Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)(=[O:29])=[O:28])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[Si:37]([O:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59]O)([C:50]([CH3:53])([CH3:52])[CH3:51])([C:44]1C=CC=CC=1)[C:38]1C=CC=CC=1.C(C=P(CCCC)(CCCC)CCCC)#N.C(OCC)(=O)C>C1(C)C=CC=CC=1>[C:50]([Si:37]([O:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][Si:5]([C:1]([CH3:4])([CH3:2])[CH3:3])([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[S:27]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)(=[O:28])=[O:29])([CH3:38])[CH3:44])([CH3:52])([CH3:53])[CH3:51]
Reactant: CC(C)(C)[Si](OCc1ccccc1CS(=O)(=O)c1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](OCCCCCO)(c1ccccc1)c1ccccc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCCCC(c1ccccc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)S(=O)(=O)c1ccc(Cl)cc1
Yield: 67.9 %

Procedure:
The t-butyl [[2-[[(4-chlorophenyl)sulfonyl]methyl]benzyl]oxy]diphenylsilane (1.00 g, 1.87 mmol) obtained in Example 280 and 5-(t-butyldiphenylsilyloxy)-1-pentanol (0.68 ml, 2.8 mmol) were dissolved in toluene (7 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (650 mg, 2.69 mmol). Under an argon atmosphere, the resulting mixture was heated under reflux for 14 hours. After the reaction mixture was allowed to cool down, 5-(t-butyldiphenylsilyloxy)-1-pentanol (0.34 ml, 1.4 mmol) and cyanomethylenetri-n-butylphosphorane (300 mg, 1.24 mmol) were added. Under an argon atmosphere, the resulting mixture was heated under reflux for 10 hours. The reaction mixture was then allowed to cool down. The residue obtained by concentrating the mixture under reduced pressure was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=15:1 eluate was concentrated under reduced pressure, whereby the title compound (932 mg, 1.27 mmol, 68%) was obtained as a pale yellowish brown oil.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=2)[N:16]=1.[OH:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1>CN(C=O)C>[F:21][C:20]([F:23])([F:22])[C:17]1[N:15]2[N:16]=[C:11]([N:34]3[CH2:33][CH2:32][N:31]([C:28]4[CH:27]=[CH:26][C:25]([OH:24])=[CH:30][CH:29]=4)[CH2:36][CH2:35]3)[CH:12]=[CH:13][C:14]2=[N:19][N:18]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: Oc1ccc(N2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Oc1ccc(N2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
DIPEA (12.15 mL, 69.78 mmol) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (10.35 g, 46.52 mmol) and 1-(4-hydroxyphenyl)piperazine (CAS 56621-48-8, 9.12 g, 51.17 mmol) in DMF (80 mL). The resulting solution was stirred at 80° C. for 1 hour. The reaction mixture was cooled to room temperature, evaporated to dryness and the residue re-dissolved in DCM (250 mL). The solution was washed with water (200 mL), dried over MgSO4 and evaporated to afford crude product, which was triturated with diethyl ether. The resulting solid was collected by filtration and dried under vacuum to give 4-[4-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]phenol (14.27 g, 84%) as a solid.
Reaction SMILES: CN([CH:4]=[C:5]([C:11](=O)[CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.Cl.[C:15]([NH2:18])(=[NH:17])[CH3:16].CC[O-].[Na+]>CCO>[CH3:16][C:15]1[N:18]=[C:11]([CH3:12])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:17]=1
Reactant: CC(=N)N
Reactant: CCOC(=O)C(=CN(C)C)C(C)=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc(C)nc1C
Yield: 42.6 %

Procedure:
Intermediate 51 (17.6 g, 95 mmol) and acetamidine hydrochloride (17.6 g, 95 mmol), were dissolved in EtOH and added NaOEt (6.5 g, 95 mmol). This mixture was refluxed for 4 h. After that, ethanol removed on rotavapour followed by work-up (AcOEt/H2O) to obtain the crude. Crude was purified by column chromatography using 60-120 mesh silicagel and AcOEt and Petether (25:75) as eluent to obtain the title compound (7.3 g).
Reaction SMILES: N#N.[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[O:14][C:13]([CH3:15])=[N:12][C:11]=2[C:16]([OH:18])=O)[CH:7]=[CH:8][CH:9]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:33]([Si:37]([CH3:54])([CH3:53])[O:38][CH:39]([C:41]1[O:42][C:43]([CH2:46][N:47]2[N:51]=[C:50]([NH2:52])[CH:49]=[N:48]2)=[CH:44][N:45]=1)[CH3:40])([CH3:36])([CH3:35])[CH3:34]>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[C:33]([Si:37]([CH3:54])([CH3:53])[O:38][CH:39]([C:41]1[O:42][C:43]([CH2:46][N:47]2[N:51]=[C:50]([NH:52][C:16]([C:11]3[N:12]=[C:13]([CH3:15])[O:14][C:10]=3[C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=3)=[O:18])[CH:49]=[N:48]2)=[CH:44][N:45]=1)[CH3:40])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1ncc(Cn2ncc(N)n2)o1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(Cl)c2)o1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: ClCCCl
Product: Cc1nc(C(=O)Nc2cnn(Cc3cnc(C(C)O[Si](C)(C)C(C)(C)C)o3)n2)c(-c2cccc(Cl)c2)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(3-chloro-phenyl)-2-methyl-oxazole-4-carboxylic acid (37 mg, 0.16 mmol) in CH2Cl2 (1.0 mL) was treated at rt with HOBt (25 mg, 0.19 mmol), EDC (74 mg, 0.38 mmol), DMAP (5 mg, 0.04 mmol) and the resulting mixture was stirred at rt for 30 min. 2-{2-[1-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-oxazol-5-ylmethyl}-2H-[1,2,3]triazol-4-ylamine (50 mg, 0.16 mmol) in CH2Cl2 (0.6 mL) was then added and the resulting mixture was stirred at rt for 16 h. CH2Cl2 (20 mL) followed by water (15 mL) were added and the aqueous phase was extracted with CH2Cl2. The combined organic phases were washed with water, brine, dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the title compound as a brown oil. LC-MS-conditions 02: tR=1.24 min, [M+H]+=542.92.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](Cl)=[O:11].[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[NH:14][NH2:15].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH:15][NH:14][C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:11]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(Cl)Cc1ccc(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NNC(=O)Cc1ccc(F)cc1F
Reaction time: 1.5 h

Procedure:
A solution of 2,4-difluorophenylacetyl chloride (10 mmol) in dry DCM (15 ml) was added over 10 min. to a mixture of t-butyl carbazate (1.32 g, 10 mmol) and DIPEA (1.77 ml, 10.2 mmol) in dry DCM (20 ml). After stirring for 1.5 h the mixture was washed with 1M HCl then with aqueous NaHCO3. The organic phase was evaporated to afford 1,1-dimethylethyl 2-[(2,4-difluorophenyl)acetyl]hydrazinecarboxylate as a white solid.
Reaction SMILES: [NH2:1][C:2](=O)[CH:3]([NH:13][C:14](=O)[CH2:15][C:16](O)([CH3:18])[CH3:17])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[O:11][CH3:12].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:10][C:8]1[CH:7]=[CH:6][C:5]([O:11][CH3:12])=[C:4]([C:3]2[N:13]=[C:14]([CH:15]=[C:16]([CH3:18])[CH3:17])[S:31][C:2]=2[NH2:1])[CH:9]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(Cl)cc1C(NC(=O)CC(C)(C)O)C(N)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(Cl)cc1-c1nc(C=C(C)C)sc1N
Temperature: 100 °C
Yield: 22.8 %

Procedure:
A mixture of N-(2-amino-1-(5-chloro-2-methoxyphenyl)-2-oxoethyl)-3-hydroxy-3-methylbutanamide (240 mg, 0.762 mmol), Lawesson's reagent (308 mg, 0.76 mmol) and pyridine (2.5 mL) was heated to 100° C. for 18 hours. After cooling, DCM was added and the mixture washed with water, sodium hydrogen carbamate (sat. aq.) and brine, and concentrated to dryness. 4-(5-chloro-2-methoxyphenyl)-2-(2-methylprop-1-enyl)thiazol-5-amine (51.0 mg) was isolated as a pale yellow solid. LCMS (ESI) m+H=295.3; NMR (400 MHz, DMSO-d6): δ 7.38 (d, 1H); 7.31 (dd, 1H); 7.09 (d, 1H); 6.24 (t, 1H); 5.50 (s, br, 2H); 3.83 (s, 3H); 2.02 (d, 3H); 1.89 (s, 3H).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:53]1[CH:58]=[CH:57][C:56]([OH:59])=[C:55]([NH:60][CH:61]=[O:62])[CH:54]=1)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[CH:22]=[C:23]([S:27]([C:30]2[CH:31]=[C:32]3[C:37](=[C:38]([CH3:40])[CH:39]=2)[N:36]=[CH:35][C:34]([C:41]([NH2:43])=[O:42])=[C:33]3[NH:44][C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([O:51][CH3:52])[CH:46]=2)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:63]OC1C=C(NC2C3C(=C(C)C=C(S(C4C=CC=C(C(=O)N(C)CCCCCC=O)C=4)(=O)=O)C=3)N=CC=2C(N)=O)C=CC=1>>[Si:1]([O:8][C@H:9]([C:53]1[CH:58]=[CH:57][C:56]([OH:59])=[C:55]([NH:60][CH:61]=[O:62])[CH:54]=1)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:63])[C:19]([C:21]1[CH:22]=[C:23]([S:27]([C:30]2[CH:31]=[C:32]3[C:37](=[C:38]([CH3:40])[CH:39]=2)[N:36]=[CH:35][C:34]([C:41]([NH2:43])=[O:42])=[C:33]3[NH:44][C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([O:51][CH3:52])[CH:46]=2)(=[O:28])=[O:29])[CH:24]=[CH:25][CH:26]=1)=[O:20])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c5ccc(O)c(NC=O)c5)c4)cc23)c1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N(C)CCCCCC=O)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N(C)CCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c5ccc(O)c(NC=O)c5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described in Intermediate 167, using Intermediate 114 in place of Intermediate 113. ES/MS calcd. C47H60N6O8SSi 896.4. Found m/z=897 (M+H)+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[NH:8][CH:7]=[C:6]([C:9]([O:11][CH2:12]C)=[O:10])[C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[Br:3][C:4]1[N:8]([S:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:28])=[O:27])[CH:7]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1c[nH]c(Br)c1-c1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cn(S(=O)(=O)c2ccccc2)c(Br)c1-c1ccccc1
Yield: 93 %

Procedure:
Using sodium hydride (60% in oil, 281 mg), ethyl 5-bromo-4-phenyl-1H-pyrrole-3-carboxylate (1.70 g) and benzenesulfonyl chloride (0.9 mL), a procedure as in Reference Example 41 was performed to give the title compound as white crystals (yield 2.51 g, 93%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[C:16]([F:17])=[CH:15][CH:14]=[C:10]([C:11](O)=[O:12])[C:9]=1[C:18](O)=[O:19]>C1COCC1>[F:7][C:8]1[C:16]([F:17])=[CH:15][CH:14]=[C:10]([CH2:11][OH:12])[C:9]=1[CH2:18][OH:19]
Reactant: O=C(O)c1ccc(F)c(F)c1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(F)c(F)c1CO
Yield: 54.3 %

Procedure:
To a suspension of LAH (6.2 g, 0.163 mol) in dry THF (100 ml) is added a solution of compound 3,4-difluoro-phthalic acid (15 g, 0.074 mol) in THF (75 mL), drop wise at 0° C. The resulting mixture is refluxed for 3 h. After 3 h the reaction mixture is cooled and quenched with saturated Na2SO4 solution. Then the reaction mass is filtered through a pad of celite and the bed is washed thoroughly with MeOH. The combined filtrate is concentrated to yield a crude product that is purified by column chromatography (silica, 5% MeOH in DCM). Combination of appropriate fractions followed by removal of the solvent yields white solid (7 g, 54.2%).
Reaction SMILES: [OH:1][N:2]=[C:3]1[C:19](=[O:20])[N:5]2[C:6]([C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12])=[C:7]([CH3:10])[CH2:8][S:9][C@H:4]12.Cl>C(O)C.C(OCC)(=O)C>[OH:1][NH:2][C@@H:3]1[C:19](=[O:20])[N:5]2[C:6]([C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:16])[Cl:17])=[O:12])=[C:7]([CH3:10])[CH2:8][S:9][C@H:4]12
Reactant: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(=NO)[C@H]2SC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](NO)[C@H]2SC1
Reaction time: 3 h
Yield: 78.6 %

Procedure:
In ethanol (0.6 ml) is dissolved 2,2,2-trichloroethyl 7-hydroxyimino-3-methyl-3-cephem-4-carboxylate (100 mg) and under ice-cooling, a solution of borane-pyridine complex (102 mg) in ethanol (0.7 ml) is added. Then, a 2 N-methanolic solution of hydrogen chloride (0.6 ml) is added dropwise in a nitrogen stream and the mixture is stirred at the same temperature for 3 hours. The mixture is further stirred at room temperature for an hour, after which time it is diluted with ethyl acetate, washed with water and aqueous sodium chloride in that order, dried over magnesium sulfate and concentrated under reduced pressure. The oily residue is subjected to silica gel (4.5 g) column chromatography and elution is carried out with ethyl acetate-hexane to give 2,2,2-trichloroethyl 7 β-hydroxyamino-3-methyl-3-cephem-4-carboxylate (79 mg) as an amorphous solid.
Reaction SMILES: O.[S:2]([C:6]1[CH:11]=[CH:10][C:9]([N:12]=[C:13]=[S:14])=[CH:8][CH:7]=1)([OH:5])(=[O:4])=[O:3].[Na:15].C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O.C[N:30](C)CC=C>O>[S:2]([C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13]([NH2:30])=[S:14])=[CH:10][CH:11]=1)([OH:5])(=[O:3])=[O:4].[Na:15]
Reactant: O=S(=O)(O)c1ccc(N=C=S)cc1
Reactant: C=CCN(C)C
Agent: O=C1c2ccccc2C(=O)C1(O)O
Agent: [Na]
Solvent: O
Product: NC(=S)Nc1ccc(S(=O)(=O)O)cc1
Temperature: 53 °C

Procedure:
A Solid sodium 4-sulfophenylisothiocyanate monohydrate (2.55g; 10 mmol) was added to a solution of poly-L-lysine (15-30 K) (Sigma Chemical Company) (1.0 g) in a mixture of water (20 ml) and N,N-dimethyl-N-allylamine buffer (pH 9.5; 15 ml). The resulting mixture was heated under nitrogen at 53° C. for 3 hours, when a ninhydrin test was negative. The cooled mixture was filtered and the filtrate concentrated to give a grey solid residue. The solid residue was redissolved in water and passed through a column of Amberlite IR 120(Na) and then concentrated. The crude product was purified by gel filtration (Sephadex LH20; water) and freeze dried to give sodium 4-sulfophenylthiourea terminated poly-L-lysine BRI2995 as a white fluffy solid (1.25 g).
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Zn+])=[CH:5][CH:4]=1.[CH3:11][O:12][C:13](=[O:39])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2I)[C:22](=[O:31])[C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:15]=1>>[CH3:11][O:12][C:13](=[O:39])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]2[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)/[C:23](=[C:24](/[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)\[CH2:7][C:6]3[CH:9]=[CH:10][C:3]([Cl:2])=[CH:4][CH:5]=3)/[C:22]2=[O:31])[CH:15]=1
Reactant: Clc1ccc(C[Zn+])cc1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2I)c1
Agent: [Br-]
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(/Cc3ccc(Cl)cc3)c3ccccc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 77 starting from 4-chloro-benzylzinc bromide (commercially available) and 3-{[(2-iodo-phenyl)-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (300 Hz, CDCl3): δppm 3.92 (s, 3H), 4.73 (s, 2H), 5.07 (s, 2H), 5.99 (d, 1H), 6.58-6.65 (m, 2H), 7.08-7.20 (m, 7H), 7.37-7.43 (m, 4H), 7.52 (d, 1H), 7.93 (d, 1H), 8.06 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1(C(OCC)=O)[CH:8]([CH:9]=[C:10]([Cl:12])[Cl:11])[C:7]1([CH3:14])[CH3:13])=[O:5])[CH3:2].O=P1(C)CCC=C1.[Cl-].[Na+]>O>[CH2:1]([O:3][C:4]([CH:6]1[CH:8]([CH:9]=[C:10]([Cl:11])[Cl:12])[C:7]1([CH3:13])[CH3:14])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(=O)OCC)C(C=C(Cl)Cl)C1(C)C
Agent: CP1(=O)C=CCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C1C(C=C(Cl)Cl)C1(C)C
Yield: 89.8 %

Procedure:
30 g (0.1 mol) of 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropane-1,1-dicarboxylic acid diethyl ester, 50 ml of 1-oxo-1-methyl-phospholine, 6 g of sodium chloride and 4 ml of water were heated to 175° C. for 9 hours. The mixture was then cooled, poured into 150 ml of water and extracted with petroleum ether. After drying with MgSO4, the mixture was fractionally distilled. 21.3 g (=90% of theory) of 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropane-1-carboxylic acid ethyl ester of boiling point 65°-75° C./0.1 mm Hg were obtained. 49.7 g of 1-oxo-1-methyl-phospholine of boiling point 75°-77° C./0.15 mm Hg were recovered by fractional distillation of the aqueous phase.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].F[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>CN(C=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: N#Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C#N)cc2)CC1
Temperature: 50 °C
Yield: 51.5 %

Procedure:
Add a solution of N-Boc-4-hydroxypiperidine (3.0 g, 14.9 mmol) in DMF (5 mL) to a suspension of sodium hydride (894 mg, 22.4 mmol) in DMF (17 mL). Stir the reaction mixture while heating at 50° C. for 45 min. Then add a solution of 4-fluoro-benzonitrile (2.16 g, 17.9 mmol) in DMF (5 mL). Stir and heat at 50° C. for 2 h. Let cool to room temperature and quench with water (0.5 mL). Evaporate DMF. Redissolved the resulting residue in EtOAc/hexanes (2/1, 20 mL) and wash with water (3×15 mL). Dry the organic layer over magnesium sulfate, filter and concentrate. Purify by chromatography (EtOAc/hexanes 20% and EtOAc/hexanes 10%) to yield the title compound (2.32 g, 52%).
Reaction SMILES: C([Zn]CC)C.F[C:7](F)(F)[C:8]([OH:10])=O.[C:13]1(CO)[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1>ClCCl>[C:7]12([CH2:8][OH:10])[CH2:16][CH:15]1[CH2:14][CH2:13][CH2:18][CH2:17]2
Reactant: OCC1=CCCCC1
Reactant: O=C(O)C(F)(F)F
Agent: CC[Zn]CC
Solvent: ClCCl
Product: OCC12CCCCC1C2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 125.8 %

Procedure:
To a solution of diethyl zinc (1.0 M in hexanes, 15.70 mL, 15.70 mmol) in anhydrous dichloromethane (15.7 mL) was added dropwise trifluoroacetic acid (1.79 g in 15.7 mL anhydrous dichloromethane, 15.7 mmol) at 0° C. over 20 minutes. The reaction mixture was stirred at the same temperature for 20 minutes, and then added dropwise a solution of diidomethane (4.20 g, 15.70 mmol) in anhydrous dichloromethane (15.7 mL) at 0° C. over 10 minutes. The reaction mixture was further stirred at the same temperature for another 20 minutes. To this reaction mixture was added a solution of cyclohexenylmethanol (1.07 g, 6.30 mmol) in anhydrous dichloromethane (17 mL) at 0° C. The resulting mixture was warmed to ambient temperature and further stirred for 1 hour. The mixture was quenched with a saturated solution of ammonium chloride (50 mL) and separated the organic layer. The aqueous layer was extracted with dichloromethane (15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography with diethyl ether in hexanes (30%) to afford the title compound as colorless oil (1.00 g, 86%): 1H NMR (300 MHz, CDCl3) δ 3.32 (dd, J=10.9, 10.9 Hz, 2H), 1.90-1.80 (m, 2H), 1.75-1.55 (m, 2H), 1.34 (br, s, 1H), 1.26-1.14 (m, 2H), 0.45 (dd, J=9.3, 4.5 Hz, 1H), 0.24 (t, J=4.9 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[C:10](OC(=O)C)(=[O:12])[CH3:11]>C1C=CC=CC=1>[C:10]([O:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: OCc1cccc(Cl)c1
Solvent: c1ccccc1
Product: CC(=O)OCc1cccc(Cl)c1
Yield: 96 %

Procedure:
Into a solution of 84.4 g. (0.592 mole) of 3-chlorobenzyl alcohol in 40 cm3. of benzene 61.5 g. (0.6 mole) of acetic acid anhydride are dropped during 15 minutes while boiling. The reaction mixture is refluxed with 100 cm3. of benzene and washed with 100 cm3. of water thoroughly. The organic phase is separated and evaporated. 105.2 g. of 3-chlorobenzyl acetate are obtained which is suitable to ether-formation. nD20 : 1.5226, yield 96%.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:25])=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[CH3:26][O:27][CH2:28][CH2:29][O:30][CH2:31]Cl.[H-].[Na+]>CN(C=O)C>[CH3:26][O:27][CH2:28][CH2:29][O:30][CH2:31][N:3]1[C:4]([CH3:25])=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:2]1[CH3:1]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCN1C(C)=C(C(=O)OC)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC)=C1C
Temperature: 25 °C

Procedure:
The presently preferred method for preparing compounds of the invention is set forth in Scheme VI. An intermediate dihydropyridine diester derivative of formula 16 is prepared by means known in the art, e.g., by following the Hantzch method (Ann. Chim., 215, 1 (1882)), using reactants selected to provide the desired R1, R2, R3, X1, and X2 substitutions. The diester is then N-protected by mixing with a slight molar excess (preferably between 1.1 and 1.3 moles per mole of compound of formula 16) α-alkoxy-ω-chloromethoxyalkane and a slight molar excess (about 1.2 mol/mol 16) of a suitable strong base, preferably NaH, in a polar, aprotic solvent (preferably DMF or DMSO) at -10° to 0° C. for between about 60 and about 100 minutes, followed by warming to about room temperature for between about 50 and 200 minutes (preferably about 60 minutes), to produce an N-protected diester of formula 17. For example, 1 mol 2,6-dimethyl-3,5-di(carbomethoxy)-4-(3-nitrophenyl)-1,4-dihydropyridine is reacted with 1.2 mol 1-methoxy-2-chloromethoxyethane and 1.2 mol NaH in DMF at -10° C. for 1 hour, then allowed to warm to about 25° C. for 1 hour to produce 1-(2-methoxyethoxy)methyl-2,6-dimethyl-3,5-di(carbomethoxy)-4-(3-nitrophenyl)-1,4-dihydropyridine (17). (Scheme VI, Step 1)
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[CH:4]=[C:3]1[C:29]([O:31]CC)=[O:30].O.[OH-].[Li+].CN(C)C=O>CO.O.C(#N)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[CH:4]=[C:3]1[C:29]([OH:31])=[O:30]
Reactant: CCOC(=O)c1cn(Cc2ccccc2-c2cccc(C(F)(F)F)c2)c2cccnc2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cn(Cc2ccccc2-c2cccc(C(F)(F)F)c2)c2cccnc2c1=O
Reaction time: 15 h
Yield: 55.2 %

Procedure:
To a light brown solution of ethyl 4-oxo-1-((3′-(trifluoromethyl)biphenyl-2-yl)methyl)-1,4-dihydro-1,5-naphthyridine-3-carboxylate (32) (114 mg, 0.252 mmol) in methanol (10 mL) was added the solid lithium hydroxide monohydrate (211 mg, 5.04 mmol) at room temperature under a nitrogen atmosphere. The resulting brown solution was stirred for 15 h at which time LCMS analysis indicated the absence of starting material. Then, the reaction mixture was diluted with water and the methanol was removed under vacuum. The basic aqueous solution contains some solids which were dissolved by addition of 5 mL of dimethylformamide and then it was neutralized with 1.0N HCl. Then, the organic compound was extracted into ethyl acetate (2×50 mL) and the combined extracts were washed with brine solution and dried over anhydrous MgSO4. Filtration and concentration gave the crude oil (may contain some dimethylformamide) which was diluted with acetonitrile and water. Then, it was frozen and lyophilized over 3 days to isolate 4-oxo-1-((3′-(trifluoromethyl)biphenyl-2-yl)methyl)-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid (33) (59 mg, 55% yield) as a light brown solid.