Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=S(Cl)Cl.[CH2:5]([N:12]1[CH2:16][CH2:15][C:14]2([CH2:21][CH2:20][C:19]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)(O)[CH2:18][CH2:17]2)[CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH2:5]([N:12]1[CH2:16][CH2:15][C:14]2([CH2:21][CH2:20][C:19]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[CH:18][CH2:17]2)[CH2:13]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: OC1(c2cccnc2)CCC2(CCN(Cc3ccccc3)C2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: C1=C(c2cccnc2)CCC2(C1)CCN(Cc1ccccc1)C2
Reaction time: 0.25 h
Yield: 71 %

Procedure:
SOCl2(1 ml) was added dropwise to a solution of 2-benzyl-8-(pyridin-3-yl)-2-azaspiro[4.5]decan-8-ol (450 mg, 1.39 mmol, 1.0 eq.) in pyridine (5 ml) at −10° C. and the reaction mixture was stirred at the same temperature for 15 min. After completion of the reaction (monitored by TLC), the reaction mixture was poured onto crushed ice and the mixture was then neutralized with sat. NaHCO3 solution (15 ml). It was extracted with methylene chloride (2×30 ml) and the combined organic layers were washed with water (20 ml) and brine (20 ml), and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the crude product which was purified by column chromatography (silica gel; 10% MeOH/DCM) to yield the desired compound as a reddish sticky solid. Yield: 71% (300 mg, 0.99 mmol).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(N(CC)CC)C.S=[C:19]1[CH2:23][S:22][C:21](=[O:24])[NH:20]1>C(O)C>[O:24]=[C:21]1[N:20]=[C:19]([NH:2][CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH2:23][S:22]1
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C1NC(=S)CS1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)CNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.9 %

Procedure:
To a solution of tert-butyl glycinate hydrochloride (4.00 g) and triethylamine (3.33 mL) in ethanol (20 mL) was added 4-thioxo-1,3-thiazolidin-2-one (2.65 g), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.70 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]([O:27]C)=O)[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:13]=[N:14][CH:15]=[N:16][CH:17]=3)[NH:9]2)=[CH:5][CH:4]=1.[NH3:29]>CO.O1CCCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]([NH2:29])=[O:27])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:17]=[N:16][CH:15]=[N:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1cccc(Cc2c(-c3cncnc3)[nH]c3cc(OC)ccc23)n1
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(Cc3cccc(C(N)=O)n3)c(-c3cncnc3)[nH]c2c1

Procedure:
A mixture of methyl 6-(6-methoxy-2-pyrimidin-5-yl-1H-indol-3-ylmethyl)pyridine-2-carboxylate (466 mg), a solution of ammonia in methanol (about 7 mol/L, 18.6 mL) and tetrahydrofuran (6.2 mL) was stirred at room temperature for 48 hours. The precipitate was collected by filtration, washed with methanol, and then dried under reduced pressure to obtain the title compound (370 mg). 1H-NMR (DMSO-d6) δ ppm: 3.79 (3H, s), 4.44 (2H, s), 6.70 (1H, dd, J=2.3, 8.5 Hz), 6.89 (1H, d, J=2.3 Hz), 7.34-7.41 (1H, m), 7.51 (1H, d, J=8.5 Hz), 7.63-7.77 (2H, m), 7.79-7.86 (2H, m), 9.13 (1H, s), 9.14 (2H, s), 11.45 (1H, s).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]1[CH:37]=[C:38]([C:42](=[O:44])[CH3:43])[CH:39]=[CH:40][CH:41]=1.CN(C)C=O>C(OCC)(=O)C>[C:42]([C:38]1[CH:37]=[C:36]([CH:41]=[CH:40][CH:39]=1)[CH2:35][N:8]1[C:9](=[O:26])[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]=[C:7]1[CH3:27])(=[O:44])[CH3:43]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2cccc(C(C)=O)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 1-[3-(bromomethyl)phenyl]ethanone (0.73 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless viscous substance (1.02 g, 61%).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20](=O)[CH:21](Cl)[C:22]([O:24][CH2:25][CH3:26])=[O:23])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH2:37])=[S:36])=[CH:33][CH:32]=1.ClCCCl.O>C(Cl)Cl>[Si:1]([O:18][CH2:19][C:20]1[N:37]=[C:35]([C:34]2[CH:33]=[CH:32][C:31]([C:30]([F:40])([F:29])[F:41])=[CH:39][CH:38]=2)[S:36][C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(Cl)C(=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Yield: 67.4 %

Procedure:
To a 500 ml round-bottom flask equipped with a magnetic stir-bar was mixed ethyl 4-{[tert-butyl(diphenyl)silyl]oxy}-2-chloro-3-oxobutanoate (20.4 g, 52.88 mmoles, 1 eq), 4-trifluoromethylthiobenzamide (12.2 g, 59.5 mmoles, 1.1 eq), 1,2-dichloroethane (150 ml, 0.44M) and H2O (3 ml). This mixture was refluxed for 12 hrs. After cooling to room temperature, the reaction mixture was diluted with CH2Cl2 (100 ml) and washed with sat. NaHCO3. Once the phases were separated, the organic phase was washed with water, brine and dried over Na2SO4. This was then filtered, concentrated in vacuo and purified via silica gel chromatography (5% EtOAc/Hexanes to 20% EtOAc/Hexanes) to yield 20.3 g (76%) of the titled compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:8][CH:9]([CH2:12][CH3:13])[CH2:10]O)=[N:4][CH:5]=[N:6][CH:7]=1.S(Cl)(Cl)=O>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[C:3]2[N:4]([CH2:10][CH:9]([CH2:12][CH3:13])[N:8]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CCC(CO)Nc1ncncc1Br
Solvent: Cc1ccccc1C
Solvent: O=S(Cl)Cl
Product: CCC1CN2C=NC=C(Br)C2=N1
Temperature: 100 °C
Reaction time: 24 h
Yield: 98.1 %

Procedure:
2-[(5-Bromo-4-pyrimidinyl)amino]-1-butanol (3.3 g) was dissolved in xylene (27 mL), then thionyl chloride (4.9 mL) was added thereto, and the mixture was heated under stirring at 100° C. for 1 day. The precipitated crystals were collected by filtration and suspended in a 1M aqueous sodium carbonate solution. This mixture was extracted with dichloromethane to give the crude title compound (3.0 g) as an orange oil. This title compound was used in the next reaction without purification.
Reaction SMILES: [Na].[P:2]([O:6][CH2:7][C@@H:8]([OH:13])[C@@H:9]([OH:12])[CH:10]=[O:11])([OH:5])([OH:4])=[O:3].[BH4-].[Na+]>CO>[P:2]([O:6][CH2:7][C@@H:8]([OH:13])[C@@H:9]([OH:12])[CH2:10][OH:11])([OH:4])([OH:5])=[O:3]
Reactant: O=C[C@H](O)[C@H](O)COP(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: O=P(O)(O)OC[C@@H](O)[C@@H](O)CO

Procedure:
The sodium salt of D-erythrose 4-phosphate (14.6 mg, 65.7 μmol) is dissolved in methanol (600 μl, 40% (v/v)). Sodium borohydride is added. The reaction is monitored by detection of the aldehyde according to the method of Stahl (Bollinger, H. R., Brenner, M., Gänshirt, H., Mangold, H. K., Seiler, H., Stahl, E. ad Waldi, D. (1964) IN: Dünnschicht-Chromatographie; Ein Laboratoriumshandbuch (ed. Stahl, E.) Springer Verlag, Berlin, Göttingen; Heidelberg). After consumption of the aidehyde the pH of the solution is adjusted with acetic acid to 4–5. The reaction mixture is lyophillized yielding D-erythritol 4-phosphate as a dry compound.
Reaction SMILES: [Li].C[Si]([N-:6][Si](C)(C)C)(C)C.[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15].[ClH:20]>CCOCC.C(O)C>[ClH:20].[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]([NH2:6])=[NH:15]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: N#Cc1ccccc1F
Agent: Cl
Agent: [Li]
Solvent: CCOCC
Solvent: CCO
Product: N=C(N)c1ccccc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
To a solution of lithium-bis(trimethylsilyl)amide (10 g, 59.8 mmol) in ether (200 ml) in a flame-dried flask, was added 2-fluorobenzonitrile (7.26 g, 59.8 mmol) dropwise over 45 min. at r.t. The mixture was stirred for a further 4 h. at r.t. then cooled to −10° C. and 6N HCl in ethanol (40 ml) added dropwise over 30 min. (exothermic). After allowing the reaction mixture to warm to r.t. overnight the precipitate was filtered and washed with ether then dried under high vacuum at 40° C. overnight. To remove LiCl the dried solid was re-suspended in ethanol (200 ml) and filtered, then the volume reduce volume to ca. 30 ml. The solution was filtered then triturated with ether, and stirred 30 min. at 4° C. Filtration of the precipitate, washing with ether and high vacuum drying overnight at 40° C., afforded the title compound (7.8 g, 44.7 mmol, 75% yield) as a white solid. MS: m/e=138 (M+).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:18]=[C:19]([CH:34]=[CH:35][CH:36]=3)[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=O)(C)(C)C.[OH-].[K+]>O1CCCC1.CO.C(OCC)(=O)C>[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:18]=[C:19]([CH:34]=[CH:35][CH:36]=3)[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:24][CH:23]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: COC(=O)CCc1ccc(OCc2cccc(-c3ccc4c(ccn4C(=O)OC(C)(C)C)c3)c2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(OCc2cccc(-c3ccc4[nH]ccc4c3)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.6 %

Procedure:
Methyl 3-(4-{[3-(1-tert-butoxycarbonyl-1H-indol-5-yl)benzyl]oxy}phenyl)propanoate (3.8 g, 7.83 mmol) was dissolved in a mixed solvent of tetrahydrofuran (30 mL) and methanol (30 mL), and the mixture was ice-cooled. An aqueous solution (10 mL) of 85% potassium hydroxide (1.0 g, 15.1 mmol) was added to the solution, and the mixture was stirred at room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, and the mixture washed successively with aqueous citric acid solution, water and aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil was crystallized from diethyl ether-hexane to give 3-(4-{[3-(1H-indol-5-yl)benzyl]oxy}phenyl)propanoic acid (2.2 g, yield 76%) as colorless needle crystals. MS: m/z 372 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:35][C:36](=[O:61])[C@@H:37]1[CH2:41][CH2:40][CH2:39][N:38]1[C:42](=[O:60])[C@H:43]([CH2:45][CH2:46][CH2:47][CH2:48][NH:49][C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[NH2:44])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.FC(F)(F)C(O)=O.C([BH3-])#N.[Na+]>C(O)C.C(N(CC)CC)C>[CH2:28]([O:35][C:36](=[O:61])[C@@H:37]1[CH2:41][CH2:40][CH2:39][N:38]1[C:42](=[O:60])[C@H:43]([CH2:45][CH2:46][CH2:47][CH2:48][NH:49][C:50]([O:52][CH2:53][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)=[O:51])[NH:44][C@@H:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][CH2:13]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: CCOC(=O)C(=O)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-oxohexanoate [prepared according to Chem. Pharm. Bull, 34, 3747 (1986)] (7.4 g) and Nε -benzyloxycarbonyl-L-lysyl-L-proline benzylester.trifluoroacetic acid salt (4.6 g) in ethanol (40 ml) is adjusted to pH 5 with triethylamine. To this solution is added 2 g of molecular sieves, and the reaction mixture is stirred for 30 minutes. A solution of sodiumcyanoborohydride (1.4 g) in ethanol (40 ml) is dropped therein under stirring for 5 hours, and is kept stirring for further one night. The ethanol is distilled under reduced pressure, thereafter the residue is transferred to ethyl acetate. The ethyl acetate layer is washed with water, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. To the residue ether is added. The ether layer is washed with water and then ether is distilled under reduced pressure. The residue is applied to silica gel chromatography (ethyl acetate:hexane=2:1) to obtain, from the first effluence, 1.34 g of Nα -[1(R)-ethoxycarbonyl- 5-(1-benzyloxycarbonyl-4-piperidyl)pentyl]-Nε -benzyloxycarbonyl-L-lysyl-L-proline benzylester (Rf=0.62, expansive solvent, F), and from the following effluence, 1.15 g of Nα -[1(S)ethoxycarbonyl-5-(1-benzyloxycarbonyl-4-piperidyl)pentyl]-Nε -benzyloxycarbonyl-L-proline benzylester (Rf=0.52, expansive solvent, F).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.C(O[CH:18]=[C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])C>>[CH3:14][N:11]1[CH2:10][CH2:9][N:8]([C:6]2[N:7]=[C:2]([NH:1][CH:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:3]=[CH:4][CH:5]=2)[CH2:13][CH2:12]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CN1CCN(c2cccc(N)n2)CC1
Product: CCOC(=O)C(=CNc1cccc(N2CCN(C)CC2)n1)C(=O)OCC
Temperature: 90 °C

Procedure:
A mixture containing 2.5 g of 6-amino-2-(4-methyl-1-piperazinyl)pyridine and 3.1 g of diethyl ethoxymethylenemalonate was heated at 90° C for 2 hours and then chilled. The resulting solid was recrystallized from benzene to give the product, m.p. 114°- 115° C.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:11].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]2[S:15][C:14]([CH3:24])=[N:13][C:12]=2[C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@H:8]([CH3:9])[C@@H:3]2[CH2:2][NH:1][C:29]2[N:28]=[C:27]([O:26][CH3:25])[CH:32]=[CH:31][N:30]=2)=[O:11])=[CH:22][CH:21]=1
Reactant: COc1ccnc(Cl)n1
Reactant: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CN)c(-c2ccc(F)cc2)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COc1ccnc(NC[C@H]2[C@@H](C)CCCN2C(=O)c2nc(C)sc2-c2ccc(F)cc2)n1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
A mixture of rac-cis-(2-(aminomethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone, 4-methoxy-2-chloropyrimidine, and DIPEA in isopropanol was stirred at 110° C. for 18 h. The reaction was cooled and concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 456.02 (M+H).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH:3]([C:6]2[CH:7]=[CH:8][C:9]([C:12]([F:15])([F:14])[F:13])=[N:10][CH:11]=2)[CH2:2]1.[N:16]#[C:17][NH2:18].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>CC#N>[F:14][C:12]([F:15])([F:13])[C:9]1[N:10]=[CH:11][C:6]([CH:3]2[CH2:4][CH2:5][S:1](=[N:18][C:17]#[N:16])[CH2:2]2)=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(C2CCSC2)cn1
Reactant: N#CN
Agent: N#C/N=S1\CCC(c2ccc(C(F)(F)F)nc2)C1
Solvent: CC(=O)O
Solvent: CC#N
Solvent: Ic1ccccc1
Product: N#CN=S1CCC(c2ccc(C(F)(F)F)nc2)C1
Temperature: 25 °C

Procedure:
5-(Tetrahydrothiophen-3-yl)-2-trifluoromethylpyridine (1.082 g, 4.64 mmol) was dissolved in 9 mL anhydrous CH3CN under nitrogen. The solution was cooled in an ice bath. Solid cyanamide (0.195 g, 4.64 mmol) was added followed by iodobenzene diacetate (1.496 g, 4.64 mmol). The reaction mixture was allowed to slowly warm to room temperature overnight. The solution was extracted with hexane (6×30 mL). The acetonitrile layer was concentrated by rotary evaporation, and the residue was triturated with ether. The resulting solid was collected and washed with ether to yield (1E)-3-[6-(trifluoromethyl)pyridin-3-yl]tetrahydro-1H-1λ4-thien-1-ylidenecyanamide (1.12 g; 88.4% yield) as an off-white powder. The 1H NMR spectrum of this solid exhibited resonances for a 1:1 mixture of diastereomers. 1H NMR (acetone-d6) δ 8.85 (d, J=2.2 Hz, 1H, pyridine H6), 8.83 (d, J=2.2 Hz, 1H, pyridine H6), 8.26 (dd, J=2.2, 8.3 Hz, 1H, pyridine H4), 8.15 (dd, J=2.2, 8.3 Hz, 1H, pyridine H4), 7.90 (d, J=8.3 Hz, 1H, pyridine H3), 7.86 (d, J=8.3 Hz, 1H, pyridine H3), 4.38 (dd, J=8.7, 14 Hz, 1H), 4.23 (tt, J=6, 12 Hz, 1H), 4.16 (ddd, J=2.6, 8.3, 11.2 Hz, 1H), 3.83 (td, J=8.7, 18 Hz, 1H), 3.68-3.48 (m, 3H), 3.29-3.17 (m, 2H), 2.95 (m, 1H), 2.85-2.79 (m, 3H), 2.33 (m, 1H). LC-MS (ELSD): 273 [m]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]=[C:12]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:13]3[S:18][C:17]([CH2:19][N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[CH:16][C:14]=3[N:15]=2)[C:5]([CH3:9])=[C:6]([NH2:8])[CH:7]=1.[N:33](OCCC(C)C)=O>C(Cl)(Cl)Cl.C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]2[C:5]([CH:9]=[N:33][NH:8]2)=[C:4]([C:10]2[N:11]=[C:12]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[C:13]3[S:18][C:17]([CH2:19][N:20]4[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]4)=[CH:16][C:14]=3[N:15]=2)[CH:3]=1
Reactant: CC(C)CCON=O
Reactant: Cc1c(N)cc(F)cc1-c1nc(N2CCOCC2)c2sc(CN3CCN(C)CC3)cc2n1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CN1CCN(Cc2cc3nc(-c4cc(F)cc5[nH]ncc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
Prepared by treatment of 5-fluoro-2-methyl-3-[6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl]-phenylamine with isoamyl nitrite in chloroform and acetic acid.
Reaction SMILES: [CH:1]([OH:8])([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH2:9]>>[CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH2:6]([OH:9])[CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:8]
Reactant: O
Reactant: CCCCCC(O)O
Product: C=CCCCCO
Product: OCCCCCCO
Temperature: 450 °C

Procedure:
The tube reactor was first charged with 10 g of the catalyst from Example 1 and subsequently heated to the desired temperature (450° C.). On reaching a constant temperature, a defined volume flow (1.95 ml/min) of the liquefied starting material (mixture of 80% by weight of hexanediol and 20% by weight of water) in the double-wall dropping funnel was conveyed by means of the metering pump through the vaporizer and superheater tube into the reactor. The temperature was regulated so as to ensure isothermal operating conditions. After leaving the reactor, the gaseous reaction product was condensed in the condenser and the downstream cold trap, collected in the interchangeable receiver and subsequently analyzed by means of gas chromatography and 1H-NMR spectroscopy. In the example described, 34% by weight of 5-hexen-1-ol plus 28% by weight of unreacted 1,6-hexanediol were obtained, which corresponds to a selectivity of 77.9 mol % and a conversion of 64.9%. This gives, as a measure of the catalyst output, a space-time yield of 40.28 mol of 5-hexen-1-ol per liter of catalyst volume and hour.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:11][CH:10]2[CH2:12][CH:7]1[CH:8]=[CH:9]2.[Mg].O1CCCC1.[Cl-].[NH4+].[CH3:21][C:22]([CH3:24])=[O:23]>>[CH3:21][C:22]([OH:23])([CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:11][CH:10]2[CH2:12][CH:7]1[CH:8]=[CH:9]2)[CH3:24]
Reactant: ClCCCCC1CC2C=CC1C2
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O)CCCCC1CC2C=CC1C2
Reaction time: 1 h
Yield: 84 %

Procedure:
A Grignard reagent was prepared from 95.5 g of 1-chloro-4-(5-norbornen-2-yl)butane, 13.3 g of magnesium, and 200 ml of anhydrous tetrahydrofuran. Then, under an atmosphere of nitrogen, 35.5 g of acetone was added thereto at 40° C. over a period of 1 hour. After this mixture was stirred for 1 hour, the reaction product was hydrolyzed by the addition of an aqueous solution of ammonium chloride, followed by separation into aqueous and organic phases. Subsequently, the organic phase was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by vacuum distillation to obtain 90.5 g of 2-methyl-6-(5-norbornen-2-yl)hexan-2-ol (boiling point: 93-98° C./66 Pa; yield: 87%).
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:16]=[C:17]([NH:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[CH:18]=[CH:19][CH:20]=2)[CH2:11][CH2:10]1.Cl.[F:28][C:29]([F:40])([F:39])[O:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37]N)=[CH:33][CH:32]=1>>[CH3:24][CH:23]([CH3:25])[C:22]([NH:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH:12]2[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][C:6]3[C:35]4[C:34](=[CH:33][CH:32]=[C:31]([O:30][C:29]([F:40])([F:39])[F:28])[CH:36]=4)[NH:37][CH:2]=3)[CH2:14][CH2:13]2)[CH:16]=1)=[O:26]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCC3OCCO3)CC2)c1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCc3c[nH]c4ccc(OC(F)(F)F)cc34)CC2)c1

Procedure:
Prepared by Procedure H and Scheme S using N-(3-{1-[3-(1,3-dioxolan-2-yl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-[4-(trifluoromethoxy)phenyl]hydrazine hydrochloride: ESMS m/e: 474.2 (M+H)+.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.Cl.[NH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:27][C:26]3[CH:25]=[N:24][N:23]([CH3:28])[C:22]=3[NH:21][C:20]3[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:19]2=3)=[O:17])=[CH:12][C:11]=1[Cl:34].CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)COP([O-])(O)=O)C2=CC=1C.[Na+].CCN(C(C)C)C(C)C>ClCCl>[Cl:34][C:11]1[CH:12]=[C:13]([C:16]([N:18]2[CH2:27][C:26]3[CH:25]=[N:24][N:23]([CH3:28])[C:22]=3[NH:21][C:20]3[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:19]2=3)=[O:17])[CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][C:4]([CH:1]1[CH2:3][CH2:2]1)=[O:5]
Reactant: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)c1ccc(CN)c(Cl)c1)C2
Reactant: O=C(Cl)C1CC1
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)COP(=O)([O-])O)c2cc1C
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)c1ccc(CNC(=O)C3CC3)c(Cl)c1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
Cyclopropanecarbonyl chloride (0.045 ml, 0.5 mmol) was added to a solution of (4-aminomethyl-3-chloro-phenyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E106.2 (220 mg, 0.5 mmol) in dichloromethane (40 ml) and DIEA (0.30 ml, 1.7 mmol) at 0° C. The mixture was stirred for 1 h at room temperature then washed with saturated NaHCO3, brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloro-methane) to give a white powder identified as the title compound (135 mg, 57%).