Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[CH2:24]([N:26](C(C)C)C(C)C)C>ClCCl.O1CCCC1>[C:24]([N:21]1[CH2:22][CH2:23][CH:18]([N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5](=[O:17])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:19][CH2:20]1)#[N:26]
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reactant: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Temperature: 25 °C

Procedure:
Bromonitirile (1.96 g) is added to a solution of N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide (3.50 g) and ethyldiisopropylamine (9.60 mL) in dichloromethane (125 mL) and tetrahydrofuran (125 mL) and the reaction mixture is stirred over night at room temperature. The reaction mixture is washed with water and the organic phase is dried over Na2SO4 and concentrated in vacuo. The residue is triturated with diethyl ether to afford the title compound. LC (method 3): tR=1.55 min; Mass spectrum (ESI+): m/z=337 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH:11]2[CH2:13][CH2:12]2)[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.Cl.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=2)=[CH:22][CH:21]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH:11]1([NH:10][C:6]2[C:7]([C:8]#[N:9])=[C:2]([N:29]3[CH2:28][CH:27]=[C:26]([C:23]4[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=4)[CH2:31][CH2:30]3)[N:3]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:5]=2)[CH2:13][CH2:12]1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NC1CC1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(NC2CC2)nc(NCCO)nc1N1CC=C(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-6-cyclopropylamino-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile (example 44a) was treated with 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride in dioxane in the presence of N-ethyl-diisopropylamine at 90° C. to yield 4-cyclopropylamino-6-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=395.
Reaction SMILES: C(O[C:5]([O:7][C:8]1[CH:17]=[CH:16][C:15]2[NH:14][C:13](=[O:18])[C:12]3[S:19][CH:20]=[CH:21][C:11]=3[C:10]=2[C:9]=1[C:22]1[CH:27]=[CH:26][C:25]([CH:28]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH3:29])=[CH:24][CH:23]=1)=[O:6])(C)C.[C:38](OC(=O)C)(=O)C>>[C:5]([O:7][C:8]1[CH:17]=[CH:16][C:15]2[NH:14][C:13](=[O:18])[C:12]3[S:19][CH:20]=[CH:21][C:11]=3[C:10]=2[C:9]=1[C:22]1[CH:27]=[CH:26][C:25]([CH:28]([NH:30][C:31]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:37])[CH3:29])=[CH:24][CH:23]=1)(=[O:6])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)OC(=O)Oc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)NC(=O)OC(C)(C)C)cc1
Product: CC(=O)Oc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)NC(=O)OC(C)(C)C)cc1
Yield: 62.7 %

Procedure:
Following Procedure Preparing tert-butyl 1-(4-(8-(isopropoxycarbonyloxy)-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)ethylcarbamate, (44 mg, 0.10 mmol) was reacted with acetic anhydride (11 μL, 0.12 mmol) to afford the desired product (30 mg, 63%) as a solid: ESI MS m/z 479 [C26H26N2O5S+H]+.
Reaction SMILES: [O:1]=[S:2]1(=[O:22])[CH2:6][CH2:5][CH2:4][CH:3]1[CH:7](O)[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=1.S(Cl)([Cl:25])=O>O1CCOCC1>[Cl:25][CH:7]([CH:3]1[CH2:4][CH2:5][CH2:6][S:2]1(=[O:22])=[O:1])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C(C)c1ccc(C(O)C2CCCS2(=O)=O)cc1
Solvent: C1COCCO1
Product: CCOC(=O)C(C)c1ccc(C(Cl)C2CCCS2(=O)=O)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
Ethyl 2-{4-[(1,1-dioxotetrahydro-1λ6-thiophen-1-yl)hydroxymethyl]phenyl} propionate (400 mg) obtained in Example 38 was dissolved in 1,4-dioxane (5.0 ml), and then to the solution was added thionyl chloride (0.2 ml), and the mixture was stirred at 70° C. overnight. The reaction mixture was quenched with saturated aqueous sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (420 mg, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[C:5]([NH:7][NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:6].[OH-].[Na+].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[C:19]([N:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[NH:7][C:5](=[O:6])[C:4]1[CH:13]=[CH:14][C:15]([Cl:16])=[C:2]([Cl:1])[CH:3]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)NNC(=O)c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)N(NC(=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1

Procedure:
3,4-Dichlorobenzoyl-2-tert-butylhydrazine (5.63 g, 0.0215 mole) is added to a rapidly stirring mixture of 40 mL of methylene chloride and 20 mL of 10% aqueous sodium hydroxide (2 g, 0.05 mole). Benzoyl chloride (d=1.211, 2.5 mL, 3.03 g, 0.0215 mole) in methylene chloride is added, and the reaction mixture stirred vigorously for approximately three hours at ambient temperature. The resulting solid is collected and washed with water and methylene chloride.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35]C(=O)C)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].C(O)C>O>[OH:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH:10]=[CH:11][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCCCCCCCCCCCCCOC(C)=O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(-c2ccc(OCCCCCCCCCCCCCCCCO)cc2)cc1
Yield: 95.6 %

Procedure:
30 m moles (15.7 g) of the above 4'-(16-acetyloxyhexadecyloxy)biphenyl-4-carboxylic acid ethyl ester and 10 g of sodium hydroxide were stirred for 10 min. at 70° C. in a mixed solution of 40 ml of ethanol and 80 ml of water. After the reaction, the reaction solution was concentrated to obtain 13.0 g of 4'-(16-hydroxyhexadecyloxy)biphenyl-4-carboxylic acid. (yield: 95%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[N:16]=[C:15](O)[O:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.O=P(Cl)(Cl)[Cl:26]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[N:16]=[C:15]([Cl:26])[O:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Oc1nc(C2(c3ccc(Br)cc3)CCC2)no1
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Clc1nc(C2(c3ccc(Br)cc3)CCC2)no1
Temperature: 90 °C
Reaction time: 18 h
Yield: 59.5 %

Procedure:
To a solution of R109 (500 mg, 1.694 mmol) in pyridine (1.618 mL, 20 mmol) is added POCl3 (1.551 mL, 16.94 mmol) in a pressure flask. The reaction mixture is stirred at 90° C. for 18 hours. After this time, the reaction mixture is poured into ice water and extracted with EA twice. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude is purified by flash chromatography (SiO2, 5-40% EA/Heptane) to afford the title compound (316 mg); no ionization.
Reaction SMILES: [CH:1]([CH:3]=O)=[O:2].C(N(CC)CC)C.[CH3:12][NH:13][C:14]([NH:16][CH3:17])=[O:15]>O>[CH3:12][N:13]1[CH2:3][C:1](=[O:2])[N:16]([CH3:17])[C:14]1=[O:15]
Reactant: CNC(=O)NC
Reactant: O=CC=O
Solvent: O
Solvent: CCN(CC)CC
Product: CN1CC(=O)N(C)C1=O
Temperature: 30 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
In a 1000 ml glass vessel equipped with a stirrer, thermometer, a dropping funnel and a distillation unit was charged 290 g (2.0 mol) of 40 wt % aqueous glyoxal solution. And then, triethylamine is added thereto to prepare a basic mixed solution (At this time, the solution had a pH of 9). To the mixed solution was gradually added dropwise a solution comprising 176 g (2.0 mol) of 1,3-dimethylurea and 176 ml of water while maintaining a liquid temperature to 25 to 35° C. After stirring the solution at room temperature for 3 hours, the mixture was reacted by elevating the temperature to 200° C. over 2 hours while removing triethylamine and water under normal pressure by distillation. After completion of the reaction, the obtained reaction mixture was distilled under reduced pressure (105 to 107° C./0.67 to 1.33 kPa) to obtain 217 g (Isolation yield; 85%) of 1,3-dimethylimidazolidin-2,4-dione as a pale yellowish liquid.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH2:9])=[O:8].[CH2:10]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@@H:21]1[C:25](O)=[O:26])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.CN(C)CCCN=C=NCC>C1COCC1>[C:7]([C:3]1[N:2]([NH:1][C:25]([C@H:21]2[CH2:22][CH2:23][CH2:24][N:20]2[C:18]([O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:19])=[O:26])[CH:6]=[CH:5][CH:4]=1)(=[O:8])[NH2:9]
Reactant: NC(=O)c1cccn1N
Reactant: O=C(O)[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: NC(=O)c1cccn1NC(=O)[C@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.2 %

Procedure:
A mixture of 1-amino-1H-pyrrole-2-carboxamide (6.00 g, 48.0 mmol) and (R)-1-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid (14.3 g, 57.5 mmol) was dissolved in THF (480 mL). To this solution was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (11.0 g, 57.5 mmol). The reaction was stirred overnight at rt then concentrated in vacuo. The residue was dissolved in CH2Cl2 (400 mL), washed with water (3×400 mL) and brine (400 mL), then dried (MgSO4), filtered, and concentrated in vacuo to give slightly impure 11A (17.65 g, >100%). 11A had an analytical HPLC retention time=2.103 min (Phenomenex Luna 3.0×50 mm, 10-90% aqueous MeOH over 5 min containing 0.1% TFA) and a LC/MS M++1=357.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[F:19][C:20]([F:31])([F:30])[S:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7]/[C:8](=[CH:26]\[C:25]3[CH:28]=[CH:29][C:22]([S:21][C:20]([F:31])([F:19])[F:30])=[CH:23][CH:24]=3)/[C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: O=Cc1ccc(SC(F)(F)F)cc1
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1ccc(SC(F)(F)F)cc1)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 13 (1.2 g, 4.858 mmol) in toluene 40 mL was added 4-((trifluoromethyl)thio)benzaldehyde 72 (1 g, 4.858 mmol). PTSA (1.84 g, 9.716 mmol) was added and the reaction mixture was stirred at 120° C. for 6 h. The reaction mass was diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound 73, which was purified through flash chromatography by using 100-200 mesh silica gel. The compound (E)-6-methoxy-5-morpholino-2-(4-((trifluoromethyl)thio)benzylidene)-2,3-dihydro-1H-inden-1-one 73 was eluted at 37% ethyl acetate in hexane to afford yellow coloured solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6](=O)[C:5](=[CH:8][NH:9][CH2:10][CH3:11])[C:4]([CH3:13])([CH3:12])[O:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>COCCOC>[CH3:1][C:2]1([CH3:14])[C:6](=[S:24])[C:5](=[CH:8][NH:9][CH2:10][CH3:11])[C:4]([CH3:13])([CH3:12])[O:3]1
Reactant: CCNC=C1C(=O)C(C)(C)OC1(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: COCCOC
Product: CCNC=C1C(=S)C(C)(C)OC1(C)C

Procedure:
A mixture of dihydro-2,2,5,5-tetramethyl-4-ethylaminomethylene-3(2H)furanone (1.0 g, 5.1 mmol) and Lawesson's Reagent (1.1 g, 2.7 mmol) was stirred in 20 mL of DME for 20 min. at room temperature. The solvent was evaporated and the residue was dissolved in methylene chloride and eluted through a plug of silica gel/basic alumina 1/1 (CH2Cl2). The eluant was evaporated to leave dihydro-2,2,5,5-tetramethyl-4-ethylaminomethylene-3(2H)furanthione as an orange solid.
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[S:7])[CH2:2][CH2:3][CH3:4].[CH2:8]([N:10](CC)C(=N)C)[CH3:9].[Cl:16][C:17]1[CH:26]=[CH:25][C:20]([C:21](=[O:24])[CH2:22]Br)=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28]>C(O)(C)C>[Cl:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([C:22]2[S:7][C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[N:10][C:8]=2[CH3:9])=[O:24])=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28]
Reactant: CCCCN=C=S
Reactant: O=C(CBr)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCN(CC)C(C)=N
Solvent: CC(C)O
Product: CCCCNc1nc(C)c(C(=O)c2ccc(Cl)c([N+](=O)[O-])c2)s1
Reaction time: 1 h

Procedure:
The same compound is also prepared as follows: 11.5 g of n-butyl isothiocyanate are added to 11.4 g of N,N-diethyl-acetamidine, whereupon the mixture becomes exothermic. The mixture is left to stand for 1 hour at 60° and the resulting adduct is used in the following experiment. A mixture of 22.9 g of the crude product and 27.9 g of 4-chloro-3-nitro-phenacyl bromide in 200 ml of isopropanol is refluxed for 2 hours. The solution is worked up as described above, yielding 4-chloro-3-nitro-1-(4-methyl-2-n-butylamino-5-thiazoloyl)-benzene.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([C:14]#[N:15])(C)C.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1>C(Cl)Cl.O>[C:1]1([CH2:7][CH:8]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([OH:32])([C:24]([F:25])([F:26])[F:27])[C:28]([F:29])([F:30])[F:31])=[CH:21][CH:22]=2)[C:14]#[N:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=CCc1ccccc1
Reactant: C[Si](C)(C)C#N
Solvent: ClCCl
Solvent: O
Product: N#CC(Cc1ccccc1)Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.2 %

Procedure:
To a mixture of phenylacetaldehyde (0.7 mL, 5.8 mmol) and trimethylsilyl cyanide 0.8 mL, 6.0 mmol) in CH2Cl2 (2 mL) was added 2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (Oakwood, 1.6 g, 6.1 mmol). The resulting mixture was stirred at ambient temperature over 18 h. The reaction mixture was diluted with CH2Cl2 and water. The organics were washed several times with water, dried (MgSO4), and concentrated in vacuo. Purification by flash chromatography (8:1 hexanes/EtOAc) afforded the title compound as a pale yellow solid (1.4 g, 63%). MS (ES+) m/z 389 (MH+).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[CH:12]=[C:11]2[C:21]([O:23][CH3:24])=[O:22])[CH2:4][CH2:3]1.[O:25]1[C:34]2[CH:33]=[C:32]([CH:35]=O)[N:31]=[CH:30][C:29]=2[O:28][CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.CO>[O:25]1[C:34]2[CH:33]=[C:32]([CH2:35][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:18]5[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=5)[CH:12]=[C:11]4[C:21]([O:23][CH3:24])=[O:22])[CH2:6][CH2:7]3)[N:31]=[CH:30][C:29]=2[O:28][CH2:27][CH2:26]1
Reactant: COC(=O)c1cc2ccc(OC)cc2n1CCN1CCC(N)CC1
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1cc2ccc(OC)cc2n1CCN1CCC(NCc2cc3c(cn2)OCCO3)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
A solution of methyl 1-[2-(4-aminopiperidin-1-yl)ethyl]-6-methoxy-1H-indole-2-carboxylate (Intermediate 12, 200 mg, 0.60 mmol) and 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (100 mg, 0.60 mmol) in dry chloroform/methanol (10 mL, 1:1) was heated over 3 Å molecular sieves at 70° C. for 3 hours. The reaction mixture was cooled to 0° C., sodium triacetoxy borohydride (384 mg, 1.8 mmol) was added and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered through a 0.45 μm membrane and concentrated to dryness under reduced pressure. The residue was taken up in dichloromethane (150 mL) and saturated aqueous sodium hydrogen carbonate solution (30 mL), the aqueous phase back extracted once with dichloromethane (70 mL) and the combined organic phases were dried over sodium sulfate. Chromatography on silica gel with dichloromethane/methanol (5:1), containing 0.125% ammonium hydroxide, gave the free base of the title compound, 239 mg (82% yield), as a colorless solid, mp 130° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.Cl.[CH3:19]O>>[CH3:19][O:14][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][C:6]1[CH:5]=[CH:4][C:3]([NH2:2])=[CH:17][CH:16]=1
Reactant: Nc1ccc(OCCCCCC(=O)O)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)CCCCCOc1ccc(N)cc1

Procedure:
To a mixture of 6-(4-Amino-phenoxy)-hexanoic acid Hydrochloride 66 (150 grams, 578 mmol), in methanol (3 liters) was passed dry HCl gas at 10° C. for 1 hour and refluxed for 48 hours. Methanol (1.5 liter) was distilled, ice water (1 liter) was added and the pH was adjusted to 7.5 with K2CO3. Crude 67 was extracted into chloroform, washed with 5% NaHCO3 solution, water, dried over Na2SO4 and distilled to give 67 (60 grams, 43.8) as a thick brown syrup. The structure was confirmed with NMR. IHNMR (CDCl3) δ 1.5 (m, 2H, CH2), 1.72 (m, 4H, CH2), 2.34 (t, 2H, CH2), 3.66 (s, 3H, ester), 3.85 (t, 2H, OCH2), 6.56 (d, 2H, Ar), 6.68 (d, 2H, Ar).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:4][C:3]=1[C:14](=O)[CH3:15].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:4][C:3]=1[CH:14]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:15]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1ccc(OCC(F)(F)F)cc1Cl
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(OCC(F)(F)F)cc1Cl
Yield: 72 %

Procedure:
The title compound is prepared in 72% yield (390 mg, clear colorless oil) from 1-(2-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethanone (390 mg, 1.6 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][C:16]=1[CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[N:6]1([CH2:5][CH2:4][CH2:3][CH2:2][N:28]2[CH2:27][CH2:26][CH:25]([C:16]3[CH:17]=[N:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:15]=3)[CH2:30][CH2:29]2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1
Reactant: c1ccc2nc(C3CCNCC3)cnc2c1
Reactant: ClCCCCn1nnc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2nc(C3CCN(CCCCn4nnc5ccccc54)CC3)cnc2c1
Temperature: 25 °C
Yield: 63 %

Procedure:
1-(4-chlorobutyl)-1H-benzotriazole (7.55 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-(2-quinoxalinyl)piperidine (6.4 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 20 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 7.3 g compound (I-123) with a yield of 62.7%. ESI-MS [M+H]+: m/z 387.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][CH:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[CH3:12].ClC(C)[CH2:26][NH:27]C1C(C)=CC=CC=1C.FC(F)(F)C1C=C(C=CC=1)N.Cl.FC(F)(F)C1C=C(C=CC=1)N>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH2:10][CH:11]([CH3:12])[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=2)[C:26]1=[NH:27]
Reactant: Cc1cccc(C)c1NCC(C)Nc1cccc(C(F)(F)F)c1
Reactant: Cc1cccc(C)c1NCC(C)Cl
Agent: Cl
Agent: Nc1cccc(C(F)(F)F)c1
Product: Cc1cccc(C)c1N1CC(C)N(c2cccc(C(F)(F)F)c2)C1=N
Yield: 42.4 %

Procedure:
1-(2',6'-Dimethylphenyl-amino)-2-(3'-trifluoromethylphenyl-amino)-propane, applied as starting substance, is prepared by reacting N-(β-chloropropyl)-2,6-dimethyl-aniline, a compound prepared as described in Example 3, Method (b), point (a), with 3-trifluoromethyl-aniline. The reaction is performed as described in Example 16, point (c) with the difference that crystalline 3-trifluoromethyl-aniline hydrochloride is separated from the reaction mixture by trituration with benzene. The aimed product is obtained with a yield of 42.4%; m.p.: 160°-166° C. (dihydrochloride).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C@H:25]3[CH2:30][CH2:29][C@H:28]([CH2:31][CH2:32][CH2:33]S(C(F)(F)F)(=O)=O)[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3].[OH:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][C:49]=1[OH:50])[C:45]#[N:46].[OH2:51]>COCCOC>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C@H:25]3[CH2:30][CH2:29][C@H:28]([CH2:31][CH2:32][CH2:33][O:41][C:42]4[CH:43]=[C:44]([CH:47]=[CH:48][C:49]=4[O:50][CH2:33][CH2:32][CH2:31][C@H:28]4[CH2:27][CH2:26][C@H:25]([C:22]5[CH:21]=[CH:20][C:19]([C:16]6[CH:15]=[CH:14][C:13]([O:51][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][C:1](=[O:4])[CH:2]=[CH2:3])=[CH:18][CH:17]=6)=[CH:24][CH:23]=5)[CH2:30][CH2:29]4)[C:45]#[N:46])[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCCCCCOc1ccc(-c2ccc([C@H]3CC[C@H](CCCS(=O)(=O)C(F)(F)F)CC3)cc2)cc1
Reactant: O
Reactant: N#Cc1ccc(O)c(O)c1
Solvent: COCCOC
Product: C=CC(=O)OCCCCCCOc1ccc(-c2ccc([C@H]3CC[C@H](CCCOc4ccc(C#N)cc4OCCC[C@H]4CC[C@H](c5ccc(-c6ccc(OCCCCCCOC(=O)C=C)cc6)cc5)CC4)CC3)cc2)cc1

Procedure:
A solution of 1.50 g of 6-[4'-[trans-4-[3-(trifluoromethanesulphonyl)-propyl]-cyclohexyl]-biphenyl-4-yloxy]-hexyl acrylate and 0.155 g of 3,4-dihydroxy-benzonitrile in 25 ml of 1,2-dimethoxyethane was treated portionwise at 20° C. with 0.286 g of potassium tertiary butylate and subsequently stirred overnight at 85° C. The cooled reaction mixture was poured into 25 ml of water and then extracted three times with 20 ml of ethyl acetate. The combined organic phases were washed twice with 50 ml of water, dried over magnesium sulphate, filtered and concentrated. Chromatographic purification of the residue on silica gel with cyclohexane/ethyl acetate (vol. 8:2) and two-fold recrystallization from a cyclohexane/ethyl acetate mixture (vol. 8:2) of the fractions which were pure according to thin-layer chromatography gave 1.10 g of 3,4-bis-[3-[trans-4-[4'-(6-acryloyloxy-hexyloxy)-biphenyl-4-yl]-cyclohexyl]-propoxy]-benzonitrile.