Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:10])[N:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[CH3:11][N:12]([CH3:14])[NH2:13]>>[CH3:11][N:12]([CH3:14])[N:13]=[C:6]1[CH2:7][CH2:8][N:3]([N:2]([CH3:10])[CH3:1])[CH2:4][CH2:5]1
Reactant: CN(C)N1CCC(=O)CC1
Reactant: CN(C)N
Product: CN(C)N=C1CCN(N(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.9 %

Procedure:
3.0 g 1-Dimethylamino-piperidin-4-one (prepared as described in Journal of Medicinal & Pharmaceutical Chemistry, 4, 423-36; 1961) is cooled to 0° C., and 3.8 g N,N-dimethylhydrazine is added at such a rate, that the internal temperature does not exceed 15° C. The mixture is stirred at ambient temperature for 3 hours. Then the excess of N,N-dimethylhydrazine is evaporated. Thus, 3.65 g [4-(Dimethyl-hydrazono)-piperidin-1-yl]-dimethyl-amine is obtained. 1H-NMR (CDCl3): 2.80 ppm (m, 2H), 2.70 ppm (m, 4H), 2.45 ppm (s, 6H), 2.42 ppm (m, 2H), 2.40 ppm (s, 6H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]=[N:8][N:9]1[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10]1.[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>O.C(OCC)C>[CH3:7][NH:8][N:9]1[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10]1
Reactant: C=NN1C[C@H]2CCCC[C@H]2C1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CNN1C[C@H]2CCCC[C@H]2C1
Yield: 83.4 %

Procedure:
To lithium aluminum hydride (204 mg, 5.38 mmol) was added diethyl ether (50 ml) and the mixture was stirred under ice-cooling. Thereto was added the compound (505 mg, 3.39 mmol) obtained in step B and the mixture was heated under reflux for 1 hr. The reaction mixture was ice-cooled, and water (0.204 ml), 15% aqueous sodium hydroxide solution (0.204 ml), water (0.615 ml) and sodium sulfate were successively added with stirring. The insoluble material was filtered off through celite, and the solution was concentrated under reduced pressure to give the title compound (436 mg, yield 85%) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(O)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1>O1CCCC1>[F:28][C:27]([F:29])([F:30])[C:24]1[CH:25]=[CH:26][C:21]([CH2:20][O:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]3)=[CH:6][CH:7]=2)=[CH:22][CH:23]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: O=C(O)N1CCN(c2ccc(O)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(COc2ccc(N3CCNCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-(4-hydroxy-phenyl)-piperazine-1-carboxylic acid tent-butyl ester (1.5 g, 5.4 mmol) in dry tetrahydrofuran (5 mL) was added to a suspension of sodium hydride (431 mg, 60% in oil, 10.8 mmol) in dry tetrahydrofuran (35 mL). After 15 min, a solution of 1-bromomethyl-4-trifluoromethyl-benzene (1.9 g, 8.1 mmol) in tetrahydrofuran (5 mL) was added. The mixture was stirred for 16 hr at room temperature, filtered, and concentrated under vacuum. The resulting residue was diluted in ethyl acetate (40 mL), and the organic layer was washed with water (3×20 mL), dried over magnesium sulfate, filtered, and concentrated under vacuum. The resulting residue was dissolved in a 1:1 mixture of dichloromethane and trifluoroacetic acid (30 mL). The mixture was then stirred for 30 min. Afterward, the mixture was concentrated under vacuum, taken up in dichloromethane (30 mL), and evaporated to dryness. The resulting residue was diluted in diethylether (5 mL) and then combined with a molar solution of HCl in diethylether (10 mL, 1M). A precipitate formed, which was filtered, washed with diethylether (10 mL), and dried under vacuum. The desired product was isolated as a hydrochloride salt with traces of solvent.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:20][C:21](=[O:33])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]5([C:31]#[N:32])[CH2:30][CH2:29]5)[CH:23]=4)[CH:15]=[CH:16][C:17]=3[O:18][CH3:19])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1.O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:31]([C:28]1([C:24]2[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=2)[C:21]([NH:20][C:14]2[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:12]([O:11][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([NH:1][C:37]([CH:34]5[CH2:36][CH2:35]5)=[O:38])[S:3][C:4]=4[CH:10]=3)[CH:13]=2)=[O:33])[CH2:30][CH2:29]1)#[N:32]
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(N)sc2c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2c1
Yield: 55.3 %

Procedure:
A solution of N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-methoxyphenyl}-3-(1-cyanocyclopropyl)benzamide (91 mg, 0.20 mmol), cyclopropanecarbonyl chloride (105 mg, 1.00 mmol) and N,N-dimethylpyridine-4-amine (122 mg, 1.00 mmol) in pyridine (2 mL) was stirred at room temperature for 18 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent:hexane/ethyl acetate=1:1), and triturated with diethyl ether to give the title compound (58 mg, 55%) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3].[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32].C(N(CC)C(C)C)(C)C>ClCCl>[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](=[O:32])(=[O:33])[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)CNCc1ccc(-c2cccc(S(C)(=O)=O)c2)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)N(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)CC(C)C

Procedure:
In analogy to example 13, step 2, isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amine (example 15, step 2) was reacted with methyl-2-(chlorosulfonyl)-benzoate and N,N-diisopropyl ethyl amine in dichloromethane to give 2-{isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-sulfamoyl}-benzoic acid methyl ester as a colorless oil. MS: 522.3 ([M+H]+)
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH:14]1[CH2:19][CH2:18][CH2:17][CH:16]=[CH:15]1>CN(C=O)C>[CH:18]1([N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[CH2:17][CH2:16][CH:15]=[CH:14][CH2:19]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrC1C=CCCC1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C1CC=CCC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 234.7 %

Procedure:
A mixture of potassium phthalimide (1.85 g, 3 mmol) and 3-bromocyclohexene (1.79 g, 3 mmol) in DMF (15 mL) was stirred in a 100° C. oil bath for 12 h. The cooled reaction mixture was poured into ice water. The solid was collected by filtration and purified by flash chromatography with CH2Cl2 as the eluent to afford compound 221 (1.6 g, 72%) as pink crystals; mp 114° C.; 1H NMR (CDCl3) δ 7.73-7.69 (m, 2H), 7.62-7.58 (m, 2H), 5.85-5.82 (m, 1H), 5.47-5.44 (m, 1H), 4.80-4.78 (m, 1H), 2.14-2.00 (m, 3H), 1.86-1.78 (m, 2H), 1.64-1.58 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:16]1[S:17][CH:18]=[C:19]2[O:24][CH2:23][CH2:22][O:21][C:20]=12)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:22]1[CH2:23][O:24][C:19]2[C:20](=[C:16]([C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=3)[S:17][CH:18]=2)[O:21]1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1scc2c1OCCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(-c2scc3c2OCCO3)cc1
Reaction time: 0.33 h
Yield: 68 %

Procedure:
To a refluxing solution of 1-bromo-4-nitrobenzene (2.762 g, 13.67 mmol) in toluene (250 mL) was added tetrakis(triphenylphosphine)palladium(0) (75 mg). After 20 min, 2-(tributylstannyl) 3,4-(ethylenedioxy)thiophene (6.05 g, 14.03 mmol) was added via a syringe. After complete addition, the mixture was refluxed for a total of 20 h. After cooling, the mixture was filtered and the solvent was evaporated to afford a solid. Filtration using hot hexane gave 1-(3,4-ethylenedioxythien-2-yl)-4-nitrobenzene, 2.46 g, yield=68%, mp=184-186° C. IR (KBr; in cm-1) 3066, 2946, 1592, 1506, 1477, 1338, 1066 and 851. 1H NMR (CDCl3 ; δ in ppm): 4.285 (m, 2H), 4.376 (m, 2H), 6.468 (s, 1H), 7.852 (d, J=9.9 Hz, 2H) and 8.197 (d, J=9.9 Hz, 2H). 13C NMR (CDCl3 ; δ in ppm): 64.25, 64.94, 100.93, 115.10, 124.03, 125.61, 139.72, 140.53, 142.43 and 145.37. MS(EI) m/z (rel int): 263 [(M)+, 27%], 233 [(M+ --NO), 8%] and 166[(M+ --C5H5O2), 9%]. Anal. Calcd for C12H9NO4S: C, 54.75; H, 3.45;, N, 5.32; S, 12.18. Found: C, 55.04; H, 2.99; N, 4.05; S, 11.57.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][NH:8][C:7](=[O:10])[CH2:6][CH2:5]1)([OH:3])=[O:2].S(Cl)(Cl)=O.[CH2:15](O)[CH3:16]>>[CH2:15]([O:2][C:1]([CH:4]1[CH2:9][NH:8][C:7](=[O:10])[CH2:6][CH2:5]1)=[O:3])[CH3:16]
Reactant: O=C1CCC(C(=O)O)CN1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1CCC(=O)NC1
Reaction time: 18 h

Procedure:
To a suspension of 250 g of 5-carboxy-2-piperidone in 2.5 liters of punctilious ethanol were added 500 g of thionyl chloride at 22° C. Stir for 18 hours. The resulting solution was evaporated to dryness and the residue triturated with ether to give 233 g of the title compound: MS m/z 171 (M+), 142, 126, 115, 98; 300-MHz 1H NMR (DMSO-d6) δ1.21 (t, J=7 Hz, 3H), 1.78-1.92 (m, 1 H), 1.95-2.08 (m, 1H), 2.15-2.31 (m, 2H), 2.78-2.89 (m, 1H), 3.25-3.40 (m, 2H), 4.12 (t, J=7 Hz, 2H), 7.95 (s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3([O:22][CH2:23][CH3:24])[CH2:21][CH2:20]3)=[C:15]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:14]=2)=[CH:7][CH:6]=1)C.[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:23]([O:22][C:19]1([C:16]2[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][C:8]3[CH:7]=[CH:6][C:5]([C:4]([OH:29])=[O:3])=[CH:10][CH:9]=3)=[CH:14][C:15]=2[C:25]([CH3:26])([CH3:28])[CH3:27])[CH2:21][CH2:20]1)[CH3:24]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCC)CC3)c(C(C)(C)C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC1(c2ccc(CCc3ccc(C(=O)O)cc3)cc2C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
Using General Procedure I; a solution of ethyl4-[4-(1-ethoxycyclopropyl)-3-tert-butyl-phenylethynyl]-benzoate (Compound 103, 70.0 mg, 0.18 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (240.0 mg, 6.0 mmols, 3.0 mL of a 2N aqueous solution) and stirred overnight at room temperature. Work-up afforded 40 mg (62%) the title compound as a pale-yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[CH2:3].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:19])[CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)=[CH:8][CH:7]=1>>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([CH2:13][N:14]3[CH:18]=[N:17][CH:16]=[N:15]3)[C:2]([CH3:4])([CH3:3])[CH2:1][O:19]2)=[CH:8][CH:7]=1
Reactant: C=C(C)C
Reactant: O=C(Cn1cncn1)c1ccc(F)cc1
Product: CC1(C)COC1(Cn1cncn1)c1ccc(F)cc1
Yield: 2 %

Procedure:
Following a procedure similar to that described in Example 39, but using 2-methylpropene and 4'-fluoro-2-(1H-1,2,4-triazol-1-yl)acetophenone, the title compound, melting at 110° C., was obtained in a 2% yield.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl.[CH3:26][C:27]1[N:28]=[C:29]([CH3:56])[N:30]2[C:35]=1[C:34]([O:36][C:37]1[CH:42]=[C:41]([O:43][CH3:44])[C:40]([O:45][CH3:46])=[C:39]([O:47][CH3:48])[CH:38]=1)=[N:33][C:32]([C:49]1[CH:50]=[C:51]([CH:53]=[CH:54][CH:55]=1)[NH2:52])=[N:31]2>>[CH3:26][C:27]1[N:28]=[C:29]([CH3:56])[N:30]2[C:35]=1[C:34]([O:36][C:37]1[CH:38]=[C:39]([O:47][CH3:48])[C:40]([O:45][CH3:46])=[C:41]([O:43][CH3:44])[CH:42]=1)=[N:33][C:32]([C:49]1[CH:50]=[C:51]([NH:52][C:1](=[O:4])[CH3:2])[CH:53]=[CH:54][CH:55]=1)=[N:31]2
Reactant: CC(=O)O
Reactant: COc1cc(Oc2nc(-c3cccc(N)c3)nn3c(C)nc(C)c23)cc(OC)c1OC
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: COc1cc(Oc2nc(-c3cccc(NC(C)=O)c3)nn3c(C)nc(C)c23)cc(OC)c1OC

Procedure:
14.25 mg (0.24 mmol) of acetic acid, 32.06 mg (0.24 mmol) of HOBt, 72.00 mg (0.71 mmol) of 4-methylmorpholine, 50.03 mg (0.26 mmol) of EDC and 100 mg (0.24 mmol) of 3-[5,7-dimethyl-4-(3,4,5-trimethoxyphenoxy)imidazo[5,1-f][1,2,4]-triazin-2-yl]aniline from example 6 are reacted analogously to example 2.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:22])([CH3:21])[C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[Br:23]Br>C(Cl)(Cl)(Cl)Cl>[Br:23][CH:5]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[CH:9][CH:8]=1)[C:4](=[O:20])[C:3]([CH3:22])([CH3:21])[CH2:2][Cl:1]
Reactant: BrBr
Reactant: CC(C)(CCl)C(=O)COc1ccc(-c2ccc(Cl)cc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(CCl)C(=O)C(Br)Oc1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
33.7 g (0.1 mol) of 4-chloro-1-[4-(4-chlorophenyl)-phenoxy]-3,3-dimethyl-butan-2-one were dissolved in 250 ml of carbon tetrachloride. 5.1 ml (0.1 mol) of bromine were added dropwise at room temperature at a rate such that the bromine was steadily consumed. The mixture was then stirred for 30 minutes at room temperature. After distilling off the solvent in vacuo, crude 1-bromo-4-chloro-1-[4-(4-chlorophenyl)-phenoxy]3,3-dimethyl-butan-2-one was obtained in quantitative yield and was directly reacted further.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[CH:12]=[C:13]([Br:16])[CH:14]=[CH:15][C:10]=2[O:9][CH:8]=1)(=O)=O.[CH3:19][O:20][CH2:21][C:22]#[CH:23]>>[Br:16][C:13]1[CH:14]=[CH:15][C:10]2[O:9][CH:8]=[C:7]([C:23]#[C:22][CH2:21][O:20][CH3:19])[C:11]=2[CH:12]=1
Reactant: O=S(=O)(Oc1coc2ccc(Br)cc12)C(F)(F)F
Reactant: C#CCOC
Product: COCC#Cc1coc2ccc(Br)cc12

Procedure:
Analogously to residue 9a, 9.31 g of 5-bromobenzofuran-3-yl trifluoromethanesulphonate [440083-74-9] and 3.52 ml of 3-methoxypropyne are reacted. The title compound is obtained as a yellowish oil. Rf=0.43 (1:10 EtOAc-heptane); Rt=5.14 (gradient I).
Reaction SMILES: C([O:3][C:4](=[O:22])[C@@H:5]([O:20][CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.[C:23]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][NH2:30])[CH:24]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[C:23]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][NH:30][C:17]([C:14]([CH3:15])([O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:20][CH3:21])[C:4]([OH:3])=[O:22])=[CH:12][CH:11]=2)[CH3:16])=[O:19])[CH:24]=1
Reactant: NCc1cccc(-c2ccccc2)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OC(C)(C)C(=O)NCc2cccc(-c3ccccc3)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (PREPARATION 5, step 2) and C-biphenyl-3-yl-methylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C27H29NO5 [M−H]−: 446.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:27]=[CH:26][C:20]4[CH2:21][NH:22][CH2:23][CH2:24][O:25][C:19]=4[CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Br[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].CCN(C(C)C)C(C)C>CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:27]=[CH:26][C:20]4[CH2:21][N:22]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:23][CH2:24][O:25][C:19]=4[CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCBr
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)OCCNC4)no2)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CCN1CCOc2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)ccc2C1
Yield: 93.1 %

Procedure:
A mixture of 8-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (Example 13) (0.036 g, 0.199 mmol), ethyl 3-bromopropanoate (0.084 g, 0.199 mmol) and DIPEA (0.097 ml, 0.557 mmol) was stirred and heated at 80° C. for 4 hours when a further portion of ethyl 3-bromopropanoate (0.084 g, 0.199 mmol) and DIPEA (0.097 ml, 0.557 mmol) were added and heated overnight when a further portion of ethyl 3-bromopropanoate (0.084 g, 0.199 mmol) and DIPEA (0.097 ml, 0.557 mmol) were added and heated for 3 more hours when all starting material gone. The cooled reaction mixture was diluted with EtOAc/water (30 ml of each) and the organics dried (magnesium sulphate), evaporated and purified by flash chromatography eluting with 1:1 EtOAc/iso-hexane to give the title compound (90 mgs) as a colourless gum. MS (ES) C25H2835ClN3O5 requires 485; found 486 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[N:14]=2)[N:11]=1.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>CN(C)C(=O)C>[C:16]([NH:15][C:13]1[N:14]=[C:9]2[CH:8]=[CH:7][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:25]([CH:22]4[CH2:24][CH2:23]4)=[O:26])[CH:21]=[CH:20][CH:19]=3)=[N:11][N:10]2[CH:12]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Nc1cn2nc(Oc3cccc(N)c3)ccc2n1
Reactant: O=C(Cl)C1CC1
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1cn2nc(Oc3cccc(NC(=O)C4CC4)c3)ccc2n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 51.2 %

Procedure:
A mixture of N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]acetamide (17 mg, 0.06 mmol), cyclopropanecarbonyl chloride (9.5 mg, 0.09 mmol) and N,N-dimethylacetamide (0.5 mL) was stirred at room temperature for 14 hr. The reaction mixture was purified by preparative HPLC to give the title compound (10.8 mg, 51%).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:8][C@H:7]1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:5])C.[OH-].[Na+]>CO>[CH:9]1([C@@H:7]2[CH2:8][C@H:6]2[C:4]([OH:5])=[O:3])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCOC(=O)[C@@H]1C[C@H]1C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@@H]1C[C@H]1C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.5 %

Procedure:
The crude ester (726 mg, 3.70 mmol, 1 equiv.) from above was dissolved in 20 mL MeOH and treated with 2.0 M aqueous NaOH solution (10 mL). The reaction mixture was stirred at room temperature for 3 h and then placed on a rotary evaporator to remove MeOH. Water was added and the mixture was washed once with ether. The aqueous layer was then acidified with 6 N HCl aqueous solution and the product was extracted with ether 3 times. The combined organics were washed once with brine, then dried (MgSO4). The solution was filtered through a small plug of SiO2 and the solvents removed in vacuo, providing 458 mg (2.72 mmol, 74%) of trans-2-cyclohexyl-cyclopropanecarboxylic acid.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][CH2:6][CH2:7][C:8]1[C:9]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:10]=2[S:11][CH:12]=1)C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O=P(Cl)(Cl)Cl>>[F:17][C:15]1[CH:14]=[CH:13][C:10]2[S:11][C:12]3[C:4](=[O:3])[NH:5][CH2:6][CH2:7][C:8]=3[C:9]=2[CH:16]=1
Reactant: CCOC(=O)NCCc1csc2ccc(F)cc12
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: O=C1NCCc2c1sc1ccc(F)cc21
Temperature: 110 °C
Yield: 19.8 %

Procedure:
[2-(5-Fluoro-benzo[b]thiophen-3-yl)-ethyl]-carbamic acid ethyl ester (I-45d: 550 mg, 2.059 mmol) was reacted with P2O5 (461 mg, 4.11 mmol) and POCl3 (7 mL). The resulting mixture was refluxed at 110° C. for 2 hours to afford the crude product. Purification by column chromatography on silica gel (2% methanol in chloroform) afforded 90 mg of the product (19.78% yield).
Reaction SMILES: CS(C)=O.[CH3:5][C:6]1[CH:7]=[C:8]([OH:20])[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[N:10][C:11]=1[CH3:12].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:33][O:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][C:28]=1[O:34][CH3:35])[N:25]=[CH:24][N:23]=[C:22]2[O:20][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[N:10][C:11]([CH3:12])=[C:6]([CH3:5])[CH:7]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Cc1ccc(-c2nc(C)c(C)cc2O)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2ncnc(Oc3cc(C)c(C)nc3-c3ccc(C)cn3)c2cc1OC
Temperature: 130 °C
Reaction time: 4 h
Yield: 90.5 %

Procedure:
Dimethyl sulfoxide (1.4 ml) was added to 5,6,5′-trimethyl-[2,2′]bipyridin-3-ol (30 mg), 4-chloro-6,7-dimethoxyquinazoline (94 mg), and cesium carbonate (137 mg), and the mixture was stirred at 130° C. for 4 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, the mixture was filtered, and the residue was washed with chloroform/methanol. The solvent was removed from the filtrate by distillation under the reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give the title compound (51 mg, yield 91%).
Reaction SMILES: ClC1C=CC(OCC2CCNCC2C2C=CC(Cl)=CC=2)=NC=1.Cl.C([N:31]1[CH2:36][CH2:35][C@H:34]([C@@H:37]([O:39][C:40]2[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][N:41]=2)[CH3:38])[C@@H:33]([C:50]2[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][CH:51]=2)[CH2:32]1)C1C=CC=CC=1>>[Cl:56][C:53]1[CH:54]=[CH:55][C:50]([C@@H:33]2[C@@H:34]([C@@H:37]([O:39][C:40]3[CH:45]=[CH:44][C:43]([C:46]([F:48])([F:47])[F:49])=[CH:42][N:41]=3)[CH3:38])[CH2:35][CH2:36][NH:31][CH2:32]2)=[CH:51][CH:52]=1
Reactant: C[C@H](Oc1ccc(C(F)(F)F)cn1)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Agent: Cl
Agent: Clc1ccc(C2CNCCC2COc2ccc(Cl)cn2)cc1
Product: C[C@H](Oc1ccc(C(F)(F)F)cn1)[C@H]1CCNC[C@@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of 5-chloro-2-[(3RS, 4RS)-3-(4-chloro-phenyl)-piperidin-4-ylmethoxy]-pyridine; hydrochloride (example 1, step h) the title compound was prepared from 2-{(S)-1-[(3S,4S)-1-Benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethoxy}-5-trifluoromethyl-pyridine as off-white foam as the respective HCl salt. MS (m/e): 385.2 [(M+H)+].