Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:5]=[C:6]([C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[CH:10][C:9]2=[O:20])[CH3:3].[F:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[C:31]([F:34])[C:32]=1[F:33].ClC(Cl)C.N1C=CC=CC=1>C(Cl)Cl.O.C(O[Cu]OC(=O)C)(=O)C>[CH3:25][N:23]([CH3:24])[C:21]([C:6]1[CH:7]=[C:8]2[C:13](=[C:4]([CH:2]([NH:1][C:29]3[CH:28]=[C:27]([F:26])[C:32]([F:33])=[C:31]([F:34])[CH:30]=3)[CH3:3])[CH:5]=1)[O:12][C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[CH:10][C:9]2=[O:20])=[O:22]
Reactant: CC(N)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Agent: CC(=O)O[Cu]OC(C)=O
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CC(Nc1cc(F)c(F)c(F)c1)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
8-(1-aminoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (232 mg, 0.67 mmol, [α]D20°: +35° in acetonitrile), 3,4,5-trifluorophenylboronic acid (236 mg, 1.34 mmol), diacetoxycopper hydrate (148 mg, 0.74 mmol) and molecular sieves 4A (1 g) were weighed out in a flask. Dichloroethane (4 mL) then pyridine (0.109 mL, 1.34 mmol) were added and the resulting mixture was stirred at RT for 2 days under an oxygen atmosphere. The mixture was diluted with DCM, filtered through a pad of celite, the filtrate was washed with a 0.5N NaOH aq. sol. and the aqueous phase extracted with DCM. The combined organics were dried over magnesium sulphate and concentrated down. The crude product was purified by flash chromatography on silica gel eluting with 0 to 10% MeOH in ethyl acetate/DCM (1:1). The solvent was evaporated to dryness to afford N,N-dimethyl-2-morpholino-4-oxo-8-(1-(3,4,5-trifluorophenylamino)ethyl)-4H-chromene-6-carboxamide single enantiomer (100 mg, 31%) as a white foam. Mass Spectrum: M+H 476. [α]D20°: −108° in MeCN. NMR Spectrum (CDCl3): 1.56 (d, 3H), 2.91 (s, 3H), 3.09 (s, 3H), 3.47-3.56 (m, 4H), 3.82-3.90 (m, 4H), 4.35 (d, 1H), 4.79-4.88 (m, 1H), 5.56 (s, 1H), 6.03 (dd, 2H), 7.70 (d, 1H), 8.12 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][C:15]([O:17][CH2:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[O:20])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[F:61][C:62]1[CH:67]=[CH:66][C:65]([C:68]2[S:72][C:71]([CH3:73])=[N:70][C:69]=2[C:74](O)=[O:75])=[CH:64][CH:63]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:74]([C:69]2[N:70]=[C:71]([CH3:73])[S:72][C:68]=2[C:65]2[CH:66]=[CH:67][C:62]([F:61])=[CH:63][CH:64]=2)=[O:75])[CH:10]([CH2:14][C:15]([O:17][CH2:18][C:19]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)=[O:20])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNC(CC(=O)OCC(=O)c2ccc(F)cc2)C1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2CC(=O)OCC(=O)c2ccc(F)cc2)c(-c2ccc(F)cc2)s1

Procedure:
(RS)-3-[2-(4-Fluorophenyl)-2-oxo-ethoxycarbonylmethyl]-piperazine-1-carboxylic acid tert-butyl ester description 110 (0.887 g) was reacted with HATU (0.932 g), diisopropylethylamine (1.30 ml) and 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (0.707 g) in dry DMF (8 ml) according to the method of description 20. Silica gel column chromatography, eluting with ethyl acetate-hexane mixtures provided the title compound as a white foam (1.168 g), mass spectrum (API+) 600 [MH+], C30H31F2N3O6S requires 599.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.C(OC(Cl)=O)C(C)C.O[NH:33][C:34](=[NH:47])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:39][CH:38]=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[O:16][N:47]=[C:34]([CH2:35][O:36][C:37]3[CH:38]=[CH:39][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:41][CH:42]=3)[N:33]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)c1ccc(OCC(=N)NO)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2nc(COc3ccc(S(C)(=O)=O)cc3)no2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (2.06 g, 9 mmol), NEt3 (1.2 g, 12 mmol) in toluene (150 mL) was added isobutylchloroformate (1.23 g, 9 mmol) at 0° C. The mixture was stirred at room temperature for 1.5 hours. N-hydroxy-2-(4-methanesulfonyl-phenoxy)-acetamidine (1.5 g, 6 mmol) was added to the mixture. The mixture was heated under reflux overnight, cooled and the mixture was washed successively with H2O and brine. After drying (Na2SO4), the solvent was removed. The residue was purified by flash chromatography on silica gel to afford the desired product. 1H NMR (CDCl3): δ 7.98 (2H, m), 7.14 (2H, m), 5.24 (2H, s), 4.2-4.05 (2H, m), 3.14 (1H, m), 3.03 (3H, s), 2.95 (2H, m), 2.12˜2.04 (2H, m), 1.80 (2H, m), 1.46 (9H, s).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][O:5][CH:4]([CH2:8][C:9]23[CH2:23][CH:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:3]1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCOCC1.C(OCC)(=O)C>[CH3:1][N:2]1[CH2:7][CH2:6][O:5][CH:4]([CH2:8][C:9]23[CH2:23][CH:16]([C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=42)[C:17]2[C:22]3=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:3]1
Reactant: CN1CCOC(CC23CC(c4ccccc42)c2ccccc23)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CN1CCOC(CC23CC(c4ccccc42)c2ccccc23)C1
Reaction time: 6 h

Procedure:
A mixture of 9-(4-methyl-3-oxo-2-morpholinylmethyl)-9,10-dihydro-9,10-methanoanthracene (170 ml) and lithium aluminum hydride (100 mg) in dioxane was stirred at 60° - 70° C. for 6 hours. Excess lithium aluminum hydride was decomposed by addition of water. The reaction mixture was diluted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-(4-methyl-2-morpholinylmethyl)-9,10-dihydro-9,10-methanoanthracene, M.P. 136° - 137° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[N:10]([N:21]=[CH:22][C:23]=2[S:24](O)(=[O:26])=[O:25])[C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[CH3:20])=[O:5])[CH3:2].[CH2:28]([NH2:30])[CH3:29]>>[CH2:28]([NH:30][S:24]([C:23]1[CH:22]=[N:21][N:10]2[C:11]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[CH3:20])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=[N:8][C:9]=12)(=[O:26])=[O:25])[CH3:29]
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)O)cnn2c1Nc1ccc(F)cc1C
Reactant: CCN
Product: CCNS(=O)(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)OCC)cnc12
Yield: 33.3 %

Procedure:
Using 6-ethoxycarbonyl-7-(4-fluoro-2-methylphenylamino)pyrazolo[1,5-a]pyrimidine-3-sulfonic acid (0.500 g, 1.268 mmol) obtained in Example 1 step 2 and ethylamine (2.0 mol/L THF solution; 2.5 mL, 5.071 mmol) instead of tert-butylamine, and in the same manner as in Example 1 step 3, the title compound (0.178 g, 33%) was obtained.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[C:15](Cl)=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([O:17][CH3:18])[CH:8]=2)=[O:5])[CH2:3][CH2:2]1.[OH-].[K+].[H][H]>CO.[C].[Pd]>[CH:1]1([C:4]([NH:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([O:17][CH3:18])[CH:8]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: COc1cc(NC(=O)C2CC2)c(Cl)cc1C(=O)O
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(NC(=O)C2CC2)ccc1C(=O)O

Procedure:
A 2.0 g portion of 4-cyclopropylcarbonylamino-5-chloro-2-methoxybenzoic acid and 856 mg of potassium hydroxide were dissolved in 30 ml of methanol, and 600 mg of 10% palladium-carbon powder was added, followed by stirring at room temperature for 9 hours in an atmosphere of hydrogen. The reaction solution was filtered, and the filtrate was concentrated under a reduced pressure, diluted with 1N hydrochloric acid aqueous solution and then extracted with chloroform. The organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. Then, the solvent was evaporated under a reduced pressure and the resulting residue was washed with diethyl ether to give 1.60 g of 4-cyclopropylcarbonylamino-2-methoxybenzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[C:19]2[CH:20]([CH3:24])[NH:21][CH2:22][CH2:23][C:18]=2[S:17][CH:16]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:22][CH2:23][C:18]4[S:17][CH:16]=[C:15]([F:14])[C:19]=4[CH:20]3[CH3:24])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2scc(F)c21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2c(F)csc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3-fluoro-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine to provide the title compound in moderate yield.
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([CH2:7][OH:8])[CH2:5][OH:6].Cl[C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:16][C:12]=2[N:13]=[CH:14][N:15]=1.Cl>C1(C)C=CC=CC=1.COCCOC.O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]2[C:11]3[C:10]([O:6][CH2:5][CH:4]([CH3:3])[CH2:7][OH:8])=[N:15][CH:14]=[N:13][C:12]=3[O:16][C:17]=2[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:24][CH:23]=1
Reactant: CC(CO)CO
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC(C)CO)c23)cc1
Temperature: 70 °C
Reaction time: 17 h

Procedure:
Add 4.8 ml of 12.5 N sodium hydroxide solution to a solution of 2.68 g (29.7 mmol) 2-methylpropane-1,3-diol in 45 ml toluene, 15 ml 1,2-dimethoxyethane and 15 ml water at 70° C. After adding 202 mg (0.59 mmol) tetra-n-butylammonium hydrogensulphate and 2.0 g (5.94 mmol) 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine, stir the reaction mixture for 17 h at 70° C. After cooling to room temperature, adjust to pH 7 with concentrated hydrochloric acid. Extract three times with 50 ml dichloromethane each time. Wash the combined organic extracts with satd. sodium chloride solution, dry over sodium sulphate, filter and concentrate by vacuum evaporation. Mix the raw product with methanol, filter, and purify the filtrate by preparative RP-HPLC (gradient: water/acetonitrile). 1.26 g (54% of theor.) of the desired product (racemate) is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccncc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-Amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 116 mg of 4-tert-Butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.25 (s, 9H), 7.02 (d, 1H, J=8.4 Hz). 7.44 (m, 3H), 7.66 (d, 2H, J=8.4), 7.79 (d, 1H, J=2.4 Hz), 8.11 (d, 2H, J=6.4), 8.88 d, 2H, J=6.0 Hz), 10.51 (s, 1H). MS: m/z 429.9 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:19]=[N:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:7]([CH:18]=1)[O:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:19][NH:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[C:7]([CH:18]=1)[O:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: COc1ccc(C=NCCc2ccccc2)c(OCCCN2CCOCC2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNCCc2ccccc2)c(OCCCN2CCOCC2)c1
Yield: 77.8 %

Procedure:
4-[3-[5-Methoxy-2-[[(2-phenylethyl)imino]-methyl]phenoxy]propyl]morpholine (33 g) is reduced with 9.8 g of sodium borohydride in 150 ml of methanol following the procedure described in Example 1C, yielding 25.8 g of the title compound, boiling point 249°-254° C. at 0.3-0.4 mm of Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[C:4]([I:11])[CH:3]=1.[F:12][C:13]([F:22])([F:21])/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(N(CC)CC)C.C(OCC)(=O)C>CS(C)=O.C(OCC)(=O)C.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([I:11])[C:5]2[O:10][CH:14]([C:13]([F:12])([F:22])[F:21])[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7][C:6]=2[CH:9]=1
Reactant: O=Cc1cc(Cl)cc(I)c1O
Reactant: CCOC(=O)/C=C/C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CCOC(=O)C1=Cc2cc(Cl)cc(I)c2OC1C(F)(F)F
Temperature: 90 °C
Reaction time: 72 h
Yield: 64 %

Procedure:
5-Chloro-3-iodosalicylaldehyde (20 g, 70.8 mmol), ethyl 4,4,4-trifluorocrotonate (17.85 g, 106 mmol), and triethylamine (14.33 g, 142 mmol) were dissolved in DMSO (200 mL). The reaction mixture was stirred at 90° C. for three days. The reaction mixture was poured into ethyl acetate (800 mL). It was extracted with 10% HCl (2×200 mL), saturated aqueous NaHCO3 (2×200 mL), and water (2×200 mL). The ethyl acetate phase was dried over MgSO4, filtered and evaporated to yield a brown solid. It was then run through a plug of silica with ethyl acetate-hexane (1:20). The solvent was evaporated to give a yellow solid, that was recrystallized in hexane to afford the ester as a white solid (19.61 g, 64%): mp 92.1–93.9° C. 1H NMR (CDCl3/300 MHz) 7.71 (d, 1H, J=2.2 Hz), 7.56 (s, 1H), 7.20 (d, 1H, J=2.2 Hz), 5.81 (q, 1H, J=6.7 Hz), 4.37–4.29 (m, 2H), 1.35 (t, 3H, J=7.2 Hz). FABLRMS m/z 431.9 (M−H). EIHRMS m/z 431.9269 (M−H, Calc'd. 431.9237).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.C1C(=O)N([Br:23])C(=O)C1>O1CCCC1>[Br:23][C:11]1[CH:12]=[N:13][N:14]([CH3:15])[C:10]=1[C:3]1[CH:4]=[C:5]([C:7]([OH:9])=[O:8])[S:6][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1nccc1-c1cc(C(=O)O)sc1Cl
Solvent: C1CCOC1
Product: Cn1ncc(Br)c1-c1cc(C(=O)O)sc1Cl
Yield: 76.2 %

Procedure:
A solution of 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (50 mg, 0.21 mmol)[prepared in Example 95] and NBS (36.7 mg, 0.21 mmol) in tetrahydrofuran (2.06 ml) was stirred in a sealed tube for 1 h at 70° C. The reaction mixture was then partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4 and concentrated yielding 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxylic acid (82 mg, 0.16 mmol, 79% yield) as a yellow oil: LCMS (ES) m/e 257, 259 (M, M+2)+.
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].O=[C:35]1[CH:40]2[CH2:41][CH2:42][CH:36]1[CH2:37][CH:38]([C:43]1[NH:51][C:50]3[C:49](=[O:52])[N:48]([CH2:53][CH2:54][CH3:55])[C:47](=[O:56])[N:46]([CH2:57][CH2:58][CH3:59])[C:45]=3[N:44]=1)[CH2:39]2>C1(C)C=CC=CC=1>[O:56]=[C:47]1[N:46]([CH2:57][CH2:58][CH3:59])[C:45]2[N:44]=[C:43]([CH:38]3[CH2:37][CH:36]4[CH:35]([CH:2]=[O:3])[CH:40]([CH2:41][CH2:42]4)[CH2:39]3)[NH:51][C:50]=2[C:49](=[O:52])[N:48]1[CH2:53][CH2:54][CH3:55]
Reactant: CCCn1c(=O)c2[nH]c(C3CC4CCC(C3)C4=O)nc2n(CCC)c1=O
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCn1c(=O)c2[nH]c(C3CC4CCC(C3)C4C=O)nc2n(CCC)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
(Methoxymethyl)triphenylphosphonium chloride (296 mg 0.86 mmol) in toluene was cooled in an ice-bath. Potassium bis(trimethylsilyl)amide (2.5 ml, 0.5M in toluene) was added dropwise through a syringe. The mixture was stirred at 0° C. for 1 h. 8-(8-Oxo-bicyclo[3.2.1]oct-3-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (100 mg) was then added to the mixture, and the mixture was allowed to warm to room temperature and was stirred overnight. Toluene was evaporated off, and the residue was treated with 1N HCl in THF at 70° C. for 3 h. Ethyl acetate was used to extract the product. Column chromatography gave 94 mg of 3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.2.1]octane-8-carbaldehyde as a mixture of cis and trans yield (90%)
Reaction SMILES: [CH:1]([N:3]([CH3:7])[C:4](=[O:6])[CH3:5])=[CH2:2].[C:8]1([PH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH3:7][N:3]([CH2:1][CH2:2][P:14]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4](=[O:6])[CH3:5]
Reactant: C=CN(C)C(C)=O
Reactant: c1ccc(Pc2ccccc2)cc1
Product: CC(=O)N(C)CCP(c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 94 %

Procedure:
A 100 ml 3-necked round bottomed flash was heated to 100° C. under a nitrogen atmosohere and 7.14 g diohenylphosphine (38.4 mmole), 0.15 g 2,2'-azobis (2-methyloropionitrile), and 3.77 g N-vinyl-N-methyl acetamide (38.1 mmole) from Polysciences were added in the stated sequence. The reaction was maintained at 100° C. for 45 minutes under a nitrogen atmosphere and then evacuated (1 mm) for 24 hours at 100° C. A viscuous oil resulted whose infrared spectrum disolayed a strong γ(CO) band at 1645 cm-1 and a small γ(P--H) band at 2300 cm-1 due to a small amount of diphenylphosphine impurity. The elemental analysis was the following: calculated (found); C, 71.58 (69.89); H, 7.02 (7.15); N, 4.91 (4.57); P, 10.87 (10.97). The yield was 94%.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]3[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=3[Se:10][C:6]=2[N:5]=[CH:4][N:3]=1.[NH2:15][C:16]1[N:17]=[C:18]([S:23][CH3:24])[S:19][C:20]=1[C:21]#[N:22].[OH-].[Na+]>CN(C=O)C>[CH3:24][S:23][C:18]1[S:19][C:20]([C:21]#[N:22])=[C:16]([NH:15][C:2]2[C:7]3[C:8]4[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=4[Se:10][C:6]=3[N:5]=[CH:4][N:3]=2)[N:17]=1
Reactant: Clc1ncnc2[se]c3c(c12)CCCC3
Reactant: CSc1nc(N)c(C#N)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CSc1nc(Nc2ncnc3[se]c4c(c23)CCCC4)c(C#N)s1
Yield: 80.5 %

Procedure:
To a solution of 4-chloro-5,6,7,8-tetrahydrobenzo[1,2-b]pyrimidino[5,4-d]selenophene (250 mg, 0.917 mmol) in DMF (8 mL) was added sequentially 4-amino-2-methylthio-thiazole-5-carbonitrile (235 mg, 1.376 mmol; Thomae, D.; Perspicace, E.; Hesse, S.; Kirsch, G.; Seek, P. Tetrahedron, 2008, 64, 9309-9314) and powdered NaOH (110 mg, 2.751 mmol) at rt. Work-up as described in example 2, gave the product as a yellow color solid (300 mg, 81%), mp 264-266° C. (decomp). 1H NMR (400 MHz, CDCl3): δ 9.72 (1H, s, H-2), 6.75 (1H, s, exchangeable with D2O, —NH), 3.38 (2H, br s, H-8), 2.98 (2H, br s, H-5), 2.82 (3H, s, —SCH3), 1.91 (4H, br s, H-6,7); LC-MS (positive ion mode): m/z 406, 408 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][C:10](=[O:19])[NH:11][C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:28][C:29](=[O:35])[NH:30][CH2:31][CH2:32][C:33]#[CH:34])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(N(CC)CC)C>[CH2:21]([O:28][C:29](=[O:35])[NH:30][CH2:31][CH2:32][C:33]#[C:34][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:10](=[O:19])[CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:20])=[CH:13][CH:14]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C#CCCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC(=O)Nc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCC(=O)Nc1ccc(C#CCCNC(=O)OCc2ccccc2)cc1
Reaction time: 0.33 h

Procedure:
To a solution of [2-(4-iodophenylcarbamoyl)ethyl]carbamic acid tert-butyl ester 310 (1.5 g, 3.84 mmol), and triethylamine (40 mL) was added trans-dichlorobis-(triphenylphosphine)palladium (II) (Ph3P, PdCl2, 0.27 g, 0.38 mmol). The reaction mixture was stirred for 20 minutes when it became a clear solution. But-3-ynyl-carbamic acid benzyl ester (0.94 g, 4.6 mmol) and copper iodide (0.14 g, 0.768 mmol) were then added and the reaction was further stirred at room temperature for 18 hours. The solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (100 mL) and washed with water (3×150 mL). The organic layer was dried over sodium sulfate and then concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 1:1, v/v hexanes/ethyl acetate) to provide 320 (1.91 g, still a mixture, but used as it was without further purification). 1H NMR (300 MHz, CDCl3) δ 1.44 (s, 9H), 2.60 (m, 4H), 3.47 (m, 4H), 5.12 (s, 2H), 7.37 (m, 7H), 7.49 (d, 2H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][CH:3]=1.[Br:13]Br>C(Cl)(Cl)Cl>[Br:13][C:3]1[N:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:6][C:2]=1[Br:1]
Reactant: Brc1cnc(-c2ccccc2)s1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: Brc1nc(-c2ccccc2)sc1Br
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
Compound 18 (5.0 g, 21 mmol) was dissolved in CHCl3 (250 mL). Br2 (16.7 g, 105 mmol) was dissolved in CHCl3 (50 mL) and added to the solution of 18 via addition funnel over 10 minutes. The reaction mixture stirred at room temperature for 5.5 hours; then was transferred to a 1 L separatory funnel and washed with Na2S2O3 (3×100 mL) followed by brine (2×150 mL). The organic fractions were dried over MgSO4 and concentrated. The crude product was purified by column (2:1 hexanes/CHCl3). 1H NMR (600 MHz, CDCl3) δ 7.85 (d, J=7.3, 2H), 7.50-7.40 (m, 3H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3]1.C([O:18]N=O)CC(C)C.Cl.O>C(O)C.C(Cl)(Cl)Cl>[OH:18][C:7]1[C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3][C:2]=1[CH3:1]
Reactant: CC1CC(=O)c2ccccc2O1
Reactant: CC(C)CCON=O
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: Cc1oc2ccccc2c(=O)c1O
Reaction time: 2 h
Yield: 51 %

Procedure:
2,3-dihydro-2-methyl-4H-1-benzopyran-4-one (1.62 g) is dissolved in ethanol 95% (50 ml) and the solution is refluxed under stirring. In 10-15 minutes isoamylnitrite (8 ml) and concentrated HCl (40 ml) are added drop by drop. Heating and stirring are stopped, and the resulting mixture is allowed to stand ca. 2 hours. Then water (200 ml) is added until precipitation of a white solid. The solvent is evaporated, obtaining a solid product which is dissolved in a little volume of chloroform and purified on silica gel in equilibrium with the same solvent. The purified product contains a low percentage of yellow impurities which can be completely eliminated by crystallisation in acetone. The residual solvent is then eliminated, obtaining 0.97 g of 3-hydroxy-2-methyl-4H-1-benzopyran-4-one (colourless crystals; m.p.=179-180° C.; IR: 1632, 1666 e 3301 cm−1; yield=51%).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:20])[C:15]([O:17]CC)=[O:16])=[CH:10][CH:9]=1.Cl.N([O-])=[O:23].[Na+]>O>[OH:23][C:10]1[CH:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)[CH:13]=[CH:12][C:11]=1[CH:14]([OH:20])[C:15]([OH:17])=[O:16]
Reactant: O=N[O-]
Reactant: CCOC(=O)C(O)c1ccc(-c2ccccc2N)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)C(O)c1ccc(-c2ccccc2)cc1O
Reaction time: 0.17 h

Procedure:
To 4.5 g. of ethyl 2'-amino-4-biphenylylglycolate supsension in 125 ml. of 80% hydrochloric acid and cooled to 0°C is added dropwise a solution of 1.2 g. of sodium nitrite in 15 ml. of water. After about 10 min., 200 ml. of 50% hydrochloric acid is added portion wise and stirred for 15 hours. The reaction mixture is then poured onto ice water and extracted with chloroform, dried over sodium sulfate and concentrated in vacuo. The residue is crystallized to obtain 3-hydroxy-4-biphenylylglycolic acid.