Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([OH:5])=O.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:5]
Reactant: C1CCNCC1
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Product: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)N1CCCCC1

Procedure:
Starting materials: 2,6,10,14,18-pentamethyl-22-oxo-2,6,10,14,18-tricosapentaenoic acid and piperidine.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[O:12][C:13]([CH2:16][NH:17][CH3:18])=[CH:14][CH:15]=1)([O-:3])=[O:2].[CH2:21]([NH2:24])[C:22]#[CH:23]>C(#N)C>[N+:1]([CH:4]=[C:5]([NH:24][CH2:21][C:22]#[CH:23])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[O:12][C:13]([CH2:16][NH:17][CH3:18])=[CH:14][CH:15]=1)([O-:3])=[O:2]
Reactant: C#CCN
Reactant: CNCc1ccc(CSCCNC(=C[N+](=O)[O-])SC)o1
Solvent: CC#N
Product: C#CCNC(=C[N+](=O)[O-])NCCSCc1ccc(CNC)o1

Procedure:
A mixture of 1-nitro-2-methylthio-2-{2-[(5-methylaminomethyl-2-furyl)methylthio]ethylamino}ethylene [prepared according to the procedure described in Belgian Pat. No. 857,388] and propargylamine in acetonitrile is stirred and heated under a positive pressure of nitrogen to give, after workup and chromatography, the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][C:12]=2[O:13][C:14]2[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>C(OCC)(=O)C>[C:1]1([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][C:12]=2[O:13][C:14]2[CH:15]=[CH:16][C:17]([NH:18][C:29]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=3)=[O:30])=[CH:19][CH:20]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccncc2-c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(Oc2ccncc2-c2ccccc2)cc1
Reaction time: 0.67 h

Procedure:
Ethyl acetate (10 ml) was added to 4-(3-phenylpyridin-4-yl)oxyaniline (84 mg, 0.32 mM), and then parafluorophenyl isocyanate (0.54 ml, 4.7 mM) was added while stirring, which was continued for 40 minutes. After adding NH type silica gel to the reaction solution, the solvent was distilled off under reduced pressure to adsorb the reaction product onto the silica gel. The silica gel was charged into a dry column packed with NH type silica gel, for column purification (chloroform:methanol=10:1). After adding ethyl acetate and n-hexane to the obtained residue, the solvent was distilled off under reduced pressure to obtain the target compound (82 mg) as a light yellow amorphous substance.
Reaction SMILES: [CH2:1]([S:3]([CH2:5][CH3:6])=O)[CH3:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl:20][C:21]1[C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=[C:23]([C:30]2[C:34]([C:35]([F:38])([F:37])[F:36])=[N:33][N:32]([C:39]3[N:44]=[CH:43][CH:42]=[CH:41][N:40]=3)[C:31]=2[NH2:45])[CH:22]=1>ClCCl.N>[Cl:20][C:21]1[C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=[C:23]([C:30]2[C:34]([C:35]([F:37])([F:38])[F:36])=[N:33][N:32]([C:39]3[N:44]=[CH:43][CH:42]=[CH:41][N:40]=3)[C:31]=2[N:45]=[S:3]([CH2:5][CH3:6])[CH2:1][CH3:2])[CH:22]=1
Reactant: Nc1c(-c2cc(Cl)c3c(c2)OCO3)c(C(F)(F)F)nn1-c1ncccn1
Reactant: CCS(=O)CC
Agent: N
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCS(CC)=Nc1c(-c2cc(Cl)c3c(c2)OCO3)c(C(F)(F)F)nn1-c1ncccn1
Reaction time: 0.33 h
Yield: 28.6 %

Procedure:
To a solution of diethyl sulfoxide (0.47 g, 4.4 mmo) in dichloromethane at −60° C. under argon was added drop-wise trifluoroacetic anhydride (0.93 g, 4.4 mmol). The solution was stirred for 20 min at this temperature. Then the 4-(7-chloro-1,3-benzodioxol-5-yl)-2-pyrimidin-2-yl-5-(trifluoromethyl)pyrazol-3-amine (0.76 g, 2 mmol) was added and the solution stirred at −60 C for 1 h. The reaction was diluted with aqueous ammonia; the organic layer was separated and further washed with water and then dried and concentrated. The residue was re-crystallized with a mixture of ethyl acetate and petrole ether to give the title compound (270 mg; 29%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][N:5]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:4][C@H:3]1[OH:13].C(=O)([O-])[O-].[K+].[K+].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH:7]1([N:5]2[CH2:4][C@@H:3]([OH:13])[C@H:2]([NH:1][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:6]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C(Cl)c1ccccc1
Reactant: N[C@@H]1CN(C2CCCCC2)C[C@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(N[C@@H]1CN(C2CCCCC2)C[C@H]1O)c1ccccc1

Procedure:
This compound was prepared in a manner analagous to Example 2, using 8.1 g of trans-4-amino-1-cyclohexyl-3-pyrrolidinol, 10 g of potassium carbonate and 6.2 g of benzoyl chloride. After filtration and solvent evaporation, the residue crystallized and was recrystallized from acetone. Yield was 5.8 g (45%), m.p. 154.0°-155.5° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([O:10]C2C=CC([N+]([O-])=O)=CC=2)=O)[CH:2]=1.[F:20][C:21]([F:35])([F:34])[C:22]1[CH:23]=[C:24]([C:28]2[CH2:29][CH2:30][NH:31][CH2:32][CH:33]=2)[CH:25]=[CH:26][CH:27]=1>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([N:31]2[CH2:30][CH:29]=[C:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:20])([F:34])[F:35])[CH:23]=3)[CH2:33][CH2:32]2)=[O:10])[CH:2]=1
Reactant: FC(F)(F)c1cccc(C2=CCNCC2)c1
Reactant: O=C(Cc1cccnc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: O=C(Cc1cccnc1)N1CC=C(c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.8 %

Procedure:
A suspension of 11.3 g of p-nitrophenyl 3-pyridylacetate and 10 g of 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine in 150 ml of ethanol is stirred 1 hour at room temperature, then concentrated under reduced pressure. The residue is dissolved in diethyl ether, the solution is washed with water, then with sodium hydroxide and again with water, dried on anhydrous sodium sulfate and concentrated. Thus, 1-(3-pyridylacetyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine (8 g) is obtained as an oil which is used for the subsequent reaction.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[N:11]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:17]N1C(=O)CCC1=O>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[N:11]=2)=[O:9])=[CH:6][C:5]([Br:17])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ncccc1C(=O)c1cccc(Br)n1
Product: Nc1ncc(Br)cc1C(=O)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.2 %

Procedure:
To a suspension of (2-aminopyridin-3-yl)(6-bromopyridin-2-yl)methanone (5.76 g, 20.7 mmol) in acetonirile (120 ml) was added N-bromosuccinimide (4.05 g, 22.77 mmol). The resulting mixture was stirred at room temperature for 1 hour before mixture was concentrated in vacuo to approximately 20 ml. The solid was then collected by filtration and washed with minimal acetonitrile and dried to leave title compound as a brown solid (4.23 g, 57%). 1H NMR (DMSO-d6) 7.93-7.89 (4H, m), 8.03-7.99 (1H, m), 8.22 (1H, d), 8.36 (1H, d). ES+ 357.99.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1.[CH2:20]([NH2:22])[CH3:21]>C(#N)C>[F:17][C:16]([F:19])([F:18])[S:13]([C:10]1[CH:11]=[CH:12][C:6]2[CH2:5][O:4][CH:3]([CH2:2][NH:22][CH2:20][CH3:21])[O:8][C:7]=2[CH:9]=1)(=[O:15])=[O:14]
Reactant: O=S(=O)(c1ccc2c(c1)OC(CBr)OC2)C(F)(F)F
Reactant: CCN
Solvent: CC#N
Product: CCNCC1OCc2ccc(S(=O)(=O)C(F)(F)F)cc2O1
Yield: 56.6 %

Procedure:
Preparation according to Example 9. 2-(bromomethyl)-7-[(trifluoromethyl)sulfonyl]-4H-1,3-benzodioxine (0.28 g, 0.76 mmol), ethanamine (70% in water, 2.0 ml, 25.2 mmol) and ACN (2.0 ml) was heated at 120° C. for 20 min. Purification by flash chromatography using EtOAc/MeOH (4:1) as eluent afforded the title compound (0.14 g, 52%). The amine was converted into hydrochloric acid salt and crystallized from EtOH/DEE. M.p. 169° C. MS m/z (rel. intensity, 70 eV) 325 (M+, 1), 239 (5), 106 (5), 77 (7), 58 (bp).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:5]([OH:8])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:33][CH2:34][CH:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:10])[F:11])[C:5]([O:8][CH2:33][CH2:34][CH:35]2[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:42])[CH2:39][CH2:40]2)=[N:6][CH:7]=1
Reactant: Oc1ncc(Br)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ncc(Br)cc2C(F)(F)F)CC1
Temperature: 20 °C
Reaction time: 18 h
Yield: 69.6 %

Procedure:
To a suspension of 5-bromo-2-hydroxy-3-(trifluoromethyl)pyridine (6.90 g) in 1,4-dioxane (100 ml), triphenylphosphine (9.44 g) and tert-butyl 4-(2-hydroxyethyl)-piperidine-1-carboxylate (7.41 g) were added. Then diisopropyl azodicarboxylate (DIAD, 7.52 ml, 7.67 g) was added dropwise and stirred at 20° C. for 18 h. Solvent was then removed under reduced pressure and residue purified by Biotage SNAP cartridge KP-Sil column (340 g, hepane:ethyl acetate=1:0, 5:1 to 4:1) to give 9.0 g orange oil as tert-butyl 4-(2-(5-bromo-3-(trifluoromethyl)pyridin-2-yloxy)ethyl)-piperidine-1-carboxylate (70%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]2[N:13]=[CH:14][CH:15]=[C:11]2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1.[OH-:16].[Na+]>O1CCOCC1>[CH:15]1[CH:14]=[N:13][N:12]2[C:11]=1[C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:4][C:2](=[O:16])[CH2:3]2
Reactant: ClCc1nc2ccccc2c2ccnn12
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C1Cn2nccc2-c2ccccc2N1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
3.1. A solution of 11.4 g of 5-(chloromethyl)pyrazolo[1,5-c]quinazoline in 160 ml of dioxan is added dropwise within 15 min. to a mixture of 130 ml of 1N aqueous sodium hydroxide solution and 130 ml of dioxan cooled to 0° to 5° C. The cooling is removed and the mixture is stirred at room temperature for 2.5 h. Then, the reaction mixture is poured into 600 ml of saturated aqueous sodium chloride solution and extracted four times with dichloromethane. The dichloromethane extracts are evaporated in a vacuum. The residue (5.4 g) is crystallized from dichloromethane/diethyl ether. There are obtained 4.15 g of 5H-pyrazolo[1,5-d][1,4]benzodiazepin-6(7H)-one of m.p. 236°-240° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:32]([C:43]1[CH:44]=[N:45][C:46]([C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=2)=[N:47][CH:48]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].[CH2:56]([CH:58]1[CH2:62][CH2:61][C:60]([CH2:63]O)=[CH:59]1)[CH3:57]>C1COCC1>[CH2:32]([C:43]1[CH:44]=[N:45][C:46]([C:49]2[CH:50]=[CH:51][C:52]([O:55][CH2:63][C:60]3[CH2:61][CH2:62][CH:58]([CH2:56][CH3:57])[CH:59]=3)=[CH:53][CH:54]=2)=[N:47][CH:48]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCC1C=C(CO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCc1cnc(-c2ccc(OCC3=CC(CC)CC3)cc2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A fully reacted mixture of equimolar amounts of diethyl azodicarboxylate and triphenylphosphine in THF is admixed with equimolar amounts of 4-(5-undecylpyrimidin-2-yl)phenol and 3-ethyl-1-cyclopenten-1-yl-methanol (prepared by LiAlH4 reduction of methyl 3-ethyl-1-cyclopentene-1-carboxylate as described by Takeda, Bull.Chem.Soc.Jpn. 50 (7), 1831 (1977)). The mixture is stirred for 24 h at room temperature and then evaporated to dryness under reduced pressure. Purification by chromatography (silica gel, dichloromethane) and recrystallization affords the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[NH2:12][C:13]1[CH:14]=[C:15]([N:19]2[CH2:23][CH2:22][CH2:21][C:20]2=[O:24])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCCl.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:12][C:13]2[CH:14]=[C:15]([N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])[CH:16]=[CH:17][CH:18]=2)=[N:6][CH:7]=1
Reactant: Nc1cccc(N2CCCC2=O)c1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C1CCCN1c1cccc(Nc2ncc(Br)cc2[N+](=O)[O-])c1
Yield: 65.4 %

Procedure:
A suspension of 5-bromo-2-chloro-3-nitropyridine (3.79 g, 16 mmol), 1-(3-aminophenyl)pyrrolidin-2-one (2.56 g, 15 mmol) and potassium carbonate (2.0 g, 15 mmol) in 1,2-dichloroethane (25 ml) was heated at reflux for 60 hours. The reaction was cooled, diluted with dichloromethane (200 ml) and extracted with water. The organic phase was then dried over anhydrous sodium sulphate, filtered and pre-adsorbed on to silica (25 g). Purification by column chromatography eluting with isohexane on a gradient of ethyl acetate (10%-40%) gave 1-[3-(5-bromo-3-nitropyridin-2-ylamino)phenyl]pyrrolidin-2-one as a red solid (3.7 g, 68%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:21][C:22]1[S:30][C:29]2[C:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[N:27][C:26]([Cl:37])=[N:25][C:24]=2[CH:23]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:21][C:22]2[S:30][C:29]3[C:28]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[N:27][C:26]([Cl:37])=[N:25][C:24]=3[CH:23]=2)[S:14]([CH3:17])(=[O:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Reactant: CC(C)(C)OC(=O)N1CCC(NS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)S(C)(=O)=O)C1
Reaction time: 0.67 h
Yield: 48.4 %

Procedure:
To a solution of 3-Methanesulfonylamino-pyrrolidine-1-carboxylic acid tert-butyl ester (0.47 g) in DMF (5 mL) was added NaH (63 mg). The mixture was stirred for 40 min. then a solution of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (0.52 g) in DMF (5 mL) was added via cannular. The resulting mixture was stirred at R.T. for 5 h. An aqueous work-up followed by purification on silica gave 3-[(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methanesulfonyl-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester (384 mg).
Reaction SMILES: CS[C:3]1[NH:4][CH:5]=[C:6]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)[C:7](=[O:9])[N:8]=1.[CH3:17][NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[CH:23][CH:22]=1>C(O)C>[CH3:17][N:18]([CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:37])[F:36])[CH:29]=2)=[CH:25][CH:26]=1)[C:3]1[NH:4][CH:5]=[C:6]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)[C:7](=[O:9])[N:8]=1
Reactant: CSc1nc(=O)c(Cc2cncnc2)c[nH]1
Reactant: CNCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Solvent: CCO
Product: CN(CCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1)c1nc(=O)c(Cc2cncnc2)c[nH]1
Temperature: 125 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
2-Methylsulfanyl-5-pyrimidin-5-ylmethyl-1H-pyrimidin-4-one (30 mg, 0.128 mmol, 1 eq) and methyl-{2-[4-(3-trifluoromethyl-phenoxy)-phenyl]-ethyl}-amine (56.7 mg, 0.192 mmol, 1.5 eq) were dissolved in dry ethanol (300 μl) and stirred at 125° C. for overnight. Reaction mixture was evaporated and crude residue was sent to HPLC/MS Purification. After HPLC/MS purification combined fractions of desired product were collected and put on lyophilisation to obtain 2-(methyl-{2-[4-(3-trifluoromethyl-phenoxy)-phenyl]-ethyl}-amino)-5-pyrimidin-5-ylmethyl-1H-pyrimidin-4-one (0.069 mmol; yield: 54%, HPLC-MS/UV: [M+H]=482.48; rt: 11.27 min; purity: 96%). 1H NMR (300 MHz; DMSO-d6) δ/ppm 2.80 (t, J=6.68 Hz, 2H), 2.94 (s, 3H), 3.52 (s, 2H), 3.69 (t, J=7.09 Hz, 2H), 7.00 (d, J=8.76 Hz, 2H), 7.19 (d, J=8.10 Hz, 1H), 7.24 (s, 1H), 7.30 (d, J=8.45 Hz, 2H), 7.44 (d, J=7.75 Hz, 1H), 7.58 (t, J=8.10 Hz, 1H), 7.66 (s, 1H), 8.66 (s, 2H), 8.95 (s, 1H)
Reaction SMILES: C([O:4][CH2:5][C:6](=[O:28])[C@:7]1([OH:27])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C:21](=[CH:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)(=O)C.CO>C(Cl)Cl>[OH:27][C@:7]1([C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C:21](=[CH:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)[C:6](=[O:28])[CH2:5][OH:4]
Reactant: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Solvent: ClCCl
Solvent: CO
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Temperature: 0 °C
Yield: 89.8 %

Procedure:
At room temperature, 1.5 g of 21-acetoxy-17-hydroxy-4,9(11)-pregnadiene-3,20-dione in 40 ml is agitated for 2 hours at room temperature with 15 ml of methanol 0.2N methanolic potassium hydroxide solution. The reaction mixture is introduced into ice water. The precipitated product is suctioned off, dissolved in methylene chloride, washed with water, and dried over sodium sulfate, thus obtaining 1.2 g of 17,21-dihydroxy-4,9(11) pregnadiene3,20-dione; mp 248.2° C.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.CI.[C:12](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[C:3](=[O:9])[N:4]([CH3:12])[C:5](=[O:8])[NH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: Cn1c(=O)[nH]cc(F)c1=O
Reaction time: 24 h

Procedure:
5-Fluorouracil, namely Compound (5) (1.30 g; 10 mmol), methyl iodide (CH3I) (2.13 g; 15 mmol) and potassium carbonate (0.69 g; 5 mmol) were added to acetone (20 ml), and the resulting mixture was stirred at 60°-70° C. for 24 hours. The reaction solution obtained was filtered to remove potassium carbonate, and the filtrate was concentrated under reduced pressure. To the resulting residue was added a small volume of chloroform, and then the residue was fractionated by column chromatography on silica gel (eluent: chloroform) to isolate 5-fluoro-3-methyluracil, namely Compound (6) shown above (355 mg) as white needle-like crystals.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:39]=[C:40]([C:42]([O:44][CH3:45])=[O:43])[CH:41]=1)[CH2:8][C:9]([CH2:16][CH2:17][CH2:18][S:19][C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(C(O)=O)[C:10]([OH:12])=[O:11])([CH3:4])([CH3:3])[CH3:2]>CS(C)=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:39]=[C:40]([C:42]([O:44][CH3:45])=[O:43])[CH:41]=1)[CH2:8][CH:9]([CH2:16][CH2:17][CH2:18][S:19][C:20]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]([OH:12])=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(CC(CCCSC(c2ccccc2)(c2ccccc2)c2ccccc2)(C(=O)O)C(=O)O)cc(C(C)(C)C)c1
Solvent: CS(C)=O
Product: COC(=O)c1cc(CC(CCCSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O)cc(C(C)(C)C)c1
Yield: 93.6 %

Procedure:
A solution of 2-(3-tert-butyl-5-methoxycarbonyl-benzyl)-2-[3-[(triphenylmethyl)thio]propyl]-malonic acid XI (6.71 g, 11 mmol) in DMSO (10 ml) was stirred at 130° C. for 1.5 hours. The solvent was removed under reduced pressure and water was added to the residual oil. The precipitate was filtered off, washed with water, and dried under vacuum to afford 2-(3-tert-butyl-5-methoxycarbonyl-benzyl)-5-[(triphenylmethyl)thio]-pentanoic acid XII (5.86 g, 10.3 mmol, 94%) as a white solid: 1H NMR (CD3OD) δ 1.3 (s, 9H), 1.3-1.5 (m, 4H), 2.1 (m, 2H), 2.4 (m, 1H), 2.7 (m, 1H), 2.8 (m, 1H), 7.1-7.4 (m, 16H), 7.7 (s, 1H), 7.9 (s, 1H); 13C NMR (CD3OD) 627.4, 31.7 (3C), 32.3, 32.7, 35.6, 39.2, 48.4, 67.7, 125.7, 127.7, 128.6, 128.9, 130.8, 131.6, .132.0, 140.8, 146.3, 152.7, 170.3, 178.8.
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][NH:10][C:11](=[O:23])[C:12]1[C:17]([O:18]C)=[CH:16][CH:15]=[C:14]([Br:20])[C:13]=1[O:21][CH3:22])[CH2:2][CH3:3].[ClH:24].CC(C)=O>CO>[ClH:24].[CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][NH:10][C:11](=[O:23])[C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]([Br:20])[C:13]=1[O:21][CH3:22])[CH2:2][CH3:3]
Reactant: CCCN1CCCC1CNC(=O)c1c(OC)ccc(Br)c1OC
Agent: Cl
Solvent: CC(C)=O
Solvent: CO
Product: CCCN1CCCC1CNC(=O)c1c(O)ccc(Br)c1OC
Yield: 55 %

Procedure:
The title compound was prepared from (-)-N-n-propyl-2-(3-bromo-2,6-dimethoxybenzamidomethyl)pyrrolidine by dealkylation in the same manner as described in Example 2. Yield 55%. M.p. (HCl) 137°-138° C. (acetone). [α]D25 =-68° C. (c=0.12; MeOH).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(C(C)C)C(C)C)C.C1(C)C=CC(S(O[CH2:31][CH2:32][CH:33]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[O:35][CH2:34]2)(=O)=O)=CC=1>CN(C)C=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:31][CH2:32][CH:33]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[O:35][CH2:34]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCCC2COc3ccccc3C2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(CCC2COc3ccccc3C2)CC1
Reaction time: 16 h
Yield: 97.1 %

Procedure:
First 3.76 g (24 mmol) of piperidine-4-carboxylic acid ethyl ester and then 3.1 g (24 mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of 3.98 g (12 mmol) of 3-[2-(p-toluenesulphonyloxy)ethyl]chroman in 50 ml of absolute dimethylformamide. The mixture is stirred for 16 hours at 60° and, after cooling, is concentrated by evaporation under a high vacuum. Water is added to the oily residue and extraction by shaking is carried out with diethyl ether. The combined organic phases are extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 3.8 g (100%) of crude product are obtained which are chromatographed on 200 g of silica gel (0.040-0.063 mm) using ethyl acetate as the eluant. 3.7 g (97.3%) of 1-[2-(chroman-3-yl)ethyl]-piperidine-4-carboxylic acid ethyl ester are then obtained in the form of a colourless oil. The 1-[2-chroman-3-yl)ethyl]-piperidine-4-carboxylic acid ethyl ester hydrochloride produced thereform using hydrochloric acid in diethyl ether crystallises from ethanol/diethyl ether and melts at 182°-186°.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:21](=[O:44])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[C:34]([CH2:35][O:36]C3CCCCO3)=[CH:33][N:32]=[N:31]2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]2[N:7]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N:30]4[C:34]([CH2:35][OH:36])=[CH:33][N:32]=[N:31]4)[CH:25]=3)[CH2:22][C:21](=[O:44])[NH:20][C:9]=2[CH:10]=1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-(methyl-propyl-amino)-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert-butyl ester (Example M27) (0.4 g, 0.64 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a pale yellow solid (110 mg).