Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:30]1[CH2:29][CH2:28][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[F:20])[CH2:32][CH2:31]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Product: COc1nc2cc(Cl)ccc2nc1NC(=O)N1CCN(c2ccccc2F)CC1
Yield: 93 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(2-fluorophenyl)piperazine were reacted by the same way with the example 106 to obtain the titled compound (yield, 93%). 1H NMR (300 MHz, CDCl3): δ 3.18 (s, 4H), 3.78 (s, 4H), 4.14 (s, 3H), 6.94-7.11 (m, 4H), 7.35-7.45 (m, 2H), 7.74-7.77 (m, 2H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:21]=[C:9]2[C:10]([NH2:20])=[N:11][C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:13][N:8]2[N:7]=1.[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[C:24]=1[CH:25]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:21]=[C:9]2[C:10]([NH2:20])=[N:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH2:25][C:24]4[C:23]([F:22])=[CH:30][C:29]([F:31])=[CH:28][C:27]=4[F:32])[CH2:16][CH2:15]3)=[CH:13][N:8]2[N:7]=1
Reactant: O=Cc1c(F)cc(F)cc1F
Reactant: Nc1nc(N2CCNCC2)cn2nc(-c3ccco3)nc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1nc(N2CCN(Cc3c(F)cc(F)cc3F)CC2)cn2nc(-c3ccco3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a solution of 2-furan-2-yl-6-piperazin-1-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine in methylene chloride (see Example 16 above) was added 2,4,6-trifluorobenzaldehyde (28 mg, 0.18 mmol), sodium triacetoxyborohydride (46 mg, 0.22 mmol) and acetic acid (6 μL, 0.1 mmol). The reaction was stirred at room temperature for overnight. After the solvent was removed, the residue was subjected to flash chromatography (ethyl acetate/hexanes=30:70, 40:60) to afford 2-furan-2-yl-6-[4-(2,4,6-trifluoro-benzyl)-piperazin-1-yl]-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine as a white solid (35 mg, 56%). 1H NMR (300 MHz, CDCl3) δ2.66 (t, J=4.5 Hz, 4H), 3.34 (t, J=4.5 Hz, 4H), 3.73 (s, 2H),5.61 (s, 2H), 6.54 (dd, J=1.8, 3.6 Hz, 1H), 6.67 (d, J=7.8 Hz, 1H), 6.70 (d, J=7.8 Hz, 1H), 7.07 (d, J=3.6 Hz, 1H), 7.26 (s, 1H), 7.57 (d, J=1.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ46.53, 48.35, 51.56, 95.63, 99.82, 100.10, 100.38, 110.29, 111.73, 134.80, 143.80, 146.00, 146.42, 149.06, 155.13.
Reaction SMILES: [CH2:1]([O:3][N:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][C:7](=[O:12])[CH2:6][C:5]1([CH3:14])[CH3:13])[CH3:2].[CH3:15][Si:16](C#N)([CH3:18])[CH3:17].II.[C:23](#[N:25])C>CCCCCC.C(OCC)(=O)C>[CH2:1]([O:3][N:4]1[C:5]([CH3:13])([CH3:14])[CH2:6][C:7]([C:23]#[N:25])([O:12][Si:16]([CH3:18])([CH3:17])[CH3:15])[CH2:8][C:9]1([CH3:11])[CH3:10])[CH3:2]
Reactant: CCON1C(C)(C)CC(=O)CC1(C)C
Reactant: CC#N
Reactant: C[Si](C)(C)C#N
Agent: II
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCON1C(C)(C)CC(C#N)(O[Si](C)(C)C)CC1(C)C
Temperature: 25 °C

Procedure:
To a solution of 0.398 g (2 mmol) 1-ethoxy-2,2,6,6-tetramethyl-piperidin-4-one in dry acetonitrile is added 0.297 g (3 mmol) trimethylsilyl cyanide and a catalytic amount of iodine. The solution is stirred at rt over night. The reaction mixture is extracted with ethyl acetate, washed with Na2CO3 solution and brine. The organic layer is separated, dried over Na2SO4, filtered and the solvent is removed under reduced pressure. A yellow oil was obtained and subsequently subjected to flash chromatography on silica gel using 4:1 hexane/ethyl acetate as eluent. The product was obtained as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][CH2:20][S:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:25])[CH:23]=[CH2:24].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CC([O-])=O.CC([O-])=O.[Pd+2].CC#N>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([C:8](=[C:16]2[CH2:21][CH2:20][S:19][CH2:18][CH2:17]2)[C:5]2[CH:6]=[CH:7][C:2](/[CH:24]=[CH:23]/[C:22]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: Oc1ccc(C(=C2CCSCC2)c2ccc(Br)cc2)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCSCC2)c2ccc(O)cc2)cc1
Temperature: 85 °C

Procedure:
Reagents 36 (0.32 g, 0.886 mmol), t-butyl acrylate (0.78 mL, 5.31 mmol), Pd(OAc)2 (0.042 g, 0.186 mmol), P(o-tolyl)3 (0.12 g, 0.381 mmol) and Et3N (0.74 mL, 5.31 mmol) were added to a flask containing CH3CN (13 mL) and the reaction mixture was heated at 85° C. for 24 h. The reaction mixture was allowed to cool at RT and partitioned between water and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4), filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by flash column chromatography on silica gel using a hexanes:EtOAc gradient (100:0 to 50:50) to give compound 37 as a yellow foam. 1H NMR (400 MHz, DMSO-d6): δ 1.46 (s, 9H), 2.65-2.66 (m, 5H), 6.45 (d, J=16 Hz, 1H), 6.68 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.5 Hz, 2H), 7.09 (d, J=8.1 Hz, 2H), 7.49 (d, J=16.1 Hz, 1H), 7.60 (d, J=8.1 Hz, 2H), 9.37 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:8]([O:24][CH3:25])=[C:9]([NH:11][C:12]([C:14]2[S:18][C:17]3[C:19]([NH2:23])=[CH:20][CH:21]=[CH:22][C:16]=3[CH:15]=2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][N:41]([S:44]([C:47]2[CH:52]=[CH:51][C:50]([C:53](O)=[O:54])=[CH:49][CH:48]=2)(=[O:46])=[O:45])[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][N:41]([S:44]([C:47]2[CH:48]=[CH:49][C:50]([C:53](=[O:54])[NH:23][C:19]3[C:17]4[S:18][C:14]([C:12](=[O:13])[NH:11][C:9]5[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=[C:7]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[C:8]=5[O:24][CH3:25])=[CH:15][C:16]=4[CH:22]=[CH:21][CH:20]=3)=[CH:51][CH:52]=2)(=[O:46])=[O:45])[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: COc1c(NC(=O)c2cc3cccc(N)c3s2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C(=O)O)cc2)CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: COc1c(NC(=O)c2cc3cccc(NC(=O)c4ccc(S(=O)(=O)N5CCN(C(=O)OC(C)(C)C)CC5)cc4)c3s2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 42 h
Yield: 14.3 %

Procedure:
7-Amino-benzo[b]thiophene-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide (0.100 g, 0.223 mmol), 4-(4-carboxy-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (0.160 g, 0.432 mmol), HOBT (0.060 g, 0.444 mmol) and EDC (0.080 g, 0.417 mmol) were dissolved in DMF (7.0 mL) and stirred at room temperature under an Ar atmosphere for 42 h. The reaction mixture was transferred to a separatory funnel containing water and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic extracts were washed with water, NH4Cl, brine and dried over MgSO4. The solvent was filtered and evaporated on a rotary evaporator. The resultant crude product was purified by chromatography (60% EtOAc/hexane) to give the desired 4-{4-[2-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-benzo[b]thiophen-7-ylcarbamoyl]-benzenesulfonyl}-piperazine-1-carboxylic acid tert-butyl ester (25.5 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])[O:28][C:29](Cl)(Cl)Cl)Cl.[CH3:35][O:36][C:37]1C=[CH:41][CH:40]=[CH:39][C:38]=1O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:28][C:29]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[O:36][CH3:35])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4OC)cc3)c2cc1OC
Yield: 49.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (151 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-methoxyphenol (63 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (75 mg, yield 46%).
Reaction SMILES: Br[CH:2]1[CH2:4][CH2:3]1.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[N:12]>>[CH:2]1([CH:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=2)[NH2:12])[CH2:4][CH2:3]1
Reactant: BrC1CC1
Reactant: N#Cc1ccccn1
Product: NC(c1ccccn1)C1CC1

Procedure:
The title compound was synthesized according to method G, utilizing Mg powder (240 mg, 10 mmol), bromocyclopropane (1.21 g, 10 mmol), picolinonitrile (520 mg, 5 mmol) and
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH3:6])[CH2:3]Br.[CH2:7]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]#N)=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].S(=O)(=O)(O)[OH:31].C1(C)C=CC=CC=1>CCOCC.O>[CH2:7]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28](=[O:31])[CH2:1][C@@H:2]([CH3:3])[CH2:5][CH3:6])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCC(C)CBr
Reactant: CCCCCCCCOc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)C[C@@H](C)CC)cc2)cc1
Reaction time: 0.5 h

Procedure:
Sliced Mg (12.4 g, 0.510 mol) and dry ether (50 ml) were placed in a three-neck flask in a dry nitrogen atmosphere and agitated, and to the mixture was dropwise added a solution obtained by dissolving (+)-2-methylbutyl bromide (prepared from (-)-2-methyl-1-butanol and phosphorus bromide) in dry ether (1 l), so as to keep the temperature of the system at 25° C. or lower. After completion of the dropwise addition, the mixture was allowed to stand at room temperature for 30 minutes, followed by dropwise adding a solution obtained by dissolving a commercially available product, 4-octyloxy-4'-cyanobiphenyl (IV) (129 g, 0.42 mol) in dry ether (1 l) so as to keep the temperature of the system at 10° C. or lower, thereafter refluxing for 4 hours, cooling pouring the reaction liquid in water (600 ml), further adding diluted sulfuric acid (conc. sulfuric acid 40 ml +water 80 ml, adding toluene (500 ml), transferring the mixture into a separating funnel, water-washing till the washing liquid became neutral, distilling off the solvent, distilling the residue under reduced pressure, collecting a fraction of bp 245°~255° C./4 mmHg and recrystalling from acetone (30 ml) to obtain 4-octyloxy-4'-((S)-3-methyl-pentanoyl)biphenyl (IIIa1) (24.6 g), which was a smectic liquid crystal exhibiting SC* phase and SA phase, and its phase transition points were as follows as shown in Table 2, column of Example 23:
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[N+:11]([O-:13])=[O:12].[NH3:14].O1CCOCC1>O>[F:8][C:7]1[C:6]([F:9])=[CH:5][C:4]([F:10])=[C:3]([N+:11]([O-:13])=[O:12])[C:2]=1[NH2:14]
Reactant: N
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1F
Solvent: O
Solvent: C1COCCO1
Product: Nc1c(F)c(F)cc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
A solution comprising 2,3,4,6-tetrafluoronitrobenzene (0.6 g, 3.1 mmol) and ammonia in dioxane (Aldrich, 0.5M, 7.5 mmol) was stirred at room temperature for 3 hours to give a fine white precipitate. The mixture was diluted with an equal volume of water to dissolve the white precipitate and give yellow crystals. The crystals were isolated were collected and dried to provide 2,3,5-trifluoro-6-nitroaniline (307 mg, 51%) as yellow needles; m.p. 66° C.; 1H NMR (CDCl3) δ 6.4 (1H, m), δ 6.0 (2H, s).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([OH:18])[CH:17]=1.C(N(CC)CC)C>O1CCOCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:18][C:16]2[CH:17]=[C:12]([Cl:11])[CH:13]=[N:14][CH:15]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: Oc1cncc(Cl)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(Oc2cncc(Cl)c2)cc1
Yield: 44.5 %

Procedure:
To a stirred solution of 4-fluoro-nitrobenzene (913 μL, 8.61 mmol, from Aldrich) in dioxane (1 mL) was added 3-chloro-5-hydroxypyridine (558 mg, 4.31 mmol, from Aldrich) followed by triethylamine (661 μL, 4.74 mmol). The solution was refluxed for 4.5 hours, evaporated and the crude solid was dissolved in ethyl acetate. The solution was washed three times with saturated K2CO3 solution, once with brine and then back-extracted with ethyl acetate. The two organic solutions were combined, concentrated and the residue was purified by chromatography (diethyl ether as eluant) to provide 481 mg of the title compound.
Reaction SMILES: [N+]([O-])(O)=O.OS(O)(=O)=O.[CH3:10][C:11]1C=C(C=CC=1)C(O)=O.CC1C([N+]([O-])=O)=C(C([N+]([O-])=O)=CC=1)C(O)=O.[CH3:36][C:37]1[C:38]([N+:49]([O-:51])=[O:50])=[CH:39][C:40]([N+:46]([O-:48])=[O:47])=[C:41]([CH:45]=1)[C:42]([OH:44])=[O:43].O=S(Cl)Cl>CCO>[CH2:10]([O:43][C:42](=[O:44])[C:41]1[CH:45]=[C:37]([CH3:36])[C:38]([N+:49]([O-:51])=[O:50])=[CH:39][C:40]=1[N+:46]([O-:48])=[O:47])[CH3:11]
Reactant: Cc1cccc(C(=O)O)c1
Reactant: Cc1cc(C(=O)O)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cc1ccc([N+](=O)[O-])c(C(=O)O)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O=S(Cl)Cl
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: CCOC(=O)c1cc(C)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 25.4 %

Procedure:
To a mixture of HNO3 (95%, 80 mL) and H2SO4 (98%, 80 mL) was slowly added 3-methylbenzoic acid (50 g, 0.37 mol) at 0° C. After addition, the mixture was stirred for 1.5 h while maintaining the temperature below 30° C. The mixture was poured into ice-water and stirred for 15 min. The precipitate was collected via filtration and washed with water to give a mixture of 3-methyl-2,6-dinitro-benzoic acid and 5-methyl-2,4-dinitro-benzoic acid (70 g, 84%). To a solution of this mixture in EtOH (150 mL) was added dropwise SOCl2 (53.5 g, 0.45 mol). The mixture was heated at reflux for 2 h and concentrated to dryness under reduced pressure. The residue was dissolved in EtOAc (100 mL) and extracted with 10% Na2CO3 solution (120 mL). The organic layer was found to contain 5-methyl-2,4-dinitro-benzoic acid ethyl ester while the aqueous layer contained 3-methyl-2,6-dinitro-benzoic acid. The organic layer was washed with brine (50 mL), dried over Na2SO4 and concentrated to dryness to provide 5-methyl-2,4-dinitro-benzoic acid ethyl ester (20 g, 20%).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:9]1)C1C=CC=CC=1.Cl[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24]>C1(C)C=CC=CC=1>[CH2:26]([O:25][C:23]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])[CH2:9]1)=[O:24])[CH:27]=[CH2:28]
Reactant: C=CCOC(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCC1CCN(Cc2ccccc2)C1
Solvent: Cc1ccccc1
Product: C=CCOC(=O)N1CCC(CO[Si](C)(C)C(C)(C)C)C1

Procedure:
A solution of 1-benzyl-3-t-butyldimethylsilyloxymethylpyrrolidine (60.10 g) and allyl chloroformate (25.27 ml) in toluene (600 ml) was heated at 60° C for one hour. The mixture was concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (500 g), and eluted with a mixture of ethyl acetate and hexane (1:9-3:7, V/V) to give 1-allyloxycarbonyl-3-t-butyldimethylsilyloxymethylpyrrolidine (30.00 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].C[O-].[Na+].[CH3:9][C:10]1[O:11][C:12]([CH2:15]Cl)=[N:13][N:14]=1>CO>[CH3:9][C:10]1[O:11][C:12]([CH2:15][S:5][CH2:4][CH2:3][NH2:2])=[N:13][N:14]=1
Reactant: Cc1nnc(CCl)o1
Reactant: NCCS
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1nnc(CSCCN)o1
Reaction time: 1 h
Yield: 110.8 %

Procedure:
Cysteamine hydrochloride (1.13 g; 0.01 mole) was added to a stirred solution of sodium methylate (1.08 g; 0.02 mole) in 20 ml of methanol at 0° under an argon atmosphere. The mixture was stirred for 1 hour at 0° and the resultant suspension was added dropwise over a period of 25 minutes to a stirred solution of 2-methyl-5-chloromethyl-1,3,4-oxadiazole (1.32 g; 0.01 mole) [prepared by the procedure described in Hel. Chim. Acta, 55, 1979 (1972)] in 15 ml of methanol at 0°. The reaction mixture was stirred at ambient temperature for 45 minutes, concentrated to near dryness, and then diluted with methylene chloride, filtered and evaporated under reduced pressure to give the title compound (1.92 g) as a yellow oil. The NMR spectrum (60 MHz) in CDCl3 gave the following resonances δ: 3.87 (s, 2H); 2.8 (m, 4H); 2.53 (s, 3H).
Reaction SMILES: [S:1]1[C:5]([C:6]2([C:10](=O)[CH2:11][Br:12])[CH2:9][CH2:8][CH2:7]2)=[CH:4][C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]1=2.[NH:18]1[CH2:22][CH2:21][NH:20][C:19]1=[S:23].C(O)C>C(O)(=O)C>[BrH:12].[S:1]1[C:5]([C:6]2([C:10]3[N:20]4[CH2:21][CH2:22][N:18]=[C:19]4[S:23][CH:11]=3)[CH2:9][CH2:8][CH2:7]2)=[CH:4][C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]1=2
Reactant: O=C(CBr)C1(c2cc3ccccc3s2)CCC1
Reactant: S=C1NCCN1
Solvent: CC(=O)O
Solvent: CCO
Product: Br
Product: C1=C(C2(c3cc4ccccc4s3)CCC2)N2CCN=C2S1
Temperature: 25 °C
Yield: 52.4 %

Procedure:
A mixture of 1-[1-(benzo[b]thiophen-2-yl)cyclobutyl]-2-bromoethanone (0.42 g), imidazolidine-2-thione (0.14 g), ethanol (15 ml) and acetic acid (10 ml) was heated under reflux for 18 hours then allowed to cool to ambient temperature. The solvents were removed in vacuo and the residue was triturated with ether (30 ml). The resulting solid was collected by filtration, dried in vacuo at 40° C. and crystallised from ethanol. The resulting product was collected by filtration, washed with ethanol (3 ml) and dried in vacuo at 40° C. to give 3-[1-(benzo[b]thiophen-2-yl)cyclobutyl]-5,6-dihydroimidazo[2,1-b]thiazole hydrobromide as an off-white solid (0.28 g), m.p. 240-242° C.
Reaction SMILES: [F:1][C:2]([F:53])([F:52])[C:3]1[CH:4]=[C:5]([CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[C:34]1[CH:39]=[C:38]([CH:40]([CH3:42])[CH3:41])[CH:37]=[CH:36][C:35]=1[O:43][CH3:44])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:10][CH:9]=1.[OH-:54].[Na+].Cl.C(Cl)Cl>C(O)C.O1CCCC1>[C:18](=[O:19])([OH:54])[OH:20].[F:51][C:48]([F:49])([F:50])[C:46]1[CH:45]=[C:5]([CH:4]=[C:3]([C:2]([F:53])([F:52])[F:1])[CH:47]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:32])([F:33])[F:31])[CH:27]=[CH:26][C:25]=1[C:34]1[CH:39]=[C:38]([CH:40]([CH3:41])[CH3:42])[CH:37]=[CH:36][C:35]=1[O:43][CH3:44])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:10][CH:9]=1
Reactant: CCOC(=O)CCCOc1ccc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2-c2cc(C(C)C)ccc2OC)nc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(OCCCC(=O)O)cn1
Product: O=C(O)O
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
Ethyl 4-{6-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyridin-3-yloxy}-butyrate (150 mg) is dissolved in a mixed solvent of ethanol (1 ml) and tetrahydrofuran (2 ml) and thereto is added a 2N-aqueous sodium hydroxide solution (0.3 ml) and the mixture is stirred at 50° C. for 3 hours and 20 minutes. The reaction solution is cooled to room temperature and neutralized with a 2N-hydrochloric acid (0.3 ml), and thereto are added methylene chloride and a saturated brine and the mixture is separated, and the organic layer is concentrated under reduced pressure. The resulting residue is purified by LCMS (column: CAPCELPACK MG2 C18, eluate: a 10 μM aqueous carbonic acid solution/acetonitrile=55/45→40/60) to give 4-{6-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyridin-3-yloxy}-butyric acid (31.4 mg). The resulting carboxylic acid is dissolved in ethanol (1 ml) and thereto is added a 2N-aqueous sodium hydroxide solution (42 μl) and the reaction solution is concentrated under reduced pressure to give 4-{6-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyridin-3-yloxy}-butyric acid sodium salt (30.6 mg). MS (m/z): 727 [M−Na]−
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@H:13]([C@@H:14]([O:16][C:17]3C=CC(Cl)=C(Cl)C=3)[CH3:15])[CH2:12][CH2:11][N:10]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][N:34]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:9]2)=[CH:4][CH:3]=1.N1CCCCC1.C(N1CC[C@H]([C@H]([OH:62])C)[C@@H](C2C=CC(Cl)=CC=2)C1)C1C=CC=CC=1.[F:70][C:71]1[CH:72]=[N:73]C(O)=[N:75][CH:76]=1.ClC(OC(Cl)=O)C.CCN(C(C)C)C(C)C>CO>[C:39]([C:36]1[CH:37]=[CH:38][C:33]([N:30]2[CH2:31][CH2:32][CH:27]([C:25]([OH:26])=[O:62])[CH2:28][CH2:29]2)=[N:34][CH:35]=1)#[N:40].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[C@@H:13]([C@@H:14]([O:16][C:17]3[N:73]=[CH:72][C:71]([F:70])=[CH:76][N:75]=3)[CH3:15])[CH2:12][CH2:11][N:10]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][N:34]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: C[C@@H](O)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Reactant: C[C@H](Oc1ccc(Cl)c(Cl)c1)[C@H]1CCN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@@H]1c1ccc(Cl)cc1
Reactant: Oc1ncc(F)cn1
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: C1CCNCC1
Product: C[C@H](Oc1ncc(F)cn1)[C@H]1CCN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@@H]1c1ccc(Cl)cc1
Product: N#Cc1ccc(N2CCC(C(=O)O)CC2)nc1

Procedure:
In analogy to the procedure described for the synthesis of 4-{(3S,4S)-3-(4-Chloro-phenyl)-4-[(S)-1-(3,4-dichloro-phenoxy)-ethyl]-piperidine-1-carbonyl}-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile (example 49) the respective piperidine derivative was prepared from (R)-1-[(3S,4S)-1-Benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethanol and 5-fluoro-pyrimidin-2-ol via Mitsunobu reaction and subsequently the benzyl group was cleaved by treatment with 1-chloroethyl-chloroformate, DIPEA and methanol. Coupling with 5′-Cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid (commercially available) yielded the title compound as viscous yellow oil. MS (m/e): 549.4 [(M+H)+].