Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:25][CH2:26][C:27]1[C:28]([OH:35])=[N:29][C:30]([CH3:34])=[CH:31][C:32]=1[CH3:33]>ClCCl>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:25][CH2:26][C:27]2[C:28]([OH:35])=[N:29][C:30]([CH3:34])=[CH:31][C:32]=2[CH3:33])=[O:15])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(Cc3ccccc3)cc2)c(O)n1
Temperature: 25 °C
Yield: 28.9 %

Procedure:
A mixture of 4-benzoylbenzoic acid (106 mg, 0.5 mmol), o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylluroniumhexafluorophosphate (285 mg, 0.75 mmol), triethylamine (152 mg, 1.5 mmol) and dichloromethane (15 mL) were stirred at 25° C. for half an hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (76 mg, 0.5 mmol) was added. The mixture was stirred at 25° C. for 12 hours. The resultant mixture was washed with water (20 mL). The organic phase was separated, dried over sodium, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give 4-benzyl-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide as a white solid (50 mg, 29%). LRMS (M+H+) m/z: 346.17. found 346. HPLC purity (214 nm): 97%. 1H NMR (300 MHz, d6-DMSO): δ 11.50 (s, 1H), 8.29 (t, J=4.8 Hz, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.28-7.13 (m, 7H), 5.85 (s, 1H), 4.30 (d, J=4.8 Hz, 2H), 3.96 (s, 2H), 2.16 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[O:20][CH2:19][CH2:18][N:17]([CH2:21][CH2:22][CH3:23])[CH2:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH2:21]([N:17]1[CH2:18][CH2:19][O:20][CH:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[CH2:16]1)[CH2:22][CH3:23]
Reactant: CCCN1CCOC(c2ccc(OCc3ccccc3)cc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCCN1CCOC(c2ccc(O)cc2)C1
Temperature: 80 °C
Yield: 70.9 %

Procedure:
Benzyl ether from example 28 (3.0 g, 9.64 mmol) was dissolved in methanol (150 ml) and 10% palladium on charcoal (800 mg) was added. The reaction mixture was stirred for a few minutes before ammonium formate (6.17 g, 96.4 mmol) was added portionwise. The reaction mixture was carefully heated to 80° C. until gas evolution had ceased. After cooling the reaction mixture was filtered through arbacel, washed with methanol (50 ml) and concentrated in vacuo to give the title compound as a white crystalline solid (1.51 g, 6.83 mmol, 71%). 1H NMR (CDCl3, 400 MHz) δ: 0.91 (t, 3H), 1.58 (q, 2H), 2.10 (t, 1H), 2.22 (t 1H), 2.40 (dd, 2H), 2.81 (d, 1H), 2.93 (d, 1H), 3.85 (t, 1H), 4.02 (dd, 1H), 4.57 (d, 1H), 6.79 (d 2H), 7.21 (d 2H). LRMS: m/z 222 (M-H+).
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1([C:45]([O:47][CH2:48][CH:49]=[CH2:50])=[O:46])[O:11][C:10]2[CH:12]=[CH:13][C:14]([CH2:16][C@H:17]([N:19]([CH2:28][C@H:29]([O:37][Si](C(C)(C)C)(C)C)[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=3)[C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21])[CH3:18])=[CH:15][C:9]=2[O:8]1)=[O:6])[CH:2]=[CH2:3].F.N1C=CC=CC=1>C1COCC1>[CH2:48]([O:47][C:45]([C:7]1([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[O:11][C:10]2[CH:12]=[CH:13][C:14]([CH2:16][C@H:17]([N:19]([CH2:28][C@@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=3)[OH:37])[C:20]([O:22][CH2:23][C:24]([Cl:25])([Cl:27])[Cl:26])=[O:21])[CH3:18])=[CH:15][C:9]=2[O:8]1)=[O:46])[CH:49]=[CH2:50]
Reactant: C=CCOC(=O)C1(C(=O)OCC=C)Oc2ccc(C[C@@H](C)N(C[C@H](O[Si](C)(C)C(C)(C)C)c3cccc(Cl)c3)C(=O)OCC(Cl)(Cl)Cl)cc2O1
Agent: F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=CCOC(=O)C1(C(=O)OCC=C)Oc2ccc(C[C@@H](C)N(C[C@H](O)c3cccc(Cl)c3)C(=O)OCC(Cl)(Cl)Cl)cc2O1
Temperature: 25 °C
Reaction time: 22 h
Yield: 83 %

Procedure:
To a 0° C. solution of 650 mg (0.82 mmol) 5-{(2R)-2-[[(2R)-2-(tert-butyl-dimethyl-siloxy)-2-(3-chloro-phenyl)-ethyl]-(2,2,2-trichloro-ethoxycarbonyl)-amino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid diallyl ester and 20 mL THF was added 1.0 mL of HF·pyridine, and the reaction mixture was warmed to room temperature. After 22 h, TLC indicated that some starting material remained (Rf =0.62 (2/1 hexanes/EtOAc), and an additional 1.0 mL of HF·pyridine was added. After a total of 26 h, TLC indicated the disappearance of starting material and the formation of the title compound (Rf =0.28 (2/1 hexanes/EtOAc). The reaction mixture was slowly quenched with 30 mL of sat. aq. NaHCO3, extracted with 2×75 mL Et2O and then with 1×75 mL EtOAc. The combined organics were washed with 1×100 mL brine, dried over MgSO4, filtered and evaporated to a colorless oil. Flash chromatography on silica gel, eluting with hexanes/EtOAc (2/1), gave 460 mg (0.68 mmol, an 83% yield) of the title compound (Rf =0.28; 2/1 hexanes/EtOAc) as a colorless oil; 1H NMR (300 MHz, CDCl3): δ 1.20-1.37 (m, 3H), 2.60-2.78 (m, 2H), 2.80-2.91 (m, 1H), 2.98-3.18 (m, 1H), 3.23-3.40 (m, 1H), 3.41-3.54 (m, 2H), 4.10-4.26 (br m, 1H), 4.73-4.92 (5H), 5.22-5.40 (complex m, 4H), 5.81-5.98 (complex m, 2H), 6.62-6.87 (m, 4H), 7.17-7.41 (m, 3H); MS (ES) m/z (relative intensity): 700 (M+ +Na, 100).
Reaction SMILES: [CH3:1][C:2]([NH:20][S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])=[O:22])([CH3:19])[C:3]([NH:5][CH:6]1[CH:13]2[CH2:14][C:9]3([C:16]([O-:18])=[O:17])[CH2:10][CH:11]([CH2:15][CH:7]1[CH2:8]3)[CH2:12]2)=[O:4].C1COCC1.CO.O[Li].O>O>[CH3:19][C:2]([NH:20][S:21]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)(=[O:23])=[O:22])([CH3:1])[C:3]([NH:5][CH:6]1[CH:13]2[CH2:14][C:9]3([C:16]([OH:18])=[O:17])[CH2:10][CH:11]([CH2:15][CH:7]1[CH2:8]3)[CH2:12]2)=[O:4]
Reactant: CC(C)(NS(=O)(=O)c1ccccc1)C(=O)NC1C2CC3CC1CC(C(=O)[O-])(C3)C2
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(NS(=O)(=O)c1ccccc1)C(=O)NC1C2CC3CC1CC(C(=O)O)(C3)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 49.3 %

Procedure:
Into a 50-mL flask, 4-(2-methyl-2-(phenylsulfonamido)propanamido)adamantane-1-carboxylate (500 mg, 1.94 mmol) was charged, and dissolved through addition of THF (6 ml), and methanol (6 ml). LiOH.H2O dissolved in H2O (6 ml) was added thereto, followed by stirring for 12 hours at room temperature. After the stirring for 12 hours, the resultant solution was vacuum-evaporated, acidified with 2N—HCl to pH 1˜2, and extracted with addition of EA (20 ml). The organic layer was dried with MgSO4, and filtered. Then, through vacuum distillation, the solvent was removed so as to obtain 4-(2-methyl-2-(phenylsulfonamido)propanamido)adamantane-1-carboxylic acid compound (402 mg, 85%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][SH:8])=[CH:3][CH:2]=1.Cl[CH2:10][CH2:11][OH:12].BrCCO.C1OC1>>[OH:12][CH2:11][CH2:10][S:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: OCCCl
Reactant: SCc1ccncc1
Agent: OCCBr
Solvent: C1CO1
Product: OCCSCc1ccncc1

Procedure:
By following the method of Examples 11-15, 4-picolyl mercaptan is reacted with 2-chloroethanol, 2-bromoethanol or ethylene oxide to yield 4-(2-hydroxyethylthiomethyl)pyridine, with 2-bromo-1-propanol to yield 4-(2-hydroxy-1-propylthiomethyl)pyridine, with 1-chloro-2-propanol to yield 4-(1-hydroxy-2-propylthiomethyl)pyridine, with bromoacetaldehyde diethyl acetal (followed by acid catalyzed hydrolysis) to yield 4-picolylthioacetaldehyde, with 3-bromo-2-butanol to yield 4-(3-hydroxy-2-butylthiomethyl)pyridine, with ethyl 2-bromoacetate to yield ethyl 4-picolylthioacetate, with ethyl 2-chloropropionate to yield ethyl 2-(4-picolylthio)acetate and with methyl 2-phenyl-2-bromoacetate to yield methyl phenyl(4-picolylthio)acetate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[CH:15]=[C:14]([C:16]4[S:17][C:18]5[C:24]([C:25]6[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=6)=[C:23]([C@H:32]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:22]([CH3:43])=[CH:21][C:19]=5[N:20]=4)[CH:13]=[CH:12][N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:51][CH3:52]>CN(C=O)C>[C:39]([O:38][C@@H:32]([C:23]1[C:22]([CH3:43])=[CH:21][C:19]2[N:20]=[C:16]([C:14]3[CH:13]=[CH:12][N:11]=[C:10]([C:6]4[CH:5]=[C:4]5[C:9](=[CH:8][CH:7]=4)[N:1]([CH2:51][CH3:52])[N:2]=[CH:3]5)[CH:15]=3)[S:17][C:18]=2[C:24]=1[C:25]1[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=1)[C:33]([O:35][CH2:36][CH3:37])=[O:34])([CH3:42])([CH3:41])[CH3:40]
Reactant: CCI
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5[nH]ncc5c4)c3)sc2c1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5c(cnn5CC)c4)c3)sc2c1-c1ccc(Cl)cc1

Procedure:
To a solution of (S)-ethyl 2-(2-(2-(1H-indazol-5-yl)pyridin-4-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (32 mg, 0.052 mmol) in DMF (1 mL), was added Cs2CO3 (34 mg, 0.104 mmol), iodoethane (5 μL, 0.062 mmol). The reaction was reacted at room temperature. After the reaction finished, the reaction mixture was washed by water, extracted by EtOAc, the organic phase was dried over MgSO4, filtered, concentrated down, purified by silica gel column, eluting by 0-100% EtOAc in hexanes to give (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-(1-ethyl-1H-indazol-5-yl)pyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate. LCMS-ESI+: calc'd for C36H35ClN4O3S: 639.2 (M+H+). found: 639.4;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[CH:19]=[CH:20][NH:21][C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1.[C:23](O)(=[O:25])[CH3:24]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[CH:19]=[CH:20][N:21]([C:23](=[O:25])[CH3:24])[C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1
Reactant: CC1c2[nH]ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1
Reactant: CC(=O)O
Product: CC(=O)n1ccc2c1C(C)N(C(=O)c1cc3ncc(Br)cn3n1)CC2

Procedure:
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-methyl-1,4,5,7-tetrahydro-pyrrolo[2,3-c]pyridin-6-yl)-methanone is reacted with acetic acid to provide the title compound.
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH2:11][C:12]([OH:14])=[O:13])=[C:5]([F:15])[CH:4]=1)#[N:2].S(Cl)(Cl)=O.[CH3:20]O>>[C:1]([C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH2:11][C:12]([O:14][CH3:20])=[O:13])=[C:5]([F:15])[CH:4]=1)#[N:2]
Reactant: CO
Reactant: COc1cc(CC(=O)O)c(F)cc1C#N
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cc(OC)c(C#N)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (4-cyano-2-fluoro-5-methoxyphenyl)acetic acid (5.0 g, 24 mmol) in methanol (50 mL) at 0° C. was added thionyl chloride (2.3 mL, 31 mmol) drop-wise. The mixture warmed slowly to rt and stirred 12 h, then was concentrated in vacuo and dried under high vacuum to provide methyl (4-Cyano-2-fluoro-5-methoxyphenyl)acetate. 1H NMR (500 MHz, CD3OD) δ 7.35 (d, J=5.3 Hz, 1H), 7.19 (d, J=5.4 Hz, 1H), 3.96 (s, 3H), 3.82 (s, 3H), 3.81 (s, 2H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH:9][CH:10]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13])[C:3]=1[O:20][CH2:21][CH:22]([OH:24])[CH3:23].[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.C(OCC)(=O)C>N1C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH:9][CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:16]([O:18][CH3:19])=[O:17])[C:3]=1[O:20][CH2:21][CH:22]([O:24][S:31]([C:28]1[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=1)(=[O:33])=[O:32])[CH3:23]
Reactant: COC(=O)C(=CNc1ccc(F)c(F)c1OCC(C)O)C(=O)OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)C(=CNc1ccc(F)c(F)c1OCC(C)OS(=O)(=O)c1ccc(C)cc1)C(=O)OC
Temperature: 5 °C
Reaction time: 72 h
Yield: 92.2 %

Procedure:
To a solution of 2.07 g of the compound obtained in Example 6 in 4.2 ml of pyridine was added 1.49 g of p-toluenesulfonyl chloride and the mixture was stirred at an external temperature of 5° C. for 3 days. To the mixture was added ethyl acetate, and the solution was washed successively with 1 N hydrochloric acid, a saturated sodium bicarbonate aqueous solution and water, and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography to yield 2.76 g of the titled compound.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][N:10]=[C:11]=[S:12]>C1C=CC=CC=1>[CH3:9][NH:10][C:11](=[S:12])[NH:8][NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN=C=S
Reactant: NNc1ccccc1
Solvent: c1ccccc1
Product: CNC(=S)NNc1ccccc1
Yield: 67.4 %

Procedure:
In 500 ml of benzene was dissolved 108 g of phenylhydrazine, and 73 g of methyl isothiocyanate was added dropwise to the solution, followed by heat refluxing. As the reaction proceeded, crystals were preicpitated. The thus formed crystals were filtered and dried to obtain 122 g of 4-methyl-1-phenylthiosemicarbazide.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:6]=[C:5]1[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl.C(=O)(O)[O-].[Na+]>[CH3:35][S:36]([O:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([CH:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:6]=[C:5]1[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C3CCOCC3)cn2CCO)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C3CCOCC3)cn2CCOS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Combine tert-butyl 4-(1-(2-hydroxyethyl)-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate (4.40 g, 11.60 mmol) and triethylamine (4.9 mL, 3.0 eq) in dichloromethane (72 mL). Cool to 0° C. and add methanesulfonyl chloride (1.1 mL, 1.2 eq). After 1 hour, dilute with additional dichloromethane and saturated aqueous sodium bicarbonate. Separate the layers. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo to give the title compound as a light yellow solid (5.05 g, 95%). MS (ES) m/z=458 [M]+.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>CO.O.O1CCCC1>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:12]=[CH:13][C:14]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:15][CH:16]=2)[C:3]([OH:25])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(C#Cc2ccccn2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCC1)c1ccc(C#Cc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 98 %

Procedure:
A solution of 3-cyclopentyl-2-(4-pyridin-2-ylethynyl-phenyl)-propionic acid methyl ester (930 mg, 2.79 mmol) in methanol (5 mL), water (2 mL) and tetrahydrofuran (1 mL) was treated with lithium hydroxide (80 mg, 1.90 mmol). The reaction mixture was stirred at 25° C. for 60 h. At this time, additional lithium hydroxide (100 mg, 2.38 mmol) was added. The reaction was stirred at 25° C. for 3 h. At this time, the reaction was diluted with water (10 mL) and then concentrated in vacuo. The resulting aqueous layer was washed with ethyl acetate (2×10 mL), acidified with a 1N aqueous hydrochloric acid solution, and then extracted with ethyl acetate (2×25 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to afford 3-cyclopentyl-2-(4-pyridin-2-ylethynyl-phenyl)-propionic acid (873 mg, 98%) as an amber solid: mp 143-147° C.; EI-HRMS m/e calcd for C21H21NO2 (M+) 319.1572, found 319.1580.
Reaction SMILES: CO[C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:7][N:6]=1)=[O:4].[NH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28].C[O-].[Na+]>>[CH2:16]([N:12]1[C:13]2[C:8](=[CH:7][N:6]=[C:5]([C:3]([NH:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:4])[C:14]=2[OH:15])[CH:9]=[CH:10][C:11]1=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2ccc(=O)n(Cc3ccccc3)c2c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2ccc(=O)n(Cc3ccccc3)c2c1O
Yield: 53.6 %

Procedure:
A mixture of 1-benzyl-8-hydroxy-2-oxo-1,2-dihydro-[1,6]naphthyridine-7-carboxylic acid methyl ester (19 mg, 0.061 mmol), β-alanine (726 mg, 8.15 mmol) and NaOMe solution (12.3 mL, 6.113 mmol, 0.5 M in MeOH) was refluxed for 16 h. Solvent was evaporated in vacuo, and the residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 1 with 4 M HCl, and the resulting precipitate was collected by filtration and dried to give 12 mg of the title compound as a pale pink solid. MS: (+) m/z 368.33 (M+1).
Reaction SMILES: CC(C)([O-])C.[K+].C[C:8]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12](=[O:13])[N:11](NC2C=CC=CC=2)[C:10]([S:21][CH3:22])=[N:9]1.CI.O>O1CCCC1>[CH3:22][S:21][C:10]1[NH:11][C:12](=[O:13])[CH:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:9]=1
Reactant: CSC1=NC(C)(c2ccccc2)C(=O)N1Nc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: CSC1=NC(c2ccccc2)C(=O)N1
Temperature: 0 °C
Yield: 110.6 %

Procedure:
0.4 g (3.5 mmol) of potassium tert-butoxide is added to a solution of 4-methyl-1-phenylamino-2-methylthio-4-phenyl-2-imidazolin-5-one (Compound 9) (1 g, 3.2 mmol) in anhydrous tetrahydrofuran (30 ml), cooled beforehand to 0° C. The mixture is left to react for 0.5 hour at 0° C. 0.5 g (3.5 mnol) of methyl iodide is then added and then the mixture is left to react for 0.5 hour at room temperature. The reaction mixture is poured into 100 ml of water and the product is extracted with 100 ml of diethyl ether. The ethereal solution is dried over magnesium sulfate and then concentrated. The product crystallizes when triturated in 10 ml of diisopropyl ether. It is filtered and then dried under vacuum. 0.73 g (yield: 70%) of Compound 22 is thus obtained in the form of a pale-yellow powder melting at 124° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[CH:11]=1)[F:9])[O:5][CH2:6][CH3:7])[CH3:2].CC1CCCC(C)N1.[F:25][CH:26]([F:36])[O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[CH:35])=[CH:30][CH:29]=1>[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.O>[CH2:1]([O:3][P:4]([CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:35]#[C:34][C:31]2[CH:30]=[CH:29][C:28]([O:27][CH:26]([F:25])[F:36])=[CH:33][CH:32]=2)[CH:11]=1)[F:9])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: C#Cc1ccc(OC(F)F)cc1
Reactant: CCOP(OCC)C(F)c1cccc(Br)c1
Agent: [Pd]
Agent: CC1CCCC(C)N1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: CCOP(OCC)C(F)c1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 53.4 %

Procedure:
A mixture of diethyl[(3-bromophenyl)(fluoro)methyl]phosphonite (5.5 g, 17.0 mmol), 2,6-dimethylpiperidine (10 mL), and 1-(difluoromethoxy)-4-ethynylbenzene (3.38 g, 20.4 mmol) was degassed with argon for 5 minutes. Then, tetrakis(triphenylphosphine) palladium (0) (983 mg, 0.85 mmol) was added and the mixture was stirred at 80° C. for 5 hours. The mixture was poured into water and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by ICSO (hexane/EtOAc 1/1) gave diethyl[(3-{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)(fluoro)methyl]phosphonite (3.6 g) as a clear oil; MS m/e (M+H)+ 413.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[NH2:10][C:11]1[N:12]([CH2:25][CH3:26])[C:13]2[C:18]([C:19](=[O:23])[C:20]=1[C:21]#[N:22])=[CH:17][CH:16]=[C:15]([I:24])[CH:14]=2>COCCOC.Cl[Cu]>[NH2:10][C:11]1[N:12]([CH2:25][CH3:26])[C:13]2[C:18]([C:19](=[O:23])[C:20]=1[C:21]([NH:6][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2])=[NH:22])=[CH:17][CH:16]=[C:15]([I:24])[CH:14]=2
Reactant: CCOC(CN)OCC
Reactant: CCn1c(N)c(C#N)c(=O)c2ccc(I)cc21
Agent: Cl[Cu]
Solvent: COCCOC
Product: CCOC(CNC(=N)c1c(N)n(CC)c2cc(I)ccc2c1=O)OCC

Procedure:
0.38 g (2.86 mmol) of aminoacetaldehyde diethylacetal and 0.155 g (1.57 mmol) of CuCl were added to 0.48 .g (1.43 mmol) of 2-amino-1-ethyl-7-iodo-4-oxo-1,4-dihydro-quinoline-3-carbonitrile dissolved in 20 ml of DME. The solution was stirred and irradiated with microwaves for 0.5 hour at 100° C.
Reaction SMILES: [N+:1](=[CH2:3])=[N-:2].[CH2:4]([O:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][C:9]=1[CH:14]=[CH2:15])[CH3:5].C(O)(=O)C>C(OCC)C>[CH2:4]([O:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][C:9]=1[CH:14]1[CH2:15][CH2:3][N:1]=[N:2]1)[CH3:5]
Reactant: C=[N+]=[N-]
Reactant: C=Cc1ncccc1C(=O)OCC
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)c1cccnc1C1CCN=N1
Reaction time: 8 h

Procedure:
An excess of diazomethane in diethylether is added to 3.35 g of 2-vinylnicotinic acid ethyl ester and stirred at -10° overnight. Acetic acid is added until gas evolution ceases and the solvent is removed by evaporation under vacuum.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH2:5][C:6]1[C:7](Cl)=[N:8][C:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][CH:11]=1.[CH2:29]([NH2:33])[CH:30]([CH3:32])[CH3:31]>>[CH2:29]([N:33]1[C:7]2[N:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[CH:11][C:6]=2[CH2:5][CH:4]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[C:3]1=[O:2])[CH:30]([CH3:32])[CH3:31]
Reactant: CC(C)CN
Reactant: COC(=O)C(Cc1cnc(Nc2ccccc2)nc1Cl)c1ccc(OC)cc1
Product: COc1ccc(C2Cc3cnc(Nc4ccccc4)nc3N(CC(C)C)C2=O)cc1

Procedure:
A mixture of 3-(4-chloro-2-phenylamino-pyrimidin-5-yl)-2-(4-methoxy-phenyl)-propionic acid methyl ester (40 mg, 0.1 mmol) (from Example 12a supra) and isobutylamine (2.0 mL) (Aldrich) was heated at reflux for 3 hours. The reaction mixture was concentrated in vacuo and purified by preparative thin layer chromatography to give 8-isobutyl-6-(4-methoxy-phenyl)-2-phenylamino-5,8-dihydro-6H-pyrido[2,3-d]pyrimidine-7-one; (Yield 4.6 mg, 11.4%); and 3-(2-phenylamino-4-isobutylamino-pyrimidin-5-yl)-2-(4-methoxy-phenyl)-propionic acid methyl ester. (Yield 18.2 mg, 41.9%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.BrCC1CCCCO1.[Cl:17][C:18]1[C:19]2[O:39][CH2:38][C:28]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:37])[C:20]=2[C:21]2[O:26][CH2:25][CH2:24][O:23][C:22]=2[CH:27]=1.N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[Cl:17][C:18]1[C:19]2[O:39][CH2:38][C:28]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]([CH2:2][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=4)[C:29]3=[O:37])[C:20]=2[C:21]2[O:26][CH2:25][CH2:24][O:23][C:22]=2[CH:27]=1
Reactant: BrCc1ccccn1
Reactant: O=C1Nc2ccccc2C12COc1c(Cl)cc3c(c12)OCCO3
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1c(Cl)cc3c(c12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(bromomethyl)pyridine to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 6-chloro-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 6-chloro-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one was obtained (81%) as a colorless solid: mp 197-199° C.; 1H NMR (300 MHz, CDCl3) δ8.60 (d, J=2.1 Hz, 1H), 7.60 (ddd, J=7.5, 7.5, 1.5 Hz, 1H), 7.32 (d, J=7.5 Hz, 1H), 7.25-7.15 (m, 3H), 7.02 (dd, J=7.5, 7.5 Hz, 1H), 6.83 (d, J=7.5 Hz, 1H), 6.79 (s, 1H), 5.35 (d, J=16.2 Hz, 1H), 5.00 (d, J=9.3 Hz, 1H), 4.89 (d, J=16.2 Hz, 1H), 4.74 (d, J=9.0 Hz, 1H), 4.16-3.86 (m, 4H); 13C NMR (75 MHz, CDCl3) δ175.9, 155.8, 151.7, 149.5, 141.8, 138.6, 138.3, 136.7, 130.9, 128.9, 123.6, 123.4, 122.6, 121.4, 118.2, 116.8, 109.4, 106.8, 81.7, 64.5, 63.8, 57.7, 46.3; MS (ES+) m/z 421.2 (M+1), 423.2 (M+1).