Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[CH:10][C:3]=1[NH:4][C@H:5]([CH3:9])[C:6]([OH:8])=[O:7].Cl.[CH2:17](O)[CH3:18]>>[F:1][C:2]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[CH:10][C:3]=1[NH:4][C@H:5]([CH3:9])[C:6]([O:8][CH2:17][CH3:18])=[O:7]
Reactant: CCO
Reactant: C[C@@H](Nc1ccc(F)c(F)c1F)C(=O)O
Agent: Cl
Product: CCOC(=O)[C@@H](C)Nc1ccc(F)c(F)c1F

Procedure:
(2R)-2-(2,3,4-trifluoroanilino)propionic acid (219 mg; 99% ee) was dissolved in ethanol (2 ml) and hydrochloric acid (5 mol/l; 0.2 ml) was added thereto at room temperature. The liquid reaction mixture was heated under reflux for 6 hours and then the solvent was evaporated. To the obtained residue was added chloroform (10 ml). Next, the organic layer was washed with a saturated aqueous solution of sodium chloride and water and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography (ethyl acetate-normal hexane=1:4) to give the title compound (245 mg) as a pale yellow oily substance. The optical purity of the product was 98% ee. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 7.
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[Cl:8][C:9]1[CH:10]=[C:11]([CH2:16][C:17]([OH:19])=[O:18])[CH:12]=[C:13]([F:15])[CH:14]=1.[C:20](O)(=O)C>CO.C1(C)C=CC=CC=1>[CH3:20][O:18][C:17](=[O:19])[CH2:16][C:11]1[CH:12]=[C:13]([F:15])[CH:14]=[C:9]([Cl:8])[CH:10]=1
Reactant: CC(=O)O
Reactant: O=C(O)Cc1cc(F)cc(Cl)c1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cc(F)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
Trimethylsilyldiazomethane (2 M solution in diethyl ether, 0.199 mL, 0.398 mmol) was added to a solution of (3-chloro-5-fluoro-phenyl)acetic acid (50 mg, 0.265 mmol) in methanol (0.5 mL) and toluene (2 mL), and the mixture was stirred at room temperature for 10 minutes. Acetic acid was added to the reaction mixture to terminate the reaction, and then the mixture was concentrated under reduced pressure to give the target compound as a colorless oil (53 mg, 99%).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:15][C:14]3([CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16]3)[CH2:13]2)[CH2:8][CH2:7]1)=[O:5])C.[Li+].[OH-].Cl>C1COCC1>[CH2:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][C:14]2([CH2:15][CH:12]([N:9]3[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]3)[CH2:13]2)[CH2:16]1)=[O:21])[CH3:24]
Reactant: CCOC(=O)C1CCN(C2CC3(CCN(C(=O)OCC)C3)C2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC2(CC(N3CCC(C(=O)O)CC3)C2)C1
Temperature: 25 °C

Procedure:
Ethyl 2-[4-(ethoxycarbonyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (0.069 g, 0.20 mmol) was dissolved in THF (4 mL) at rt and 1 M LiOH sol. (0.31 mL) was added. The reaction mixture was stirred at rt over the weekend. The reaction mixture was adjusted to pH 5 by addition of 1 M HCl sol. and solvents were removed in vacuo, to give 1-[6-(ethoxycarbonyl)-6-azaspiro[3.4]oct-2-yl]piperidine-4-carboxylic acid which was used directly without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=O.[CH3:12][CH2:13][CH2:14][CH:15]([NH2:19])[CH2:16][CH2:17][CH3:18]>>[CH3:12][CH2:13][CH2:14][CH:15]([NH:19][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([OH:11])=[C:2]([OH:1])[CH:3]=1)[CH2:16][CH2:17][CH3:18]
Reactant: O=C(O)c1ccc(O)c(O)c1
Reactant: CCCC(N)CCC
Product: CCCC(CCC)NC(=O)c1ccc(O)c(O)c1
Yield: 25 %

Procedure:
N-(heptan-4-yl)-3,4-dihydroxybenzamide was prepared in a similar manner to example 4 using 3,4-dihydroxybenzoic acid and heptan-4-amine. Yield: 25%. MS (M+H, 252.1).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:4]=[C:5]([N:9]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[C:11]([C:18]([OH:20])=O)=[CH:10]2)[CH:6]=[CH:7][CH:8]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:44][C:45]([NH2:47])=[NH:46]>O1CCCC1>[CH3:21][N:2]([CH3:1])[C:3]1[CH:4]=[C:5]([N:9]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[C:11]([C:18]([NH:46][C:45]([NH2:47])=[NH:44])=[O:20])=[CH:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)c1cccc(-n2cc(C(=O)O)c3cccnc32)c1
Reactant: N=C(N)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CN(C)c1cccc(-n2cc(C(=O)NC(=N)N)c3cccnc32)c1
Temperature: 20 °C
Reaction time: 384 h

Procedure:
1-(3-(Dimethylamino)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid, 0.46 g (2.4 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.027 g (0.2 mmol) of 1-hydroxybenzotriazole were added to 0.59 g (10 mmol) of guanidine in 15 cm3 of tetrahydrofuran under an argon atmosphere. After stirring at a temperature in the region of 20° C. for 16 days, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa) and the residue was triturated in 20 cm3 of methanol and then filtered. The filtrate was concentrated to dryness under reduced pressure (2.7 kPa) and the residue was purified by flash chromatography on silica gel, elution being carried out with a 100% of dichloromethane to dichloromethane/methanol/triethylamine (50/48/2 by volume) gradient over 90 minutes. After concentrating the fractions comprising the expected product to dryness under reduced pressure (2.7 kPa), the solid obtained was triturated in 20 cm3 of ethanol and filtered off, resulting in 0.004 g of N-[1-(3-(dimethylamino)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine in the form of a powder melting at 269–271° C. 1H N.M.R. spectrum (300 MHz, (CD3)2SO with addition of a few drops of CD3COOD, δ in ppm): 3.00 (s, 6H), 6.84 (dd, J=8.5 and 2 Hz, 1H), 7.09 (dd, J=8.5 and 2 Hz, 1H), 7.15 (t, J=2 Hz, 1H), 7.39 (t, J=8.5 Hz, 1H), 7.42 (dd, J=8 and 5 Hz, 1H), 8.46 (dd, J=5 and 2 Hz, 1H), 8.55 (dd, J=8 and 2 Hz, 1H), 8.84 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[O:23]=[C:24]([CH2:28][C:29](O)=O)C(O)=O.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C>[CH:18]1([O:17][C:11]2[CH:10]=[C:9]([N:8]3[C:24](=[O:23])[C:28]([CH3:29])=[N:1][C:2]4[CH:7]=[CH:6][CH:5]=[N:4][C:3]3=4)[CH:14]=[CH:13][C:12]=2[O:15][CH3:16])[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: O=C(O)CC(=O)C(=O)O
Reactant: COc1ccc(Nc2ncccc2N)cc1OC1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(-n2c(=O)c(C)nc3cccnc32)cc1OC1CCCC1
Yield: 47.3 %

Procedure:
A mixture of 3-amino-2-[(3-cyclopentyloxy-4-methoxyphenyl)amino]pyridine (180 mg) and 2-oxosuccinic acid (90 mg) in ethanol (4 ml) was stirred under reflux for 1.5 hours. The mixture was cooled and then poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was washed with ethanol to give 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-methyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (100 mg).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[O:30])[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:37]1[CH2:39][C@@H:38]1[CH2:40][O:41][C:42]1[CH:51]=[CH:50][CH:49]=[C:48]2[C:43]=1[CH:44]=[CH:45][CH:46]=[N:47]2>C(O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:24][CH2:25][N:26]([C:29]([CH:31]3[CH2:36][CH2:35][N:34]([CH2:39][C@@H:38]([OH:37])[CH2:40][O:41][C:42]4[CH:51]=[CH:50][CH:49]=[C:48]5[C:43]=4[CH:44]=[CH:45][CH:46]=[N:47]5)[CH2:33][CH2:32]3)=[O:30])[CH2:27][CH2:28]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCN(C(=O)C2CCNCC2)CC1
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Solvent: CCO
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCN(C(=O)C2CCN(C[C@@H](O)COc3cccc4ncccc34)CC2)CC1
Temperature: 25 °C
Yield: 58.2 %

Procedure:
1-(Piperidine-4-carbonyl)-piperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (71) (243.4 mg; 0.497 mmol) is dissolved in ethanol (12 mL) at ambient temperature. (R)-5-Oxiranylmethoxy-quinoline (2) (100.0 mg; 0.497 mmol) is added, then the mixture is refluxed for 16 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (50%→100% acetone in hexanes, then 5%→20% ethanol in acetone) affording the desired product (200 mg) as a white solid. ESMS: MH+ 691.6
Reaction SMILES: [N:1]1[N:2]=[C:3]([S:10][C:11]2[CH:12]=[CH:13][C:14]3[N:15]([CH:17]=[C:18]([NH:20]C(=O)OC(C)(C)C)[N:19]=3)[N:16]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl.C(O)(C(F)(F)F)=O>O1CCOCC1>[N:1]1[N:2]=[C:3]([S:10][C:11]2[CH:12]=[CH:13][C:14]3[N:15]([CH:17]=[C:18]([NH2:20])[N:19]=3)[N:16]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)OC(=O)Nc1cn2nc(Sc3nnc4ccccn34)ccc2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Nc1cn2nc(Sc3nnc4ccccn34)ccc2n1
Yield: 91 %

Procedure:
A solution of tert-butyl 6-([1,2,4]triazolo[4,3-a]pyridin-3-ylthio)imidazo[1,2-b]pyridazin-2-ylcarbamate (300 mg, 0.78 mmol) in dioxane (5 ml) was treated with 4M HCl in dioxane (5 ml) at 80° C. for 1 hr. The mixture was concentrated and purified by LCMS to give the title compound, 6-([1,2,4]triazolo[4,3-a]pyridin-3-ylthio)imidazo[1,2-b]pyridazin-2-amine (201 mg, 68% yield) as the TFA salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.00 (d, J=9.35 Hz, 1 H) 7.16 (t, J=6.44 Hz, 1 H) 7.22 (s, 1 H) 7.54-7.65 (m, 1 H) 7.73 (d, J=9.35 Hz, 1 H) 8.00 (d, J=9.09 Hz, 1 H) 8.47 (d, J=6.82 Hz, 1 H). ESI-MS:m/z 284.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17])[CH3:2].C(N(C(C)C)CC)(C)C.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[CH2:1]([O:3][C:4](=[O:19])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:14])(=[O:13])[NH:36][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)Nc1ccc(S(=O)(=O)Cl)cc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)Nc1ccc(S(=O)(=O)NCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of (4-chlorosulfonyl-2-nitro-phenyl)-carbamic acid ethyl ester (2 g, Reference Example 63) in dichloromethane (50 ml) at 0° C., under a nitrogen atmosphere, was added diisopropylethylamine (2.71 ml) and benzylamine (0.850 ml). The reaction was warmed to ambient temperature and stirred for 12 hours. The reaction mixture was then washed with water (2×20 ml) and brine (2×20 ml), dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo to give the title compound (2.29 g) as a brown solid. LC-MS (METHOD J): RT=3.83 minutes, 380.12 (M+H)+.
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([CH3:18])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:30]([C:29]1[CH:28]=[CH:27][C:26]([CH:23]2[CH2:24][CH2:25][N:20]([C:9]([C:8]3[C:7]([CH3:18])=[CH:6][C:5]([CH:1]4[CH2:2][CH2:3][CH2:4]4)=[C:13]([CH:12]=3)[C:14]([O:16][CH3:17])=[O:15])=[O:11])[CH2:21][CH2:22]2)=[CH:33][CH:32]=1)#[N:31]
Reactant: COC(=O)c1cc(C(=O)O)c(C)cc1C1CCC1
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)c(C)cc1C1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a round-bottom flask was added a solution of 4-cyclobutyl-5-(methoxycarbonyl)-2-methylbenzoic acid (compound 230.2, 2.10 g, 8.46 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL). 4-(Piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 1.88 g, 8.44 mmol, 1.00 equiv), EDC.HCl (3.22 g, 16.8 mmol, 2.00 equiv), and 4-dimethylaminopyridine (3.10 g, 25.4 mmol, 3.00 equiv) were added to the reaction. The resulting solution was stirred overnight at 25° C., then diluted with 100 mL of ethyl acetate. The mixture was washed with 2×30 mL of NH4Cl (aq., sat.) and 2×30 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (0:1-1:3) as eluent to yield 3.20 g (91%) of methyl 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzoate as a white solid.
Reaction SMILES: [NH:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:8])=[CH:5][N:4]=1)[NH2:2].C(=O)([O-])[O-].[K+].[K+].C([O:27][CH:28]=[C:29]([C:35](OCC)=O)[C:30]([O:32][CH2:33][CH3:34])=[O:31])C.Cl>O>[OH:27][C:28]1[N:1]([C:3]2[CH:18]=[CH:17][C:6]([C:7](=[O:8])[NH:9][CH2:10][CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:5][N:4]=2)[N:2]=[CH:35][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: NNc1ccc(C(=O)NCC2CCOCC2)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cnn(-c2ccc(C(=O)NCC3CCOCC3)cn2)c1O
Temperature: 100 °C
Reaction time: 14 h
Yield: 74.4 %

Procedure:
Combined 6-hydrazinyl-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide (1.0 g, 4.00 mmol) and potassium carbonate (2.209 g, 15.98 mmol) in water (25 mL) and added diethyl 2-(ethoxymethylene)malonate (0.807 mL, 4.00 mmol) at 23° C. The reaction mixture was stirred at 100° C. for 14 hours, then 3N HCl (10 mL, 7.5 eq) was added to give a tan suspension. The solid was filtered, rinsed with water (3×5 mL), and dried in vacuo to give the title compound (1.114 g, 74.5% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.24 (m, 2H) 1.26 (t, J=7.07 Hz, 3H) 1.56-1.68 (m, 2H) 1.81 (qdd, J=11.16, 11.16, 11.16, 6.95, 3.79 Hz, 1H) 3.19 (t, J=6.32 Hz, 2H) 3.27 (td, J=11.75, 2.02 Hz, 2H) 3.82-3.90 (m, 2H) 4.18 (q, J=7.24 Hz, 2H) 8.12 (br. s., 1H) 8.13-8.24 (m, 1H) 8.46 (dd, J=8.84, 2.27 Hz, 1H) 8.76 (t, J=5.68 Hz, 1H) 8.89 (dd, J=2.27, 0.76 Hz, 1H) 13.73 (br. s., 1H). MS m/z [M+H]+ 329.3, 375.4.
Reaction SMILES: [N:1]([CH2:4][C:5]1([CH3:24])[O:22][C:8]2=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=[C:7]2[CH:6]1[CH3:23])[NH:13][C:12](=[O:18])[C:11]([CH:19]([CH3:21])[CH3:20])=[CH:10]3)=[N+]=[N-].[H][H].[ClH:27].CO>CN(C)C=O.CO.[Pd]>[NH2:1][CH2:4][C:5]1([CH3:24])[O:22][C:8]2=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=[C:7]2[CH:6]1[CH3:23])[NH:13][C:12](=[O:18])[C:11]([CH:19]([CH3:20])[CH3:21])=[CH:10]3.[ClH:27]
Reactant: Cc1cc2c(c3cc(C(C)C)c(=O)[nH]c13)OC(C)(CN=[N+]=[N-])C2C
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc2c(c3cc(C(C)C)c(=O)[nH]c13)OC(C)(CN)C2C
Yield: 83.7 %

Procedure:
2-Azidomethyl-8-isopropyl-2,3,5-trimethyl-6,7-dihydrofuro[2,3-f]quinoline-7-one (1.25 g, 3.83 mmol) was dissolved in dimethylformamide (200 ml). To the solution, 10% palladium-on-carbon (1.45 g) was added, followed by stirring at room temperature for 90 minutes in the atmosphere of hydrogen. The reaction mixture was filtered, and the filtrate was condensed under reduced pressure. The resultant residue was suspended in methanol (50 ml), and the suspension was dissolved with 1.37 N HCl-methanol (4 ml, 5.31 mmol). The reaction mixture was condensed under reduced pressure, and the residue was recrystallized from methanol-ether to obtain 1.08 g of the title compound as colorless powdery crystals (83.7%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]2[O:19][CH2:18]2)=[N:5][N:6]=1.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]([OH:19])[CH2:18][NH:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:5][N:6]=1
Reactant: CC(C)(C)N
Reactant: Cc1nnc(C=Cc2ccccc2OCC2CO2)s1
Solvent: Cc1ccccc1
Product: Cc1nnc(C=Cc2ccccc2OCC(O)CNC(C)(C)C)s1

Procedure:
7 g (0.025 mole) of 2-methyl-5-[2-(2,3-epoxy-propoxy)styryl]-1,3,4-thiadiazole and 2.1 g (0.028 mole) of tert.butylamine are reacted similarly to the Example relating to compound 3. 3.8 g (44% of theory) of yellow crystals, of melting point 110°-112° C., are obtained from toluene.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[O:17])=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[NH2:26][CH2:27][C:28]1([OH:37])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:26][CH2:27][C:28]2([OH:37])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30][CH2:29]2)=[O:17])=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(CC(=O)Cl)ccc1OCc1ccccc1
Reactant: NCC1(O)CCc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(CC(=O)NCC2(O)CCc3ccccc32)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
To a solution of 4-benzyloxy-3-methoxyphenylacetyl chloride (18 mmol), the product of Example 4, in 50 mL of methylene chloride was added 50 mL of saturated aqueous sodium bicarbonate solution, followed by a solution of 1-aminomethyl-1-hydroxyindan (3.15 g, 19 mmol), the product of Example 1, in 20 mL of methylene chloride. The resulting two-phase mixture was stirred vigorously at ambient temperature for 2 hours. The aqueous and organic phases were separated and the aqueous phase was extracted with methylene chloride (75 mL). The combined organic layers were washed with 100 mL of 1M aqueous hydrochloric acid solution, dried over anhydrous magnesium sulfate, filtered and concentrated to give a yellow oil. The oil was purified by flash chromatography on silica gel eluting with 1:1 ethyl acetate/methylene chloride to give 6.17 g (82% yield) of the title compound as a white solid; 1H NMR (CDCl3).δ.1.96-2.08 (m, 1H), 2.18-2.28 (m, 1 H), 2.67-2.80 (m, 1H), 2.87-2.98 (m, 1H), 3.29-3.37 (m, 2H), 3.53-3.65 (m, 3H), 3.88 (s, 3H), 5.16 (s, 2H), 5.80-5.88 (m, 1H), 6.71 (dd, 1H, J=8.7, 3.0 Hz), 6.79 (d, 1H, J=3.0 Hz), 6.85 (d, 1H, J=8.7 Hz), 7.10-7.47 (m, 9H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3]1[CH2:8][CH2:7][C:6](=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:5][CH2:4]1.[H][H]>C(OCC)(=O)C.[Pd]>[F:1][C:2]([F:15])([F:16])[CH:3]1[CH2:4][CH2:5][CH:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C=C1CCC(C(F)(F)F)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CCC(C(F)(F)F)CC1
Yield: 79.3 %

Procedure:
To a stirred solution of [4-(trifluoromethyl)cyclohexylidene]-acetic acid, ethyl ester (Example 8 (a)) (1 g) in ethyl acetate (20 mL) was added 5% palladium on carbon (450 mg). The mixture was stirred at room temperature under a 2 bar atmosphere of hydrogen. The reaction mixture was then filtered through diatomaceous earth and concentrated. Purification (SiO2, ethyl acetate:isohexane 1:19 as eluant) gave 4-(trifluoromethyl)-cyclohexaneacetic acid, ethyl ester (800 mg), which was dissolved in methanol (3 mL). Potassium hydroxide (1 g) in water (3 mL) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and subsequently acidified to pH1 with aqueous 2M hydrochloric acid. The resulting solution was extracted with dichloromethane (3×10 mL) and the combined organic extracts dried, filtered and evaporated to give the sub-title compound as an oil (660 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=O.[CH3:18][S:19]([CH2:22][C:23](=O)[CH3:24])(=[O:21])=[O:20].[Na]>CC(O)C>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:23]([CH3:24])[C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[C:9]2[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1
Reactant: CC(=O)CS(C)(=O)=O
Reactant: Nc1ccc(Br)cc1C(=O)c1ccc(F)cc1
Agent: [Na]
Solvent: CC(C)O
Product: Cc1nc2ccc(Br)cc2c(-c2ccc(F)cc2)c1S(C)(=O)=O
Yield: 27.2 %

Procedure:
(2-Amino-5-bromo-phenyl)-(4-fluoro-phenyl)-methanone (compound of example A.1) (4 g, 14 mmol), methanesulfonylacetone (2.78 g, 20 mmol) and sodium tetrachloroaureate(III) dihydrate (0.27 g, 0.7 mmol) were heated at reflux in 2-propanol (50 ml) for 4 days. The resulting mixture was evaporated to dryness and the residue extracted with dichloromethane (2×), 1 N NaOH (2×) and NaCl (1×). The crude product was purified by chromatography in heptane/ethyl acetate with a gradient from 100:0 to 70:30. One obtained a light brown solid (1.5 g, 28%). MS: m/z=394 (M).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([C:11]2[CH:12]=[C:13]([N:17]3[C:21]4[CH:22]=[CH:23][C:24]([CH:26]([NH:28]C=O)[CH3:27])=[CH:25][C:20]=4[N:19]=[CH:18]3)[CH:14]=[CH:15][CH:16]=2)=[CH:5][N:4]=1.C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([C:11]2[CH:12]=[C:13]([N:17]3[C:21]4[CH:22]=[CH:23][C:24]([CH:26]([NH2:28])[CH3:27])=[CH:25][C:20]=4[N:19]=[CH:18]3)[CH:14]=[CH:15][CH:16]=2)=[CH:5][N:4]=1
Reactant: COc1ncc(-c2cccc(-n3cnc4cc(C(C)NC=O)ccc43)c2)c(OC)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ncc(-c2cccc(-n3cnc4cc(C(C)N)ccc43)c2)c(OC)n1
Yield: 24.4 %

Procedure:
A solution of N-(1-{1-[3-(2,4-dimethoxy-pyrimidin-5-yl)-phenyl]-1H-benzoimidazol-5-yl}-ethyl)-formamide (0.53 g, 1.31 mmol) in hydrochloric acid (2.2 ml, 6M) was stirred at 60° C. for 3 hours. To the cooled solution was added ethyl acetate and aqueous sodium carbonate to basic reaction. The layers were separated and the organic layer was dried over magnesium sulphate and concentrated in vacuo. The concentrate was eluted through silica gel with a mixture of dichloromethane, methanol and aqueous ammonia (9:1:0.1 v/v/v) to afford the desired product (0.12 g, 25%). LC-ESI-HRMS of [M+H]+ shows 376.1794 Da. Calc. 376.17735 Da. dev. 5.4 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](N)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.N([O-])=O.[Na+].C1C=CN=CC=1.[FH:25]>>[Cl:1][C:2]1[CH:11]=[C:10]([F:25])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: F
Reactant: COc1ccc2nc(Cl)cc(N)c2c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc2nc(Cl)cc(F)c2c1
Temperature: 30 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
A solution of 2-chloro-6-methoxyquinolin-4-amine (4.50 g, 21.6 mmol) in HF-pyridine (45 mL) was cooled to −10-0° C. Then NaNO2 (1.80 g, 26.1 mmol) was added portionwise and the mixture was stirred at 0° C. for 1 hour and at 30° C. for 1 hour. Then the mixture was heated to 65° C. for 1.5 hours. The mixture was quenched with ice-water (100 mL); the aqueous layer was neutralized with 2 M NaOH to pH 7. The mixture was filtered off and the filtrate was extracted with EtOAc (50 mL×3), the organic layer was washed with brine (100 mL), dried over Na2SO4 and concentrated in vacuo. Purification by column chromatography on silica gel (PE/EtOAc=15/1) gave Intermediate 7 (3.60 g, yield: 40%). 1H NMR (CDCl3 400 MHz): δ 7.92 (dd, J=9.2, 1.6 Hz, 1H), 7.40 (dd, J=9.2, 2.8 Hz, 1H), 7.25 (s, 1H), 7.10 (d, J=9.2 Hz, 1H), 3.97 (s, 3H).