Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:12])=O>>[Cl:12][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1cc(O)ncn1
Product: CCc1cc(Cl)ncn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
12.4 g (0.10 mol) of 4-hydroxy-6-ethylpyrimidine, prepared according to EP 326 389, are introduced into 25 ml of phosphorus oxychloride, the temperature rising spontaneously to 70° C. A clear solution is formed, which is kept at 70° C. for a further 2 hours and, after cooling, is stirred into ice-water. Extraction with ether yields 12.0 g of liquid crude product which is distilled in a bulb tube at 105° C. under a pressure of 26 mbar to give 11.0 g of pure substance. Analysis: C6H7ClN2 (M=142.59).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7](O)=[O:8])(=O)[CH3:2].[NH2:14][N:15]1[C:27](=[O:28])[C:25]2[C:26]3[N:18]([C:19]([O:29][CH3:30])=[CH:20][C:21]=3[CH2:22][CH2:23][CH:24]=2)[C:17]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:16]1.P(Cl)(Cl)Cl.[P].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:30][O:29][C:19]1[N:18]2[C:17]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:16][N:15]([N:14]3[C:7](=[O:8])[C:6]4[C:5](=[CH:13][CH:12]=[CH:11][CH:10]=4)[N:4]=[C:1]3[CH3:2])[C:27](=[O:28])[C:25]3=[CH:24][CH2:23][CH2:22][C:21]([CH:20]=1)=[C:26]23
Reactant: CC(=O)Nc1ccccc1C(=O)O
Reactant: COc1cc2c3n1C(c1ccccc1)=CN(N)C(=O)C3=CCC2
Agent: O=C([O-])O
Agent: [Na+]
Agent: [P]
Solvent: ClCCl
Solvent: ClP(Cl)Cl
Product: COc1cc2c3n1C(c1ccccc1)=CN(n1c(C)nc4ccccc4c1=O)C(=O)C3=CCC2
Temperature: 25 °C
Yield: 17.3 %

Procedure:
0.834 g (4.65 mmol) of acetylanthranilic acid and 1.3 g (4.23 mmol) of 3-amino-9-methoxy-1-phenyl-6,7-dihydro-3H-[1,4]diazepino[6,7,1-hi]indol-4-one are dissolved in 13 ml of CH2Cl2, the mixture is stirred at room temperature and 0.7 g (5 mmol) of phosphorus trichloride is added. The mixture is stirred for 20 h and 0.35 g of phosphorus trichlonrde is added, followed by a fuirther 0.35 g 8 h later. The mixture is cooled, 50 ml of saturated NaHCO3 solution and 100 ml of CH2Cl2 are added and the organic phase is separated out after settling has taken place and washed with water. This solution is dried, evaporated and purified by chromatography in the mixture DM1. 0.33 g of yellow powder is obtained. M.p.=277° C.—Yld 17%.—TLC (DM3): Rf=0.47.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]#[N:12])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.[CH3:22][NH:23][C:24]([CH3:27])([CH3:26])[CH3:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[C:24]([N:23]([CH3:22])[C:8]([C:5]1[C:4]([C:11]#[N:12])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[O:10])([CH3:27])([CH3:26])[CH3:25]
Reactant: CNC(C)(C)C
Reactant: N#Cc1cc(Br)cnc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ncc(Br)cc1C#N)C(C)(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 65.2 %

Procedure:
To a solution of 5-bromo-3-cyano-pyridine-2-carboxylic acid (100 mg, 0.44 mmol) in dichloromethane (5 ml) at 0° C. were added DIPEA (0.226 ml, 1.32 mmol, 3 equiv.), methyl tert-butyl amine (0.079 ml, 0.661 mmol, 1.5 equiv.) and HBTU (250 mg, 0.661 mmol, 1.5 equiv.). The reaction mixture was stirred at 25° C. for 14 hours. The solvent was removed in vacuum and the resulting crude material was purified by column chromatography over normal silica gel (10-20% EtOAc in hexane) to afford 5-bromo-3-cyano-pyridine-2-carboxylic acid tert-butyl-methyl-amide (85 mg, 65%) as colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7](O)=O.Cl.CN(C)CCCN=C=NCC.N1C=CC=CC=1.[F:28][C:29]([F:64])([F:63])[C:30]([N:32]1[CH2:36][CH2:35][CH2:34][CH:33]1[C:37]1[C:51]([O:52][C:53]2[CH:58]=[CH:57][C:56]([S:59]([CH3:62])(=[O:61])=[O:60])=[CH:55][CH:54]=2)=[CH:50][C:40]2[N:41]=C(C3C=CC=CN=3)[NH:43][C:39]=2[CH:38]=1)=[O:31]>C(OCC)(=O)C>[F:64][C:29]([F:28])([F:63])[C:30]([N:32]1[CH2:36][CH2:35][CH2:34][CH:33]1[C:37]1[C:51]([O:52][C:53]2[CH:58]=[CH:57][C:56]([S:59]([CH3:62])(=[O:61])=[O:60])=[CH:55][CH:54]=2)=[CH:50][C:40]2[N:41]=[C:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)[NH:43][C:39]=2[CH:38]=1)=[O:31]
Reactant: O=C(O)c1cnccn1
Reactant: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2C(=O)C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4cnccn4)[nH]c3cc2C2CCCN2C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
14.5 mg of pyrazine-2-carboxylic acid and 27.0 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride were added in order to a pyridine (1 ml) solution of 53 mg of 1-(2-(4,5-diamino-2-(4-methanesulfonyl-phenoxy)-phenyl)-pyrrolidin-1-yl)-2,2,2-trifluoro-ethanone obtained in Example 162 (step 6), and the reaction liquid was stirred at room temperature for 3 hours. The reaction liquid was diluted with saturated saline, and extracted with ethyl acetate. The organic layers were combined, washed with aqueous saturated ammonium chloride and aqueous saturated sodium bicarbonate in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was dissolved in 1 ml of toluene. 9.9 mg of p-toluenesulfonic acid monohydrate was added to it, and the reaction liquid was stirred at 120° C. for 6 hours. After cooled, the reaction liquid was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=9/1) to obtain the entitled compound as an oily substance.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:32]=[CH:31][C:6]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]2[CH2:15][C:16]([C:29]#[N:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-:34].[K+].[K+]>S(=O)(=O)(O)O>[C:29]([C:16]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:15][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][N:9]1[CH2:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([Cl:2])=[CH:32][CH:31]=1)(=[O:34])[NH2:30]
Reactant: N#CC(CC1CCCCN1CCc1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: Br
Agent: O=S(=O)(O)O
Agent: [K+]
Product: NC(=O)C(CC1CCCCN1CCc1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Yield: 65 %

Procedure:
A solution of 1-(4-chlorophenethyl)-2-(2-cyano-2,2-diphenylethyl)piperidine hydrobromide (Example 26) (122 mg, 0.24 mmol) in 90% sulphuric acid (2 ml) was stirred at 90° C. for 1.5 hours, diluted with ice, basified with excess solid potassium carbonate and extracted into dichloromethane. The combined dichloromethane extracts were dried over sodium sulphate and evaporated. The residue was purified by chromatography on silica using dichloromethane plus 0-5% methanol as eluant. Appropriate fractions were combined and evaporated to give the title compound (70 mg, 65%) as a colourless foam which was characterised as a dihydrate.
Reaction SMILES: P(Br)(Br)([Br:3])=O.[Br:6][C:7]1[N:8]=[CH:9][C:10]2[N:16]=[C:15](O)[CH:14]=[CH:13][C:11]=2[N:12]=1>CN(C)C=O>[Br:6][C:7]1[N:8]=[CH:9][C:10]2[N:16]=[C:15]([Br:3])[CH:14]=[CH:13][C:11]=2[N:12]=1
Reactant: Oc1ccc2nc(Br)ncc2n1
Reactant: O=P(Br)(Br)Br
Solvent: CN(C)C=O
Product: Brc1ccc2nc(Br)ncc2n1
Temperature: 90 °C
Reaction time: 0.02 h

Procedure:
A roundbottom flask was charged with N,N-dimethylformamide (4.2 L). Phosphorus oxybromide (646.9 g, 2.26 mol, 2.30 equiv) was added followed by dropwise addition of 2-bromopyrido-[3,2-d]-pyrimidin-6-ol (170 g, 752.1 mmol). The resulting solution was allowed to react, with stirring, for 1 minute while the temperature was maintained at 90° C. The reaction mixture was then quenched by the addition of 10 L of water/ice. The resulting solution was extracted once with ethyl acetate. The organic layer was washed with aqueous NaHSO4 and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified via silica gel chromatography eluting with dichloromethane to afford the title compound.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([O:16][CH3:17])[CH:8]=1.[N+:18]([O-])([O-:20])=[O:19].[K+]>>[F:6][C:7]1[C:12]([N+:18]([O-:20])=[O:19])=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([O:16][CH3:17])[CH:8]=1
Reactant: COc1cc(F)ccc1C(C)=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COc1cc(F)c([N+](=O)[O-])cc1C(C)=O
Temperature: 0 °C
Yield: 92.8 %

Procedure:
In nitrogen atmosphere, conc. sulfuric acid 36 mL was added to 1-(4-fluoro-2-methoxyphenyl)ethanone 5.50 g, followed by heating to homogeneity. Cooling the same with salt-ice, potassium nitrate 3.47 g was added little by little, followed by an hour's stirring. The reaction liquid was poured in ice water, and the precipitated crystals were recovered by filtration and washed with water. Drying the crystals, 6.47 g of the title compound was obtained.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH2:8][C:7]1=[O:12])C.O.[NH2:15][NH2:16].O>C(O)C>[O:12]=[C:7]1[N:6]([CH2:5][C:4]([NH:15][NH2:16])=[O:3])[CH2:11][CH2:10][O:9][CH2:8]1
Reactant: CCOC(=O)CN1CCOCC1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)CN1CCOCC1=O
Temperature: 80 °C

Procedure:
Ethyl-2-(3-oxomorpholino)acetate (600 mg, 3.21 mmol) was dissolved in ethanol (3 mL) and hydrazine hydrate (160.46 mg, 3.21 mmol) was added at room temperature. The reaction mixture was heated at 80° C. for 1 h. The reaction mixture was transferred into 50 mL water and extracted with EtOAc (3×50 mL) The combined organic layers was washed with brine, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to give the crude product, which was used without further purification in the subsequent step (Crude yield: 54%). LCMS m/z 174.05 [M+H]+ tR 2.489 min.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([F:39])([F:38])([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[O:24][CH:25]=1.Cl>CN(C)C=O.O>[F:37][S:34]([F:35])([F:36])([F:38])([F:39])[C:31]1[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][C:7]4[N:6]=[N:5][NH:4][N:3]=4)=[CH:17][CH:16]=3)[N:22]=2)=[CH:29][CH:30]=1
Reactant: Oc1ccc(CCCCc2nnn[nH]2)cc1
Reactant: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FS(F)(F)(F)(F)c1ccc(/C=C/c2nc(COc3ccc(CCCCc4nn[nH]n4)cc3)co2)cc1
Reaction time: 0.25 h
Yield: 21.9 %

Procedure:
46.3 mg (1.84 mmol) 95% sodium hydride were given at 0° C. to a solution of 200 mg (0.916 mmol) 4-(4-tetrazol-5-yl-butyl)-phenol in 5.0 ml N,N-dimethylformamide and stirred for 15 min. 317 mg (0.916 mmol) 4-chloromethyl-2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazole were added and stirring continued at 25° C. for 2 h. The reaction mixture was neutralized with HCl, poured into water and the resulting precipitate was purified by HPLC-MS, treated with diethyl ether, filtered and dried to yield 106 mg (22%) of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][N:18]=[C:17]3[NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=3)=[C:27]([CH3:39])[CH:26]=2)[N:13]=1)(C)(C)C.Cl.C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.O>[NH2:7][CH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][N:18]=[C:17]3[NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=3)=[C:27]([CH3:39])[CH:26]=2)[N:13]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(-c5csc(CNC(=O)OC(C)(C)C)n5)cc34)cc2C)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(-c5csc(CN)n5)cc34)cc2C)cn1
Yield: 67.9 %

Procedure:
(4-{4-[3-Methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]quinazolin-6-yl}-thiazol-2-ylmethyl)-carbamic acid ter-butyl ester (81 mg, 0.14 mmol) is treated with concentrated aqueous hydrochloric acid (0.5 ml) in EtOAc (6 ml). Reaction progress is followed by LC/MS. Upon reaction completion saturated aqueous potassium carbonate solution is added, the reaction mixture is diluted with water and thoroughly extracted with DCM and EtOAc. The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure to yield 45 mg (0.095 mmol, 68%) of clean desired product.
Reaction SMILES: [CH2:1]([C@@H:4]1[C@@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:7][C:6]([CH3:16])([CH3:15])[N:5]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH:2]=C.I([O-])(=O)(=O)=[O:28].[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[CH3:16][C:6]1([CH3:15])[N:5]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[C@H:4]([CH2:1][CH:2]=[O:28])[C@@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:7]1
Reactant: C=CC[C@@H]1[C@@H](c2ccccc2)OC(C)(C)N1C(=O)OCc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)O[C@H](c2ccccc2)[C@@H](CC=O)N1C(=O)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
To the crude (4R,5R)-benzyl 4-allyl-2,2-dimethyl-5-phenyloxazolidine-3-carboxylate (1.29 g, 3.66 mmol) in THF (50 mL) and water (20 mL) was added osmium tetroxide (0.45 ml, 0.0180 mmol, 4%) solution. The reaction was stirred for 10 min, after which sodium periodate (3.91 g, 18.3 mmol) was added portion wise over 1 hr. Stirring was continued for 2 h. Saturated aqueous Na2S2O3 was added and the reaction was stirred for 15 min. The volatiles were removed in vacuo and the aqueous residue extracted with Et2O (3×50 mL). The combined ether layers were washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated. The crude residue was evaporated onto silica gel and purified via flash chromatography (0% to 20%; EtOAc in hexanes) to afford (4R,5R)-benzyl 2,2-dimethyl-4-(2-oxoethyl)-5-phenyloxazolidine-3-carboxylate. MS m/z=354 [M+1]+. Calc'd for C21H23NO4: 353.
Reaction SMILES: S(Cl)(Cl)=O.[O:5]=[C:6]1[NH:11][C@H:10]([C:12]([OH:14])=[O:13])[CH2:9][CH2:8][CH2:7]1.[CH2:15](O)[CH3:16]>>[CH2:15]([O:13][C:12]([C@@H:10]1[CH2:9][CH2:8][CH2:7][C:6](=[O:5])[NH:11]1)=[O:14])[CH3:16]
Reactant: CCO
Reactant: O=C1CCC[C@@H](C(=O)O)N1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@@H]1CCCC(=O)N1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Absolute ethanol (300 mL) was cooled at −5° C. then thionyl chloride (14.01 mL, 192.1 mmol) was added keeping the temperature below 0° C., followed by portionwise addiction of (S)-6-oxopiperidine-2-carboxylic acid (25.0 g, 174.6 mmol). The mixture was stirred at room temperature for 6 hours. The solvent was evaporated, then toluene (300 mL) and Et3N (48.7 mL) were added. After 0.5 hour the precipitate was filtered and washed with toluene and Et2O. The filtrate was evaporated and the residue treated with Et2O. The precipitate was eliminated and the solution was concentrated to give the title compound as yellow oil. Yield (29.9 g, 100%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([CH3:13])[C@H:10]([C:14]([OH:16])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:29]1([NH2:32])[CH2:31][CH2:30]1>ClCCl>[CH2:1]([N:8]1[CH2:12][C@@H:11]([CH3:13])[C@H:10]([C:14]([NH:32][CH:29]2[CH2:31][CH2:30]2)=[O:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CN(Cc2ccccc2)C[C@H]1C(=O)O
Reactant: NC1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccccc2)C[C@H]1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
trans-1-Benzyl-4-methyl-3-pyrrolidine carboxylic acid (4.04 g) was dissolved in dichloromethane (50 mL). To this solution, 1,1′-carbonyl bis-1H-imidazole (3.58 g) was added and the mixture was stirred at room temperature for 1 hour. While the mixture was chilled in an ice bath, cyclopropylamine (1.53 mL) in dichloromethane (15 mL) was added drop wise and the mixture was stirred at room temperature for 3 hours. Subsequently, the reaction mixture was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from a hexane/diisopropyl ether mixture, and the crystals were filtered, washed with a hexane/diisopropyl ether mixture, and dried under reduced pressure to give trans-1-benzyl-N-cyclopropyl-4-methyl-3-pyrrolidine carboxamide as white crystals (4.07 g).
Reaction SMILES: [C:1]([C:3]1[C:4](=O)[NH:5][C:6]([CH3:15])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1)#[N:2].C1(P(Cl)([Cl:25])=O)C=CC=CC=1>>[Cl:25][C:4]1[C:3]([C:1]#[N:2])=[CH:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([CH3:15])[N:5]=1
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: Cc1[nH]c(=O)c(C#N)cc1-c1ccccc1
Product: Cc1nc(Cl)c(C#N)cc1-c1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
A mixture of 100.34 g 3-cyano-6-methyl-5-phenyl-1H-pyridin-2-one [Walker and Weaver, J. Org. Chem. 26, 4441 (1961)]and 192 ml phenylphosphonic dichloride (C6H5POCl2) was warmed to 160-170° C. and kept at that temperature for about 16 hours. The reaction mixture was cooled and poured into ice water. The solid product was collected, dried in a vacuum oven and extracted with ether. The ether solution was concentrated, and the residue was washed with hexane and extracted with 300 ml 15% aqueous potassium bicarbonate. The resulting solid was dried in a vacuum oven to give 92.71 g (85%) 2-chloro-3-cyano-6-methyl-5-phenylpyridine, m.p. 134-135° C.
Reaction SMILES: [P:1]([O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[C:26]3[N:25]=[C:23]([NH2:24])[NH:22][C:20](=[O:21])[C:19]=3[N:18]=[CH:17]2)[C@H:13]([OH:27])[C@@H:12]1[OH:28])([O:4]P(O)(O)=O)(=[O:3])[OH:2].[CH3:29]OP(OC)(OC)=O.P(Cl)(Cl)(Cl)=O>C(OCC)C>[P:1]([O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[C:26]3[N:25]=[C:23]([NH2:24])[NH:22][C:20](=[O:21])[C:19]=3[N:18]=[CH:17]2)[C@H:13]([OH:27])[C@@H:12]1[O:28][CH3:29])([OH:4])([OH:2])=[O:3]
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: COP(=O)(OC)OC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: CO[C@H]1[C@@H](O)[C@H](n2cnc3c(=O)[nH]c(N)nc32)O[C@@H]1COP(=O)(O)O

Procedure:
In a clean, dry 500 mL round bottom flask equipped with a stirring bar and under a stream of argon slowly add dry and finely powdered 3′-O-Me-Guanosine (1), (6 g, 20 mmol) to a mixture of trimethylphosphate ((OMe)3P) (50 mL) and phosphorous oxychloride (POCl3) (6 mL, 60 mmol) at 0° C. in small portions with continuous stirring under argon. The mixture was kept at 0-4° C. and allowed to stir at least 19 hrs. Diethyl ether (200 mL) was added to extract the excess phosphorous oxychloride and to simultaneously precipitate the 3′-O-methylguanosine-5′-phosphodichloridate, which was then pelleted by centrifugation and dissolved in 100 mL ice-cold 5% NaHCO3 in water. The resulting aqueous solution was adjusted to pH ˜1.5 using 1 N NaOH. After stirring at 0-4° C. for an additional 20 h, the pH was adjusted to 7.0 and the resulting mixture was applied to a column of DEAE Sephadex A25. The column was washed with 5 mM TEAB buffer, pH 7.5 and then eluted with freshly prepared 1M Triethylammonium bicarbonate (TEAB) buffer, pH 7.5. Fractions containing the 3′-O-Me GMP TEA salt (2) were pooled, concentrated to dryness.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].[F:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)CCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[C:2]1[C:3]([OH:9])=[CH:4][C:5]([OH:6])=[CH:7][CH:8]=1
Reactant: Oc1ccc(Br)c(O)c1
Reactant: COc1ccc(F)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Product: COc1ccc(F)c(-c2ccc(O)cc2O)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
Under a nitrogen atmosphere, to a solution of 4-bromoresorcinol (10.1 g) in 1-butanol (200 mL) were added 2-fluoro-5-methoxyphenylboronic acid (10.8 g), tetrakis(triphenylphosphine)palladium(0) (3.00 g) and 2.0 M aqueous sodium carbonate solution (54 mL), and the mixture was stirred at 90° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (10.6 g) as a pale-yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:25][C:26]([OH:30])([C:28]#[CH:29])[CH3:27].C(NC(C)C)(C)C>C1COCC1.[Cu]I.[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>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:29]#[C:28][C:26]([OH:30])([CH3:27])[CH3:25])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCCCCCCCOc1ccc(-c2ccc(C#CC(C)(C)O)cc2)cc1

Procedure:
A stirred mixture of compound 68 (15.00 g, 0.039 mol), 2-methylbut-3-yn-2-ol (7.15 g, 0.085 mol), copper(I) iodide (0.34 g, 1.80 mmol), tetrakis (triphenylphosphine) palladium(0) (2.89 g, 2.50 mmol) and diisopropylamine (150 ml) was heated under reflux in a dry nitrogen atmosphere for 24 h. The resultant mass was dissolved in THF and filtered over hyflo filter aid to remove inorganic materials. Volatile materials were removed in vacuo and the brown solid was recrystallised from ethanol to give a white, fluffy solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:23][NH:24][O:25][CH3:26].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:26][O:25][N:24]([CH3:23])[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:9]
Reactant: CNOC
Reactant: O=C(O)c1ccccn1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Picolinic acid (12.3 g, 100 mmol), N,N-carbonyldiimidazole (17.8 g, 110 mmol) and anhydrous CH2Cl2 (150 mL) were combined and stirred at room temperature for 60 minutes. To the reaction mixture was added a solution of N,O-dimethylhydroxylamine hydrochloride (10.7 gr, 0.11 mole), anhydrous CH2Cl2 (50 mL) and diisopropylethylamine (20 mL), and stirring continued overnight. The reaction mixture was concentrated in vacuo and purified by flash chromatography (silica gel 60, MeOH/CH2Cl2, 9:1) to afford pyridine-2-carboxylic acid methoxy-methyl-amide (a pale yellow liquid, 15.9 g, 95%); ESI) m/z 167.