Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14](F)=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[K+].CS(C)=[O:22]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:22])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CS(C)=O
Reactant: O=S(=O)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)(c1ccc(O)cc1)c1ccc(F)cc1

Procedure:
Bis-(4-fluorophenyl) sulphone (100 g; 0.394 mole), potassium hydroxide solution (91.98 g; 0.787 mole KOH) and dimethyl sulphoxide (400 cm3) were stirred together in a stainless steel vessel under nitrogen at 57° C. for 24 hours. Two liquid phases remained throughout the reaction. The reaction mixture was diluted with water and twice extracted with diethyl ether to recover non-phenolic material (9 g). The aqueous phase was then acidified and the phenolic component (86 g; m.p. 150°-154° C.) was extracted with more ether. By subliming this product under a diffusion pump at 180° C., followed by recrystallisation from toluene (400 cm3), 4-(4-fluorophenylsulphonyl)phenol (72.5 g) was obtained, m.p. 158°-159° C. The potassium salt was obtained from this phenol as a very pale yellow solid.
Reaction SMILES: [CH2:1]([Si:8]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[O:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@@:12]3([O:32][C@@H:13]3[C@H:14](O)[C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[C@@H:17]3[CH2:30][C@@H:18]3[C:19]2=[O:29])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)[Cl:67]>C(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1>[CH2:1]([Si:8]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[O:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@@:12]3([O:32][C@@H:13]3[C@@H:14]([Cl:67])[C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[C@@H:17]3[CH2:30][C@@H:18]3[C:19]2=[O:29])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: C[C@]12CC[C@H]3[C@@H]([C@@H](O)[C@H]4O[C@]45C[C@@H](O[Si](Cc4ccccc4)(Cc4ccccc4)Cc4ccccc4)CC[C@]35C)[C@@H]1[C@@H]1C[C@@H]1C2=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: C[C@]12CC[C@H]3[C@@H]([C@H](Cl)[C@H]4O[C@]45C[C@@H](O[Si](Cc4ccccc4)(Cc4ccccc4)Cc4ccccc4)CC[C@]35C)[C@@H]1[C@@H]1C[C@@H]1C2=O

Procedure:
24 g of 3β-tribenzylsilyloxy-5,6β-epoxy-7β-hydroxy-15β,16β-methylene-5β-androstan-17-one is dissolved in a mixture of 250 ml of methylene chloride, 250 ml of carbon tetrachloride, and 125 ml of pyridine and stirred with 24 g of triphenylphosphine for 3 hours. The mixture is then washed with water, dried over sodium sulfate, and concentrated under vacuum. After chromatography on silica gel with hexane-acetone, 19.8 g of 3β-tribenzylsilyloxy-7α-chloro-5,6β-epoxy-15β,16β-methylene-5β-androstan-17-one is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26](Br)=[CH:25][N:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[C:21][C:26]4[CH:27]=[CH:28][C:23]([NH2:22])=[N:24][CH:25]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Reactant: Nc1ccc(Br)cn1
Product: Nc1ccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)cn1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.5) (73 mg, 0.25 mmol) and 2-amino-5-bromopyridine (43 mg, 0.25 mmol) according to general procedure II. Obtained as an orange solid (14 mg, 15%). MS (ISP) 386.3 [(M+H)+]; mp 233-235° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[C:4]([NH2:15])[N:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:33]=[C:32]3[C:27]([CH2:28][CH2:29][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31]3)=[CH:26][CH:25]=2)O1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.CO>[NH2:15][C:4]1[N:3]=[C:2]([C:24]2[CH:33]=[C:32]3[C:27]([CH2:28][CH2:29][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31]3)=[CH:26][CH:25]=2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=1
Reactant: CN1CCN(c2cc(Cl)nc(N)n2)CC1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)CC4)nc(N)n2)CC1
Temperature: 110 °C
Yield: 74.9 %

Procedure:
A mixture of 4-chloro-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (0.10 g, 0.44 mmol), tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.16 g, 0.44 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane (1:1) complex (0.02 g, 0.02 mmol) and potassium carbonate (0.18 g, 1.3 mmol) in 1,4-dioxane (3 mL), and water (1 mL) was heated at 110° C. overnight. After cooled to r.t., the mixture was diluted with MeOH, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with 10% MeOH in dichloromethane (DCM) to afford the desired product (0.14 g, yield: 75%). Analytic LCMS (M+H)+: m/z=425.4.
Reaction SMILES: C([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:11]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=2)[CH2:10]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:17]([O:16][C:14]([N:12]1[CH2:13][C@H:9]([OH:8])[CH2:10][CH:11]1[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: [H][H]
Reactant: Cc1cccc(CCc2ccccc2OCC2C[C@@H](OCc3ccccc3)CN2C(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1cccc(CCc2ccccc2OCC2C[C@@H](O)CN2C(=O)OC(C)(C)C)c1
Yield: 82 %

Procedure:
Following a procedure similar to that described in Example 65(b), 550 mg of (4R)-4-benzyloxy-1-t-butoxycarbonyl-2-{2-[2-(3-methylphenyl)ethyl]phenoxymethyl}pyrrolidine [prepared as described in step (a) above] were dissolved in 20 ml of ethanol and hydrogenated in an atmosphere of hydrogen at atmospheric pressure and in the presence of 120 mg of 5% w/w palladium-on-charcoal as a catalyst. The mixture was then worked up as described in Example 65(b), and the crude product thus obtained was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 370 mg (yield 82%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:19]=[C:15]([C:16](Cl)=[O:17])[C:14]([OH:20])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[NH2:21][CH2:22][C:23]1[NH:27][N:26]=[N:25][N:24]=1>>[OH:20][C:14]1[CH:13]=[CH:12][C:11]([N:10]=[N:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:19][C:15]=1[C:16]([NH:21][CH2:22][C:23]1[NH:27][N:26]=[N:25][N:24]=1)=[O:17]
Reactant: NCc1nnn[nH]1
Reactant: COc1ccc(N=Nc2ccc(O)c(C(=O)Cl)c2)cc1
Product: COc1ccc(N=Nc2ccc(O)c(C(=O)NCc3nnn[nH]3)c2)cc1

Procedure:
5-(4-Methoxyphenylazo)salicoyl chlorine and 5-aminomethyltetrazole were reacted together under the conditions described for the preparation of Dye 6 to form Dye 16, m.p. 220°-225° decomp., after crystallization from aqueous acetic acid, λmax (methanol) = 350 nm.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CN(C)C=[O:17].S(Cl)(Cl)=O.[CH2:23]([NH:26][CH2:27][CH2:28][CH3:29])[CH2:24][CH3:25]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:23]([N:26]([CH2:27][CH2:28][CH3:29])[C:1](=[O:17])[C:2]1[CH:10]=[CH:9][C:5]([CH3:6])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])[CH2:24][CH3:25]
Reactant: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CCCNCCC
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCN(CCC)C(=O)c1ccc(C)cc1[N+](=O)[O-]
Temperature: 20 °C

Procedure:
To a mixture of 4-methyl-3-nitrobenzoic acid (36.23 g, 0.2 mmol), N,N-dimethylformamide (5 mL), and toluene (85 mL) was added with stirring thionyl chloride (30 mL, 48.8 g, 0.41 mole). The mixture was stirred at gentle reflux for four hours, then distilled to approximately half the volume (67.77 g residual net weight) to remove excess thionyl chloride. This solution was cooled to 20° C., and 22.6 grams of it (nominally 6.67 mmol) was added to a solution of N,N-di-n-propylamine (22.0 g, 0.22 mole) in ethyl acetate (100 mL) resulting in immediate formation of a slurry that was stirred at ambient temperature overnight. This was then quenched into water (150 mL). The organic layer was washed with cold 0.5 N hydrochloric acid (100 mL), then with 5% aqueous sodium bicarbonate, dried (MgSO4) and evaporated to give a colorless oil weighing 16.55 g (94.0%). This was characterized by proton and carbon nmr, as well as electrospray mass spectrum (M+1 at m/e 265.1).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].[F:20][C:21]1[C:22]([I:30])=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](O)=[O:25].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[F:20][C:21]1[C:22]([I:30])=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([N:4]1[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[C@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19])=[O:25]
Reactant: O=C(O)c1cccc(F)c1I
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@@H]1CCCN(C(=O)c2cccc(F)c2I)[C@@H]1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione (0.4 g, 1.55 mmol), 3-fluoro-2-iodobenzoic acid (0.37 g, 1.4 mmol), DIPEA (0.49 mL, 2.8 mmol) and HATU (0.53 g, 1.4 mmol) in DMF (10 mL) was stirred at rt for 1 h. The reaction mixture was diluted with ethyl acetate and washed with satd. aq. NaHCO3 and brine successively. The organic layer was separated, dried with MgSO4 and concentrated in vacuo. The crude product was purified by chromatography on silica gel (EtOAc/hex) to afford the title compound. MS (ESI) 507 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:13]2[C:21]3[C:16](=[C:17]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)([CH2:11][CH3:12])[CH:9]=O)=[CH:4][CH:3]=1.[N+](=[C:32](P(=O)(OC)OC)C(=O)C)=[N-]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:13]2[C:21]3[C:16](=[C:17]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)([CH2:11][CH3:12])[C:9]#[CH:32])=[CH:4][CH:3]=1
Reactant: CCC(C=O)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Solvent: CO
Product: C#CC(CC)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of tert-butyl 1-(2-(4-chlorophenyl)-1-oxobutan-2-yl)-1H-indol-4-ylcarbamate (500 mg, 1.21 mmol), as described in Example 21 Step B, and dimethyl 1-diazo-2-oxopropylphosphonate (244 mg, 1.27 mmol) in MeOH (10 mL) was stirred at rt for 4 hours. After removing the solvent in vacuo, the residue was purified via column chromatography (0-30% EtOAc/hexanes) to provide the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([NH2:35])=[N:23][C:24]([C:26]2[C:31]([NH2:32])=[N:30][C:29]([NH2:33])=[C:28]([Cl:34])[N:27]=2)=[O:25])=[CH:13][CH:12]=1)(C)(C)C.Cl.C(Cl)Cl.CO>CO>[NH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([NH:23][C:24]([C:26]2[C:31]([NH2:32])=[N:30][C:29]([NH2:33])=[C:28]([Cl:34])[N:27]=2)=[O:25])=[NH:35])=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: N=C(NCCCCc1ccc(OCCN)cc1)NC(=O)c1nc(Cl)c(N)nc1N
Reaction time: 1 h
Yield: 125.9 %

Procedure:
[2-(4-{4-[N′-(3,5-Diamino-6-chloropyrazine-2-carbonyl)guanidino]butyl}phenoxy)ethyl]-carbamic acid tert-butyl ester 3 (2.63 g, 5.0 mmol) was dissolved in methanol (25 mL). 12N HCl (30 mL) was added in 10 ml portions. After stirring for 1 h, the reaction was complete by TLC (silica gel, methylene chloride/methanol/concentrated ammonium hydroxide, 100:10:1). The solvent was evaporated and methanol (300 mL) was added and, this process was repeated. The residue was placed under high vacuum overnight to afford the product (2.65 g, 99%) as a yellow solid, which was used without further manipulation. 1H NMR (300 MHz, DMSO-d6) δ 1.58 (m, 4H), 2.57 (m, 2H), 3.16 (m, 2H), 3.37 (m, 2H), 4.18 (t, 2H), 6.91 (d, 2H), 7.15 (d, 2H), 7.45 (m, 4H), 8.45 (br s, 3H), 9.03 (br s, 2H), 9.46 (t, 1H), 10.63 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[C:37]([C:41]1[CH:46]=[CH:45]C(O)=[CH:43][CH:42]=1)([CH3:40])([CH3:39])[CH3:38].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][C:26]2[CH:45]=[CH:46][C:41]([C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:42][CH:43]=2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)Oc4ccc(C(C)(C)C)cc4)c(C)c3C)c2cc1OC
Yield: 44.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 4-(tert-butyl)phenol (35 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (34 mg, yield 42%).
Reaction SMILES: [C:1]([O:10][CH2:11][CH2:12]Br)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:14][NH:15][CH3:16]>C(#N)C>[C:1]([O:10][CH2:11][CH2:12][N:15]([CH3:16])[CH3:14])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CNC
Reactant: CCCCCCCC(=O)OCCBr
Solvent: CC#N
Product: CCCCCCCC(=O)OCCN(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.8 %

Procedure:
2-Bromoethyl octanoate (0.2 g, 0.72 mmol) and 40% aqueous dimethylamine (4.2 mL, 36 mmol) were dissolved in acetonitrile (10 mL). The reaction mixture was stirred at room temperature for 48 hours. After removal of acetonitrile under vacuum, chloroform (30 mL) was added. The chloroform layer was extracted with potassium carbonate solution (20 mL, 0.01N) and water (2×20 mL), then was dried over sodium sulfate. The drying agent was suction filtered, and the chloroform removed in vacuo. The resulting material was applied to a silica gel column (discontinuous gradient of chloroform/methanol 95:5, 8:2 as eluent) affording 0.13 g pure product. Yield 77%; liquid; 1H NMR (CDCl3) 0.85-0.95 (t, CH3 (CH2)4), 1.20-1.40 (m, CH3 (CH2)4), 1.55-1.70 (m, CH2 CH2 CO), 2.25-2.40 (t, CH2 CH2 CO), 2.45-2.55 (s, (CH3)2 N) 2.75-2.85 (t, O CH2 CH2 N), 4.25-4.35 (t, O CH2 CH2 N).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:19])([F:18])[C:7]1[CH:17]=[CH:16][C:10](/[CH:11]=[CH:12]/[C:13](O)=[O:14])=[CH:9][CH:8]=1.N1C=CC=CC=1>C(Cl)Cl>[F:5][C:6]([F:19])([F:18])[C:7]1[CH:17]=[CH:16][C:10](/[CH:11]=[CH:12]/[C:13]([Cl:3])=[O:14])=[CH:9][CH:8]=1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cl)/C=C/c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (335 ml, 4.6 mmol) was added at 0° C. to 4-trifluoromethyl-E-cinnamic acid (1 g, 4.6 mmol) and pyridine (375 ml, 4.6 mmol) in dry CH2Cl2. The mixture was then stirred for 1 h without cooling, again cooled to 0° C. and filtered with the exclusion of moisture. The filtrate (10 ml) contained the title compound and was used in aliquots for the next reaction step.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH3:18])=[CH:13][CH:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:31]1([O:37][CH2:38][CH2:39]Br)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(N(CC)CC)C.O.C1(C)C=CC=CC=1>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([NH:1][CH2:2][CH2:3][CH:4]2[CH2:9][CH2:8][N:7]([CH2:39][CH2:38][O:37][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:6][CH2:5]2)[CH3:18])=[CH:13][CH:12]=1
Reactant: BrCCOc1ccccc1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: NCCC1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(NCCC1CCN(CCOc2ccccc2)CC1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
In a similar manner to Example 31, a mixture of 4-(2-aminoethyl)piperidine (5.0 g), 4'-chloroacetophenone (6.04 g), p-toluenesulphonic acid (catalytic amount) and toluene (100 ml) was boiled under reflux for 10 hours with water removal using a Dean and Stark apparatus. The mixture was cooled to ambient temperature and 2-bromoethyl phenyl ether (7.85 g) and triethylamine (5.4 ml) added. The mixture was boiled under reflux for 6 hours. The solvent was evaporated off and the residue dissolved in ethanol (100 ml) and sodium borohydride (3.4 g) was added. The mixture was boiled under reflux for 4 hours then worked up to give an oil which was purified by flash column chromatography on silica using ethyl acetate/triethylamine (95:5) as the mobile phase to give 4-{2-[1-(4-chlorophenyl)ethylamino]ethyl}-1-(2-phenoxyethyl)piperidine as an oil.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[NH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCCN1CCC[C@@H](N)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
To an ice-cooled solution of 2,2-dimethylpropionic acid 2-((R)-3-tert-butoxycarbonylaminopiperidin-1-yl)ethyl ester (2.86 g, 8.72 mmol) in DCM (100 mL) was added TFA (25 mL) and the mixture stirred at RT for 3 h. Toluene was added and volatiles were removed in vacuo. The resulting residue was dissolved in MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 1M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo affording the title compound as a colourless oil (1.678 g, 84%). 1H NMR (CDCl3, 300 MHz): 4.18 (2H, t, J=6.0 Hz), 2.89-2.77 (2H, m), 2.68-2.59 & 2.62 (3H, m & t, J=6.0 Hz), 2.19-2.11 (1H, m), 2.00-1.94 (1H, m), 1.84-1.65 (2H, m), 1.60-1.46 (1H, m), 1.23 (2H, bs), 1.20 (9H, s), 1.15-1.03 (1H, m).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][CH2:4][O:5][CH2:6][CH2:7][OH:8].[C:10](Cl)(=[O:16])/[CH:11]=[CH:12]/[C:13](Cl)=[O:14].[CH3:18][N:19]([CH3:25])[C:20](N(C)C)=N>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:9])[CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:10](=[O:16])[CH:11]=[CH:12][C:13]([O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:20][N:19]([CH3:25])[CH3:18])=[O:14]
Reactant: CN(C)C(=N)N(C)C
Reactant: CN(C)CCOCCO
Reactant: O=C(Cl)/C=C/C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CN(C)CCOCCOC(=O)C=CC(=O)OCCOCCN(C)C
Reaction time: 0.67 h
Yield: 40.3 %

Procedure:
The solution of 2-[2-(dimethylamino)-ethoxy]ethanol (6.65 g, 50 mmol, 2.5 equiv.) and 4-dimethylaminopyridine (11 mg) in toluene (20 ml) is cooled to −20° C. Separate solutions of fumaryl chloride (2.3 ml, 20 mmol, 1.0 equiv.) and 1,1,3,3-tetramethylguanidine (5.0 ml, 40 mmol, 2.0 equiv.) in toluene (each 25 ml) are added dropwise simultaneously via syringe pump over 80 min. A dark suspension is formed. After complete addition, the cooling bath is removed and stirring continued at 23° C. for 40 min. Active charcoal (1.0 g) is added and the mixture is filtered over a short pad of basic Al2O3, which is further rinsed with toluene/EtOAc (360 ml). The solution is concentrated and dried in vacuo (0.05 mbar) to yield the product as a yellow oil (2.79 g, 40%).
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[CH2:11]([NH2:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[CH3:24][C:25]1[CH2:29][C:28](=[O:30])[O:27][N:26]=1>>[CH2:11]([NH:23][CH:1]=[C:29]1[C:28](=[O:30])[O:27][N:26]=[C:25]1[CH3:24])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CC1=NOC(=O)C1
Reactant: CCCCCCCCCCCCN
Reactant: CCOC(OCC)OCC
Product: CCCCCCCCCCCCNC=C1C(=O)ON=C1C
Temperature: 60 °C
Yield: 29 %

Procedure:
3 g of triethyl orthoformate are added to 3.7 g of n-dodecylamine and 2 g of 3-methylisoxazol-5(4H)-one and the reaction mixture is heated at 60° C. for 20 hours. Thereupon, it is filtered over silica gel in hexane/ether/CH2Cl2 =1:1:3 and the desired product obtained is recrystallized in hexane. Yield 29%, m.p. 57° C., UV (EtOH): 311 nm (ε=18530).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[C:20]3[C:11](=[CH:12][C:13]4[C:18]([CH:19]=3)=[C:17]([C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH:16]=[CH:15][CH:14]=4)[C:10]([CH3:33])([CH3:32])[CH2:9][CH:8]=2)=[CH:4][CH:3]=1.CO.[Li+].[OH-].O>C1COCC1>[CH3:1][C:2]1[S:6][C:5]([C:7]2[C:20]3[C:11](=[CH:12][C:13]4[C:18]([CH:19]=3)=[C:17]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH:16]=[CH:15][CH:14]=4)[C:10]([CH3:33])([CH3:32])[CH2:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(-c2cccc3cc4c(cc23)C(c2ccc(C)s2)=CCC4(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C2=CCC(C)(C)c3cc4cccc(-c5ccc(C(=O)O)cc5)c4cc32)s1
Reaction time: 16 h

Procedure:
To a stirred solution of ethyl 4-[1-(5-methyl-thien-2-yl)-3,4-dihydro-4,4-dimethyl-anthracen-8-yl]-benzoate (Compound 3, 33 mg, 0.07 mmol), in THF (2 mL), MeOH (2 mL), was added aqueous LiOH (1M solution, 0.2 mL, 0.2 mmol). After 16 hours, water (2 mL) was added to the reaction mixture, about 50% of the organic solvents were removed by distillation, and the mixture was further diluted the mixture with water (5 mL). The reaction mixture was washed with ether (10 mL) and the aqueous layer was acidified to pH 4 and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed water (5 mL), brine (10 mL), dried with MgSO4 and the solvent was removed by distillation. The product was recrystallized from acetone to obtain the title compound as a white solid.