Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)[C:2]#[CH:3].C(NC(C)C)(C)C.I[C:19]1[CH:24]=[CH:23][C:22](/[C:25](/[C:42]2[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][CH:43]=2)=[CH:26]\[CH2:27][O:28][C:29]2[CH:40]=[CH:39][C:32]([O:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[C:31]([CH3:41])[CH:30]=2)=[CH:21][CH:20]=1>O1CCCC1.[Cu]I.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>[OH:10][CH:7]1[CH2:8][CH2:9][N:4]([CH2:1][C:2]#[C:3][C:19]2[CH:20]=[CH:21][C:22](/[C:25](/[C:42]3[CH:43]=[CH:44][C:45]([C:48]([F:49])([F:50])[F:51])=[CH:46][CH:47]=3)=[CH:26]\[CH2:27][O:28][C:29]3[CH:40]=[CH:39][C:32]([O:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[C:31]([CH3:41])[CH:30]=3)=[CH:23][CH:24]=2)[CH2:5][CH2:6]1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Reactant: C#CCN1CCC(O)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCC(O)CC3)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1-Propargylpiperidin-4-ol (215 mg, 1.55 mmol) and diisopropylamine (0.51 mL, 3.64 mmol) were added to a solution of methyl (Z)-[4-[3-(4-iodophenyl)-3-(4-trifluoromethyl-phenyl)-allyloxy]-2-methylphenoxy]acetate (450 mg, 0.773 mmol; example 4) in tetrahydrofuran (10 mL). The mixture was degassed and copper(I) iodide (12 mg, 0.063 mmol) and bis(triphenylphosphine)palladium(II) dichloride (27 mg, 0.039 mmol) were added. The reaction mixture was stirred at ambient temperature for 20 h and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, dichloromethane/methanol 98:2-97:3-95:5) yielding methyl (E)-[4-[3-[4-[3-(4-hydroxypiperidin-1-yl)propynyl]-phenyl]-3-(4-trifluoromethylphenyl)allyloxy]-2-methylphenoxy]acetate as yellow oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([Cl:25])=[C:12]([NH:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=2[C:22](O)=[O:23])[C:13]=1[Cl:14].C[N:27](C)C=O.[OH-].[NH4+]>C(Cl)Cl.O1CCCC1>[Cl:14][C:13]1[C:8]([CH3:7])=[CH:9][CH:10]=[C:11]([Cl:25])[C:12]=1[NH:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=1[C:22]([NH2:27])=[O:23]
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C(=O)O)c1Cl
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(Cl)c(Nc2ccccc2C(N)=O)c1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (1.90 g, 14.8 mmol) is added dropwise to a 0° C. suspension of meclofenamic acid (2.00 g, 6.7 mmol) and dimethylformamide (530 μl, 6.7 mmol) in 100 ml of methylene chloride. The clear yellow solution is stirred at 0° C. for one hour and then added by cannula to 3.6 ml of ammonium hydroxide (29% aqueous solution) in tetrahydrofuran at room temperature. After one hour the volatiles are removed and the residue partioned between ethyl acetate and water. The organic layer is washed with brine and dried over magnesium sulfate and concentrated. The white solid is recrystallized from ethyl acetate and isopropanol to give 1.30 g (69%), mp 185°-187° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[O:11][CH2:12][CH3:13])[CH3:2].O[CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].S(=O)(=O)(O)O.O>COCCOC>[CH2:12]([O:11][C:5]1[C:6]([F:10])=[C:7]([CH:8]=[CH:9][C:4]=1[O:3][CH2:1][CH3:2])[CH2:15][N:16]1[C:20](=[O:21])[C:19]2[C:18](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]1=[O:26])[CH3:13]
Reactant: O=C1c2ccccc2C(=O)N1CO
Reactant: CCOc1cccc(F)c1OCC
Agent: O=S(=O)(O)O
Solvent: O
Solvent: COCCOC
Product: CCOc1ccc(CN2C(=O)c3ccccc3C2=O)c(F)c1OCC
Temperature: 25 °C
Yield: 0 %

Procedure:
To a solution of 1,2-diethoxy-3-fluorobenzene (2.28 g, 12.4 mol) and N-(hydroxymethyl)phthalimide (2.41 g, 13.6 mol) in 1,2-dimethoxyethane (8 mL), a solution of sulfuric acid (8 mL) in 1,2-dimethoxyethane (8 mL) was added dropwise on ice, and the mixture was stirred at room temperature for twelve hours. The reaction mixture was poured into water (100 mL), and crystals were filtered. The obtained crystals were recrystallized from acetone and water, and the precipitated crystals were filtered. After the filtrate was concentrated under reduced pressure, the residue was crystallized from acetone to give 0.96 g of the title compound (yield: 23%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[O:12][C:11]([CH3:14])=[CH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[Br:15]Br>C(Cl)Cl.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:13]2[O:12][C:11]([CH3:14])=[C:10]([Br:15])[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2cc(C)oc12
Reactant: BrBr
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c(Br)c(C)oc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A solution of 2-methyl-benzofuran-7-carboxylic acid methyl ester (0.55 g, 2.87 mmol), prepared according to a literature procedure (Ishikawa, T.; Nagai, K.; Ohkubo, N.; Ishii, H. Heterocycles 1994, 39, 371), in CH2Cl2 (15 mL) at 0° C. is treated with bromine (147 μL, 2.87 mmol). The reaction is stirred at 0° C. for 30 min, then at RT overnight. The reaction is diluted with EtOAc 960 mL); washed with 5% Na2S2O3 (2×20 mL); brine (20 mL); dried with Na2SO4, filtered and concentrated gives the title compound (0.79 g, 2.87 mmol, 100%). 1H NMR (CDCl3): δ 2.55 (s, 3H), 4.00 (s, 3H), 7.33 (t, J=7.5 Hz, 1H), 7.63 (dd, J=7.9, 0.9 Hz, 1H), 7.93 (dd, J=7.9, 0.9 Hz, 1H) ppm.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[CH3:7][CH:8]1[CH2:12][O:11][S@@:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(OCC)(=[O:22])C>O.C(#N)C.[Ru](Cl)(Cl)Cl>[CH3:7][C@@H:8]1[CH2:12][O:11][S:10](=[O:22])(=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CC1CO[S@@](=O)N1c1ccccn1
Reactant: CCOC(C)=O
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: C[C@@H]1COS(=O)(=O)N1c1ccccn1

Procedure:
A solution of sodium periodate (21 g, 0.10 moles) in water (150 ml) was added slowly to a solution of (R)4-methyl-3-pyridin-2-yl-[1,2,3]oxathiazolidine-2-oxide (15.4 g, 0.78 moles) and ruthenium(III)chloride (20 mg) in acetonitrile (1540 ml) whilst the temperature was kept below 5° C. A heavy precipitate developed. The mixture was poured into a mixture of ethyl acetate (500 ml) and water (500 ml) and then shaken. The organic phase was retained and the aqueous phase was extracted with further ethyl acetate (2×500 ml). The organic phases were combined, backwashed with water (500 ml), dried (MgSO4) and then evaporated in vacuo to give (R)-4-methyl-3-(2-pyridyl)-[1,2,3]-oxathiazolidine-2,2-dioxide (15.5 g) as a yellow oil.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14]([OH:16])=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:24][O:25][C:26]1[N:31]=[C:30]2[S:32][C:33]([NH2:35])=[N:34][C:29]2=[CH:28][CH:27]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:14]([NH:35][C:33]3[S:32][C:30]4[C:29]([N:34]=3)=[CH:28][CH:27]=[C:26]([O:25][CH3:24])[N:31]=4)=[O:16])=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:2][CH2:3]1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: COc1ccc2nc(N)sc2n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1ccc2nc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)sc2n1
Yield: 42.1 %

Procedure:
The compound of example A80 was obtained by similar method described in example A75 using (4-cyclopropanesulfonyl-phenyl)-[(tetrahydro-pyran-4-yloxy)]-acetic acid (Preparation 14) (0.5 g,1.32 mmol), 5-methoxy-thiazolo[5,4-b]pyridin-2-ylamine (0.286 g, 1.59 mmol), HOBt (0.267 g, 1.98 mmol), and EDCI (0.378 g,1.98 mmol), N-methyl morpholine (0.4 g, 3.97 mmol) in DMF (10 mL) to provide the title compound (0.280 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]1([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([OH:12])=O)=[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.CCN(C(C)C)C(C)C.[N:53]1([S:58]([NH:61][C:62]([C@@:64]2([NH:69][C:70]([C@@H:72]3[CH2:83][C@:75]4([C:80]([CH3:82])([CH3:81])[C:76]54[CH2:79][CH2:78][CH2:77]5)[CH2:74][N:73]3[C:84](=[O:94])[C@@H:85]([NH2:93])[C:86]3(C)[CH2:91][CH2:90][O:89][CH2:88][CH2:87]3)=[O:71])[CH2:66][C@H:65]2[CH:67]=[CH2:68])=[O:63])(=[O:60])=[O:59])[CH2:57][CH2:56][CH2:55][CH2:54]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:12])[NH:93][C@@H:85]([CH:86]1[CH2:91][CH2:90][O:89][CH2:88][CH2:87]1)[C:84]([N:73]1[C@H:72]([C:70](=[O:71])[NH:69][C@:64]2([C:62]([NH:61][S:58]([N:53]3[CH2:57][CH2:56][CH2:55][CH2:54]3)(=[O:59])=[O:60])=[O:63])[CH2:66][C@H:65]2[CH:67]=[CH2:68])[CH2:83][C@:75]2([C:80]([CH3:82])([CH3:81])[C:76]32[CH2:79][CH2:78][CH2:77]3)[CH2:74]1)=[O:94])[C:13]1([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1(C)CCCCC1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@]2(CN1C(=O)[C@@H](N)C1(C)CCOCC1)C(C)(C)C21CCC1)C(=O)NS(=O)(=O)N1CCCC1
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: ClCCl
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@]2(CN1C(=O)[C@@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C1(C)CCCCC1)C1CCOCC1)C(C)(C)C21CCC1)C(=O)NS(=O)(=O)N1CCCC1
Reaction time: 3 h

Procedure:
A solution of (S)-tert-Butoxycarbonylamino-(1-methyl-cyclohexyl)-acetic acid (0.15 g; 0.55 mmol) (prepared according to Tetrahedron Let. 2007, 48, 6343-6347) and HATU (0.31 g; 0.82 mmol) in DCM (15 mL) was stirred for 30 min at ambient temperature. After addition of DIPEA (0.56 mL; 3.27 mmol) and (5R,8S)-7-[(S)-2-Amino-2-(4-methyl-tetrahydro-pyran-4-yl)-acetyl]-10,10-dimethyl-7-aza-dispiro-[3.0.4.1]decane-8-carboxylic acid [(1R,2S)-1-(pyrrolidine-1-sulfonylaminocarbonyl)-2-vinyl-cyclopropyl]-amide (0.412 g; 0.55 mmol) in DCM (5 mL) the reaction mixture was stirred for 3 h, the solvent was removed in vacuo and the residue was purified by preparative HPLC (method L) to yield the title compound. LC-MS (method E): Rt=2.78 min; M/z=859 [M+], HPLC (method A3) Rt=6.81 min
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([N:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([Cl:17])[C:11]2=[O:18])[C:7]([CH3:19])=[CH:6][N:5]=1)(=[O:3])[CH3:2].Cl[CH2:21][C:22]1[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[C:1]([C:4]1[CH:9]=[C:8]([N:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:21][C:22]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][N:23]=3)=[C:12]([Cl:17])[C:11]2=[O:18])[C:7]([CH3:19])=[CH:6][N:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(-n2ccc(O)c(Cl)c2=O)c(C)cn1
Reactant: Fc1cnc(CCl)c(F)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cc(-n2ccc(OCc3ncc(F)cc3F)c(Cl)c2=O)c(C)cn1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of 2′-acetyl-3-chloro-4-hydroxy-5′-methyl-[1,4′]bipyridinyl-2-one of part D (500 mg, 1.7 mmol) in N,N-dimethylformamide (3 mL) was added 2-chloromethyl-3,5-difluoro-pyridine (277 mg, 1.7 mmol), potassium carbonate (590 mg, 4.28 mmol) and 18-crown-6 (10 mg) and the reaction was stirred at 60° C. for 4 h. After cooling the solution was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The solution was filtered and concentrated in vacuo. The crude material was purified using normal phase chromatography (ethyl acetate/heptane) to provide alkylated product as a yellow solid (397 mg): MS (ES) m/e 420 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:20](=[O:24])[N:21]([CH3:23])[CH3:22])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[OH-].[Li+]>C1COCC1.O>[C:29]([O:28][C:26]([NH:25][CH:19]([C:20](=[O:24])[N:21]([CH3:23])[CH3:22])[C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:33])=[O:2])=[CH:7][CH:8]=2)=[CH:14][CH:15]=1)=[O:27])([CH3:31])([CH3:30])[CH3:32]
Reactant: COC(=O)CCc1ccc(Oc2ccc(C(NC(=O)OC(C)(C)C)C(=O)N(C)C)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Oc2ccc(CCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
Amide 32 (3.6 g, 7.9 mmol) was dissolved in THF (40 mL) and diluted with water (40 mL). Lithium hydroxide (0.76 g, 31.0 mmol) was added and the reaction mixture was stirred at room temp for about 2 h. The THF was evaporated and the resulting aqueous layer was acidified with 2.0 M HCl and extracted into EtOAc (2×100 mL). The organic layer was washed with water (1×150 mL) and brine (1×200 mL), dried and concentrated to yield the desired acid compound 33 (3.4 g, 97%). 1H NMR (400 MHz, DMSO-d6): 12.2 (br, 1H), 7.34 (d, J=8.4 Hz, 2H), 7.25 (d, J=8.4 Hz, 2H), 7.12 (d, J=8.0 Hz, 1H), 6.93 (d, J=8.4 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 5.50 (d, J=8.0 Hz, 1H), 2.90 (s, 3H), 2.84 (s, 3H), 2.81 (t, J=7.6 Hz, 2H), 2.53 (t, J=7.6 Hz, 2H), 1.37 (s, 9H).
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:26])[C@H:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:16][CH:17]=[CH2:18])C1C=CC=CC=1.[OH:27]O.O[Li].O>C1COCC1.O>[CH2:19]([C@H:15]([CH2:16][CH:17]=[CH2:18])[C:14]([OH:26])=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: OO
Reactant: C=CC[C@@H](CCCCCCC)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: C=CC[C@@H](CCCCCCC)C(=O)O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
To a solution of 8.69 g (0.024 mol) of the product from Example 3 in 425 mL of THF/H2O (3:1), cooled to 0 degrees, was added 10.8 mL (0.097 mol) of 30% hydrogen peroxide solution followed by 2.03 g (0.049 mol) of LiOH-H2O. The resulting solution was stirred at 0° C. for 1.5 h and then quenched with a solution of 15.4 g of sodium sulfite in 100 mL of H2O. The reaction mixture was then acidified to pH 3 with aqueous HCl and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:10) to provide 4.33 g (90%) of the desired product as a colorless oil. CI Mass Spec: 199 (M+H).
Reaction SMILES: FC(F)(F)S([O:6][C:7]1[C:8]2[S:16][C:15](=[O:17])[N:14]([C@H:18]3[C@H:22](OS(C(F)(F)F)(=O)=O)[CH2:21][C@@H:20]([CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[O:19]3)[C:9]=2[N:10]=[C:11]([NH2:13])[N:12]=1)(=O)=O.[C-:42]#[N:43].[Na+].CCOC(C)=O>CN(C=O)C>[NH2:13][C:11]1[NH:12][C:7](=[O:6])[C:8]2[S:16][C:15](=[O:17])[N:14]([C@H:18]3[C@H:22]([C:42]#[N:43])[CH2:21][C@@H:20]([CH2:31][O:32][Si:33]([C:36]([CH3:38])([CH3:39])[CH3:37])([CH3:34])[CH3:35])[O:19]3)[C:9]=2[N:10]=1
Reactant: [C-]#N
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](OS(=O)(=O)C(F)(F)F)[C@H](n2c(=O)sc3c(OS(=O)(=O)C(F)(F)F)nc(N)nc32)O1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](C#N)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 118 %

Procedure:
To a stirred solution of [5-amino-3-[(2R,3R,5S)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-(trifluoromethylsulfonyloxy)tetrahydrofuran-2-yl]-2-oxo-thiazolo[4,5-d]pyrimidin-7-yl] trifluoromethanesulfonate (compound 38g, crude, 120 mg, 0.2 mmol) in DMF (2 mL) was added sodium cyanide (100 mg, 2.3 mmol). After being stirred at room temperature for 2 hours, the resulting solution was diluted by EtOAc, washed with brine, dried over Na2SO4 and concentrated in vacuo to afford 100 mg crude product of (2R,3S,5S)-2-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]tetrahydrofuran-3-carbonitrile (compound 38h), which was used in next step without further purification. MS obsd. (ESI+) [(M+H)+]: 424.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.C([Si](C)(C)C)#C.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]2[CH2:18][CH2:19][C:20](=[O:21])[C:13]=12>C1COCC1.O>[C:1]([C:20]1([OH:21])[C:13]2=[N:12][CH:17]=[CH:16][CH:15]=[C:14]2[CH2:18][CH2:19]1)#[CH:2]
Reactant: O=C1CCc2cccnc21
Reactant: [Li]CCCC
Agent: C#C[Si](C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: C#CC1(O)CCc2cccnc21
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of n-butyllithium (2.5M in hexane, 19.5 ml, 48.75 mmol) in THF (15 ml) at −78° C. was added dropwise ethynyl(trimethyl)silane (6.41 ml, 45.06 mmol). The reaction was stirred at −78° C. for 20 minutes and then a solution of 5,6-dihydro-7H-cyclopenta[b]pyridin-7-one (5 g, 7.51 mmol) in THF (25 mL) was added. The reaction mixture was stirred at −78° C. to RT for 4 hr. The mixture was then diluted with water and the volatiles removed in vacuo. The product was extracted with CHCl3:IPA (2:1 ratio, 3×30 ml) and the organic phase was washed with water (30 mL), brine (30 mL); dried over Na2SO4, filtered and concentrated in vacuo. Purification by column chromatography (Biotage), eluting with 0-5% MeOH-DCM followed by another column chromatography purification with 30% EtOAc/heptanes gave the title compound; 1H NMR (500 MHz, CDCl3) 2.49 (1H, ddd, J=13.44, 8.24, 6.07 Hz), 2.63-2.76 (2H, m), 2.90-3.02 (1H, m), 3.03-3.13 (1H, m), 3.42 (1H, s), 7.22 (1H, dd, J=7.57, 4.89 Hz), 7.62 (1H, d, J=7.57 Hz), 8.51 (1H, d, J=4.73 Hz); LC-MS: m/z=+159.9 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=2[F:18])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][CH:21]=1.C1(C)C=CC=CC=1>C(OCC)C>[F:18][C:11]1[C:12]([F:17])=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)=[S:28])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1OCc1c(F)ccc(F)c1F
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Fc1ccc(F)c(COc2cccnc2NC(=S)Nc2ccc(Cl)cc2)c1F

Procedure:
A mixture of 2-amino-3-(2,3,6-trifluorobenzyloxy)pyridine (2.00 g, 0.0078 mol), 4chlorophenyl isothiocyanate (1.6 g, 0.094 mol) and toluene (10 ml) was refluxed for 3 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield 2.82 g (85.5%), m.p.174°-176 ° C.
Reaction SMILES: C(Cl)(Cl)Cl.[C:5]([O:8][C@@H:9]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@@H:13]([O:19][C:20](=[O:22])[CH3:21])[C@@H:12]([CH2:23][N:24]2[C:28](=[O:29])[C:27]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]3[C:25]2=[O:34])[O:11][C@H:10]1[S:35]C(=N)N)(=[O:7])[CH3:6].S(S([O-])=O)([O-])(=O)=O.[K+].[K+]>O>[C:5]([O:8][C@@H:9]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@@H:13]([O:19][C:20](=[O:22])[CH3:21])[C@@H:12]([CH2:23][N:24]2[C:28](=[O:29])[C:27]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]3[C:25]2=[O:34])[O:11][C@H:10]1[SH:35])(=[O:7])[CH3:6]
Reactant: CC(=O)O[C@H]1[C@@H](OC(C)=O)[C@@H](CN2C(=O)c3ccccc3C2=O)O[C@@H](SC(=N)N)[C@@H]1OC(C)=O
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](S)O[C@H](CN2C(=O)c3ccccc3C2=O)[C@@H]1OC(C)=O
Yield: 80.4 %

Procedure:
Chloroform (9.0 ml.) is added to a solution of 2-S-(2,3,4-tri-O-acetyl-6-deoxy-6-phthalimido-β-D-galactopyranosyl)-2-thiopseudourea (3.4 g.) in water (10 ml.) containing potassium metabisulfite (1.38 g.). The mixture is heated with stirring under reflux for 15 minutes. The cooled solution is separated, and the organic layer is dried and evaporated in vacuo to give the title compound (2.5 g.). This material is used directly for the preparation of 6-(5-cholesten-3β-yloxy)hexyl 2,3,4-tri-O-acetyl-6-deoxy-6-phthalimido-1-thio-β-D-galactopyranoside.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26]Br)=[CH:21][CH:20]=1.C(N(CC)CC)C>CN(C=O)C>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][N:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:17][CH2:16]2)=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(CCN2CCNCC2)cc1
Reactant: BrCCc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(CCN2CCN(CCc3ccc(Br)cc3)CC2)cc1

Procedure:
A solution of 1-[2-(4-nitrophenyl)ethyl]piperazine (300 mg, 1.3 mmol), 1-bromo-4-(2-bromoethyl)benzene (400 mg, 1.5 mmol), and triethylamine (0.89 mL, 6.4 mmol) in DMF (5 mL) was heated to 60° C. for 16 hours. LC showed formation of the desired product. The desired product was purified by silica gel chromatography (10% MeOH in EtOAc). LC-MS (IE, m/z): 420 (M+1)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([S:15](=[O:18])(=[O:17])[NH2:16])[CH:9]=[C:10]([C:11]([O:13]C)=O)[C:4]=2[O:3]1.[CH2:19]([N:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[CH2:28][NH2:29])[CH:20]([CH3:22])[CH3:21].O>C(O)COCCO>[CH2:19]([N:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[CH2:28][NH:29][C:11]([C:10]1[C:4]2[O:3][CH:2]([CH3:1])[CH2:6][C:5]=2[CH:7]=[C:8]([S:15](=[O:18])(=[O:17])[NH2:16])[CH:9]=1)=[O:13])[CH:20]([CH3:22])[CH3:21]
Reactant: COC(=O)c1cc(S(N)(=O)=O)cc2c1OC(C)C2
Reactant: CC(C)CN1CCCC1CN
Solvent: OCCOCCO
Solvent: O
Product: CC(C)CN1CCCC1CNC(=O)c1cc(S(N)(=O)=O)cc2c1OC(C)C2
Temperature: 25 °C
Reaction time: 18.5 h

Procedure:
A suspension of 5.2 g of methyl 2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxylate and 4.5 g of 1-isobutyl-2-aminomethylpyrrolidine in 20 ml of diethylene glycol is heated at 130°-140° C. and stirred for 18-19 hours. The reaction solution is cooled to room temperature and poured into 150-200 ml of water while stirring. Under ice-cooling crystals are deposited thoroughly and collected by suction filtration. The crude crystals are washed with cold water, dissolved in chloroform and separated on a column of silica gel (developing solvent: methanol/chloroform=1/9). Crystals obtained are recrystallized from about 35 ml of methanol to give crystals of N-(1-isobutyl-2-pyrrolidinylmethyl)-2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxamide, m.p. 182°-184° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]4[C:21](=O)[C:22](=[O:27])[C:23]=4[O:24]CC)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[NH4+:30]>C(O)C>[NH2:30][C:21]1[C:22](=[O:27])[C:23](=[O:24])[C:20]=1[NH:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: [NH4+]
Reactant: CCOc1c(Nc2ccc3ncnc(Nc4cccc(Br)c4)c3c2)c(=O)c1=O
Agent: [OH-]
Solvent: CCO
Product: Nc1c(Nc2ccc3ncnc(Nc4cccc(Br)c4)c3c2)c(=O)c1=O
Temperature: 25 °C

Procedure:
A mixture of 0.8 g of 3-[4-(3-Bromo-phenylamino)-quinazolin-6-ylamino]-4-ethoxy-cyclobut-3-ene-1,2-dione, 8 mL of ammonium hydroxide, and 8 mL of ethanol was refluxed for 1 hr. The mixture was cooled to room temperature and the solid was collected and washed with ethanol and ether giving 0.65 g of 3-Amino-4-[4-(3-bromo-phenylamino)-quinazolin-6-ylamino]-cyclobut-3-ene-1,2-dione as a yellow powder: mass spectrum (m/e): M+H 412.1.