Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][NH:11][C:12](=[O:34])[C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH2:21][C:22]2[N:23]=[C:24]3[C:29](=[N:30][CH:31]=2)[N:28]=[C:27]([NH2:32])[N:26]=[C:25]3[NH2:33])[CH3:20])=[CH:15][CH:14]=1)(=[O:8])[O:5]CC)C.C[Si](Br)(C)C>CN(C=O)C>[NH2:32][C:27]1[N:26]=[C:25]([NH2:33])[C:24]2[C:29](=[N:30][CH:31]=[C:22]([CH2:21][N:19]([CH3:20])[C:16]3[CH:15]=[CH:14][C:13]([C:12]([NH:11][CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5])=[O:34])=[CH:18][CH:17]=3)[N:23]=2)[N:28]=1
Reactant: CCOP(=O)(CCNC(=O)c1ccc(N(C)Cc2cnc3nc(N)nc(N)c3n2)cc1)OCC
Agent: C[Si](C)(C)Br
Solvent: CN(C)C=O
Product: CN(Cc1cnc2nc(N)nc(N)c2n1)c1ccc(C(=O)NCCP(=O)(O)O)cc1
Temperature: 70 °C
Reaction time: 12 h
Yield: 53 %

Procedure:
To a solution of crude (2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-ethyl)-phosphonic acid diethyl ester post silica column chromatography (61 mg, 125 μmol) in dry DMF (1.00 mL) was added TMSBr (129.0 μL, 999.2 μmol) at ambient temperature. The solution was then heated at 70° C. for 5.5 hours, when LCMS analysis demonstrated the reaction to be 90% complete. The reaction mixture was allowed to cool to room temperature and stirred for an additional 12 hours. The reaction was worked up by removal of the solvent in vacuo and dissolving the residue in DMF/H2O (800 μL, 1:1) and 1N aqueous NaOH (15 μL). The product was purified by RP HPLC on C18 column using H2O/acetonitrile (2-95%) to provide 29 mg (53%) of the desired compound as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 1.67-1.85 (m, 2H), 3.19 (s, 3H), 3.25-3.40 (m, 2H), 4.76 (s, 2H), 6.71 (br s, 2H), 5.80 (d, 2H, J=9 Hz), 7.64 (d, 2H, J=9 Hz), 7.73 (br s, 2H), 8.15 (br s, 1H), 8.56 (s, 1H). 31P (121.4 MHz, DMSO-d6) δ 23.0. MS (m/z) 431.3 [M−H]−.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:48])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:39]([CH2:40][O:41][CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)=[CH:38][N:37]=[N:36]2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:48])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:39]([CH2:40][O:41][CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)=[CH:38][N:37]=[N:36]2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Product: CC(C)(C)OC(=O)Nc1cc(F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1

Procedure:
The title compound was prepared from (2-amino-5-fluoro-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J10) (294 mg. 1.0 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert.-butyl ester (Example K5) (442 mg, 1.1 mmol) according to the general procedure M. Obtained as an orange solid (509 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](O)=[O:6].O=S(Cl)[Cl:16]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([Cl:16])=[O:6]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a suspension of 3-fluoro-4-nitrobenzoic acid (30 g, 162.0 mmol) in toluene (500 mL) was added SOCl2 (35 mL, 486 mmol). The reaction was heated to 110° C. at which point the reaction became homogeneous. The reaction was stirred at 110° C. for 3 h. The reaction had not gone to completion so an additional portion of SOCl2 (10 mL) was added. The reaction was stirred for an additional 3 h. A small amount of starting material remained thus a final portion of SOCl2 (10 mL) was added and the reaction was heated for 2 h. The resulting green solution was cooled to room temperature and allowed to stand over night. The reaction mixture was filtered and concentrated in vacuo. Toluene (300 mL) was added to the resulting oil and removed under reduced pressure (2×). The product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C@@H:9]([NH2:11])[CH3:10].C([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[C:40]3[C:35](=[CH:36][C:37]([C:41](O)=[O:42])=[CH:38][CH:39]=3)[C:34]([CH3:44])=[C:33]2[CH3:45])=[CH:27][CH:26]=1)=[O:18])(C)(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C@@H:9]([NH:11][C:41]([C:37]1[CH:36]=[C:35]2[C:40](=[CH:39][CH:38]=1)[N:32]([CH2:31][C:28]1[CH:27]=[CH:26][C:25]([C:20]3[C:19]([C:17]([OH:18])=[O:16])=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:30][CH:29]=1)[C:33]([CH3:45])=[C:34]2[CH3:44])=[O:42])[CH3:10]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@H](N)c1c(Cl)cccc1Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3c(Cl)cccc3Cl)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using (S)-1-(2,6-dichlorophenyl)ethanamine and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 571 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Cl[C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18]([CH2:21][O:22][C:23]3[C:32]4[C:27](=[CH:28][C:29]([O:33][CH3:34])=[CH:30][CH:31]=4)[N:26]=[CH:25][CH:24]=3)=[N:19][N:20]=2)[N:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([CH2:21][O:22][C:23]4[C:32]5[C:27](=[CH:28][C:29]([O:33][CH3:34])=[CH:30][CH:31]=5)[N:26]=[CH:25][CH:24]=4)=[N:19][N:20]=3)[N:17]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COc1ccc2c(OCc3nnc4ccc(Cl)nn34)ccnc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2c(OCc3nnc4ccc(-c5cccc(F)c5)nn34)ccnc2c1
Temperature: 80 °C
Yield: 44.2 %

Procedure:
3-fluorophenylboronic acid (0.092 g, 0.66 mmol) was added to a suspension of 4-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline (0.150 g, 0.44 mmol) in 2.5 mL dimethylformamide, followed by the addition of potassium carbonate (0.18 g, 1.3 mmol) in 0.6 mL water. PdCl2(dppf)-CH2Cl2 adduct (0.018 g, 0.022 mmol) was added and the flask was purged with argon, sealed and heated at 80° C. for four hours. Purification by MPLC (eluted with 5 then 10% MeOH in CH2Cl2) afforded the product as an off-white solid (78 mg, 44%). (ESI, pos. ion) m/z: 402.1 (M+H).
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([OH:33])=[O:32])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.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>[OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31]([OH:33])=[O:32])=[CH:26][CH:25]=2)=[CH:7][CH:6]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H](Oc1ccc(-c2ccc(CC(=O)O)cc2)cc1)[C@H](O)CCc1cccnc1
Temperature: 100 °C
Yield: 55.3 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.6 g, Example 33), 4-bromophenylacetic acid (0.624 g), 2M aqueous sodium carbonate (2.5 ml) and tetrakis(triphenylphosphine)palladium (0) (0.5 g) in ethanol (15 ml). The reaction mixture was heated at 100° C. for 3 hours. After cooling, the solution was concentrated under reduced pressure. Water was added to the residue then washed with diethyl ether. The aqueous layer was acidified with 2M hydrochloric acid and washed with diethyl ether. The aqueous layer was neutralised to pH 7.11 and the solid filtered off washing with diethyl ether to give the title compound as a solid (0.431 g).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:23]=[C:22]2[C:14]([N:15]3[C:20](=[CH:21]2)[C:19](=[O:24])[NH:18][CH2:17][CH2:16]3)=[N:13][CH:12]=1.FC(F)(F)S(O[CH2:31][C:32]([F:35])([F:34])[F:33])(=O)=O.[H-].[Na+]>>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:23]=[C:22]2[C:14]([N:15]3[C:20](=[CH:21]2)[C:19](=[O:24])[N:18]([CH2:31][C:32]([F:35])([F:34])[F:33])[CH2:17][CH2:16]3)=[N:13][CH:12]=1
Reactant: C[C@H]1CCCN1CCCOc1cnc2c(c1)cc1n2CCNC1=O
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Product: C[C@H]1CCCN1CCCOc1cnc2c(c1)cc1n2CCN(CC(F)(F)F)C1=O
Yield: 12 %

Procedure:
The title compound was synthesized in analogy to example 17, from 7-[3-((S)-2-methyl-pyrrolidin-1-yl)-propoxy]-3,4-dihydro-2H-2,4a,5-triaza-fluoren-1-one (example 85), 2,2,2-trifluoroethyl trifluoromethanesulfonate and sodium hydride, to give the desired product as a colorless solid (12%).
Reaction SMILES: C(N(CCCC)CCCC)CCC.FC(F)(F)S(O[C:20]1[C:21]([C:26]([O:28][CH3:29])=[O:27])=[N:22][CH:23]=[CH:24][CH:25]=1)(=O)=O.[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[CH2:38])=[CH:35][CH:34]=1>CN(C=O)C.[Cu]I>[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[CH:38][C:20]2[C:21]([C:26]([O:28][CH3:29])=[O:27])=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:35][CH:34]=1
Reactant: C=Cc1ccc(F)cc1
Reactant: COC(=O)c1ncccc1OS(=O)(=O)C(F)(F)F
Agent: [Cu]I
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: COC(=O)c1ncccc1C=Cc1ccc(F)cc1
Temperature: 90 °C

Procedure:
Tributylamine (24.6 ml) was added to a stirred mixture of methyl 3-(trifluoromethanesulfonyloxy)pyridin-2-carboxylate (19.6 g), bis (triortho-tolylphosphine)palladium(II) chloride (1.08 g), copper (I) iodide (0.1 3 g) and 4-fluorostyrene (12.3 ml) in DMF (300 ml). The solution was heated under an inert atmosphere at 90° C. for 26 hours then cooled to ambient temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane (300 ml), the solid filtered and the filtrate washed with 1M. citric acid (3×100 ml), saturated aqueous sodium bicarbonate (150 ml), dried and concentrated under reduced pressure. The brown oil obtained was pre-absorbed onto silica then purified on a silica flash column eluting with ethyl acetate/iso-hexane (4:6) to give methyl 3-[2-(4-fluorophenyl)ethenyl]pyridin-2-carboxylate as a pale yellow solid (12.4 g).
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([I:28])[CH:25]=[CH:24][C:3]=1[NH:4][C:5]1[C:6]([C:21]([NH2:23])=[O:22])=[CH:7][N:8]([CH2:12][CH2:13][O:14]C2CCCCO2)[C:9](=[O:11])[CH:10]=1.Cl>CCO.O>[F:1][C:2]1[CH:27]=[C:26]([I:28])[CH:25]=[CH:24][C:3]=1[NH:4][C:5]1[C:6]([C:21]([NH2:23])=[O:22])=[CH:7][N:8]([CH2:12][CH2:13][OH:14])[C:9](=[O:11])[CH:10]=1
Reactant: NC(=O)c1cn(CCOC2CCCCO2)c(=O)cc1Nc1ccc(I)cc1F
Agent: Cl
Solvent: CCO
Solvent: O
Product: NC(=O)c1cn(CCO)c(=O)cc1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
4-(2-Fluoro-4-iodoanilino)-6-oxo-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1,6-dihydro-3-pyridinecarboxamide (118 mg, 0.24 mmol) was dissolved in EtOH (8 mL), to which was added 1 M HCl (2 mL). This mixture was stirred at R.T. for 2 h., then diluted with water (80 mL). The resulting solution was extracted with EtOAc (3×40 mL), then the combined EtOAc fractions washed with water (2×50 mL) and brine (50 mL), then dried (Na2SO4). Removal of the solvent under reduced pressure afforded 4-(2-fluoro-4-iodoanilino)-1-(2-hydroxyethyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a white solid (95 mg, 97%), m.p. (EtOAc/MeOH) 212-215° C. 1H NMR [(CD3)2SO, 400 MHz] δ 10.45 (s, 1H), 8.27 (s, 1H), 7.94 (br s, 1H), 7.74 (dd, J=10.1, 1.7 Hz, 1H), 7.57 (br d, J=8.6 Hz, 1H), 7.48 (br s, 1H), 7.29 (t, J=8.5 Hz, 1H), 5.55 (s, 1H), 4.93 (t, J=5.3 Hz, 1H), 3.85 (t, J=5.5 Hz, 2H), 3.60 (q, J=5.4 Hz, 2H). Anal. Calcd for C14H13FIN3O3: C, 40.3; H, 3.1; N, 10.1. Found: C, 40.4; H, 2.9; N, 9.8.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)#[N:2].[CH2:12]=[O:13].C(N(CC)CC)C>CC(C)=O>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][OH:13])[CH:4]=1)#[N:2]
Reactant: N#Cc1c[nH]c2ccccc12
Reactant: C=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: N#Cc1cn(CO)c2ccccc12
Temperature: 130 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
The mixture of 1.42 g of 3-cyano-1H-indole, 0.60 g of paraformaldehyde and 0.1 g of triethylamine was stirred at 130 ° C. for 1 hour. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.69 g of 3-cyano-1H-indole-1-ylmethanol.
Reaction SMILES: S([C:5]1[CH:11]=CC(C)=[CH:7][CH:6]=1)([O-])(=O)=O.[Na+].[CH3:13][C:14]([NH2:20])([CH2:18][CH3:19])[C:15](=[S:17])[NH2:16]>CCC(C)=O>[CH2:5]([C:6]1([CH3:7])[NH:16][C:15](=[S:17])[C:14]([CH2:18][CH3:19])([CH3:13])[NH:20]1)[CH3:11]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: CCC(C)(N)C(N)=S
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCC1(C)NC(=S)C(C)(CC)N1
Reaction time: 16 h

Procedure:
The thione can be purified by column chromatography on silica gel using hexane to elute an odorous fraction before the thione. The effect of variation of temperature and concentration of the reactants on yield and reaction rate was examined in a sealed NMR tube using D20 as a solvent and sodium tosylate as an internal standard. What was observed was a smooth decrease in concentration of starting materials and smooth increase in concentration of product. The reaction time can be reduced from 16 hours at 50° C. to 6 hours at 80° C. The compound, 2-methyl-2-aminobutyrothioamide, was not observed indicating that this alicyclic intermediate reacts with MEK in a fast step to yield the cyclic product
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:11])[CH:2]=[CH2:3].C[SiH](C)Cl>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:11])=[CH:2][CH3:3]
Reactant: C=CCc1ccccc1OC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: C[SiH](C)Cl
Agent: [H+]
Product: CC=Cc1ccccc1OC
Temperature: 70 °C
Reaction time: 4 h

Procedure:
148 g (1.0 mol) of 2-allylanisole are mixed with 8 mg of hexachloroplatinic acid under a nitrogen atmosphere and heated to 70° C. 114 g (1.2 mol) of dimethylchlorosilane are metered into the mixture over the course of two hours and the mixture is stirred at 70° C. for a further four hours. Excess dimethylchlorosilane is then removed in vacuo and 2-propenylanisole which is formed by isomerization is separated off using a short Vigreux column. 204 g of 3-(2-anisyl)propyldimethylchlorosilane are obtained as a clear liquid having an acid number of 227.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C@H]2CC[C@H](C=O)CC2)=[C:6]([F:18])[C:5]=1[F:19])[CH3:2].C[C:21](C)=[O:22].CC(C)=[O:26].OS(O)(=O)=O.O=[Cr](=O)=O.C1(C)C=CC=CC=1>O>[CH2:1]([O:3][C:4]1([C:21]([OH:22])=[O:26])[CH2:9][CH2:8][CH2:7][C@@H:6]([F:18])[C@@H:5]1[F:19])[CH3:2]
Reactant: CCOc1ccc([C@H]2CC[C@H](C=O)CC2)c(F)c1F
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC1(C(=O)O)CCC[C@@H](F)[C@@H]1F
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
The compound (16) (10.0 g) and acetone (50 ml) were mixed and the mixture was stirred at 35° C. for 30 minutes. Jones reagent (8N) (4.7 ml) was added to the mixture in the temperature range of 30 to 40° C. and the mixture was stirred at 35° C. for 2 hours. After the reaction mixture had been cooled to 30° C., toluene (200 ml) and water (200 ml) were added to the mixture and mixed with it. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and the extraction into an organic phase was carried out. The resulting organic phase was separated, and washed successively with water, an aqueous solution of sodium thiosulfate and water, and then dried over anhydrous magnesium sulfate, giving 4-ethoxy-2,3-difluoro-(trans-4-cyclohexyl)-carboxylic acid (31) (8.8 g). The yield based on the compound (16) was 83.1%.
Reaction SMILES: C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)C1C=CC=CC=1.[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=3)[C:33]2=[O:49])[S:27][C:28]=1[C:29]([OH:31])=O.[NH2:50][CH2:51][C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1>>[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:39]=[CH:40][C:41]([O:44][C:45]([F:46])([F:47])[F:48])=[CH:42][CH:43]=3)[C:33]2=[O:49])[S:27][C:28]=1[C:29]([NH:50][CH2:51][C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1)=[O:31]
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 77 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine in place of benzylamine, the title compound was obtained as a white powder in 77% yield: nip 165-166° C.; 1H NMR (300 MHz, CDCl3) δ 8.57 (s, 1H), 8.46 (d, J=4.5 Hz, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.29-7.14 (m, 5H), 6.46 (t, J=5.4 Hz, 1H), 4.56 (d, J=5.4 Hz, 2H), 4.43 (s, 2H), 4.04 (t, J=8.1 Hz, 2H), 3.43 (t, J=8.1 Hz, 2H), 2.56 (s, 3H): 13C NMR (75 MHz, CDCl3) δ 162.6, 157.2, 155.4, 153.5, 149.0, 148.0, 135.8, 134.3, 129.6, 118.6, 117.0, 47.2, 42.0, 41.7, 41.3, 17.2; MS (ES+) m/z 492.3 (M+1).
Reaction SMILES: C(N1CCN(C2C=CC(N)=CC=2C)CC1)(=O)C.[C:18]([N:21]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][CH:29]=2)[CH2:23][CH2:22]1)(=[O:20])[CH3:19]>>[C:18]([N:21]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)[CH2:23][CH2:22]1)(=[O:20])[CH3:19]
Reactant: CC(=O)N1CCCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: CC(=O)N1CCN(c2ccc(N)cc2C)CC1
Product: CC(=O)N1CCCN(c2ccc(N)cc2)CC1
Yield: 97 %

Procedure:
Following the general procedure of Intermediate 36 but using 1-acetyl-4-(4-nitrophenyl)-1,4-diazepane (Intermediate 70) as starting material there was thus obtained the title compound in 97% yield; 1H NMR δ: 6.55-6.46 (4H, m), 4.30 (2H, br s), 3.59-3.48 (3H, m), 3.41-3.26 (5H, m), 1.99-1.72 (5H, m); MS m/e MH+: 234.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[C:31]#[N:32])[O:5][CH2:6][C:7]1[S:11][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:9][C:8]=1[CH2:22][O:23]S(C)(=O)=O.[H-].[Na+].[C:35]([O:38][CH2:39]C)(=O)[CH3:36]>COCCO>[Cl:1][C:2]1[CH:3]=[C:4]([O:5][CH2:6][C:7]2[S:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=3)=[N:9][C:8]=2[CH2:22][O:23][CH2:36][CH2:35][O:38][CH3:39])[CH:28]=[CH:29][C:30]=1[C:31]#[N:32]
Reactant: CCOC(C)=O
Reactant: CS(=O)(=O)OCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C#N)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCO
Product: COCCOCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C#N)c(Cl)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
120 mg Methanesulfonic acid 5-(3-chloro-4-cyano-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethyl ester were dissolved in 5 ml 2-methoxyethanol. 10.0 mg sodium hydride were added and the mixture stirred at 50° C. for one hour. The reaction mixture was diluted by addition of 50 ml ethyl acetate, washed with brine then dried over MgSO4. The solvent was removed in vacuo and the residue purified by RP-HPLC to provide 30 mg of 2-Chloro-4-[4-(2-methoxy-ethoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzonitrile as lyophilisate.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20](#[N:23])[CH:21]=[CH2:22]>[Ni].[OH-].[K+].[OH-].[Na+].O>[CH2:1]([O:19][CH2:22][CH2:21][CH2:20][NH2:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C=CC#N
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: [Ni]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOCCCN
Temperature: 60 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
An autoclave equipped with a stirrer and a temperature gage was charged with 270.5 g of octadecanol and 0.1 g of potassium hydroxide and the mixture was dehydrated at 120° C. under a vacuum of 2.6 kPa for one hour. Then, the mixture was cooled to 60° C. and 58.4 g of acrylonitrile was introduced into the autoclave over one hour, which was then kept as it was for one hour to complete the reaction. Next, 1.9 g of Raney nickel, 0.3 g of sodium hydroxide and 16.1 g of ion exchange water were introduced into the autoclave, which was then reacted for hydrogenation and reduction at 130° C. for 3 hours. Then, the reaction mixture was subjected to filtration to remove the catalyst, distilled and refined to obtain 294.3 g of a corresponding 3-octadecyloxypropylamine.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[OH:13])=[O:5].C(O)(=O)C>CO>[Cl:12][C:10]1[CH:9]=[CH:8][C:7]([OH:13])=[C:6]([CH:4]([OH:5])[CH3:3])[CH:11]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(O)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
Sodium borohydride (0.5 g) was added in small portions to a cooled solution of 5-chloro-2-hydroxyacetophenone (5 g) in methanol (50 ml). The solution was stirred at room temperature for 0.5 hr and was then poured into ice-water and acidified with dilute acetic acid. The product was extracted with ether, the ethereal solution was washed with water and then 5% aqueous sodium bicarbonate solution. The ethereal solution was dried (Na2SO4) and the solvent removed under reduced pressure. The colourless oil crystallised from hexane/ethyl acetate to give 4-chloro-2-(1-hydroxyethyl)phenol (4.8 g); m.p. 98° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[O:6][CH:7]=1.C([O-])(=[O:23])C.[Na+]>C(O)(=O)C>[F:18][C:17]([F:20])([F:19])[O:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]=[CH:8][C:5]2[O:6][CH:7]=[C:3]([CH2:2][OH:23])[N:4]=2)=[CH:11][CH:12]=1
Reactant: FC(F)(F)Oc1ccc(C=Cc2nc(CCl)co2)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: OCc1coc(C=Cc2ccc(OC(F)(F)F)cc2)n1
Temperature: 25 °C

Procedure:
A solution of 4-chloromethyl-2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-oxazole (0.300 g, 0.99 mmol) and sodium acetate (0.162 g, 1.976 mmol) in acetic acid (5 ml) is refluxed for 48 h. The reaction mixture is cooled to r.t., concentrated in vacuo and the resulting residue is dissolved in ethanol (2 ml) and 5M potassium hydroxide (KOH) (5 ml). The solution is refluxed for 5 h and cooled to r.t. Saturated ammonium chloride (NH4Cl) is added and the mixture is extracted with ethyl acetate (3×). The extract is washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product is purified by flash column chromatography (ethyl acetate/hexanes 1:1) yielding {2-[2-(4-Trifluoromethoxy-phenyl)-vinyl]-oxazol-4-yl}-methanol as a colorless solid. Yield 200 mg (71%).