Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][CH:7]2[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:28])([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=3)[CH2:8]2)=[CH:4][CH:3]=1.[C:31](Cl)(=O)[O:32]C1C=CC([N+]([O-])=O)=CC=1.[CH:44]1([CH2:47][NH2:48])[CH2:46][CH2:45]1.C(N(CC)CC)C>O1CCCC1.ClCCl>[CH:44]1([CH2:47][NH:48][C:31]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][CH:7]3[CH2:11][CH2:10][N:9]([CH2:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:28])([C:20]([F:21])([F:22])[F:23])[C:24]([F:27])([F:25])[F:26])=[CH:17][CH:18]=4)[CH2:8]3)=[CH:29][CH:30]=2)=[O:32])[CH2:46][CH2:45]1
Reactant: NCC1CC1
Reactant: Nc1ccc(OC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)C2)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC1CC1)Nc1ccc(OC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.4 %

Procedure:
A solution of 2-(4-((3-(4-aminophenoxy)pyrrolidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.345 mmol, 150 mg) and 4-nitrophenyl carbonochloridate (0.345 mmol, 69.6 mg) in tetrahydrofuran (5 mL) was stirred at room temperature for 30 minutes. Cyclopropylmethanamine (0.691 mmol, 49.1 mg) was added, followed by triethylamine (0.691 mmol, 0.096 mL, 69.9 mg) and the reaction stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane/saturated sodium bicarbonate solution and filtered through a hydrophobic frit. The organic layer was concentrated under vacuum. The residue was purified by prep-HPLC (acidic conditions) and SCX chromatography to give title compound (30 mg).
Reaction SMILES: Br[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][CH3:15].[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[OH:24].C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[CH2:2]([O:24][C:18]1[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: Cc1ccc(C)c(O)c1
Reactant: CCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCCCCCCCCCCCOc1cc(C)ccc1C
Yield: 86.4 %

Procedure:
1-bromotetradecane (44.4 mL, 0.149 mol), 2,5-dimethylphenol (20.0 g, 0.164 mol) and K2CO3 (82.4 g, 0.596 mol) were combined in a round bottom flask in acetonitrile (200 mL). The flask was equipped with a stir-bar, and a water-cooled condenser and protected under a nitrogen atmosphere. The mixture was heated at reflux for overnight. Synthetic progress was monitored by the disappearance of the signal (triplet) from the C1 hydrogens on the alkyl bromide (˜3.5 ppm) in 1H NMR. Upon completion, the reaction was removed from heat and excess K2CO3 was removed by gravity filtration (rinsed with CH2Cl2). The crude product was concentrated in vacuo and the resulting material was dissolved in CH2Cl2, washed with 1 M NaOH (2×, to remove unreacted 2,5-dimethylphenol or p-cresol), dH2O (2×) and brine (1×), dried over Na2SO4, gravity filtered, and concentrated in vacuo to remove the solvent. The material was of sufficient purity (by 1H and 13C NMR) to be used in the subsequent reactions. Yielded 41.0 g (86%) of an off-white solid, mp=36.9-37.9° C. 1H NMR (CDCl3, 400 MHz) δ: 7.01 (d, 3J=7.4 Hz, 1H, Ar—H); 6.66 (d, 3J=7.6 Hz, 1H, Ar—H); 6.65 (s, 1H, Ar—H); 3.95 (t, 3J=6.5 Hz, 2H, OCH2); 2.33 (s, 3H); 2.20 (s, 3H); 1.80 (m, 2H, OCH2CH2); 1.49 (m, 2H, OCH2CH2CH2); 1.42-1.26 (m, 20H); 0.90 (t, 3J=6.8 Hz, 3H, CH2CH3). 13C NMR (CDCl3, 100 MHz) δ: 157.15, 136.40, 130.25, 123.65, 120.53, 112.01, 67.88, 31.93, 29.70, 29.68, 29,66, 29.62, 29.42, 29.40, 29.37, 26.16, 22.70, 21.40, 15.78, 14.11. HRMS (DART): [M+H]+=319.29460 (calcd for C22H39O 319.29954).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11](C(O)=O)=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]1=2.C([O:22][C:23](=[O:41])[CH2:24][C:25]1C=CC2C(=O)C3C=CC=CC=3C=CC=2C=1)C.O=C1C2C=CC(CC(O)=O)=CC=2C=CC2C=CC=CC1=2>>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:24]([CH3:25])[C:23]([OH:41])=[O:22])=[CH:12][C:7]=2[CH:6]=[CH:5][C:19]2[CH:18]=[CH:17][CH:16]=[CH:4][C:3]1=2
Reactant: O=C(O)c1ccc2c(=O)c3ccccc3ccc2c1
Reactant: CCOC(=O)Cc1ccc2c(=O)c3ccccc3ccc2c1
Agent: O=C(O)Cc1ccc2c(=O)c3ccccc3ccc2c1
Product: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
The compounds of Formula I can be prepared by conducting an Arndt-Eistert reaction upon 5-oxo-5H-dibenzo[a,d]-cycloheptene-2-carboxylic acid to afford, in various steps thereof, 5-oxo-5H-dibenzo[a,d]cyclohepten -2-acetic acid ethyl ester and 5-oxo-5H-dibenzo[a,d]cyclohepten-2-acetic acid. 2-(5-Oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid, and the corresponding esters of the aforementioned acids can be obtained via alkylation and/or esterification.
Reaction SMILES: [CH:1]1([C:4]([CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)=[CH2:5])[CH2:3][CH2:2]1>O.[Ru](=O)=O.C(O)(C)C>[CH:1]1([CH:4]([CH:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:10][CH2:11]2)[CH3:5])[CH2:3][CH2:2]1
Reactant: C=C(C1CC1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=[Ru]=O
Solvent: O
Solvent: CC(C)O
Product: CC(C1CC1)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 92.8 %

Procedure:
Add ruthenium dioxide monohydrate (2.0 g, 15.0 mmol) to a 500 mL Parr shaker bottle and wet with isopropyl alcohol (25 mL). Add tert-butyl 4-(1-cyclopropylethenyl)piperidine-1-carboxylate (3.8 g, 15.1 mmol) and isopropyl alcohol (100 mL) and place on Parr shaker. React under H2 atmosphere (30 psi) at ambient temperature for a total of 12 hours. Vent and purge the bottle, filter and concentrate in vacuo to give the title compound as a clear oil (3.55 g, 92.9%). MS (m/z): 198 (M+1-tBu)
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][C:14]2[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20](OCC)=[O:21])=[C:16]([CH2:27][CH3:28])[CH:15]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][OH:10].[CH2:29]([Mg]Br)[CH3:30].[Cl-].[NH4+].[CH2:35]1COC[CH2:36]1>>[CH2:27]([C:16]1[CH:15]=[C:14]([CH2:13][CH2:12][CH2:11][C:5]2[CH:6]=[CH:7][C:8]([CH2:9][OH:10])=[C:3]([CH2:2][OH:1])[CH:4]=2)[CH:26]=[CH:25][C:17]=1[O:18][CH2:19][C:20]([CH2:29][CH3:30])([OH:21])[CH2:35][CH3:36])[CH3:28]
Reactant: CC[Mg]Br
Reactant: CCOC(=O)COc1ccc(CCCc2ccc(CO)c(CO)c2)cc1CC
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Product: CCc1cc(CCCc2ccc(CO)c(CO)c2)ccc1OCC(O)(CC)CC
Reaction time: 0.5 h

Procedure:
640 mg (1.65 mmol) of ethyl {4-[3-(3,4-bis-hydroxymethyl-phenyl)-propyl]-2-ethyl-phenoxy}-acetate are dissolved in 30 ml of THF. 2.2 ml (6.6 mmol) of a 3M ethylmagnesium bromide solution are added dropwise. The reaction medium is stirred for 30 minutes, and is then treated with a saturated ammonium chloride solution. The residue obtained after extraction and concentration is purified by chromatography on a silica column. A colorless oil is obtained (m=510 mg, y=77%).
Reaction SMILES: C1(P(O[C:16]2[C@H:17]([CH3:40])[C@@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:41][C@@H:42]1[CH2:46][N:45]([C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=2)=[O:48])[C@@H:44](/[CH:60]=[CH:61]/[C:62]([N:64]2[CH2:68][CH2:67][C@H:66]([NH:69][C:70]([O:72][CH2:73][C:74]3[CH:79]=[CH:78][C:77]([N+:80]([O-:82])=[O:81])=[CH:76][CH:75]=3)=[O:71])[CH2:65]2)=[O:63])[CH2:43]1>C(#N)C.C(N(C(C)C)CC)(C)C>[N+:57]([C:54]1[CH:53]=[CH:52][C:51]([CH2:50][O:49][C:47]([N:45]2[CH2:46][C@@H:42]([S:41][C:16]3[C@H:17]([CH3:40])[C@@H:18]4[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]4[C:20]=3[C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])[CH2:43][C@@H:44]2/[CH:60]=[CH:61]/[C:62]([N:64]2[CH2:68][CH2:67][C@H:66]([NH:69][C:70]([O:72][CH2:73][C:74]3[CH:75]=[CH:76][C:77]([N+:80]([O-:82])=[O:81])=[CH:78][CH:79]=3)=[O:71])[CH2:65]2)=[O:63])=[O:48])=[CH:56][CH:55]=1)([O-:59])=[O:58]
Reactant: O=C(N[C@H]1CCN(C(=O)/C=C/[C@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@H](/C=C/C(=O)N4CC[C@H](NC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reaction time: 24 h
Yield: 70.5 %

Procedure:
To a solution of 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (1.01 g) in anhydrous acetonitrile (10 ml), a solution of (2R,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-2-[(3S)-3-(4-nitrobenzyloxycarbonylamino)pyrrolidin-1-ylcarbonyl-(E)-ethenyl]-pyrrolidine (972 mg) in anhydrous acetonitrile (10 ml) and diisopropylethylamine (0.296 ml) were added under ice cooling. The resulting mixture was allowed to stand at the same temperature for one day. The reaction mixture was concentrated by evaporation under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed successively with water and saline and then dried over anhydrous sodium sulfate. The solvent was distilled off. The residue was subjected to chromatography on a silica gel column and eluted with methylene chloride-acetone of ratio from (6:1) to (1:1). Desired fractions were combined, followed by distilling off, whereby 4-nitrobenzyl (1R,5S,6S)-2-[(2R,4S)-1-(4-nitrobenzyloxycarbonyl)-2-[(3S)-3-(4-nitrobenzyloxycarbonylamino)pyrrolidin-1-ylcarbonyl-(E)-ethenyl]pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (1.079 g) was obtained as a powder.
Reaction SMILES: [NH2:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)([CH3:5])[CH2:3]O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:23]2)=CC=1>C1(C)C=CC=CC=1>[NH2:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)([CH3:5])[CH2:3][SH:23]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(C(C)(N)CO)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(C(C)(N)CS)cc1
Temperature: 25 °C

Procedure:
A solution of 1 mmol of 2-amino-2-(4-methoxyphenyl)propan-1-ol (Example 3k) and 0.5 mmol of 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (Lawesson's reagent) [19172-47-5] in 10 ml of toluene is heated to reflux for 2 hours. The reaction mixture is cooled to room temperature and evaporated. The title compound is identified from the residue on the basis of the Rf by flash chromatography (SiO2 60 F).
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].ON1C2C=CC=CC=2N=N1.[Cl:25][C:26]1[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29]>C(Cl)(Cl)Cl>[Cl:25][C:26]1[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:29]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a mixture of 3.0 g of tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, 3.2 g of 1-(3-dimethyl-aminopropyl) -3-ethylcarbodiimide hydrochloride, 2.6 g of 1-hydroxybenzotriazole, 2.9 g of 2,3-dichlorobenzoic acid and 60 ml of chloroform was stirred at room temperature for 17 hours and then diluted with chloroform. An insoluble matter was filtered off using Celite and the resulting mixture was washed with water with saturated brine. The resulting organic layer was dried over magnesium sulfate and filtered, the filtrate was concentrated in vacuo and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=9/1 to 1/1) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][CH2:10][CH2:9][CH:8]2[C:13]([OH:15])=O.[CH3:16][N:17]([CH3:35])[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1>>[CH3:16][N:17]([CH3:35])[C:18]1[CH:19]=[CH:20][C:21]([CH2:24][N:25]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:33])[CH3:34])=[CH:28][CH:27]=2)[C:13]([CH:8]2[C:7]3[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=3)[O:11][CH2:10][CH2:9]2)=[O:15])=[CH:22][CH:23]=1
Reactant: COc1cccc2c1OCCC2C(=O)O
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Product: COc1cccc2c1OCCC2C(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(C(C)C)cc1
Yield: 48.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 8-methoxychroman-4-carboxylic acid, (0.64 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.83 g) as starting materials, N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-8-methoxychroman-4-carboxamide (0.69 g) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[CH2:8][CH2:7][CH:6]=2>[Pd].C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CN1CCN(C2=c3cc(O)ccc3=CCC2)CC1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CN1CCN(c2cccc3ccc(O)cc23)CC1
Yield: 34.7 %

Procedure:
10% Palladium on carbon (1.16 g) and 7-hydroxy-1-(4-methyl-1-piperazinyl)-2,3-dihydronaphthalene (1.48 g, 6.06 mmol) were slurried in toluene (100 mL) and refluxed 16.5 h. The mixture was cooled, filtered, and concentrated. The product was purified by flash chromatography on silica gel (1×6 inches). Elution with 50 % ethyl acetate/hexane followed by 100% ethyl acetate gave 0.51 g (34%) of the title product as a light pink foam. A sample was recrystallized from ether to give a cream colored solid for analysis: mp 184°-185° C. Analysis calculated for C15H18N2O: C, 74.35; H, 7.49; N, 11.56. Found: C, 74.05;H, 7.03; N, 11.42.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4]P(OCC(F)(F)F)(OCC(F)(F)F)=O.[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>C1COCC1.[NH4+].[Cl-].C(Cl)Cl>[CH3:1][O:2][C:3](=[O:19])/[CH:4]=[CH:25]\[C:24]1[CH:27]=[CH:28][C:21]([Br:20])=[CH:22][CH:23]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)/C=C\c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of [Bis-(2,2,2-trifluoro-ethoxy)-phosphoryl]-acetic acid methyl ester (1.0 eq.) and 18—C-6 (5.0 eq.) in THF (0.05M) at −78° C. was added dropwise KN(TMS)2 (1.0 eq.). The mixture was stirred at −78° C. for 15 min then 4-bromobenzaldehyde (1.0 eq.) was added. The final mixture stirred for 1 h at −78° C., poured in saturated aqueous NH4Cl and extracted with Et2O (3×). The combined organic extracts were washed with, brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (Hex:EtOAc 10 to 25%) afforded a mixture of desired material and the starting aldehyde. Upon treatment in CH2Cl2 of the mixture with Amino-Merrifield resin for 10 min, the aldehyde was removed. Filtration and concentration afforded the title compound as an oil.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH:21]2[CH2:26][CH2:25][CH:24]([O:27][C:28](=[O:30])[CH3:29])[CH2:23][CH:22]2[C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=2)=O)=[CH:14][CH:13]=1)[CH2:8][CH2:9][CH3:10].C(N(CC)CC)C.O>ClCCl>[CH2:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:36]3[C:31](=[CH:32][C:33]([O:39][CH3:40])=[C:34]([O:37][CH3:38])[CH:35]=3)[CH:22]3[CH:21]([CH2:26][CH2:25][CH:24]([O:27][C:28](=[O:30])[CH3:29])[CH2:23]3)[N:20]=2)=[CH:14][CH:13]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCOc1ccc(C(=O)NC2CCC(OC(C)=O)CC2c2ccc(OC)c(OC)c2)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCOc1ccc(C2=NC3CCC(OC(C)=O)CC3c3cc(OC)c(OC)cc32)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 87.4 %

Procedure:
1670 mg of phosphorous pentachloride are suspended in 2.5 ml of dichloromethane. 1119 mg of (±)-acetic acid (1RS,3RS,4RS)-4-{[1-(4-butoxy-phenyl)-methanoyl]-amino}-3-(3,4-dimethoxyphenyl)-cyclohexyl ester (compound A7) dissolved in 15 ml of dichloromethane are added and the mixture stirred for 18 h. The mixture is cooled to 0° C. and 10 ml of triethylamine added, then 5 ml of water. After phase separation and removal of solvent the solid residue is purified by flash chromatography [silica, toluene/dioxane=2:1 (containing 0.5% of ammonia)] to give 940 mg of the title compound as a colorless foam (87% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)=[N:9]2)[CH:3]=1>COCCOC.C(OCC)(=O)C.O.[Fe].[Fe](Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[CH:8]=[C:4]2[CH:3]=1
Reactant: Cc1ccc(C2=NC2c2cc(Br)ccn2)cc1
Agent: Cl[Fe]Cl
Agent: [Fe]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1ccc(-c2cc3cc(Br)ccn3n2)cc1
Reaction time: 3 h

Procedure:
0.746 g of 4-bromo-2-(3-p-tolyl-2H-azirin-2-yl)pyridine obtained in step 13.2 is dissolved in the presence of 6.6 mg (0.052 mmol) of iron (H) chloride in 30 mL of 1,2-dimethoxyethane. The medium is then refluxed for 6 hours. A further 10 mg (0.078 mmol) of iron (II) chloride are then added and the mixture is refluxed again with stirring for 3 hours. The medium is then diluted with 50 mL of ethyl acetate and 50 mL of water. The organic phase is then recovered, dried over sodium sulfate and filtered. 2 g of silica are then added to the filtrate, followed by concentrating under reduced pressure. The powder obtained is used as a solid deposit for a chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (85/15). 0.534 g (71%) of expected compound is recovered in the faun of a yellow powder.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C([Sn](CCCC)(CCCC)[C:18]([O:20][CH2:21][CH3:22])=[CH2:19])CCC>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.C1(C)C=CC=CC=1>[CH2:21]([O:20][C:18]([C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH2:19])[CH3:22]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)c1cccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=C(OCC)c1ncccc1C(=O)OCC
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a mixture of ethyl 2-chloronicotinate (23 g), tributyl(1-ethoxyvinyl)tin (64 mL) and toluene (400 mL) was added tetrakis(triphenylphosphine)palladium(0) (7.3 g), and the mixture was stirred overnight at 80° C. under an argon atmosphere. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and then purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (27 g).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].O=[CH:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1>C1COCC1>[C:7](/[CH:9]=[CH:19]/[CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)#[N:8]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C/C=C/C#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
To a solution of 1.0 M of potassium tert-butoxide in THF (45.8 mL, 0.0458 mol) at 0° C. was added dropwise a solution of diethyl cyanomethylphosphonate (7.8 mL, 0.0480 mol) in THF (58.4 mL). The reaction was warmed to RT and then cooled to 0° C. again. To the reaction mixture was added a solution of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (9.91 g, 0.0436 mol) in THF (11.7 mL). The reaction was allowed to warm up to RT and stirred at RT overnight. After being quenched with water, the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried and evaporated to dryness. The crude mixture was purified on silica gel, eluting with 0 to 40% EtOAc in hexanes, to provide the desired product (8.22 g, 75.3%). LCMS calculated for C14H22N2O2Na(M+Na)+: m/z=273.2; Found: 273.0.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][NH:9][CH2:10][CH2:11][OH:12]>>[CH3:8][N:9]([CH2:10][CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccccn1
Reactant: CNCCO
Product: CN(CCO)c1ccccn1

Procedure:
The reaction of 2-chloropyridine with 2-(N-methyl amino)ethanol provides 2-(N-methyl-N-(2-pyridyl)amino)ethanol (II), which on coupling reaction with 4-fluorobenzaldehyde (III) in an aprotic polar solvent with an alkali metal hydroxide or an alkali metal alkoxide as base yields 4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzaldehyde (IV) with an 88% yield (Reaction I).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([OH:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[CH3:15][C:16]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:20])[CH2:17][CH:18]=O>CCCCCC.CCOC(C)=O>[OH:14][C:8]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][CH2:18][CH2:17][C:16]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:20])[CH3:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Nc1ccccc1C1(O)CCCCC1
Reactant: CC(C)(CC=O)NC(=O)OC(C)(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(CCNc1ccccc1C1(O)CCCCC1)NC(=O)OC(C)(C)C

Procedure:
The product is prepared analogously to intermediate product 1b starting from 1-(2-amino-phenyl)-cyclohexanol and tert-butyl (1,1-dimethyl-3-oxo-propyl)-carbamate. After column chromatography (silica gel, hexane/EtOAc 7:1) the product is obtained as a colourless oil. Yield: 2.65 g (66%); Rf=0.50 (silica gel, hexane/EtOAc 4:1).
Reaction SMILES: [CH:1]#[C:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.S(=O)(=O)(O)O>C(COC)OC>[C:3]([O:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[CH2:1])=[CH:4][CH:5]=1)([CH3:8])([CH3:4])[CH3:2].[OH:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[CH2:1])=[CH:4][CH:5]=1
Reactant: C#Cc1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: COCCOC
Product: C=Cc1ccc(O)cc1
Product: C=Cc1ccc(OC(C)(C)C)cc1
Reaction time: 1 h

Procedure:
To a solution of poly(p-hydroxystyrene) (4.0 g) [MARUKA LYNCUR-M, manufactured by Maruzen Petrochemical Co., Ltd., Mw 10000 and Mn 5000] in dimethoxyethane (70 ml) in a pressure vessel, isobutyrene (60 g) and conc. sulfuric acid (0.3 g) were added at -60° C. or lower. The mixture was brought to 45° C. for 1 hour with stirring, and then stirring was continued at room temperature for 22 hours. After reaction, the mixture was evaporated, and the residue was neutralized by sodium carbonate and poured into H2O. The precipitate was filtered by suction, washed was H2O and dried in vacuo to give 4.1 g of poly(p-tert-butoxystyrene/p-hydroxystyrene) as a white powder having Mw 10000 (GPC with polystyrene calibration). 1HNMR analysis indicated that 50% of p-hydroxy group was converted into p-tert-butoxy group.