Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][NH2:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:13]([O:17][C:18]([NH:20][C@H:21]([CH2:25][CH2:26][S:27][CH3:28])[C:22](O)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:13]([O:17][C:18](=[O:19])[NH:20][C@H:21]([CH2:25][CH2:26][S:27][CH3:28])[C:22]([NH:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:23])([CH3:16])([CH3:15])[CH3:14]
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1ccc(CN)cc1OC
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CNC(=O)[C@@H](CCSC)NC(=O)OC(C)(C)C)cc1OC
Temperature: 25 °C

Procedure:
To a 0° C. solution of (3,4-dimethoxyphenyl)methanamine (2 g, 12 mmol) in DCM (20 mL) was added sequentially (R)-2-((tert-butoxycarbonyl)amino)-4-(methylthio)butanoic acid (3.28 g, 13.2 mmol), PyBOP (6.85 g, 13.2 mmol) and DIPEA (4.18 mL, 23.92 mmol). The reaction mixture was stirred and allowed to warm up to ambient temperature over 2 h. The reaction was then quenched by the addition of water and the mixture was extracted twice with 100 mL DCM. The organic fraction was washed with 50 mL water, 50 mL brine, and the layers were separated. The organic fraction was dried over sodium sulfate, filtered, and evaporated. The residue was purified via silica gel chromatography, eluting with 30% ethyl acetate/petroleum ether. Yield 3.5 gms (R)-tert-butyl(1-((3,4-dimethoxybenzyl)amino)-4-(methylthio)-1-oxobutan-2-yl)carbamate. LCMS (Method F) RT 2.3 min, m/z 399.2 (MH+); 1H NMR (400 MHz, chloroform-d) δ 1.41 (s, 9H), 1.91-1.98 (m, 1H), 2.07 (s, 3H), 2.10-2.14 (m, 1H), 2.47-2.61 (m, 2H), 3.65 (s, 6H), 4.25-4.27 (br s, 1H), 4.33-4.42 (m, 2H), 5.16 (br s, 1H), 6.47 (br s, 1H), 6.80 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]=[C:17]([CH2:19][O:20]S(C)(=O)=O)[O:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)(=[O:28])=[O:27].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[N:18]=[C:17]([CH2:19][O:20][C:32]3[CH:33]=[CH:34][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:30][CH:31]=3)[O:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2noc(COS(C)(=O)=O)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2noc(COc3ccc(S(C)(=O)=O)cc3)n2)CC1
Temperature: 50 °C

Procedure:
A mixture of 4-(5-methanesulfonyloxymethyl-[1,2,4]oxadiazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.12 g, 0.33 mmol), 4-methanesulfonyl-phenol (86 mg, 0.5 mmol) and Cs2CO3 (0.33 g, 1 mmol) in acetonitrile (5 mL) was heated at 50° C. for 2 hours. After cooling, the solid was filtered through a pad of celite. The filtrate was concentrated in vacuo. The residue was purified on silica gel (EtOAc-hexanes, 1:1) to afford the desired product. 1H NMR (CDCl3): δ 7.9 (2H, d, J=8.8 Hz), 7.12 (2H, d, J=8.8 Hz), 5.24 (2H, s), 4.2˜4.05 (2H, m), 3.03 (3H, s), 3.04˜2.85 (3H, m), 2.05˜1.96 (2H, m), 1.8˜1.7 (2H, m), 1.45 (9H, s).
Reaction SMILES: [OH-].[Na+].C(O)CO.N1(C([N:14]2[CH2:19][CH2:18][CH:17]([O:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([N:27]4[C:35]5[C:30](=[CH:31][C:32]([S:36]([CH2:39][CH2:40][CH3:41])(=[O:38])=[O:37])=[CH:33][CH:34]=5)[CH2:29][CH2:28]4)[CH:22]=3)[CH2:16][CH2:15]2)=O)C=CN=C1>O>[NH:14]1[CH2:15][CH2:16][CH:17]([O:20][C:21]2[N:26]=[CH:25][N:24]=[C:23]([N:27]3[C:35]4[C:30](=[CH:31][C:32]([S:36]([CH2:39][CH2:40][CH3:41])(=[O:38])=[O:37])=[CH:33][CH:34]=4)[CH2:29][CH2:28]3)[CH:22]=2)[CH2:18][CH2:19]1
Reactant: CCCS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCN(C(=O)n3ccnc3)CC2)ncn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: CCCS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCNCC2)ncn1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 72.5 %

Procedure:
A 2 N aqueous sodium hydroxide solution (363 mL, 0.726 mmol) was added to an ethylene glycol (3.6 mL) solution of the 1-(6-{[1-(1H-imidazol-1-ylcarbonyl)piperidin-4-yl]oxy}pyrimidin-4-yl)-5-(propylsulfonyl)indoline (180 mg, 0.363 mmol) produced in Reference Example 33, and the mixture was stirred at 100° C. for 2.5 hours. To the reaction solution, water was added, followed by extraction with ethyl acetate three times. The obtained organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound as white powder (106 mg, yield: 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](Cl)=[N:7][OH:8])=[CH:4][N:3]=1.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])#[CH:13].N>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[O:8][N:7]=2)=[CH:10][CH:11]=1
Reactant: C#Cc1ccc(F)cc1F
Reactant: ON=C(Cl)c1ccc(Cl)nc1
Agent: N
Product: Fc1ccc(-c2cc(-c3ccc(Cl)nc3)no2)c(F)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 95B (79 mg, 0.5 mmol) and 1-ethynyl-2,4-difluorobenzene (Aldrich, 68 mg, 0.5 mmol). 1H NMR (300 MHz, CDCl3) δ 6.93-7.14 (m, 3H), 7.47 (d, J=7.5 Hz, 1H), 8.02 (td, J=8.6, 6.3 Hz, 1H), 8.18 (dd, J=8.1, 2.7 Hz, 1H), 8.86 (dd, J=2.5, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 293 (M+H)+, 295 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[N:22]=[CH:23][S:24][CH:25]=2)=[N:10]1.C1C(=O)N([Br:33])C(=O)C1>>[Br:33][CH2:20][C:13]1[NH:12][C:11]([C:21]2[N:22]=[CH:23][S:24][CH:25]=2)=[N:10][CH:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(C)NC(c2cscn2)=NC1c1ccc(Cl)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)C1=C(CBr)NC(c2cscn2)=NC1c1ccc(Cl)cc1Cl
Yield: 57 %

Procedure:
Ethyl 4-(2,4-dichlorophenyl)-6-methyl-2-(thiazol-4-yl)-1,4-dihydropyrimidine-5-carboxylate (5.31 g, 13.4 mmol) (The compound was synthesized according to the procedure as described in CN200610098646.3) was reacted with NBS (2.87 g, 16.1 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (3.63 g, 57%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [OH:1][CH:2]1[CH:10]([N+:11]([O-])=O)[C:9]2[CH2:8][C:7](=[O:14])[CH:6]=[CH:5][C:4]=2[CH2:3]1.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:11][CH:10]1[C:9]2[CH2:8][C:7](=[O:14])[CH:6]=[CH:5][C:4]=2[CH2:3][CH:2]1[OH:1]
Reactant: O=C1C=CC2=C(C1)C([N+](=O)[O-])C(O)C2
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC1C2=C(C=CC(=O)C2)CC1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 0 %

Procedure:
A mixture of 2-hydroxy-3-nitro-5-indanone (1.50 g, 7.80 mmol) and tin (II) chloride (5.25 g, 23.3 mmol) in ethanol (150 mL) was heated at 80° C. under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2CH2) gave the desired product (0.00 g, 79%). 1H NMR (CD3OD): d 6.85 (d, 1H), 6.45 (d, 1H), 2.95 (d, 2H), 2.60 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[O:3]1.CN(C)CCN(C)C.[Li]CCCC.[CH2:25]([N:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CCCCCCC.CCCCCC>[CH2:25]([N:32]1[CH2:37][CH2:36][C:35]([C:10]2[C:4]3[O:3][C:2]([CH3:11])([CH3:1])[CH2:6][C:5]=3[CH:7]=[CH:8][CH:9]=2)([OH:38])[CH2:34][CH2:33]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CC1(C)Cc2ccccc2O1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCCCCCC
Product: CC1(C)Cc2cccc(C3(O)CCN(Cc4ccccc4)CC3)c2O1
Temperature: -40 °C
Reaction time: 1.5 h
Yield: 19.3 %

Procedure:
A mixture of 2,3-dihydro-2,2-dimethylbenzofuran (25 g) and tetramethylethylenediamine (46 g) in heptane (250 ml) was treated dropwise at room temperature with 1.6M BuLi in hexane (250 ml). After stirring for 1.5 h at 30°-40° C. the mixture was cooled to -40° C. and 1-benzyl-4-piperidinone (32 g) was added dropwise at -40° C. The reaction mixture was allowed to warm to room temperature during 3 h followed by quench with water. After concentrating the reaction mixture in vacuo dichloromethane (500 ml) was added followed by wash with water (3×500 ml). Removal of solvent in vacuo gave an oil which was purified by flash chromatography (silica gel, heptane/ethyl acetate/triethylamine 50:48:2) giving an oil. Addition of heptane gave the product, 7-(1-benzyl-4-hydroxy-4-piperidinyl)-2,3-dihydro-2,2-dimethylbenzofuran as a solid (11 g).
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:10](=[C:15]([Cl:20])[C:16]([F:19])([F:18])[F:17])[C:11]([F:14])([F:13])[F:12]>>[Cl:20][CH:15]([C:10]1([C:11]([F:12])([F:13])[F:14])[O:1][C:2]2=[N:3][CH:4]=[CH:5][CH:6]=[C:7]2[O:8]1)[C:16]([F:19])([F:18])[F:17]
Reactant: Oc1cccnc1O
Reactant: FC(F)(F)C(Cl)=C(Cl)C(F)(F)F
Product: FC(F)(F)C(Cl)C1(C(F)(F)F)Oc2cccnc2O1

Procedure:
11 g of 2,3-dihydroxypyridine were reacted with 23.5 g of 2,3-dichloro-1,1,1,4,4,4-hexafluoro-2-butene as described in Example 2. After distillation under a high vacuum, the product was obtained in the form of colourless crystals in an amount of 15.5 g (=50% of theory). The NMR spectra showed the following characteristic absorptions: 19F-NMR: -68.5 and -81.6 ppm. 1H-NMR 4.81 ppm.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][NH:6][C:7]([C:9]1[N:13]2[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:12]2=[N:11][C:10]=1[CH3:19])=[O:8])=[O:4].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:19][C:10]1[N:11]=[C:12]2[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]2[C:9]=1[C:7]1[O:8][CH2:2][C:3](=[O:4])[NH:5][N:6]=1
Reactant: Cc1nc2c(C)cccn2c1C(=O)NNC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2c(C)cccn2c1C1=NNC(=O)CO1
Yield: 38.3 %

Procedure:
A mixture of 6 g of N'-chloroacetyl-2,8-dimethylimidazo[1,2-a]pyridine-3-carbohydrazide and 10 g of potassium carbonate in 50 ml of dimethylformamide is stirred under heating at 70°-90° C. for 1.5 hours. After the reaction mixture is allowed to cool, insoluble substances are collected by filtration, washed with water and recrystallized from a mixted solvent of chloroform and methanol to give 2.0 g of 2-(2,8-dimethylimidazo[1,2-a]pyridin-3-yl)-4,6-dihydro-1,3,4-oxadiazin-5-one as white crystals, melting at 310°-313° C. with decomposition.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.[CH3:11][C:12]([CH3:14])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:12]([CH3:14])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: CC(C)Nc1ccc(F)cc1
Yield: 90 %

Procedure:
A process according to claim 1, wherein the N-alkyl-arylamine (I) is of the formula ##STR31## 4-fluoro-nitrobenzene is employed as the nitroarene and acetone as the carbonyl compound, the reaction mixture consisting of the stated catalyst and the reactants, wherein the acetone is employed in excess and constitutes the sole diluent for the reaction, the 4-fluoro-N-isopropyl-aniline of the above formula (3) being produced in a yield of at least 90% of theory.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Mg]Cl.C1COCC1.[Cl-].[NH4+]>C(OCC)C>[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([OH:4])[CH2:2][CH3:3]
Reactant: Cc1ccccc1[Mg]Cl
Reactant: CCC(=O)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(O)(c1ccccc1)c1ccccc1C
Yield: 92 %

Procedure:
Propiophenone (6.7 g, 50 mmol) was added dropwise to a solution of 2-methylphenylmagnesium chloride (30 ml of a 2.0 M solution in diethyl ether) and dry THF (50 ml) under a nitrogen atmosphere. When the addition was complete the reaction mixture was heated at reflux temperature for 5 h. Excess of a saturated ammonium chloride solution was added and the mixture was extracted with diethyl ether (2×100 ml). The combined organic extracts were dried over potassium carbonate and the solvent was evaporated in vacuo to give 10.4 g (92%) of 1-(2-methyl phenyl)-1-phenyl-1- propanol. TLC: rf=0.50 (SiO2 ; n-heptane/THF=7:3).
Reaction SMILES: [NH2:1][C:2]1[C:6]([Br:7])=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:4][C:3]=1[C:14]([O:16]C)=O.[Cl:18][CH2:19][C:20]#[N:21]>Cl.O1CCOCC1>[Br:7][C:6]1[C:2]2[N:1]=[C:20]([CH2:19][Cl:18])[NH:21][C:14](=[O:16])[C:3]=2[S:4][C:5]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1sc(-c2ccccc2)c(Br)c1N
Reactant: N#CCCl
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]c(CCl)nc2c(Br)c(-c3ccccc3)sc12
Temperature: 110 °C
Yield: 58.6 %

Procedure:
A mixture of EXAMPLE 8A (1.47 g, 4.7 mmol), chloroacetonitrile (0.43 g, 5.7 mmol) in 4N hydrochloric acid in dioxane (10 mL) was stirred overnight at ambient temperature. The solvent was removed and the residue heated in N,N-dimethylformamide (15 mL) at 110° C. for 2 hours. After cooling, the mixture was partitioned between ethyl acetate and water and the aqueous layer extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was triturated with 1:1 ethyl acetate/hexanes to give 0.98 g (59%) of the title compound. 1H NMR (DMSO-d6) δ 13.13 (s, 1H), 7.75-7.78 (m, 2H), 7.56-7.60 (m, 3H), 4.64 (s, 2H).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6].[CH:10]1(CO)[CH2:12][CH2:11]1>>[C:1]([O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1)(=[O:7])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6]
Reactant: CCC/C=C/C(=O)OC
Reactant: OCC1CC1
Product: CCC/C=C/C(=O)OCC1CC1

Procedure:
Prepared from (E)-methyl hex-2-enoate and cyclopropanemethanol according to the ester preparation method B described above.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][N:13]=2)[CH2:8]1.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26]>ClCCl.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:2][C:3]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])=[CH:14][N:13]=2)[CH2:8]1
Reactant: C#C[Si](C)(C)C
Reactant: Clc1ccc(CN[C@H]2CCN(c3ccc(I)cn3)C2)c(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)C#Cc1ccc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
Dissolve (S)-(2,4-dichlorobenzyl)-[1-(5-iodopyridin-2-yl)-pyrrolidin-3-yl]-amine hydrochloride (250 mg, 0.52 mmol) in dichloromethane (15 mL) and triethylamine (10 mL). Add trans-dichlorobis(triphenylphosphine)palladium (II) (24 mg, 0.034 mmol), copper (I) iodide (6 mg, 0.032 mmol) and (trimethylsilyl)acetylene (370 μL, 2.62 mmol). Stir the mixture at room temperature for 1 h, filter through a pad of Celite®, concentrate and chromatograph on silica gel, eluting with a gradient of 20:80 to 1:1 ethyl acetate:hexanes, to give (S)-(2,4-dichlorobenzyl)-[1-(5-trimethylsilanylethynyl-pyridin-2-yl)-pyrrolidin-3-yl]-amine as a yellow oil (190 mg, 88%). MS (ES): m/z=418 [M+H].
Reaction SMILES: [N:1]12[CH2:8][C:5]([C:9]([O:11]CC)=O)([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2.C[Si](C)(C)[C:16]1[S:17][CH:18]=[CH:19][N:20]=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[S:17]1[CH:18]=[CH:19][N:20]=[C:16]1[CH:9]([OH:11])[CH:5]1[CH:4]2[CH2:3][CH2:2][N:1]([CH2:7][CH2:6]2)[CH2:8]1
Reactant: C[Si](C)(C)c1nccs1
Reactant: CCOC(=O)C12CCCN(CC1)C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: OC(c1nccs1)C1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (±) 3-formyl-1-azabicyclo[2.2.2]octane (D32) (2 5g, 0.018 moles) and 2-trimethylsilyl-1,3-thiazole (2.7g, 0.017 moles) was stirred together without solvent at room temperature for 3h. The mixture was diluted with tetrahydrofuran (100ml) and then treated with tetrabutylammonium fluoride trihydrate (5.4g, 0.017 moles). After 1h the mixture was concentrated in vacuo and the residue partitioned between saturated potassium carbonate solution and chloroform. The organic layer was dried (Na2SO4) and evaporated to dryness. The residue was subjected to column chromatography on TLC alumina eluting with 0.5% methanol/chloroform. This gave an oil which was triturated with diethylether/methanol to yield the title compound (D33) as a buff solid (0.5g, 13%).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1.C(N(CC)CC)C.[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH2:27][NH:26][CH2:25][CH2:24]2>CN(C)C=O>[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH2:27][N:26]([CH2:3][C:4]1[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1)[CH2:25][CH2:24]2
Reactant: Cc1ncc(CCl)c(N)n1
Reactant: COc1ccc2c(c1)CCNC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CCN(Cc1cnc(C)nc1N)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.2 %

Procedure:
A suspension of 0.80 g (0.00412 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine hydrochloride in 17 ml of dimethylformamide was treated with 1.7 ml (0.0124 mol) of triethylamine and 0.87 g (0.0053 mol) of 6-methoxy-1,2,3,4-tetrahydro-isoquinoline and the mixture was stirred at room temperature under argon for 3 hours. The mixture was completely freed from the solvents and the residue was triturated in 20 ml of water. The resulting crystals were filtered off under suction, chromatographed over silica gel with dichloromethane/methanol 9:1 as the eluent and recrystallized from ethyl acetate/n-hexane. 0.26 g (22%) of 5-(6-methoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-2-methyl-pyrimidin-4-ylamine was obtained as white crystals; m.p. 142°-143°.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[O:12][C@:11]([CH3:19])([CH:14]([O:17][CH3:18])[O:15][CH3:16])[C@H:10]3[O:20][C@H:9]3[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH2:29][C:30]2[N:31]=[N:32][N:33]([CH3:35])[N:34]=2)=[CH:24][CH:23]=1>>[N+:1]([C:4]1[C:13]2[O:12][C@:11]([CH3:19])([CH:14]([O:17][CH3:18])[O:15][CH3:16])[C@@H:10]([OH:20])[C@H:9]([N:28]([C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=3)[CH2:29][C:30]3[N:31]=[N:32][N:33]([CH3:35])[N:34]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COC(OC)[C@@]1(C)Oc2c(cccc2[N+](=O)[O-])[C@@H]2O[C@@H]21
Reactant: Cn1nnc(CNc2ccc(Cl)cc2)n1
Product: COC(OC)[C@@]1(C)Oc2c(cccc2[N+](=O)[O-])[C@@H](N(Cc2nnn(C)n2)c2ccc(Cl)cc2)[C@@H]1O
Yield: 51.3 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using (2S,3S,4S)-8-nitro-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran (751 mg, 2.67 mmol) and N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine (597 mg, 2.67 mmol). The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=2:1), to give desired compound (691 mg, yield: 51%).
Reaction SMILES: O[N:2]1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:24][C:25]1([CH3:39])[CH2:30][C:29]([CH3:32])([CH3:31])[CH2:28][C:27]([CH2:35][C:36](O)=[O:37])([CH:33]=[CH2:34])[CH2:26]1.[NH4+].[OH-]>C1COCC1>[CH3:24][C:25]1([CH3:39])[CH2:30][C:29]([CH3:32])([CH3:31])[CH2:28][C:27]([CH2:35][C:36]([NH2:2])=[O:37])([CH:33]=[CH2:34])[CH2:26]1
Reactant: O=C1CCC(=O)N1O
Reactant: C=CC1(CC(=O)O)CC(C)(C)CC(C)(C)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CC1(CC(N)=O)CC(C)(C)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.1 %

Procedure:
N-Hydroxysuccinimide (0.25 g, 2.2 mmol) and N,N′-dicyclohexyl carbodiimide (0.45, 2.2 mmol) was added to a solution of cyclohexylacetic acid 17 (0.45 g, 2 mmol) in THF (5 ml). The mixture was stirred for 18 h at room temperature and cooled in an ice bath. 25% aqueous NH4OH (2 ml) was added in one portion and the mixture was stirred at room temperature for 2 h. The precipitate was filtered off and washed with diethyl ether (30 ml). The organic phase of filtrate was separated and washed with 5% aqueous KHSO4 (10 ml) and brine. The extract was dried over MgSO4, filtered and evaporated. The residue was purified by flash chromatography on silica gel (light petroleum ether-ethyl acetate, 4:1 to 1:1) to give 18 (0.34 g, 76%) as a colorless solid with m.p. 44-46° C. 1H-NMR (CDCl3, TMS): 0.91 (6H, s, 3,5-CH3); 1.02 (6H, s, 3,5-CH3); 1.00-1.30 (4H, m, 4-CH2 and 2,6-CH); 1.85 (2H, d, 14 Hz, 2,6-CH); 2.13 (2H, s, CH2C═O); 5.18 and 5.19 (total 2H, both d, 18 and 11 Hz, ═CH2); 5.40 and 5.60 (total 2H, both br s, NH2) and 6.03 ppm (1H, dd, 18 and 11 Hz, ═CH).
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[O:5][C:6]1[C:7]([O:16][C:17]2[CH:18]=[N:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)=[CH:8][C:9]([N+:13]([O-])=O)=[C:10]([NH2:12])[CH:11]=1)#[N:2].[H][H]>[Ni].CO>[C:1]([C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[O:5][C:6]1[CH:11]=[C:10]([NH2:12])[C:9]([NH2:13])=[CH:8][C:7]=1[O:16][C:17]1[CH:18]=[N:19][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:21][CH:22]=1)#[N:2]
Reactant: CS(=O)(=O)c1ccc(Oc2cc([N+](=O)[O-])c(N)cc2Oc2ccccc2C#N)cn1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CS(=O)(=O)c1ccc(Oc2cc(N)c(N)cc2Oc2ccccc2C#N)cn1

Procedure:
20 mg of developed Raney nickel catalyst was added to a methanol (5 ml) solution of 161 mg of 5-(2-cyano-phenoxy)-4-(6-methanesulfonyl-pyridin-3-yloxy)-2-nitro-phenylamine obtained in (step 4), and the reaction liquid was stirred overnight in a hydrogen atmosphere. The catalyst was removed through filtration, and the solvent was evaporated away under reduced pressure to obtain the entitled compound.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22](C)[C:23](=O)OC(C)(C)C)[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:23][NH:22][CH2:21][C:17]1[CH:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([CH2:8][CH:4]3[S:3][C:2](=[O:1])[NH:6][C:5]3=[O:7])=[CH:14][CH:13]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CN(Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105 %

Procedure:
18 g (42 mmol) of tert-butyl [4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]methylcarbamate in 250 ml of dichloromethane are introduced into a round-bottomed flask and under a nitrogen stream, and 16 ml (208 mmol) of trifluoroacetic acid are added. The mixture is stirred at room temperature overnight and the reaction medium is hydrolysed with a saturated potassium carbonate solution. The mixture is extracted with dichloromethane, the organic phase decanted off, washed with water, dried over magnesium sulphate and evaporated off. The residue obtained is triturated in ethyl acetate and 14.4 g (78%) of the expected product are obtained.