mechanically stirred solution of styrene (1.0 mol), dodecane (0.1 mol) urea (20.8 mol), sodium bicarbonate (0.3 mol) and manganese sulphate (0.001 mol) in 500 ml of water at 20° C. is added 50% aqueous hydrogen peroxide (2.2 mol) drop-wise over a period of 5 h. After 5 h a separating funnel separated the organic layer of the reaction mixture. The aqueous layer was extracted with 4×20 mL diethyl ether. The combined organic layer was distilled to yield styrene oxide. The conversion to epoxide is 99% with selectivity 94%.
Reaction SMILES: [S:1]([Cl:5])(=[O:4])(=[O:3])O.C(Cl)Cl.[C:9]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(Cl)(Cl)Cl>[Cl-].[Na+].O>[C:9]1([C:15]2[CH:16]=[CH:17][C:18]([S:1]([Cl:5])(=[O:4])=[O:3])=[CH:19][CH:20]=2)[CH:14]=[CH:13][C:12]([S:1]([Cl:5])(=[O:4])=[O:3])=[CH:11][CH:10]=1
Reactant: c1ccc(-c2ccccc2)cc1
Reactant: O=S(=O)(O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc(-c2ccc(S(=O)(=O)Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Under the nitrogen gas atmosphere, chloro sulfuric acid is diluted by adding chloro sulfuric acid (21.184 mmol) into methylene chloride (40 ml), and biphenyl (6.168 g, 40.00 mmol) is added gradually into a container in which diluted chloro sulfuric acid is contained keeping the temperature at 0° C., then stirred at the room temperature for 6 hours. The obtained reacted mixture is poured into brine, and deposited white insoluble is removed by suction filtration. Since the small amount of product is possible to be remained, the residue is washed well by methylene chloride. Then the filtrate is extracted by methylene chloride (150 ml×3), and the separated organic phase is dried up using magnesium sulfate. Solvent is vaporized off under vacuum condition, and the obtained crude product is isolated by a column chromatography (φ=50 mm, h=100 mm×2; CH2Cl2), further refined by recrystallization (CHCl3) and 4,4′-biphenyldisulfonylchloride is obtained as a colorless crystal (8.201 g, 23.349 mmol, 58%) (compound A).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:16]=[C:15]3[CH:17]=[CH:18][N:19]([CH3:20])[C:14]3=[CH:13][C:12]=2[CH:21]2[CH2:26][CH2:25][CH:24]([NH:27]C(=O)OC(C)(C)C)[CH2:23][CH2:22]2)[CH3:10])[C:5]([C:35]#[N:36])=[C:4]([CH3:37])[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:16]=[C:15]3[CH:17]=[CH:18][N:19]([CH3:20])[C:14]3=[CH:13][C:12]=2[CH:21]2[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]2)[CH3:10])[C:5]([C:35]#[N:36])=[C:4]([CH3:37])[N:3]=1
Reactant: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2C2CCC(NC(=O)OC(C)(C)C)CC2)c1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2C2CCC(N)CC2)c1C#N
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 51.5 %

Procedure:
A scintillation vial was charged with (S)-tert-butyl (4-(5-(1-((2-amino-5-cyano-6-methylpyrimidin-4-yl)amino)ethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)cyclohexyl)carbamate (0.012 g, 0.024 mmol), DCM (1 mL), and TFA (0.916 mL, 11.89 mmol). The reaction mixture was stirred at room temperature for 45 minutes. The solvent was evaporated via a stream of nitrogen. The crude product was dissolved in a mixture of DMSO and MeOH (1:1) and was purified by preparative HPLC (basic mode, 25-50% ACN/H2O gradient). The product-containing fractions were dried in vacuo to give the title compound as a white solid (5 mg, 53%). 1H NMR (400 MHz, CD3OD) δ ppm 1.31 (br s, 1H), 1.55 (d, J=6.57 Hz, 5H), 1.62-1.82 (m, 2H), 1.85-2.04 (m, 7H), 2.05-2.26 (m, 2H), 2.36 (s, 3H), 2.94-3.12 (m, 2H), 3.84-3.89 (m, 3H), 5.77-5.97 (m, 1H), 6.57 (d, J=4.72 Hz, 1H), 7.46 (d, J=4.49 Hz, 1H), 7.94 (s, 1H), 7.78 (s, J=64.10 Hz, 1H); ESI-MS m/z [M+H]+ calc'd for C22H28N8, 405. found 405.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(C)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(C(C)O)cn1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 79.8 %

Procedure:
To a stirring solution of 1-(6-methyl-3-pyridinyl)ethanone (1.0 g, 7.4 mmol) in absolute ethanol (10 ml) at 0° C. was added sodium borohydride (0.14 g, 3.7 mmol) portionwise over 20 minutes. The reaction mixture was stirred at 0° C. for 1.5 hours before warming to room temperature. The mixture was partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate. The organic phase was dried over sodium sulphate, filtered, and evaporated in vacuo to give the crude product 1-(6-methyl-3-pyridinyl)ethanol (810 mg).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([N:21]([S:28]([C:31]4[CH:32]=[CH:33][CH:34]=[C:35]5[C:40]=4[N:39]=[CH:38][CH:37]=[CH:36]5)(=[O:30])=[O:29])[CH2:22][C:23]([O:25]CC)=[O:24])=[CH:17][C:15]=3[N:16]=2)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[OH-].[Na+]>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([N:21]([S:28]([C:31]4[CH:32]=[CH:33][CH:34]=[C:35]5[C:40]=4[N:39]=[CH:38][CH:37]=[CH:36]5)(=[O:29])=[O:30])[CH2:22][C:23]([OH:25])=[O:24])=[CH:17][C:15]=3[N:16]=2)=[CH:6][CH:5]=1)(=[NH:2])[NH2:3]
Reactant: CCOC(=O)CN(c1ccc2oc(CCc3ccc(C(=N)N)cc3)nc2c1)S(=O)(=O)c1cccc2cccnc12
Agent: [Na+]
Agent: [OH-]
Product: N=C(N)c1ccc(CCc2nc3cc(N(CC(=O)O)S(=O)(=O)c4cccc5cccnc45)ccc3o2)cc1

Procedure:
Prepared analogously to Example 3 from 2-[2-(4-amidinophenyl)-ethyl]-5-[N-(ethoxycarbonylmethyl)-quinoline-8-sulphonylamino]-benzoxazole and sodium hydroxide solution.
Reaction SMILES: C([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@@H:7]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=3)=[O:34])=[CH:27][CH:26]=2)[CH2:6]1)(=O)C.[OH-].[Na+].Cl>O1CCCC1CO>[SH:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[O:11])[C@H:7]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=3)=[O:34])=[CH:27][CH:26]=2)[CH2:6]1
Reactant: CC(=O)S[C@H]1C[C@H](CCc2ccc(CNC(=O)OCc3ccc([N+](=O)[O-])cc3)cc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: OCC1CCCO1
Product: O=C(NCc1ccc(CC[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h

Procedure:
To a solution of (2S,4S)-4-acetylthio-N-(p-nitrobenzyloxycarbonyl)-2-[4-[N-(p-nitrobenzyloxycarbonyl)aminomethyl]phenethyl]pyrrolidine (495 mg, 0.777 mmol) in tetrahydrofuran-methanol (2:1, 15 ml), 1N aqueous sodium hydroxide (1.5 ml, 1.5 mmol) was added in a nitrogen stream under cooling with ice. After this reaction solution was stirred at the same temperature for 2 hours, 1N aqueous hydrochloric acid (2.0 ml, 2.0 mmol) was added thereto, and this mixed solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo to give a crude product of (2R,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-[4-[N-(p-nitrobenzyloxycarbonyl)aminomethyl]phenethyl]-pyrrolidine.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].S(Cl)(Cl)=O.[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[C:21]1[S:22][CH:23]=[CH:24][CH:25]=1>O>[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[C:21]1[S:22][C:23]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:24][CH:25]=1
Reactant: Brc1ccc2ncnc(-c3cccs3)c2c1
Reactant: O=S(=O)(O)Cl
Solvent: O
Solvent: O=S(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(-c2ncnc3ccc(Br)cc23)s1
Temperature: 60 °C

Procedure:
0.18 mL chlorosulfonic acid and 0.19 mL thionyl chloride were added to 0.1 g of 6-bromo-4-(2-thienyl)quinazoline (compound in Production Example 96) under ice-cooling in a stream of nitrogen, and the mixture was heated for 13 hours at 60° C., then neutralized by adding water and a sodium bicarbonate solution and extracted with dichloromethane. 5-(6-Bromoquinazolin-4-yl)-thiophen-2-sulfonyl chloride obtained by drying the organic layer over anhydrous sodium sulfate was dissolved in 3 mL tetrahydrofuran, then 0.3 mL morpholine was added thereto, and the mixture was stirred at room temperature for 1 hour. The solvent was removed, and the positional isomers were separated and purified by silica gel column chromatography (ethyl acetate/hexane) to give 57 mg of the title compound (colorless crystals).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:14]([C@H:17]2[C@H:22]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@@H:21]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@H:20]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@@H:19]([CH2:47][O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[O:18]2)=[CH:13][C:3]=1[CH2:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.CC#N.[CH:59]1([NH2:62])[CH2:61][CH2:60]1.[BH3-]C#N.[Na+]>C(Cl)Cl.C(O)(=O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:14]([C@H:17]2[C@H:22]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@@H:21]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@H:20]([O:39][CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C@@H:19]([CH2:47][O:48][CH2:49][C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[O:18]2)=[CH:13][C:3]=1[CH2:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:62][CH:59]2[CH2:61][CH2:60]2)=[CH:7][CH:6]=1
Reactant: NC1CC1
Reactant: O=Cc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CC#N
Product: Clc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(CNC2CC2)cc1
Reaction time: 0.5 h

Procedure:
A solution of 4-(2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)benzaldehyde (intermediate AP) (40 mg) in CH2Cl2:CH3CN (v/v=1:1) (1.0 mL) was cooled to 0° C., followed by addition of cyclopropylamine (15 mg) and acetic acid (1 mg). After 30 min, NaBH3CN (17 mg) was added. The reaction was monitored by LC-MS. After the starting material was consumed, ethyl acetate (20 mL) and water (5 mL) were added to quench the reaction. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic extracts were combined and washed with brine. Removal of ethyl acetate under reduced pressure and purification of the crude product by preparative TLC gave intermediate AQ (30 mg). MS ESI (m/z): 794 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[N:13]=[CH:12][CH:11]=1>CCO>[Cl:20][C:16]1[CH:15]=[C:14]2[C:19]([C:10]([NH:1][C:2]3[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=3)=[CH:11][CH:12]=[N:13]2)=[CH:18][CH:17]=1
Reactant: Nc1cccc(O)c1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Solvent: CCO
Product: Oc1cccc(Nc2ccnc3cc(Cl)ccc23)c1
Yield: 180.2 %

Procedure:
3-aminophenol (5.00 g, 25.25 mmol) and 4,7-dichloroquinoline (2.76 g, 1 eq) were refluxed overnight in 5 mL of EtOH. The reaction mixture was then evaporated and purified by flash chromatography (DCM/MeOH/NH4OH 9:1:0.1) to yield expected compound as a pale yellow solid (6.8 g, 99% yield). LC-MS: m/z (ESI) 271.2 [M+H]+;
Reaction SMILES: [F:1][C:2]1([F:27])[CH2:4][CH:3]1[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:14][C:9]=2[N:8]([CH3:24])[S:7]1(=[O:26])=[O:25].Cl[C:29]1[CH:36]=[C:35]([OH:37])[CH:34]=[CH:33][C:30]=1[C:31]#[N:32].P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>O1CCOCC1.O.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1([F:27])[CH2:4][CH:3]1[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:29]3[CH:36]=[C:35]([OH:37])[CH:34]=[CH:33][C:30]=3[C:31]#[N:32])=[CH:14][C:9]=2[N:8]([CH3:24])[S:7]1(=[O:25])=[O:26]
Reactant: N#Cc1ccc(O)cc1Cl
Reactant: CN1c2cc(B3OC(C)(C)C(C)(C)O3)ccc2N(CC2CC2(F)F)S1(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CN1c2cc(-c3cc(O)ccc3C#N)ccc2N(CC2CC2(F)F)S1(=O)=O
Temperature: 100 °C

Procedure:
1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (12-1) (2.0 g, 5.0 mmol, 1 eq), 2-chloro-4-hydroxybenzonitrile (0.84 g, 5.5 mmol, 1.1 eq), tripotassium phosphate (2.1 g, 10.0 mmol, 2.0 eq), S-Phos (0.20 g, 0.5 mmol, 0.1 eq), and palladium(II) acetate (56 mg, 0.25 mmol, 0.05 eq) were combined in dioxane (20 mL) and water (3 mL). The resulting mixture was heated at 100° C. for 16 hours. The reaction mixture was allowed to cool to room temperature. The mixture was then diluted with EtOAc (100 mL), washed with water (20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified by flash chromatography (80 g SiO2, 0-80% EtOAc in hexanes) to afford 2-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl}-4-hydroxybenzonitrile (12-2) as a white solid. LRMS m/z (M+H) 392.3 found, 392.1 required.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.CC1(C)COB([C:16]2[CH:17]=[N:18][S:19][CH:20]=2)OC1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:16]2[CH:17]=[N:18][S:19][CH:20]=2)[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC1(C)COB(c2cnsc2)OC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Brc1cccc(-c2cnsc2)n1
Temperature: 25 °C
Yield: 76.9 %

Procedure:
A degassed solution of 2,6-dibromopyridine (0.86 g, 3.56 mmol) and 4-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)isothiazole (0.35 g, 1.78 mmol) in dry 1,4-dioxane (10 ml) was stirred under an atmosphere of nitrogen, then cesium carbonate (1.20 g, 3.68 mmol) and tetrakis(triphenylphosphine)-palladium(0) (0.10 g, 5 mol %) added. This mixture was heated to reflux for 18 h. After cooling to ambient temperature, solvent was removed in vacuo, the residue dissolved in dichloromethane, washed with water and saturated brine, then dried over magnesium sulfate, filtered and evaporated in vacuo to give a solid. Purification by chromatography on silica gel, eluting with dichloromethane on a gradient of methanol (0-5%), gave 2-bromo-6-(isothiazol-4-yl)pyridine (0.33 g) as a white solid: δH (400 MHz, CDCl3) 7.42 (1H, dd, J 7 and 2), 7.60 (2H, m), 9.01 (1H, s), 9.16 (1H, s); m/z (ES+) 240/242 (M++H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:20][C:21]4[N:26]([CH2:27][CH2:28][C:29]#[N:30])[C:25](=[O:31])[CH2:24][O:23][C:22]=4[N:32]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C>C(O)(C(F)(F)F)=O>[NH2:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:20][C:21]4[N:26]([CH2:27][CH2:28][C:29]#[N:30])[C:25](=[O:31])[CH2:24][O:23][C:22]=4[N:32]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CCC#N)C(=O)CO4)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Product: N#CCCN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Reaction time: 0.01 h
Yield: 97.5 %

Procedure:
tert-butyl(1-(4-(1-(2-cyanoethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (15 mg, 0.029 mmol) was dissolved in TFA (0.5 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (1 mL) and concentrated to dryness under reduced pressure three times. The residue was then slurried in diethyl ether (0.5 mL) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and dried to give the desired product as an off-white solid (12 mg). 1H NMR (500 MHz, CH3OD) 7.77 (1H, s), 7.43 (2H, d), 7.39 (2H, d), 7.3 (3H, m), 7.27 (2H, m), 4.99 (2H, s), 4.37 (2H, t), 2.94 (2H, t), 2.73-2.79 (2H, m), 2.55-2.61 (2H, m), 2.2-2.27 (1H, m), 1.93-1.99 (1H, m). LCMS (Method A): RT=3.73 min, M+H+=425.
Reaction SMILES: [CH2:1]([O:8]C1C=C(C=CC=1OCCC)C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH2:32][CH3:33])[CH2:25][OH:26].C(Cl)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[K+]>C(O)C.O>[CH2:1]([O:8][C:23]1[CH:22]=[C:29]([O:30][CH2:31][CH2:32][CH3:33])[CH:28]=[CH:27][C:24]=1[CH:25]=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCOc1ccc(C=O)cc1OCc1ccccc1
Reactant: CCCOc1ccc(CO)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCc1ccccc1
Solvent: CCO
Product: CCCOc1ccc(C=O)c(OCc2ccccc2)c1

Procedure:
2,4,6-tribenzyloxyacetophenone is obtained by the common procedure of reacting 2,4,6-trihydroxyacetophenone with excess benzyl chloride and excess potassium carbonate in dimethylformamide and giving the reaction mixture an aqueous work up. 3-benzyloxy-4-n-propoxybenzaldehyde is similarly prepared from 3-hydroxy-4-n-propoxybenzyl alcohol, excess benzyl chloride and excess potassium carbonate. A warm solution of 2.19 g of the 2,4,6-tribenzyloxyacetophenone and 1.35 g of the benzyloxy-4-n-propoxybenzaldehyde is prepared in 10 ml of absolute ethanol. 15 Milliliters of warm aqueous 60% potassium hydroxide is added all at once. The mixture is stirred and a yellow solid product is formed. 16 Milliliters of absolute ethanol is added and the mixture is added to 300 ml of water and extracted three times with ethyl acetate. The extracts are dried and concentrated to yield 3.2 g of a solid, which is recrystallized to yield 2.6 g (75% yield) of 2,4,6,3'-tetrabenzyloxy-4'-n-propoxychalcone. ##SPC5## 1.38 Grams of this material is dissolved in about 50 ml of ethyl acetate and 200 mg of 5% palladium on charcoal is added. The reaction flask is flushed with hydrogen and then the mixture is stirred under hydrogen at room temperature for about 35 hours. The product is checked by thin layer chromatography and observed to contain essentially a single product. The reaction mixture is filtered and concentrated to yield 0.66 g of a colorless oil, which by NMR is determined to be 2,4,6,3'-tetrahydroxy-4'-n-propoxy dihydrochalcone, ##SPC6##
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH3:25])[C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=4)=[O:17])[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[O:26]=[C:27]1[NH:31][C@H:30]([CH2:32][O:33][C:34](=[O:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:29][O:28]1>>[C:34]([O:33][CH2:32][C@@H:30]1[CH2:29][O:28][C:27](=[O:26])[N:31]1[C:21]1[CH:22]=[CH:23][C:18]([C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:7]3[C:6]([CH3:25])=[CH:5][C:4]([CH:1]4[CH2:3][CH2:2]4)=[CH:9][N:8]=3)[CH2:11][CH2:12]2)=[O:17])=[CH:19][CH:20]=1)(=[O:41])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(I)cc2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3COC(=O)c3ccccc3)cc2)CC1
Yield: 91.1 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 91 and using [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (2.08 g) described in Preparation Example 97 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (1.06 g), the title compound (2.29 g) was obtained.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[CH:7]=[CH:8][C:9](O)=[O:10])[CH:2]=[CH2:3].S(Cl)(Cl)=O.[N-:23]=[N+:24]=[N-:25].[Na+]>C1C=CC=CC=1>[CH2:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[CH:7]=[CH:8][C:9]([N:23]=[N+:24]=[N-:25])=[O:10])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(C=CC(=O)O)ccc1OC(C)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: C=CCc1cc(C=CC(=O)N=[N+]=[N-])ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
22.2 g (0.09 mol) of 3-allyl-4-acetoxy-cinnamic acid are suspended in 100 ml of benzene and 13.2 ml (0.18 mol) of thionyl chloride are added. The reaction mixture is heated to the boil for half an hour under a reflux condenser and thereafter the solvent and excess thionyl chloride are removed by distillation under reduced pressure. The residual crude 3-allyl-4-acetoxy-cinnamic acid chloride is dissolved in 100 ml of absolute 1,2-dimethoxyethane, 17.5 g (0.27 mol) of sodium azide are added and the mixture is subsequently stirred for 48 hours at room temperature. The inorganic salts are then filtered off and the filtrate is concentrated under reduced pressure at 30°C. Hereupon, colourless crystals separate out. The crystallisation is completed by adding ether. 3-Allyl-4-acetoxy-cinnamic acid azide of melting point 87°-89°C (decomposition) is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:18][C:19]1[C:24]([C:25](Cl)=[O:26])=[C:23]([Cl:28])[N:22]=[CH:21][N:20]=1>O1CCCC1.ClCCl>[Cl:18][C:19]1[C:24]([C:25]([O:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:26])=[C:23]([Cl:28])[N:22]=[CH:21][N:20]=1
Reactant: COc1ccc(CO)cc1
Reactant: O=C(Cl)c1c(Cl)ncnc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(COC(=O)c2c(Cl)ncnc2Cl)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.6 %

Procedure:
(4-Methoxyphenyl)methanol (356 mg, 2.58 mmol) was dissolved in tetrahydrofuran (10 ml) and triethylamine (790 μl, 5.67 mmol) was added. Then a solution of 4,6-dichloropyrimidine-5-carbonyl chloride (600 mg, 2.84 mmol, prepared according to E. V. Tarasov et al. Synlett 2000, 5, 625-626) in tetrahydrofuran (4 ml) was dropwise added. The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was then diluted with dichloromethane, washed with 4% sodium bicarbonate solution, dried over magnesium sulphate, filtered and evaporated to give 732 mg (81% yield) of the title compound, that was used in the next step without further purification. Purity 84%.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:22]1[N:23]=[C:24]([NH2:40])[C:25]2[N:26]=[CH:27][N:28]([C:38]=2[N:39]=1)[C@@H:29]1[O:37][C@H:34]([CH2:35][OH:36])[C@@H:32]([OH:33])[C@H:30]1[OH:31]>>[F:20][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[F:19])[O:12][C:10]([N:7]1[CH2:6][CH2:5][CH:4]([CH2:1][C:2]#[C:3][C:22]2[N:23]=[C:24]([NH2:40])[C:25]3[N:26]=[CH:27][N:28]([C:38]=3[N:39]=2)[C@@H:29]2[O:37][C@H:34]([CH2:35][OH:36])[C@@H:32]([OH:33])[C@H:30]2[OH:31])[CH2:9][CH2:8]1)=[O:11]
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C#CCC1CCN(C(=O)Oc2ccc(F)c(F)c2)CC1
Product: Nc1nc(C#CCC2CCN(C(=O)Oc3ccc(F)c(F)c3)CC2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
3,4-Difluorophenyl 4-(prop-2-ynyl)piperidine-1-carboxylate (1.830 g, 6.55 mmol) was added to a solution of 2-iodoadenosine (0.611 g, 1.554 mmol) according to general procedure 2: yield 201 mg, 24%. 1H NMR (CD3OD) δ 8.30 (s, 1H), 7.25 (m, 1H), 7.12 (m, 1H), 6.96-6.89 (m, 1H), 5.93 (d, 1H, J=6.5 Hz), 4.71 (dd, 1H, J=5.1 Hz, J=6.4 Hz), 4.35-4.24 (m, 2H), 4.23-4.13 (m, 2H), 3.89 (dd, 1H, J=2.3 Hz, J=12.6 Hz), 3.74 (dd, 1H, J=2.5, J=12.6 Hz), 3.05, 2.91 (2×br t, 2H), 2.46 (d, 2H, J=6.2 Hz), 2.01-1.79, 1.52-1.27 (2×m, 5H). LRMS ESI (M+H+) 545.2. HPLC rt=9.1 min.