Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]=[C:8]2[NH:12][CH2:11][CH2:10][NH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C1COCC1.CCCCCC>[S:24]([N:12]1[CH2:11][CH2:10][NH:9][C:8]1=[N:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:26])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccc(N=C2NCCN2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCNC2=Nc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
2-(Phenylimino)imidazolidine (0.773 g, 4.8 mmoles) is dissolved in dry THF (15 ml), cooled to -78° C. under nitrogen protected from moisture and 2.4 N butyllithium in hexane (2.0 ml) is added. Then p-toluenesulfonyl chloride (0.953 g, 5 mmoles) in THF (3 ml) at -78° C. is added. The mixture is stirred for 90 minutes and allowed to warm to ambient temperature. The volatiles are evaporated in vacuo and water and ether are added. Crystals separate in the ether layer which are filtered and recrystallized from isopropanol to remove some bistosyl derivative. The major product, confirmed by n.m.r is N'-Tosyl-2-(phenylimino)imidazolidine, (610 mg, 40%), m.p. 174°-177° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[O:16][CH2:17][CH:18]([OH:25])[CH2:19][NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:4][CH:3]=1.O.[NH2:27][NH2:28]>C(O)C>[C:21]([NH:20][CH2:19][CH:18]([OH:25])[CH2:17][O:16][C:9]1[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:8]=1[C:5]1[N:6]=[N:7][C:2]([NH:27][NH2:28])=[CH:3][CH:4]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: COc1ccc(-c2ccc(Cl)nn2)c(OCC(O)CNC(C)(C)C)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2ccc(NN)nn2)c(OCC(O)CNC(C)(C)C)c1

Procedure:
A stirred mixture of 6-chloro-3-[2-(3-t-butylamino-2-hydroxypropoxy)-4-methoxyphenyl]pyridazine and hydrazine hydrate in ethanol was heated under reflux for 3 hours. Evaporation of the reaction mixture under reduced pressure gave the title compound.
Reaction SMILES: C[Al](C)C.[NH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C([O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:25][CH2:24][CH:23]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)[C:22]2=[O:40])=[CH:17][CH:16]=1)C.CO>ClCCCl>[CH3:39][N:36]1[CH2:37][CH2:38][N:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH2:26][CH:23]2[CH2:24][CH2:25][N:21]([C:18]3[CH:19]=[CH:20][C:15]([C:14]([N:5]4[CH2:10][CH2:9][O:8][CH2:7][CH2:6]4)=[O:13])=[CH:16][CH:17]=3)[C:22]2=[O:40])[CH2:34][CH2:35]1
Reactant: CCOC(=O)c1ccc(N2CCC(Cc3ccccc3N3CCN(C)CC3)C2=O)cc1
Reactant: C1COCCN1
Agent: C[Al](C)C
Solvent: ClCCCl
Solvent: CO
Product: CN1CCN(c2ccccc2CC2CCN(c3ccc(C(=O)N4CCOCC4)cc3)C2=O)CC1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
Trimethyl aluminum (2 M in toluene, 700 uL, 1.4 mmol) was added dropwise to a solution of morpholine (124 uL, 1.4 mmol) in 1,2-dichloroethane (4 mL) at 0° C. Upon completion of addition, the cold bath was removed and the solution was stirred 30 minutes at 23° C. A solution of 4-{3-[2-(4-methyl-piperazin-1-yl)-benzyl]-2-oxo-pyrrolidin-1yl}-benzoic acid ethyl ester (Example 2, 150 mg, 0.36 mmol) in 1,2-dichloroethane (2 mL) was then added and the solution was heated at 70° C. for ca. 18 hours. The solution was cooled to room temperature, methanol was carefully added to quench excess methyl aluminum species, and the mixture was then treated with sodium sulfate decahydrate (1.5 g). The mixture was stirred rapidly for 3 hours, the salts were filtered off, the solvent was removed in vacuo and the residue was purified by silica gel chromatography (20:1 chloroform-methanol w/1% ammonium hydroxide) to afford 160 mg (96% yield) of the title compound. 13C NMR (100 MHz, CDCl3) d 176.28, 170.23, 152.12, 141.26, 135.00, 130.88, 130.52, 128.25, 127.71, 124.54, 120.84, 119.35, 67.14, 67.09, 55.90, 54.36, 52.97, 46.81, 46.36, 44.91, 32.48, 24.58; MS (AP/Cl) 463.2 (M+H)+. The enantiomers were separated by HPLC (60/40 heptane/ethanol; Chiralcel OJ, 10 cm×50 cm; 27.5 mL/min). Approximate retention times: t1=45 minutes; t2=60 minutes.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:18]=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1.[I:21]Cl>>[F:1][C:2]1[C:3]2[N:4]([C:18]([I:21])=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: ClI
Reactant: Fc1cc(-c2ccc(C(F)(F)F)cc2)cn2ccnc12
Product: Fc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(I)cnc12
Yield: 78 %

Procedure:
Prepared from 8-fluoro-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.29 step 5) (1.95 g, 7.9 mmol) and iodine monochloride as described in example C.20 step 3. Obtained the title compound as a light brown solid (1.8 g, 78%). MS (ISP) 407.0 [(M+H)+].
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][NH:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C@H:22]([N:29]([C:37](=[O:39])[CH3:38])[C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[CH2:21][C@@H:20]2[CH3:40])=[O:18])=[CH:13][CH:12]=1)C.C(O)C.[OH-].[Na+]>O1CCCC1>[C:37]([N:29]([C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1)[C@H:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:19]([C:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][NH:6][CH2:5][C:4]([OH:41])=[O:3])=[CH:12][CH:13]=2)=[O:18])[C@@H:20]([CH3:40])[CH2:21]1)(=[O:39])[CH3:38]
Reactant: CCOC(=O)CNCCCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCNCC(=O)O)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
{[3-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)propyl]amino}acetic ethyl ester was hydrolyzed to the acid by dissolving in tetrahydrofuran and ethanol and sodium hydroxide (1N) was added. The mixture was stirred at room temperature overnight. The mixture was cooled to rt, acidified to form a white precipitate. The solid was filtered to give {[3-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)propyl]amino}acetic acid 0.005 g, 75% yield.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[C:5]([C:21](=[O:23])[CH3:22])=[N:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[CH:8][N:9]=1.[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO>[NH2:3][C:4]1[C:5]([C:21](=[O:23])/[CH:22]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:6][C:7]([N:10]2[CH2:11][CH2:12][N:13]([S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])[CH2:14][CH2:15]2)=[CH:8][N:9]=1
Reactant: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(C)=O)n2)CC1
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(=O)/C=C/c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
A solution of NaOH in methanol (191.5 μl, of 10% w/v, 0.4787 mmol) was added to a solution of 1-(3-amino-6-(4-(ethylsulfonyl)piperazin-1-yl)pyrazin-2-yl)ethanone (150 mg, 0.4787 mmol) and benzaldehyde (50.80 mg, 48.66 μL, 0.4787 mmol) in methanol (4 mL) (1 mL of dichloromethane was added to aid solubility). The reaction mixture was allowed to stir overnight at RT and then filtered and washed with a small amount of methanol. The bright orange coloured solid was taken through crude to the next stage. (104.6 mg, 54% Yield). 1H NMR (400.0 MHz, DMSO) d 1.21 (t, 3H), 3.13 (q, 2H), 3.35-3.37 (m, 4H), 3.54-3.57 (m, 4H), 7.47-7.51 (m, 3H), 7.55 (br s, 2H), 7.72 (d, 1H), 7.79-7.81 (m, 2H), 8.28 (d, 1H), 8.41 (s, 1H) ppm; MS (ES+) 402.01
Reaction SMILES: Cl.[CH:2]12[O:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][NH:4][CH2:3]2.[Cl:10][C:11]1[N:16]=[C:15](Cl)[N:14]=[C:13]([N:18]2[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[N:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH:6]12[O:9][CH:2]([CH2:8][CH2:7]1)[CH2:3][N:4]([C:15]1[N:16]=[C:11]([Cl:10])[N:12]=[C:13]([N:18]3[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]3)[N:14]=1)[CH2:5]2
Reactant: C1CC2CNCC1O2
Reactant: O=C1CCN(c2nc(Cl)nc(Cl)n2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C1CCN(c2nc(Cl)nc(N3CC4CCC(C3)O4)n2)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To an aqueous solution of 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (66 mL) was added 1-(4,6-dichloro-1,3,5-triazin-2-yl)piperidin-4-one (2.7 g, 11 mmol) as a suspension in acetone (40 mL). To the mixture was added solid sodium carbonate (2.5 g, 24 mmol). The suspension was stirred at 80° C. for two hours and then allowed to cool to room temperature. The title compound was collected by filtration, washed with water, and dried under vacuum; MS (ES+) 324.4 (M+H)+
Reaction SMILES: [C:1]([CH2:4][C:5]1[N:6]=[C:7]([S:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])[S:8][CH:9]=1)([OH:3])=O.[CH2:17]([O:19][C:20](=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)[CH3:18].C1C=C2N=NN(O)C2=CC=1.O.C(N=C=NC(C)C)(C)C>CN(C)C=O>[CH2:17]([O:19][C:20](=[O:29])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:1](=[O:3])[CH2:4][C:5]2[N:6]=[C:7]([S:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])[S:8][CH:9]=2)=[CH:26][CH:27]=1)[CH3:18]
Reactant: CC(C)(Sc1nc(CC(=O)O)cs1)C(=O)O
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(NC(=O)Cc2csc(SC(C)(C)C(=O)O)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An operation similar to that of Example 461-5 was performed 3 times using 2-{[4-(carboxymethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid resin obtained in Example 461-4 and 4-aminophenylacetic acid ethyl ester. To a suspension of the obtained resin in dimethylformamide (30 mL) were added HOBT monohydrate (0.92 g), diisopropylcarbodiimide (0.93 ml) and 4-aminophenylacetic acid ethyl ester (1.1 g), and the mixture was stirred at room temperature overnight. The resin was collected by filtration from the reaction mixture, washed once each with dimethylformamide and methanol, twice with dimethylformamide, once with methanol, three times with tetrahydrofuran and finally once with methanol, and vacuum dried to give the title pale-brown resin (3.1 g).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[Cl:12][C:13]1[C:14](F)=[CH:15][C:16]2[O:21][CH:20]([C:22]([F:25])([F:24])[F:23])[C:19]([C:26]([O:28]CC)=[O:27])=[CH:18][C:17]=2[CH:31]=1>>[Cl:12][C:13]1[C:14]([O:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=2)=[CH:15][C:16]2[O:21][CH:20]([C:22]([F:24])([F:23])[F:25])[C:19]([C:26]([OH:28])=[O:27])=[CH:18][C:17]=2[CH:31]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccc(C(F)(F)F)cc3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 4-(trifluoromethyl)phenol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 230.9-232.0° C. 1H NMR (acetone-d6 /300 MHz) 7.93 (s, 1H), 7.77 (m, 3H), 7.27 (d, 2H, J=8.7 Hz), 6.86 (s, 1H), 5.87 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6 /282 MHz) -62.8 (s, 3F), -79.4 (d, 3F, J=7.2 Hz). ESLRMS m/z 437 (M-H). ESHRMS m/z 437.0008 (M-H, Calc'd 437.0015). Anal. Calc'd for C18H9ClF6O4 : C, 49.28; H, 2.07; Cl, 8.08. Found: C, 49.25; H, 2.08; Cl, 8.24.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C@@:9]2([OH:18])[O:14][CH2:13][C:12]([CH3:16])([CH3:15])[NH:11][C@@H:10]2[CH3:17])[CH:6]=[CH:7][CH:8]=1.C(OCC)C.[OH-].[Na+]>O>[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2([OH:18])[O:14][CH2:13][C:12]([CH3:15])([CH3:16])[NH:11][CH:10]2[CH3:17])[CH:6]=[CH:7][CH:8]=1
Reactant: C[C@H]1NC(C)(C)CO[C@]1(O)c1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CC1NC(C)(C)COC1(O)c1cccc(Cl)c1
Reaction time: 0.5 h

Procedure:
(+/−)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-tiimethyl-2-morpholinol hydrochloride may be converted back to its free base by the following process. A 3.0 g sample of (+/−)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol hydrochloride was dissolved in water (100 mL) and diethyl ether was added (200 mL). The mixture was chilled in an ice bath and the pH was adjusted to>10 with 1.0N aqueous sodium hydroxide. After stirring for 30 min., the phases were separated and the aqueous phase was extracted with diethyl ether. The combined diethyl ether extracts were dried (Na2SO4) and concentrated in vacuo to give 2.6 g of (+/−)-(2R*, 3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol as a white solid. This was used without further purification for the chiral chromatography described below.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[F:13][C:14]([F:24])([F:23])[C:15]([F:22])([F:21])[C:16](OCC)=[O:17]>>[O:5]1[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=[C:4]1[C:1](=[O:3])[CH2:2][C:16](=[O:17])[C:15]([F:22])([F:21])[C:14]([F:24])([F:23])[F:13]
Reactant: CCOC(=O)C(F)(F)C(F)(F)F
Reactant: CC(=O)c1cc2ccccc2o1
Product: O=C(CC(=O)C(F)(F)C(F)(F)F)c1cc2ccccc2o1

Procedure:
The compound was synthesized according to example 1 using 2-acetylbenzofuran and ethyl pentafluoropropionate as starting materials. The product was crystallized from petroleum ether. 1H NMR (CDCl3): 6.75 (s, 1 H); 7.35 (ddd, 1H, J=0.9 & 7.1 & 7.9 Hz); 7.51 (ddd, 1H, J=1.3 & 7.1 & 8.4 Hz); 7.58-7.60 (m, 1 H); 7.67 (d, 1H, J=0.9 Hz); 7.71-7.73 (m, 1 H). IR (film): 1614 (C═O); 1211, 1200 (C—F).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:9][CH:10]=O)=[CH:4][CH:3]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26][NH2:27].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:9][CH2:10][NH:27][CH2:26][CH2:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)=[CH:4][CH:3]=1
Reactant: O=CCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: NCCc1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: Fc1ccc(C(CCNCCc2ccccn2)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 3,3-bis(4-fluorophenyl)propanal (0.967 g, 3.93 mmol) in DCE (15 mL) at room temperature was added 2-(pyridin-2-yl)ethanamine (1.73 g, 14.2 mmol) and NaBH(OAc)3 (1.08 g, 5.10 mmol). The reaction mixture was stirred at room temperature for 17 h, diluted with EtOAc, washed with 5 M NaOH (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 2% to 8% MeOH (2M NH3) in DCM) followed by purification by flash column chromatography on silica gel (eluted with 50% to 100% EtOAc (10% 2M NH3 in MeOH) in hexanes) gave 3,3-bis(4-fluorophenyl)-N-(2-(pyridin-2-yl)ethyl)propan-1-amine.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:12]=1>>[CH3:27][C:25]1[NH:24][N:23]=[C:22]([NH:21][C:13]2[N:12]=[C:11]([O:1][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[C:20]3[C:15]([CH:14]=2)=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:26]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(Oc3ccc(C#N)cc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from 4-hydroxy-benzonitrile and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give 4-[3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-yloxy]-benzonitrile. LC-MS m/e 342(MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:6]=[CH:7][CH:8]=1.Cl[P:23]([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25]>C1(C)C=CC=CC=1>[CH:24]([P:23]([CH:27]([CH3:29])[CH3:28])[C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=1[N:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:16]2[C:21]1=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:26])[CH3:25]
Reactant: COc1cccc(-n2c3ccccc3c3ccccc32)c1
Reactant: CC(C)P(Cl)C(C)C
Solvent: Cc1ccccc1
Product: COc1cccc(-n2c3ccccc3c3ccccc32)c1P(C(C)C)C(C)C
Yield: 70.2 %

Procedure:
Title compound (1-2) (5.0 g) was obtained as a colorless powder by the same procedure as in the second step of Example 1, except that the reaction was conducted by use of the toluene solution of the crude product of N-(3-methoxyphenyl) carbazole (4-1) in an amount equivalent to 18.3 mmol, that chlorodiisopropylphosphine was used instead of Cy2PCl, and further that the product was isolated and purified by crystallization from toluene/methanol. Two Steps Overall Isolated Yield: 70.2%.
Reaction SMILES: [N:1]1([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3][CH2:2]1.[O:20]=[C:21]1[N:27]([CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C@@H:37]([C:48](O)=[O:49])[CH2:38][C:39]3[CH:44]=[C:43]([CH3:45])[C:42]([OH:46])=[C:41]([CH3:47])[CH:40]=3)=[O:35])[CH2:30][CH2:29]2)[CH2:26][CH2:25][C:24]2[CH:51]=[CH:52][CH:53]=[CH:54][C:23]=2[NH:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:20]=[C:21]1[N:27]([CH:28]2[CH2:29][CH2:30][N:31]([C:34]([O:36][C@H:37]([CH2:38][C:39]3[CH:40]=[C:41]([CH3:47])[C:42]([OH:46])=[C:43]([CH3:45])[CH:44]=3)[C:48]([N:17]3[CH2:16][CH2:15][CH:14]([N:1]4[CH2:2][CH2:3][CH:4]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:6]4)[CH2:19][CH2:18]3)=[O:49])=[O:35])[CH2:32][CH2:33]2)[CH2:26][CH2:25][C:24]2[CH:51]=[CH:52][CH:53]=[CH:54][C:23]=2[NH:22]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1O
Reactant: CCOC(=O)CCC1CCN(C2CCNCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CCC1CCN(C2CCN(C(=O)[C@@H](Cc3cc(C)c(O)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Reaction time: 2 h

Procedure:
410 mg (1.20 mmol) ethyl 3-[1,4′]bipiperidinyl-4-yl-propionate (used as the bis-hydrochloride salt) were added at RT to a solution of 500 mg (1.04 mmol) (R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1h), 385 mg (1.20 mmol) TBTU and 0.48 mL (3.40 mmol) triethylamine in 10 mL DMF and the mixture was stirred for 2 h. The reaction mixture was purified by HPLC without any further working up. The fractions containing the product were combined, concentrated by evaporation i.vac. and the residue was stirred with saturated NaHCO3 solution. The precipitate formed was filtered off and dried.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH:24]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[CH2:23][N:22]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:21][CH:20]2[CH2:44][OH:45])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:47][C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1>>[CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH:20]([CH2:44][O:45][CH2:47][C:48]3[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=3)[CH2:21][N:22]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[CH2:23][CH:24]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C(c2ccc(COCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: ClCc1cccnc1
Product: CC(C)(C)OC(=O)N1CC(COCc2cccnc2)C(c2ccc(COCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3SR,4RS,5RS)-4-[4-(2-benzyloxy-ethoxymethyl)-phenyl]-3-hydroxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with 3-(chloromethyl)-pyridine there was obtained tert-butyl (3RS,4RS,5SR)-4-[4-(2-benzyloxy-ethoxymethyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-5-(pyridine-3-ylmethoxymethyl)-piperidine-1-carboxylate as a colourless oil; MS: 703 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Br:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1>>[Br:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]([C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[OH:13])=[CH:10][CH:9]=1
Reactant: Brc1nccs1
Reactant: O=Cc1ccc(Br)cc1
Product: OC(c1ccc(Br)cc1)c1nccs1

Procedure:
Using the same protocol as described in example 22, step 1, 2-bromothiazole (451 μL, 5.0 mmol) was added to 4-bromobenzaldehyde (1.018 g, 5.5 mmol). The crude residue was chromatographed on silica gel using 50% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[O:4]1[CH2:9][CH2:8][O:7][CH2:6][C:5]1=[O:10]>O1CCOCC1>[CH3:1][N:2]([CH3:3])[C:5](=[O:10])[CH2:6][O:7][CH2:8][CH2:9][OH:4]
Reactant: O=C1COCCO1
Reactant: CNC
Solvent: C1COCCO1
Product: CN(C)C(=O)COCCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
Into a round-bottom flask of the volume of 100 ml are transferred 50 ml dioxane and the solvent is cooled to 5° C. Subsequently 8.1 g (0.18 mole) dimethylamine is absorbed in the solvent at the temperature of 5-10° C. in 20 minutes. To the solution of dimethylamine, 10.2 g (0.1 mole) of [1,4]-dioxane-2-one are added at the same temperature in 5 minutes and the reaction mixture is stirred at room temperature for 2 hours. After the reaction period, the solvent is evaporated in vacuo at the temperature of 50° C. in one hour. Thus 14.1 g (95.9%) of the title product are obtained, which has the purity of 98% as determined by gas chromatography. Optionally the product can be purified by distilling in vacuo (boiling temperature 130-135° C./13 Pa). The raw product is directly suitable for the preparation of 2-chloroethoxy-acetic acid-N,N-dimethyl-amide.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]([CH2:17][O:18][C:19](=[O:37])[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][CH2:35][CH3:36])[CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:11](=[O:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]1=2.[C:38]([NH:45][C@H:46]([C:51](O)=[O:52])[C@H:47]([CH2:49][CH3:50])[CH3:48])([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CN(C=O)C>[C:38]([NH:45][C@H:46]([C:51]([O:1][CH2:2][CH2:3][C@@H:4]([CH2:17][O:18][C:19](=[O:37])[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][CH2:35][CH3:36])[CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:11](=[O:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]1=2)=[O:52])[C@H:47]([CH2:49][CH3:50])[CH3:48])([O:40][C:41]([CH3:43])([CH3:44])[CH3:42])=[O:39]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC[C@H](CCO)Cn1cnc2c(=O)[nH]c(N)nc21
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCC(=O)OC[C@H](CCOC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)CC)Cn1cnc2c(=O)[nH]c(N)nc21

Procedure:
(R)-9-[4-Hydroxy-2-(stearoyloxymethyl)butyl]guanine (135 mg, 0.26 mmole) and N-BOC-L-isoleucine (180 mg, 0.78 mmole) was coevaporated with dry DMF twice and dissolved in the same solvent (3.5 ml). To the solution was added 1,3-dicyclohexylcarbodiimide (160 mg, 0.78 mmole) and 4-dimethylaminopyridine (4.8 mg, 0.039 mmole). After reaction for 18 hours, the reaction mixture was filtered through Celite and worked up in a conventional manner. The product was isolated by silica gel column chromatography, eluting at 5% MeOH in CH2Cl2. (Yield 160 mg)