Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[OH:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30](O)=[O:31]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:30](=[O:31])[CH2:29][C:28]([OH:27])([CH3:34])[CH3:33])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: CC(C)(O)CC(=O)O
Agent: Cl
Product: CC(C)(O)CC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, light yellow solid (59 mg, 55%), MS (ISP) m/z=427.3 [(M+H)+], mp 150° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 3-hydroxy-3-methyl-butyric acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:9]([O-])=O)=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[OH:8]
Reactant: O=[N+]([O-])c1c(O)cccc1Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(O)cccc1Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
A mixture of 3-chloro-2-nitrophenol(250 mg, 1.4 mmol) and tin (II) chloride (1.2 g, 5.3 mmol) in ethanol(50 mL) was heated at 80° C. under argon. After 2 hours, the starting material has disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(143 mg, 69%). 1H NMR (CD3OD): δ 6.75 (t, 1H), 6.70 (d, 1H), 6.65 (d, 1H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH3:21]>O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:25]4[CH2:26][CH2:27][N:22]([CH2:20][CH3:21])[CH2:23][CH2:24]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCN1CCNCC1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Solvent: O
Product: CCN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Yield: 94.7 %

Procedure:
26.5 parts by weight of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid and 35.3 parts by weight of 1-ethyl-piperazine in 200 parts by volume of water are heated under reflux for 90 minutes, and the mixture is cooled, brought to pH 7.5 using acid and worked up. 34.0 g (94.7%) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-ethyl-1-piperazinyl)-3-quinolinecarboxylic acid are obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([OH:9])=[C:4]([O:10][CH3:11])[CH:3]=1.[CH2:12](I)[CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)C>[CH2:12]([O:9][C:5]1[CH:6]=[C:7]([I:8])[C:2]([F:1])=[CH:3][C:4]=1[O:10][CH3:11])[CH3:13]
Reactant: COc1cc(F)c(I)cc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOc1cc(I)c(F)cc1OC
Temperature: 40 °C
Yield: 84.4 %

Procedure:
A mixture of 64C (580 mg, 2.16 mmol), ethyl iodide (0.23 mL, 2.92 mmol) and K2CO3 (598 mg, 4.32 mmol) in DMF (5.0 mL) was heated at 40° C. for 3.0 h. It was diluted with diethyl ether, washed with brine and dried over Na2SO4. After evaporation of the solvent, the crude product was purified by silica gel chromatography (EtOAc:hexanes=1:5) to give 64D (540 mg, 85% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.42 (t, J=7.03 Hz, 3H) 3.82 (s, 3H) 4.01 (q, J=7.03 Hz, 2H) 6.64 (d, J=9.23 Hz, 1H) 7.09 (d, J=6.15 Hz, 1H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])[CH:2]=[CH:3][CH3:4].[C:12]1(O)[CH:17]=CC=[CH:14][CH:13]=1.C(OC(=O)C)(=O)C.[C:26]([NH:29][C:30]1[CH:35]=[C:34](Cl)[C:33]([OH:37])=[C:32](Cl)[CH:31]=1)(=[O:28])[CH3:27].NC1C=C(Cl)C(O)=C(Cl)C=1>>[NH2:29][C:9]1[CH:8]=[CH:7][C:6]([OH:11])=[C:5]([CH2:1][CH:2]=[CH:3][CH3:4])[CH:10]=1.[C:26]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([OH:37])=[C:32]([CH2:17][CH:12]=[CH:13][CH3:14])[CH:31]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)Nc1cc(Cl)c(O)c(Cl)c1
Reactant: Oc1ccccc1
Reactant: CC=CCc1ccccc1O
Agent: Nc1cc(Cl)c(O)c(Cl)c1
Solvent: CC(=O)OC(C)=O
Product: CC=CCc1cc(N)ccc1O
Product: CC=CCc1cc(NC(C)=O)ccc1O

Procedure:
Similarly 4-amino-2-but-2-enyl phenol (used as starting material in Example 40) was prepared from 2-but-2-enylphenol. Treatment of this phenol with acetic anhydride (using the method described above for the preparation of 4-acetamido-2,6-dichlorophenol from 4-amino-2,6-dichlorophenol) gave 4-acetamido-2-but-2-enylphenol.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:6][CH:5]=1)([OH:3])=O.[N:18]#[C:19][NH2:20]>>[C:19]([N:20]=[C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:6][CH:5]=1)[OH:3])#[N:18]
Reactant: N#CN
Reactant: O=C(O)c1ccc(OCCn2ccnc2)cc1
Product: N#CN=C(O)c1ccc(OCCn2ccnc2)cc1

Procedure:
Treatment of 1-[2-(4-carboxyphenoxy)ethyl]imidazole with N,N'-carbonyldiimidazole followed by cyanamide as described in Example 36 above gave N-cyano-4-[2-(1-imidazolyl)ethoxy]benzenecarboximidic acid, m.p. 199°-200° C. (d) (from water). Found: C, 60.59; H, 4.64; N, 22.20. C13H12N4O2 requires: C, 60.93; H, 4.72; N, 21.87%.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[C:7]([CH3:9])[NH:6][N:5]=1.Cl[C:11]1[N:16]2[CH:17]=[CH:18][N:19]=[C:15]2[N:14]=[C:13]([Cl:20])[C:12]=1[C:21]1[C:26]([F:27])=[CH:25][C:24]([F:28])=[CH:23][C:22]=1[F:29].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(Cl)(Cl)Cl>[CH3:3][C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([C:11]2[N:16]3[CH:17]=[CH:18][N:19]=[C:15]3[N:14]=[C:13]([Cl:20])[C:12]=2[C:21]2[C:26]([F:27])=[CH:25][C:24]([F:28])=[CH:23][C:22]=2[F:29])[N:5]=1
Reactant: Fc1cc(F)c(-c2c(Cl)nc3nccn3c2Cl)c(F)c1
Reactant: Cc1cc(C)[nH]n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)n(-c2c(-c3c(F)cc(F)cc3F)c(Cl)nc3nccn23)n1
Yield: 47.7 %

Procedure:
Into a mixture of 0.040 g of sodium hydride (60% in oil) and 2 ml of tetrahydrofuran, a solution of 0.096 g of 3,5-dimethylpyrazole in 3 ml of tetrahydrofuran was added dropwise. The mixture was added to a solution of 0.32 g of 5,7-dichloro-6-(2,4,6-trifluorophenyl)imidazo[1,2-a]pyrimidine in 5 ml of tetrahydrofuran under ice-cooling. To the reaction mixture, chloroform and aqueous citric acid solution were added. The separated organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 0.18 g of 5-(3,5-dimethylpyrazol-1-yl)-6-(2,4,6-trifluorophenyl)-7-chloroimidazo[1,2-a]pyrimidine.
Reaction SMILES: F[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([CH2:27]Br)[CH:24]=[CH:23][C:22]=1[O:29][CH3:30])[CH3:18]>>[CH2:17]([O:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([CH2:27][N:14]2[CH2:15][CH2:16][CH:11]([C:6]3[C:5]4[C:9](=[CH:10][CH:2]=[CH:3][CH:4]=4)[NH:8][CH:7]=3)[CH2:12][CH2:13]2)[CH:24]=[CH:23][C:22]=1[O:29][CH3:30])[CH3:18]
Reactant: Fc1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: CCOC(=O)c1cc(CBr)ccc1OC
Product: CCOC(=O)c1cc(CN2CCC(c3c[nH]c4ccccc34)CC2)ccc1OC
Yield: 84.6 %

Procedure:
This compound was prepared following the procedure described in example 1 (part D) starting with 0.5 g (2.5 mmol) of 6-fluoro-3-piperidin-4-yl-1H-indole and 0.88 g (3.2 mmol) of 5-bromomethyl-2-methoxy-benzoic acid ethyl ester. After standard purification, 0.83 g (91% of yield) of 5-[4-(1H-indol-3-yl)-piperidin-1-ylmethyl]-2-methoxy-benzoic acid ethyl ester were obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:9]([C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)([OH:11])=[O:10]>>[NH2:8][C:5]1[CH:4]=[CH:3][C:2]([C:15]2[CH:16]=[CH:17][C:12]([C:9]([OH:11])=[O:10])=[CH:13][CH:14]=2)=[CH:7][N:6]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Nc1ccc(Br)cn1
Product: Nc1ccc(-c2ccc(C(=O)O)cc2)cn1

Procedure:
In the same manner as in Example 2, a reaction was conducted using 5-bromo-2-aminopyridine and 4-carboxyphenyboronic acid as starting materials, whereby 4-(2-aminopyridin-5-yl)benzoic acid was obtained.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([OH:20])[C:5]=1[O:21]C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(#N)C>[F:23][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([O:20][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:36][CH:37]=2)[C:5]=1[OH:21]
Reactant: COc1c(OC(F)F)ccc(-c2ccc3c(c2)COC3=O)c1O
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(COc2c(-c3ccc4c(c3)COC4=O)ccc(OC(F)F)c2O)cc1
Temperature: 80 °C
Yield: 42 %

Procedure:
To a stirring solution of 5-(4-(difluoromethoxy)-2-hydroxy-3-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.25 mmol) in acetonitrile (5 mL), was added potassium carbonate (103.5 mg, 0.75 mmol) and 1-bromomethyl-4-methanesulfonyl-benzene (186.8 mg, 0.75 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in pet ether) to afford title compound as a solid (50 mg, 41%).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[F:6][C:7]([F:22])([F:21])[C:8]1[CH:9]=[C:10]([N:18]=[C:19]=S)[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1.[CH3:23][CH:24]([CH3:28])[CH2:25][CH2:26][NH2:27].S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl.[Hg]=O.C(N(CC)CC)C>[F:6][C:7]([F:22])([F:21])[C:8]1[CH:9]=[C:10]([NH:18][C:19]([NH:27][CH2:26][CH2:25][CH:24]([CH3:28])[CH3:23])=[C:2]([C:1]#[N:5])[C:3]#[N:4])[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1
Reactant: N#CCC#N
Reactant: FC(F)(F)c1cc(N=C=S)cc(C(F)(F)F)c1
Reactant: CC(C)CCN
Agent: O=S(=O)([O-])[O-]
Agent: O=[Hg]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CCNC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)C#N
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 62.5 %

Procedure:
To a solution of malononitrile (0.33 g, 5.00 mmol) in DCM at 0° C. first 3,5-bis(trifluoromethyl)phenylisothiocyanate (1.41 g, 5.20 mmol) and then triethylamine (1.0 mL) were added. The mixture was stirred at room temperature for 1 h 45 min and then DCM (5 mL), 3-methylbutylamine (1.0 mL, 8.60 mmol), magnesium sulfate (0.57 g) and mercury(II) oxide (2.54 g, 11.7 mmol) were added. The resulting mixture was stirred at room temperature for 17 h, whereby it turned black. This mixture was then filtrated (Celite), diluted with DCM (60 mL), washed with an ice-cold mixture of water (100 mL) and conc. HCl (2.0 mL), with brine (3×50 mL), dried (magnesium sulfate) and concentrated. The residue was purified by column chromatography (50 g silica gel, heptane/ethyl acetate gradient), to yield 1.22 g (63%) of the title compound as a foam. This foam could be crystallized from toluene/heptane, yielding 1.08 g of almost colourless crystals, mp. 158-159° C. 1H NMR (300 MHz, DMSO-d6): δ=0.87 (d, J=7 Hz, 6H), 1.45 (q, J=7 Hz, 2H), 1.60 (nonett, J=7 Hz, 1H), 3.31 (m, 2H), 7.72 (s, 2H), 7.78 (s, 1H), 8.22 (s, br, 1H), 9.79 (s, 1H); 13C NMR (75 MHz, DMSO-d6): δ=22.04, 24.99, 36.85, 37.14, 59.66, 116.52, 117.52, 121.21, 123.02 (q, J=275 Hz), 131.02 (q, J=33 Hz), 141,35, 161.27. Anal. Calcd. for C17H16F6N4 (390.33): C, 52.31; H, 4.13; N, 14.35. Found: C, 52.80; H, 4.29; N, 13.83.
Reaction SMILES: [N:1]1([CH2:7][P:8](=[O:11])([OH:10])[OH:9])[CH2:6][CH2:5][O:4]CC1.[OH-:12].[Na+].Cl>O>[P:8]([CH2:7][NH:1][CH2:6][C:5]([OH:12])=[O:4])([OH:9])([OH:10])=[O:11].[NH2:1][CH2:7][P:8](=[O:9])([OH:11])[OH:10]
Reactant: O=P(O)(O)CN1CCOCC1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NCP(=O)(O)O
Product: O=C(O)CNCP(=O)(O)O
Temperature: 250 °C
Yield: 31.5 %
Yield: 34.1 %

Procedure:
To a 100 mL Monel autoclave were added 2.23 g (12.3 mmol) of 4-morpholinylmethylphosphonic acid 7.88 g (98.5 mmol) of a 50% solution of NaOH, and 10 mL of H2O to give a slurry. The vessel was flushed with N2, sealed and heated to 250° C. This temperature was maintained for five and one-half hours with little noticeable reaction occurring. The temperature was then raised to 300° C. for three hours. During this period the internal pressure in the vessel rose from 4.5×106N/M2 to 5.7×106N/M2. The vessel was cooled to room temperature and the residual pressure was released. The resulting solution was diluted with water and neutralized with 8.1 mL (98.5 mmol) of conc. HCl. The solution was concentrated to dryness. The residue was taken up in conc. HCl and the precipitated NaCl was filtered away. The final filtrate was concentrated and purified by ion exchange chromatography to yield 0.71 g (34.1 %) of N-phosphonomethylglycine and 0.43 g (31.5%) of aminomethylphosphonic acid.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:14](C(OC(C)(C)C)=O)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=O>CC#N.CN(C1C=CN=CC=1)C>[C:18]([O:17][C:15]([N:9]1[CH2:10][CH2:11][CH2:12][CH2:13][C@H:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:14])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCCN1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)[C@@H]1CCCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (S)-piperidine-2-carboxylic acid tert-butyl ester (M. Egbertson and S. J. Danishefsky, J. Org. Chem., 1989, 54, 1, 11-12) (5.78 g, 31.2 mmol) in CH3CN (30 mL) at 0° C. was added DMAP (763 mg, 6.2 mmol) followed by BOC2O (10.22 g, 46.8 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 20 h. The solvents were evaporated under reduced pressure and the residue was purified by flash chromatography (10% ethyl acetate in hexane). The title compound was obtained as a colorless oil which crystallized upon standing (8.33 g, 94%): 1H NMR (400 MHz, CDCl3) δ 1.21-1.32 (2H, m), 1.47-1.48 (18H, 2s), 1.59-1.72 (3H, m), 2.18 (1H, m), 2.85-3.00 (1H, m), 3.89-4.01 (1H, 2d, J 11.9 Hz), 4.47-4.58 (1H, 2br s).
Reaction SMILES: [CH2:1]([O:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][CH:19]([CH:22]4[CH2:31][CH2:30][C:25]5(OCC[O:26]5)[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[C:12]([F:32])[CH:11]=2)[CH2:6][CH2:5]1)[CH3:2].C(O)=O.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][CH:4]1[CH2:5][CH2:6][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][CH:19]([CH:22]4[CH2:31][CH2:30][C:25](=[O:26])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[C:12]([F:32])[CH:11]=2)[CH2:8][CH2:9]1)[CH3:2]
Reactant: CCOC1CCC(c2ccc(C3CCC(C4CCC5(CC4)OCCO5)CC3)c(F)c2)CC1
Solvent: O
Solvent: O=CO
Solvent: Cc1ccccc1
Product: CCOC1CCC(c2ccc(C3CCC(C4CCC(=O)CC4)CC3)c(F)c2)CC1
Temperature: 25 °C
Yield: 26.5 %

Procedure:
The compound (25) (31.4 g), formic acid (90 g) and toluene (90 ml) were put in a reaction vessel under a nitrogen atmosphere, heated under reflux for 3 hours, and cooled slowly to room temperature. Water (200 ml) and toluene (200 ml) were added and mixed thereto. The mixture was allowed to stand until it had separated into two phases, the organic and aqueous phases, and an extractive operation to an organic phase was carried out. The organic phase was fractionated, and washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified with a fractional operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene:ethyl acetate=9:1 by volume) as an eluent and silica gel as a stationary phase powder, and further purified by means of recrystallization from a mixed solvent of toluene and heptane (toluene: heptane=1:1 by volume), and dried, giving 7.51 g of 4′-(4-(4-ethoxycyclohexyl)-2-fluorophenyl)bi(cyclohexane)-4-one (26). The yield based on the compound (25) was 26.6%.
Reaction SMILES: [CH:1]1(C=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH:8](C=O)[CH2:7][CH2:6][CH2:5][CH:4](C=O)[CH2:3][CH2:2]1.C=CC=C>>[CH:1]1[CH2:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH:2]=1
Reactant: O=CC1CCCCC(C=O)CCC(C=O)CCC1
Agent: C=CC=C
Product: C1=CCCC=CCCCC=CC1

Procedure:
The cyclododecane-1,4,8-tricarbaldehyde can be prepared by a process comprising trimerizing 1,3-butadiene to give 1,4,8-cyclododecatriene, and hydroformylating the 1,4,8-cyclododecatriene.
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]([CH:10]=[O:11])[CH:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2].[CH:12]([O-])=O.[NH4+:15]>[N+](C)([O-])=O>[NH2:15][CH2:12][CH:10]([C:8]1[CH:7]=[CH:6][N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:9]=1)[OH:11]
Reactant: CC(C)c1nccc(C=O)n1
Reactant: O=C[O-]
Reactant: [NH4+]
Solvent: C[N+](=O)[O-]
Product: CC(C)c1nccc(C(O)CN)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
In a 100 mL round-bottomed flask, 2-isopropylpyrimidine-4-carbaldehyde (865 mg, 5.76 mmol) was combined with nitromethane (7.00 ml) to give a colorless solution. TEA (583 mg, 803 μl, 5.76 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Complete by LCMS. The reaction mixture was concentrated in vacuo, kept on the vacuum pump for 30 min. and used as is immediately. The resulting yellow oil was taken up in 20 mL of THF and 20 mL of methanol and placed under a nitrogen atmosphere. To that was added 240 mg of 10% Pd/C (pre-wet with ethanol). Ammonium formate (1.82 g, 28.8 mmol) was added. The reaction mixture was stirred at room temperature for 2 days. Complete by LCMS. The reaction mixture was purged with argon, filtered through Celite and the filtercake washed several times with methanol. The combined filtrate and washes were concentrated in vacuo and loaded onto column in dichloromethane/methanol approx. 95:5. The crude material was purified by flash chromatography (silica gel, 40 g, 10% to 50% [(60:10:1 dichloromethane:MeOH:NH4OH) in dichloromethane gradient] to afford 2-amino-1-(2-isopropylpyrimidin-4-yl)ethanol (0.54 g) as a white solid. (M+H)+=182 m/e.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[NH:28][C:20]3[C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH:23]=[CH:24][C:19]=3[N:18]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:36]([C:38]1[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=1[CH2:40]Br)#[N:37]>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:29])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[N:28]([CH2:40][C:39]3[CH:42]=[CH:43][CH:44]=[CH:45][C:38]=3[C:36]#[N:37])[C:20]3[C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH:23]=[CH:24][C:19]=3[N:18]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCn1ccc2nc(C3CCCC(NC(=O)OCc4ccccc4)C3)[nH]c2c1=O
Reactant: N#Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ccc2nc(C3CCCC(NC(=O)OCc4ccccc4)C3)n(Cc3ccccc3C#N)c2c1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 54.9 %

Procedure:
To a solution of [3-(5-ethyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-yl)-cyclohexyl]-carbamic acid benzyl ester (0.1 g, 0.25 mmol) in DMF (3 mL) were added Cs2CO3 (0.17 g, 0.51 mmol) and 60 mg (0.30 mmol) of 2-cyanobenzyl bromide as a solution in 3 mL of DMF. After stirring at room temperature for 17 h, the reaction mixture was diluted with water (10 mL) then extracted with CH2Cl2. The combined extracts were dried with MgSO4, and concentrated in vacuo. The crude product was purified by flash chromatography, eluting with 1% MeOH in CH2CH2 to give {3-[3-(2-cyano-benzyl)-5-ethyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-yl]-cyclohexyl}-carbamic acid benzyl ester (70 mg, 54% yield). 1H-NMR (CDCl3): δ 7.73 (m, 1H), 7.49 (m, 1H), 7.34 (m, 6H), 7.13 (m, 1H), 6.89 (d, 1H, J=8.4 Hz), 6.69 (m, 1H), 6.19 (m, 1H), 5.94 (m, 1H), 5.06 (s, 2H), 4.73 (m, 1H), 4.07 (m, 2H), 3.58 (m, 1H), 2.79 (m, 1H), 2.02 (m, 2H), 1.87 (m, 1H), 1.68 (m, 2H), 1.51 (m, 2H), 1.38 (t, 3H, J=7.2 Hz), 1.16 (m, 1H). MS: calculated for C30H31N5O3+H 510.3; found: 510.5.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH2:6])[CH3:2].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.C(N(C(C)C)C(C)C)C.C([O-])(O)=O.[Na+]>O1CCCC1>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CCOCCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCNS(=O)(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 90.2 %

Procedure:
(2-Ethoxyethyl)amine (0.178 g, 2.0 mmol) was added to a stirred solution of 4-bromobenzenesulfonyl chloride (0.256 g, 1.0 mmol) in tetrahydrofuran (10 mL) at 0 C, followed by addition of N-ethyl-N,N-diisopropylamine (0.260 g, 2.0 mmol). The resulting mixture was stirred at 0° C. for 10 min, and was then allowed to return to room temperature. A saturated solution of NaHCO3 (aq) was added and the phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over Na2SO4, and the solvent was evaporated to give the crude product. Purification by column chromatography using ethyl acetate/heptane (1:10 to 1:1) as the eluent gave 0.278 g (90% yield) of the title compound: MS (ES) m/z 294 and 296 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([N:10]2[CH2:14][CH2:13][O:12]C2=O)=[CH:5][C:4]=1[N:16]1[CH2:20][CH2:19][O:18]C1=O.[OH-].[K+].Cl>O>[OH:18][CH2:19][CH2:20][NH:16][C:4]1[CH:5]=[C:6]([NH:10][CH2:14][CH2:13][OH:12])[CH:7]=[C:8]([CH3:9])[C:3]=1[O:2][CH3:1]
Reactant: COc1c(C)cc(N2CCOC2=O)cc1N1CCOC1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1c(C)cc(NCCO)cc1NCCO
Temperature: 25 °C

Procedure:
33.5 g of 3,3′-(4-methoxy-5-methyl-1,3-phenylene)bis-(1,3-oxazolidin-2-one) were heated under reflux in 500 ml of 20% strength KOH for 10 h. The mixture was cooled to room temperature and poured onto 1.5 l of iced water. The mixture was then neutralized with HCl and extracted several times with ethyl acetate. The combined ethyl acetate phases were evaporated on a Rotavapor and then distilled in a Kugelrohr (250–290° C., 0.08 mbar).