Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]1[NH:21][C:22]([C:24]1[S:25][C:26]3[CH2:27][NH:28][CH2:29][CH2:30][C:31]=3[N:32]=1)=[O:23])=[O:13])=[CH:6]2.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>N1C=CC=CC=1>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]1[NH:21][C:22]([C:24]1[S:25][C:26]3[CH2:27][N:28]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:29][CH2:30][C:31]=3[N:32]=1)=[O:23])=[O:13])=[CH:6]2
Reactant: O=C(N[C@@H]1CCCC[C@@H]1NC(=O)c1nc2c(s1)CNCC2)c1cc2cc(Cl)ccc2[nH]1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCc2nc(C(=O)N[C@H]3CCCC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(±)-cis-N1-[(5-chloroindol-2-yl)carbonyl]-N2-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-carbonyl]-1,2-cyclohexanediamine hydrochloride (100 mg) was dissolved in pyridine (3 ml), triethylamine (168 μl) and methanesulfonyl chloride (48 μl) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and dichloromethane and 1N hydrochloric acid were added to the residue to separate an organic layer. The resultant organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane:methanol=100:1) to obtain the title compound (79 mg) as a pale yellow foamy substance.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:17]=[C:16]([SH:18])[N:15]=[C:14]([OH:19])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[CH3:22]I>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:17]=[C:16]([S:18][CH3:22])[N:15]=[C:14]([OH:19])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cc(CCCOCc2ccccc2)nc(S)n1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Product: CSc1nc(O)cc(CCCOCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-(3-benzyloxy-propyl)-2-mercapto-pyrimidin-4-ol (7.94 g), potassium hydroxide (32 mL of 1N solution in methanol) and methyl iodide (1.97 mL) was stirred at room temperature overnight. The precipitate was filtered, washed successively with methanol (2×20 mL), isopropanol (2×20 mL) and water (2×20 mL), then dried to afford 6-(3-benzyloxy-propyl)-2-methylsulfanyl-pyrimidin-4-ol as a white powder (7.0 g). MS m/z 291.0 (M+1), 100%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[C:12]([O:17][CH3:18])(=[O:16])[C:13](C)=[CH2:14]>C(O)(C)(C)C>[CH3:18][O:17][C:12](=[O:16])[CH2:13][CH2:14][C:9]([C:10]#[N:11])([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:14][CH2:13][C:12]([O:17][CH3:18])=[O:16]
Reactant: COc1ccc(CC#N)cc1
Reactant: C=C(C)C(=O)OC
Solvent: CC(C)(C)O
Product: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccc(OC)cc1
Yield: 70.2 %

Procedure:
A mixture of 36.75 g. (0.25 mole) of the known compound (p-methoxyphenyl)acetonitrile and 116 ml. of methyl methacrylate in 120 ml. of t-butyl alcohol is heated to reflux. The heat is removed and 38 ml. of 40% methanolic Triton B in 56 ml. of t-butyl alcohol quickly added. After about 4 hours of heating at reflux the mixture is allowed to cool and taken up in water and benzene. The organic layer is washed successively with 2.5 N hydrochloric acid, water and brine and then evaporated to dryness. The residue is distilled under vacuum, first at 40 mm. of mercury to remove excess methyl acrylate and then at 0.6 to 0.75 mm. to give 55.9 g. (70.2% yield) of dimethyl-4-cyano-4-(4-methoxyphenyl)pimelate, having a boiling point of 205° to 210°C. The NMR spectrum of the compound confirms its expected structure.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5](=[O:13])[CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:3].[SH2:14]>C(O)C>[CH2:2]([O:4][C:5](=[O:13])[CH2:6][CH:7]([SH:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:3]
Reactant: CCCCCC=CC(=O)OCC
Reactant: S
Agent: [Na]
Solvent: CCO
Product: CCCCCC(S)CC(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.2 g of sodium are dissolved in 10 ml of absolute ethyl alcohol. After completed alcoholate-formation, 5 g of 2-octenoic acid ethyl ester are added and the solution is cooled to -70°. At this temperature, 10 ml of hydrogen sulphide are condensed into the solution. Subsequently, the whole mixture is immediately transferred into an autoclave, pre-cooled to about -30°, and left by itself overnight at room temperature in the sealed pressure vessel. On the next morning, the autoclave is heated at 50° for a further 2 hours. After cooling to room temperature, the excess hydrogen sulphide is vented off, the reaction product washed with saturated common salt solution, dried and distilled. There are obtained 1.6 g of 3-mercapto-octanoic acid ethyl ester of boiling point 74°/0.4 mm Hg, nD20 1.4538.
Reaction SMILES: Cl.[S:2]1[C:6]([CH2:7][O:8][CH:9]2[CH2:12][NH:11][CH2:10]2)=[CH:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[O:48]=[C:49]1[NH:58][C:57]2[N:56]=[CH:55][C:54](/[CH:59]=[CH:60]/[C:61](O)=[O:62])=[CH:53][C:52]=2[CH2:51][CH2:50]1>CN(C)C=O.O.C(OCC)(=O)C>[S:2]1[C:6]([CH2:7][O:8][CH:9]2[CH2:10][N:11]([C:61](=[O:62])/[CH:60]=[CH:59]/[C:54]3[CH:53]=[C:52]4[C:57](=[N:56][CH:55]=3)[NH:58][C:49](=[O:48])[CH2:50][CH2:51]4)[CH2:12]2)=[CH:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: c1ccc2sc(COC3CNC3)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCc2cc(/C=C/C(=O)N3CC(OCc4cc5ccccc5s4)C3)cnc2N1
Reaction time: 72 h

Procedure:
3-(Benzo[b]thiophen-2-ylmethoxy)-azetidine hydrochloride (136 mg, 0.76 mmol), EDCI (146 mg, 0.76 mmol), HOBt (103 mg, 0.76 mmol) and diisopropylethylamine (222 μL, 1.27 mmol) were successively added to a solution of (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acid hydrochloride (130 mg, 0.51 mmol) in dimethylformamide (10 mL) at room temperature. The reaction mixture was stirred for 3 days. The reaction mixture was then diluted by addition of ethyl acetate (50 mL) and water (50 mL). The aqueous phase was extracted with ethyl acetate (3×100 mL) and dichloromethane (3×100 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×50 mL), dried over sodium sulfate and concentrated to dryness. The residue was purified by chromatography on silica gel using dichloromethane/methanol (1:0 to 95:5) as eluent. After trituration in acetone and methanol, the title product was obtained as a white solid (112 mg, 45%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:24])=[O:16])=[CH:10][CH:9]=1)[NH2:6].[CH3:26][O:27][CH2:28][CH2:29][C:30]1([C:35](O)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]([C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:24])=[O:16])=[CH:12][CH:13]=1)[NH:6][C:35]([C:30]1([CH2:29][CH2:28][O:27][CH3:26])[CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:36]
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Reactant: COCCC1(C(=O)O)CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COCCC1(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)OC)CCCC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 84.1 %

Procedure:
To a solution of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester hydrochloride salt (43.03 mmol, 11.75 g) and 1-(2-methoxyethyl)cyclopentane carboxylic acid (43.5 mmol, 7.5 g) in DMF (130 mL) was added HBTU (43.5 mmol, 16.5 g) and diisopropylethylamine (108.8 mmol, 19.02 mL) at room temperature. The clear solution was stirred 23 h at room temperature and was diluted with 200 mL of ethyl acetate. The ethyl acetate layer was washed successively with 0.5 N hydrochloric acid (2×100 mL), saturated sodium bicarbonate solution (2×100 mL), brine solution and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent gave 18.86 g (84%) of a white solid, mp 85-87° C. 1H NMR (DMSO-d6) (400 MHz) δ 10.65 (s, 1H), 7.88 (d, 1H, J=19 Hz), 7.47-7.59 (m, 5H), 7.21 (d, 2H, J=19 Hz), 4.47-4.53 (m, 1H), 3.64 (s, 3H), 2.88-3.1 (m, 7H), 1.76-1.98 (m, 4H), 1.23-1.47 (m, 6H). HR MS C26H30Cl2N2O5): Obs. mass, 521.1586. Calcd. mass, 521.1610 (M+H).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@H:9]([F:10])[CH2:8][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1)=[N+]=[N-].[H][H]>C(O)C.[Pt](=O)=O>[NH2:1][CH2:4][C@@H:5]1[C@H:9]([F:10])[CH2:8][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1
Reactant: [N-]=[N+]=NC[C@H]1CN(Cc2ccccc2)C[C@H]1F
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: NC[C@H]1CN(Cc2ccccc2)C[C@H]1F
Yield: 99.9 %

Procedure:
(3R,4S)-3-Azidomethyl-1-benzyl-4-fluoropyrrolidine (215 mg) was dissolved in ethanol (3 mL) and platinum (IV) oxide (30.0 mg) was added. The mixture was stirred at room temperature for 5 hours under a stream of hydrogen gas (blown by a balloon). The catalyst in the reaction mixture was filtered through a Celite pad, and the catalyst and the Celite pad were washed with ethanol. The filtrate and the washings were then combined and concentrated under reduced pressure to give (3S,4S)-3-aminomethyl-1-benzyl-4-fluoropyrrolidine as a pale brown oil (191 mg).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([CH3:7])[C@@H:4]([C:8]([OH:10])=O)[O:3]1.[N+]([O-])(O)=O.[N+:15]([O:18][CH2:19][CH2:20][NH2:21])([O-:17])=[O:16].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>>[N+:15]([O:18][CH2:19][CH2:20][NH:21][C:8]([C@H:4]1[O:3][C:2](=[O:1])[NH:6][C@@H:5]1[CH3:7])=[O:10])([O-:17])=[O:16]
Reactant: C[C@H]1NC(=O)O[C@@H]1C(=O)O
Reactant: NCCO[N+](=O)[O-]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O=[N+]([O-])O
Product: C[C@H]1NC(=O)O[C@@H]1C(=O)NCCO[N+](=O)[O-]
Yield: 14.9 %

Procedure:
Following a procedure similar to that described in Example 1, but using 167 mg of (4R,5S)-2-oxo-4-methyl-oxazolidine-5-carboxylic acid, 234 mg of N-(2-nitrooxyethyl)amine nitrate and 0.30 ml of diphenylphosphoryl azide, 40 mg of the title compound were obtained as a colorless oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:11][CH3:12])[CH:8]=2)[CH2:3]1.Cl[C:14]1[C:15]2[C:22]([CH3:23])=[CH:21][S:20][C:16]=2[N:17]=[CH:18][N:19]=1.C(N(CC)CC)C>C(O)C>[CH3:12][O:11][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH2:3][CH:2]([NH:1][C:14]1[C:15]3[C:22]([CH3:23])=[CH:21][S:20][C:16]=3[N:17]=[CH:18][N:19]=1)[CH2:10]2
Reactant: COc1ccc2c(c1)CC(N)C2
Reactant: Cc1csc2ncnc(Cl)c12
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc2c(c1)CC(Nc1ncnc3scc(C)c13)C2
Yield: 12.8 %

Procedure:
Using 2-amino-5-methoxyindan (90 mg) synthesized in b) in the above Preparation Example 1, 4-chloro-5-methylthieno[2,3-d]pyrimidine (90 mg, 0.50 mmol), triethylamine (0.23 ml, 1.7 mmol) and ethanol (1 ml), a similar procedure to b) in Example 19 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to obtain the title compound (20 mg, 0.064 mmol) having the following physical properties:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CCC1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (+/−)-benzyl 3-(tert-butoxycarbonylamino)-4-hydroxypiperidine-1-carboxylate in dichloromethane (0.1 M solution) was added Dess-Martin periodinane (1.5 equiv.). The reaction mixture was stirred at room temperature for 16 h. Then, the saturated NaHCO3 and 0.1 N Na2S2O3 aqueous solutions were added to the reaction mixture, which was stirred for 30 min and worked up with ethyl acetate. The crude benzyl 3-(tert-butoxycarbonylamino)-4-oxopiperidine-1-carboxylate was purified by flash chromatography (30% EtOAc in hexanes, 70%). LCMS (m/z): 249.2 (MH+); LC Rt=3.98 min. 1H NMR (CDCl3): 1.41 (1H, s), 2.1-2.59 (1H, m), 2.73 (1H, m), 3.09 (1H, m), 4.30 (1H, m), 4.52 (1H, m), 4.90 (1H, m), 5.19 (2H, m), 5.45 (1H, m), 7.39 (5H, m).
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:11])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[Cl:12][C:13]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:14]=1[O:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH:20]=[CH:19][O:18]1>C(OCC)C.O=P(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:12][C:13]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:14]=1[O:15][CH2:16][C@@H:17]1[O:18][C@@H:19]([O:11][CH:3]([C:4]2[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=2)[CH2:2][Br:1])[CH2:20][CH2:21][CH2:22]1
Reactant: OC(CBr)c1ccc(Cl)cc1
Reactant: Clc1ccc(OCC2CCC=CO2)c(Cl)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Clc1ccc(C(CBr)O[C@H]2CCC[C@H](COc3ccc(Cl)cc3Cl)O2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.3 %

Procedure:
To a solution of 259 mg of α-bromomethyl-4-chlorobenzyl alcohol and 311 mg of 2-(2,4-dichlorophenoxymethyl)-3,4-dihydro-2H-pyran in 6 ml of diethyl ether was added one drop of phosphorus oxytrichloride, and the mixture was stirred at room temperature for 1 day. After 3 drops of triethylamine had been added, the solvent was evaporated off under reduced pressure and the residue was purified by column chromatography through silica gel eluted with a 5:50:11 by volume mixture of benzene, hexane and ethyl acetate, to give 147 mg of the isomer of lesser polarity of trans-6-(2,4-dichlorophenoxymethyl)-2-[2-bromo-1-(4-chlorophenyl)ethoxy]tetrahydropyran melting at 86°-87° C., 165 mg of the isomer of greater polarity melting at 97°-98° C., and 80 mg of a mixture thereof.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C[N:8](C)[CH:9]=[O:10].[CH3:12][C:13]1[N:17]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[N:16]=[CH:15][C:14]=1C(O)=O>ClCCl.O>[CH3:12][C:13]1[N:17]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=2)[N:16]=[CH:15][C:14]=1[C:9]([NH2:8])=[O:10]
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(C(F)(F)F)cc1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Product: Cc1c(C(N)=O)cnn1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (3.8 ml) and N,N-dimethylformamide (catalytic amounts) were added at room temperature to a solution of 5-methyl-1-[4-(trifluoromethyl)phenyl]-1H-pyrazole-4-carboxylic acid (3.0 g) described in Reference Example 23 in dichloromethane (50 ml) and stirred at room temperature for two hours. The solvent and an excess amount of oxalyl chloride were evaporated, tetrahydrofuran (50 ml) was added to the residue, 28% aqueous ammonia was added under ice-cooling, and stirred at room temperature for two hours. After the reaction, the reaction solution was diluted with water and extracted with ethyl acetate. The resulting organic layer was washed with 1N hydrochloric acid aqueous solution, 4N aqueous solution of sodium hydroxide, water and saturated brine successively, dried over anhydrous sodium sulfate and concentrated to give 5-methyl-1-[4-(trifluoromethyl)phenyl]-1H-pyrazole-4-carboxamide (2.92 g) as a pale brown solid.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:17][C:18]1[N:19]=[C:20]([NH2:23])[S:21][CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:17][C:18]1[N:19]=[C:20]([NH:23][C:2]2[C:7]([O:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]#[N:12])=[CH:6][CH:5]=[CH:4][N:3]=2)[S:21][CH:22]=1
Reactant: Cc1csc(N)n1
Reactant: N#Cc1ccccc1Oc1cccnc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1csc(Nc2ncccc2Oc2ccccc2C#N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
A 50 mL round bottom flask was charged with 2-(2-chloropyridin-3-yloxy)benzonitrile (0.667 g, 2.89 mmol), 4-methylthiazol-2-amine (0.300 g, 2.63 mmol), potassium phosphate (0.614 g, 2.89 mmol) and toluene (7 mL). The reaction mixture was degassed with nitrogen. Tris(dibenzylideneacetone)-dipalladium (0) (0.0602 g, 0.0657 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.0418 g, 0.0723 mmol) were added, and the reaction mixture was degassed with nitrogen. The reaction mixture was warmed to 90° C. and degassed water (2 mL) was added. The reaction mixture was stirred at 90° C. overnight. Water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography using 10-40% ethyl acetate in hexanes as eluent to afford the title compound as a yellow solid (0.385 g, 46.6% yield). 1H NMR (CDCl3) δ 8.19 (dd, 1H), 7.68 (dd, 1H), 7.49 (m, 1H), 7.19 (dd, 1H), 7.15 (dd, 1H), 6.85 (m, 2H), 6.39 (m, 1H), 2.29 (d, 3H); Mass spectrum (esi) m/z=309 (100).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=2)(Cl)Cl)[CH:5]=[CH:6][CH:7]=1.[F:18][C:19]1[CH:24]=[C:23]([OH:25])[C:22]([OH:26])=[CH:21][C:20]=1[C:27]([N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:28]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=3)[O:25][C:23]3[CH:24]=[C:19]([F:18])[C:20]([C:27]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:28])=[CH:21][C:22]=3[O:26]2)[CH:5]=[CH:6][CH:7]=1
Reactant: ClC(Cl)(c1cccc(Br)c1)c1cccc(Br)c1
Reactant: O=C(c1cc(O)c(O)cc1F)N1CCOCC1
Product: O=C(c1cc2c(cc1F)OC(c1cccc(Br)c1)(c1cccc(Br)c1)O2)N1CCOCC1

Procedure:
79 mg bis-(3-bromophenyl)-dichloromethane and 48 mg (2-fluoro-4,5-dihydroxy-phenyl)-morpholin-4-yl-methanone were heated to 180° C. for one hour. Chromatography of the dark residue gave 30 mg of an off-white waxy solid, MS: m/e=564 ([M+H])+.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10](S(C)=O)[N:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]1=[O:16])[CH3:2].[O:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1>C(OCC)(=O)C>[CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:27][C:26]3[CH:25]=[CH:24][C:23]([N:20]4[CH2:21][CH2:22][O:17][CH2:18][CH2:19]4)=[CH:29][CH:28]=3)[N:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]1=[O:16])[CH3:2]
Reactant: CCn1c(=O)ccc2cnc(S(C)=O)nc21
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: CCOC(C)=O
Product: CCn1c(=O)ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nc21
Temperature: 175 °C

Procedure:
A mixture of 8-ethyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (136 mg, 0.57 mmol) and 4-morpholinoaniline (205 mg, 1.15 mmol) was heated at 175° C. for 10 minutes then cooled to room temperature, and ethyl acetate was added. The precipitate was collected by filtration and purified by flash chromatography eluting with ethyl acetate. The fractions containing product were concentrated, and ethyl acetate and hexane were added to the residue. The resultant precipitate was collected by filtration to give 114 mg (57%) yield of 8-ethyl-2-(4-morpholin-4-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, mp 227-228° C.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=3[F:51])[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH2:52][OH:53])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O>ClCCl>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=3[F:51])[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH:52]=[O:53])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: ClCCl
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](C=O)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Temperature: 25 °C
Yield: 98.3 %

Procedure:
To a solution of [(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl) methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 23j (4.20 g, 5.64 mmol) in dichloromethane (70 mL) was added 2-iodoxybenzoic acid (4.70 g, 16.91 mmol) at room temperature. The mixture was refluxed for 36 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was washed with saturated sodium chloride (50 mL×3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 23k as a yellow solid (4.12 g, 97.8%). This material was not further purified.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](Cl)=[CH:9][C:8]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][N:6]=1)=[O:4].[CH2:20]([Sn](CCCC)(CCCC)CCCC)[CH:21]=[CH2:22]>C1(C)C=CC=CC=1.CCOC(C)=O.[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>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH2:22][CH:21]=[CH2:20])=[CH:9][C:8]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ncc(COc2ccccc2)cc1Cl
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCc1cc(COc2ccccc2)cnc1C(=O)OC
Temperature: 125 °C
Reaction time: 20 h
Yield: 83.4 %

Procedure:
Tetrakis (triphenylphosphine) palladium (0) (54 mg, 0.046 mmol) was added to a stirred solution of 3-chloro-5-phenoxymethyl-pyridine-2-carboxylic acid methyl ester (130 mg, 0.47 mmol) and allyltri-n-butyltin (0.25 mL, 0.79 mmol) in degassed toluene (1.5 mL) under nitrogen. The mixture was stirred at 125° C. for 20 h. Then further tetrakis (triphenylphosphine) palladium (0) (54 mg, 0.046 mmol) and allyltri-n-butyltin (0.25 mL, 0.79 mmol) were added and the mixture was stirred at 125° C. for 16 h. The mixture was diluted with EtOAc, filtered through a diatomaceous earth pad. The filtrate was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; EtOAc in DCM 0/100 to 100/0). The desired fractions were collected and the solvents evaporated in vacuo to yield 3-allyl-5-phenoxymethyl-pyridine-2-carboxylic acid methyl ester (111 mg, 84% yield) as a yellow oil.