Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([S:12]([N:15]=[C:16]=[O:17])(=[O:14])=[O:13])[CH:3]=1.[NH2:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([CH3:27])[N:20]=1>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([S:12]([NH:15][C:16]([NH:18][C:19]2[N:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([CH3:27])[N:20]=2)=[O:17])(=[O:14])=[O:13])[CH:3]=1
Reactant: COc1nc(C)nc(N)n1
Reactant: COC(=O)c1ccc(I)cc1S(=O)(=O)N=C=O
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(I)cc1S(=O)(=O)NC(=O)Nc1nc(C)nc(OC)n1
Reaction time: 4 h
Yield: 99.2 %

Procedure:
Under protective gas, a 14.5% strength solution (1465 g) of methyl 4-iodo-2-isocyanatosulfonylbenzoate in xylene is added over 4 hours at a constant rate at 50° C. to a suspension of 84.5 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine in 670 g of ethyl acetate. After the addition has ended, the mixture is stirred at the same temperature for approximately 4 hours, and the ethyl acetate is then distilled off under reduced pressure (80–60 mbar, T=50° C.). The suspension that remains is filtered off with suction and the solid is washed repeatedly with dilute hydrochloric acid and dried; if appropriate, acetone can be added to the hydrochloric acid. This gives 297 g (content>98%) of the title compound; yield 99.2% of theory.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:22]([I:23])=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[C:15]([F:24])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O.[OH-].[Li+].Cl.C(OCC)(=O)C>O1CCCC1.O>[C:1]12([CH2:11][O:12][C:13]3[C:22]([I:23])=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[C:15]([F:24])[CH:14]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: COC(=O)c1cc(I)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1cc(I)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.4 %

Procedure:
To a solution of methyl 4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoate (1.80 g, 4.05 mmol) in tetrahydrofuran (10 mL) was added a solution of lithium hydroxide monohydrate (0.85 g, 20.30 mmol) in water (4 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. After addition of 1 N hydrochloric acid (10 mL) and ethyl acetate (150 mL), the organic phase was separated, washed with 1 N hydrochloric acid (10 mL) and brine (10 mL); dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate in vacuo yielded the title compound (1.75 g, quant) as an off-white solid, which was used without further purification: MS (ES−) m/z 429.1 (M−1).
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([CH:10]([NH:18][CH:19]=O)[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.O=P(Cl)(Cl)Cl.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C1COCC1>[C:1]1([CH3:21])[CH:2]=[CH:3][C:4]([S:7]([CH:10]([N+:18]#[C-:19])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)C(NC=O)c2ccc(F)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: [C-]#[N+]C(c1ccc(F)cc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
A stirred suspension of α-(p-toluenesulfonyl)-4-fluorobenzylformamide produced in step (a) above, (100 g, 325 mmoles) in THF (650 mL, 6.5 volumes) was cooled to 0° C. and POCl3 (46 mL, 487 mmoles, 1.5 equiv.) was added. A 1° C. exotherm was observed. After 15 minutes at 0° C., the white slurry was cooled to -5° C. Triethylamine (166 g, 1.62 moles, 5 equiv.) was added dropwise to the slurry over 45 minutes at such a rate to keep the reaction temperature below 0° C. but above -5° C. Caution should be exercised at the beginning of the addition because the reaction has a tendency to exotherm quickly. After complete addition, the yellow slurry was stirred for 30 minutes at 0° C. The reaction slurry has a tendency to darken during the stirring period. The reaction was poured into a mixture of saturated aqueous sodium bicarbonate (1L) and ethyl acetate (1L), both pre-cooled to 0° C. The organic phase was subsequently washed with water followed by brine. The organic phase was concentrated under vacuum via rotary evaporation until about 10% of the initial volume remained. 1-Propanol (200 mL) was added and concentrated again under vacuum at 35° C. until about 10% of the initial volume remained. This process was repeated with fresh 1-propanol (200 mL). A fine, yellow precipitate was observed. The precipitate was cooled to 0° C. and the product was collected by suction filtration and rinsed with 1-propanol. (50 mL). The off-white solid was dried to a constant weight at 40° C./<1 mm to give 65.7 g (227 mmoles) of desired product, affording a 70% yield. 1H NMR (300 MHz, CDCl3) δ 7.62 (2H, d, J=6.7 Hz), 7.46 (4H, m), 7.08 (2H, t, J=8.6 Hz), 5.62 (1H, s), 2.46 (3H, s).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:20]1([C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=2[OH:33])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O[CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH:20]1([C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=2[O:33][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: Oc1ccc(Cl)cc1C1CCCCC1
Reactant: OCCN1CCOCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc(OCCN2CCOCC2)c(C2CCCCC2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.1 %

Procedure:
Triphenylphosphine (7.47 g, 19.58 mmol) was added to a solution of 2-cyclohexyl-4-chlorophenol (6 g, 28.48 mmol) and 2-hydroxyethylmorpholine (3.5 g, 28.48 mmol) in tetrahydrofuran (50 ml), followed by the dropwise addition of diethylazodicarboxylate (4.5 ml, 28.48 mmol). The mixture stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure and triturated with dichloromethane/hexanes and then washed with more hexanes. Chromatography (silica, 10-20-30% ethyl acetate/hexanes) afforded 8.4 g (95%) of 3-cyclohexyl-4-morpholinoethoxy-chlorobenzene as a yellowish oil.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH2:22][C:21]([C:27]4[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=4)([C:23]([F:26])([F:25])[F:24])[O:20][N:19]=3)=[CH:14][CH:13]=2)[CH2:9]1)=O)(C)(C)C.Cl>CO>[ClH:33].[NH:8]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH2:22][C:21]([C:27]4[CH:28]=[C:29]([Cl:34])[CH:30]=[C:31]([Cl:33])[CH:32]=4)([C:23]([F:24])([F:25])[F:26])[O:20][N:19]=3)=[CH:14][CH:13]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2)C1
Agent: Cl
Solvent: CO
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(C3CNC3)cc2)=NO1
Temperature: 70 °C

Procedure:
To a stirred solution of 3-{4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}azetidine-1-carboxylic acid tert-butyl ester (Preparation 40, 1 g, 1.94 mmol, 1 eq) in MeOH (10 mL) was purged HCl (g) at 0° C. for 0.5 hours and then reaction mixture was refluxed at 70° C. for 0.5 hours. Progress of reaction was monitored by TLC, after complete consumption of starting material reaction mixture was evaporated under reduced pressure to dryness to give 1.15 g (crude) Which was washed with methyl t-butyl ether (10 mL×2) to afforded 1.1 g (95.21%). 1H-NMR and LC-MS were consistent. 1H NMR (400 MHz, DMSO-d6) δ 4.05 (t, J=8 Hz, 2H), 4.15-4.21 (m, 1H), 4.24-4.39 (m, 4H), 7.55 (d, J=8 Hz, 2H), 7.62 (d, J=1 Hz, 2H), 7.74 (d, J=8 Hz, 2H), 7.81 (t, J=2 Hz, 1H), 8.99 (bs, 2H). LC-MS (m/z):=415 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[O:18][C:17](=[O:19])[NH:16][N:15]=2)=[CH:4][CH:3]=1.[C:20](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(Cl)Cl>C(N(CC)CC)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[O:18][C:17](=[O:19])[N:16]([C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:15]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccccc2-c2n[nH]c(=O)o2)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2ccccc2-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c(=O)o2)cc1

Procedure:
2.03 g of the compound prepared in step B, 2.5 g of trityl chloride, 50 ml of DCM and 1.6 ml of triethylamine are placed in a round-bottomed flask and the mixture is refluxed for 1 and a half hours. It is evaporated, the residue is taken up with an ethyl ether/water mixture and the organic phase is washed with a 3% solution of potassium hydrogensulfate, dried over sodium sulfate, filtered and evaporated. The product is used in the crude form for the next step.
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]#[C:22][Si](C)(C)C)[C:7]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:6]([CH:32]([CH3:34])[CH3:33])[N:5]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>C(O)C.C(OCC)(=O)C>[CH:32]([C:6]1[C:7]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]#[CH:22])[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH:1]([CH3:2])[CH3:3])[N:5]=1)([CH3:34])[CH3:33]
Reactant: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(C(=O)OCC)c1-c1ccccc1C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C#Cc1ccccc1-c1c(C(=O)OCC)c(C(C)C)nc(C(C)C)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.7 %

Procedure:
A solution of 5.68 g (11.9 mmole) of the intermediate obtained in Step B in 800 mL ethanol was treated with 2.8 g (20.3 mmole) of potassium carbonate and the reaction mixture was allowed to stir at room temperature for 16 hours. The mixture was diluted with ethyl acetate and washed with saturated aqueous solution of ammonium chloride, brine and separated. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash silica gel chromatography, eluting with 10 ethyl acetate/n-hexane, to give 3.95 g (9.6 mmole) of the product. 1H NMR (300 MHz, CDCl3): δ 0.90 (t, J=7.0 Hz, 6 H), 1.32 (m, 12 H), 2.97 (s, 1 H), 3.21 (septet, J=6.6, 2 H), 3.90 (q, J=7.0, 4 H), 7.2-7.6 (m, 4 H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:3]=1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:3]=[C:2]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[N:7]=1
Reactant: C1CCNC1
Reactant: CC(C)(C)Nc1cc(Cl)nc(Cl)n1
Product: CC(C)(C)Nc1cc(Cl)nc(N2CCCC2)n1
Yield: 73.8 %

Procedure:
By reacting 2,4-dichloro-6-(1,1-dimethylethylamino)pyrimidine with pyrrolidine as described in Example 12, the title product is obtained in a yield of 73.8%, m.p.: 148°-150° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[C:11]3[S:15][C:14](SC)=[N:13][C:12]3=[O:18])=[CH:9][C:4]=2[O:3][CH2:2]1.CC(C)([O-])C.[K+].CCCCCC.[N:31]#[C:32][NH2:33].[OH-].[K+].[K]>CN1C(=O)CCC1.O.CCOC(C)=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[C:11]3[S:15][C:14](=[N:33][C:32]#[N:31])[NH:13][C:12]3=[O:18])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: N#CN
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(c2)OCO3)S1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [K]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N#CN=C1NC(=O)C(=Cc2ccc3c(c2)OCO3)S1
Temperature: 80 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
200 mg (0.72 mmol) of 5-Benzo[1,3]dioxol-5-ylmethylene-2-methylsulfanyl-thiazol-4-one were dissolved in NMP to which was added a solution of potassium tert.butoxide in hexane (1.1 eq.). The colour changed to orange. To this was added as a solid cyanamide (1.2 eq.). The reaction was heated at 80° C. under Ar. for 3 h HPLC indicated complete transformation. 150 ml EtOAc were added and washed with 0.1N HCl twice. The organic layer was then washed extensively with brine. The solvent was dried and evaporated to dryness leading to a yellowish solid. The crude was purified on Parallel Flex system affording a yellow solid, which was dissolved in TBF followed by 1 equivalent of 1N KOH. 20 ml of water were added and the frozen solution was lyophilised yielding 107 mg (51%) of 5-Benzo[1,3]dioxol-5-ylmethylene-4-oxo-thiazolidin-2-ylidene-cyanamide as potassium salt.
Reaction SMILES: FC1C=CC=CC=1C1C=CC(C2C(C)=C([C:25]([OH:27])=[O:26])C3C(=CC=C(CCN)C=3)N=2)=CC=1.[Na].[C:32]1(=[O:38])[O:37][C:35](=[O:36])[CH2:34][CH2:33]1.C([O-])(=O)CCC([NH-])=[O:43].[Na+].[Na+]>CN(C)C=O.C(=O)(O)[O-].[Na+].C(N(CC)CC)C>[C:35]1(=[O:36])[O:37][C:32](=[O:38])[CH2:33][CH2:34]1.[C:25](=[O:26])([O-:43])[O-:27]
Reactant: [NH-]C(=O)CCC(=O)[O-]
Reactant: Cc1c(-c2ccc(-c3ccccc3F)cc2)nc2ccc(CCN)cc2c1C(=O)O
Agent: O=C([O-])O
Agent: O=C1CCC(=O)O1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C([O-])[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stock solution of succinic anhydride was prepared by dissolving 24.3 mg in 1.635 ml of dimethylformamide (DMF). 2-(2'-Fluoro-1,1'-Biphenyl-4-yl)-3-Methyl-6-(2-Aminoethyl)-4-Quinolinecarboxylic Acid, Sodium Salt (10 mg) was placed in a glass vial along with 161 μl succinic anhydride stock solution and 9 μl dry triethylamine. This was stirred overnight in the dark at room temperature. A stock solution of Disuccinimdyl carbonate (DSC) was prepared by dissolving 62.4 mg of DSC into 1.59 ml of dry DMF. 174 μl of the DSC stock and 9 μl of dry triethylamine were added to the 2-(2'-Fluoro-1,1'-Biphenyl-4-yl)-3-Methyl-6-(2-Aminoethyl)-4-Quinolinecarboxylic Acid, Sodium Salt-succinamic acid solution for activation. This was stirred for one hour in the dark at room temperature. Half of the activated 2-(2'-Fluoro-1,1'-Biphenyl-4-yl)-3-Methyl-6-(2-Aminoethyl)-4-Quinolinecarboxylic Acid, Sodium Salt-succinamic acid solution was rapidly added to either BSA or KLH solutions (26 mg protein dissolved in 43.3 ml of 0.15M sodium bicarbonate, pH 8.1) and gently agitated overnight in the dark at 4° C. After coupling, the immunogens were dialyzed against three changes of PBS to remove any free hapten and excess coupling reagents as described in Chemistry of Protein Conjugation and Cross-Linking, S. Wong, CRC Press, 1991, which is hereby incorporated by reference. Haptens were also conjugated to OA using this method.
Reaction SMILES: [OH:1][C:2]1([C:8]2[S:9][C:10]([S:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH:3]1[CH3:7].[CH3:24]I>>[CH3:24][O:1][C:2]1([C:8]2[S:9][C:10]([S:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH:3]1[CH3:7]
Reactant: CI
Reactant: CC1OCCC1(O)c1ccc(Sc2ccc3ccccc3c2)s1
Product: COC1(c2ccc(Sc3ccc4ccccc4c3)s2)CCOC1C
Yield: 75 %

Procedure:
Using the procedure described in Example 1, (2RS,3RS)-3-hydroxy-2-methyl-3-[5-(naphth-2-ylthio)thien-2-yl]tetrahydrofuran was reacted with methyl iodide to give (2RS,3RS)-3-methoxy-2-methyl-3-[5- (naphth-2-ylthio)thien-2-yl]tetrahydrofuran in 75% yield as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[CH:6]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1.[C:15]1([C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C@H:23]2[CH2:27][CH2:26][CH2:25][NH:24]2)[OH:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[C:15]1([C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C@H:23]2[CH2:27][CH2:26][CH2:25][NH:24]2)[OH:22])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1.[OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C@H:6]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C(O)CC1COc2cc(O)ccc21
Agent: OC(c1ccccc1)(c1ccccc1)[C@H]1CCCN1
Solvent: CO
Product: O=C(O)C[C@@H]1COc2cc(O)ccc21

Procedure:
A racemate (19 mg, 0.1 mmol) of (6-hydroxy-2,3-dihydro-1-benzofuran-3-yl)acetic acid was charged, methanol was added, and the racemate was dissolved. This solution and (R)-α,α-diphenyl-2-pyrrolidinemethanol (25.3 mg, 0.1 mmol) were mixed and stood. The precipitated crystals were collected by filtration to give the title compound. 9.9% de
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15](O[Si](CC(C)C)(C)C)=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34]CC)=[O:33])=[CH:30][CH:29]=3)[CH:5]=[CH:4][C:3]1=2.O[Li].O.[CH2:43]1COCC1.O>>[CH3:39][C:2]1([CH3:1])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:43])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:37][CH:38]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: C1CCOC1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(O[Si](C)(C)CC(C)C)cc2)=CCC3(C)C)cc1
Agent: [Li]O
Solvent: O
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cc1

Procedure:
A solution of 142.6 mg (0.339 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 1) and 35.6 mg (0.848 mmol) of LiOH—H2O in 12 ml of THF/water (4:1, v/v), was stirred overnight at room temperature. The reaction mixture was extracted with hexanes, and the hexane fraction extracted with 5% aqueous NaOH. The aqueous layers were combined and acidified with 1 M HCl, and then extracted with EtOAc and Et2O. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the title compound as a colorless solid. 1H NMR (d6-DMSO): δ 7.91 (2H, d, J=8.4 Hz), 7.60 (2H, d, J=8.4 Hz), 7.47 (2H, s), 7.23 (4H, q, J=8.1 Hz), 7.01 (1H, s), 6.01 (1H, t, J=4.6 Hz), 2.35 (3H, s), 2.33 (2H, d, J=4.8 Hz), 1.30 (6H, s).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[OH:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]#[N:14].O>C(OCC)(=O)C>[OH:10][C:11]1[CH:18]=[CH:17][C:16]([N+:1]([O-:4])=[O:2])=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=[N+]([O-])O
Reactant: N#Cc1ccccc1O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cc([N+](=O)[O-])ccc1O
Temperature: 20 °C
Reaction time: 24 h

Procedure:
A solution of 70 ml. 40% nitric acid and 10 ml. concentrated sulphuric acid is added dropwise at 10° C. in the course of 1 hour to 24 g. (0.2 mole) 2-hydroxybenzonitrile in 20 ml. water. The reaction mixture is subsequently stirred for 24 hours at 20° C. and then shaken out with 100 ml. ethyl acetate. After evaporation of the organic solvent, the solid residue obtained is extracted twice with 500 ml. amounts of boiling n-hexane. Purification takes place by means of column chromatography on silica gel (silica gel 60; elution agent ethyl acetate). After evaporation of the solvent and crystallisation from ethyl acetate/toluene, there are obtained 2 g. of the desired product in the form of white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.Br[CH:11]([CH3:14])[CH:12]=O>C(O)C>[CH3:14][C:11]1[N:3]2[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]2=[N:1][CH:12]=1
Reactant: N#Cc1ccc(N)nc1
Reactant: CC(Br)C=O
Solvent: CCO
Product: Cc1cnc2ccc(C#N)cn12
Temperature: 80 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
To a solution of 6-aminonicotinonitrile (1.2 g, 10.1 mmol) in ethanol (80 mL) was added 2-bromopropanal (6-1) (6.9 g, 50.5 mmol). The reaction mixture was stirred at 80° C. overnight. The solution was concentrated, diluted with water (20 mL) and adjusted to PH>7 with saturated aqueous NaHCO3 solution. The precipitate was collected to afford the title compound (430 mg). MS (m/z): 158 (M+H)+.
Reaction SMILES: [Cl:1][CH:2]([Cl:31])[C:3]([NH:5][C@H:6]([CH2:29][F:30])[C@@H:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:19][C:18]([CH2:20][NH:21]C(=O)OC(C)(C)C)=[N:17][N:16]=2)=[CH:11][CH:10]=1)[OH:8])=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:21][CH2:20][C:18]1[S:19][C:15]([C:12]2[CH:13]=[CH:14][C:9]([C@@H:7]([OH:8])[C@H:6]([NH:5][C:3](=[O:4])[CH:2]([Cl:1])[Cl:31])[CH2:29][F:30])=[CH:10][CH:11]=2)=[N:16][N:17]=1
Reactant: CC(C)(C)OC(=O)NCc1nnc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1nnc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)s1
Yield: 135.3 %

Procedure:
To a stirred solution of tert-butyl ((5-(4-((1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-hydroxypropyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)carbamate (100 mg, 0.203 mmol) in CH2Cl2 (10 mL) is added trifluoroacetic acid (1.0 mL). After 2 hours the reaction mixture is concentrated in vacuo and the residue washed with diethyl ether. The residue is dissolved in 10% methanol in CH2Cl2 and evaporated to dryness, washed with n-pentane, dried under vacuum to give the title compound (108 mg): 1H-NMR (400 MHz, DMSO-d6) δ 4.27-4.28 (m, 1H), 4.31-4.35 (m, 0.5H), 4.43-4.47 (m, 0.5H), 4.59-4.61 (m, 0.5H), 4.64 (s, 2H), 4.70-4.74 (m, 0.5H), 4.96 (t, J=2.76 Hz, 1H), 6.10 (d, J=4.28 Hz, 1H), 6.48 (s, 1H), 7.54 (d, J=8.32 Hz, 2H), 7.94 (d, J=8.32 Hz, 2H), 8.60 (bs, 2H), 8.64 (d, J=9.12 Hz, 1H). LC-Ms (m/z): [M+H]=393.10.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[N:13]=2)=[C:7]([O:19][CH3:20])[CH:6]=1)O.CCN(S(F)(F)[F:29])CC>ClCCl>[F:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([CH:3]([F:29])[C:2]([F:22])([F:21])[F:1])=[CH:6][C:7]=2[O:19][CH3:20])[N:13]=1
Reactant: COc1cc(C(O)C(F)(F)F)ccc1Oc1cccc(F)n1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(F)C(F)(F)F)ccc1Oc1cccc(F)n1
Reaction time: 2 h
Yield: 36.4 %

Procedure:
To a solution of 2,2,2-trifluoro-1-{4-[(6-fluoropyridin-2-yl)oxy]-3-methoxyphenyl}ethanol (0.22 mmol; 70 mg) under argon in dichloromethane (2 mL) at −78° C. was added dropwise DAST (0.22 mmol; 29 μl). The reaction mixture was let come back to rt for 2 h and quenched with brine (3 ml). The aqueous phase was collected, neutralized with sodium bicarbonate and extracted twice with chloroform. The organic phases were combined, dried over MgSO4, concentrated and purified by preparative TLC on silica gel (ethyl acetate/cyclohexane—30/70) to yield the title compound (25 mg; 0.08 mmol; 37%).