Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[C:14]=1[NH:22][C:23](=[O:38])[CH2:24][NH:25][CH2:26][C:27]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1)[CH3:12]>C(OCC)(=O)C>[CH3:12][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:20])[CH3:21])[C:14]=1[NH:22][C:23](=[O:38])[CH2:24][N:25]([C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[S:9])[CH2:26][C:27]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1)[CH3:10]
Reactant: S=C=Nc1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNCC1(c2ccccc2)CCCC1
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN(CC1(c2ccccc2)CCCC1)C(=S)Nc1ccccc1
Reaction time: 96 h

Procedure:
Phenylisothiocyanate (0.103 g) was added to the product of Example 6 in a few mL ethyl acetate at room temperature. This mixture was allowed to sit 4 days at room temperature, concentrated, and the resulting solid collected by filtration from a slurry in hexane. 0.31 g (84%). NMR (CDCl3) δ 1.21 (12H, d), δ 1.74-2.14 (8H, m), δ 3.08 (2H, m), δ 3.89 (2H, s), δ 4.92 (2H, bs), δ 618 (1H, s), δ 6.67 (2H, d), δ 7.06-7.51 (11H, m), δ 8.88 (1H, s). IR (KBr) 2963, 2871, 1668, 1600, 1518, 1499, 1350, 1204, 703 cm-1.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][C:17]1[N:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:20]2[CH:21]=[N:22][C:17]([CH3:16])=[CH:18][CH:19]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: Cc1ccc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)cn1

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.50 g, 2.02 mmol), 6-methylpyridin-3-ylboronic acid (0.276 g, 2.02 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 24 h to give 4-chloro-5,7-difluoro-3-methyl-2-(6-methylpyridin-3-yl)quinoline as a white solid. Mass Spectrum (ESI) m/e=305.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[CH:31]=2)[N:9]2[CH2:12][CH:11]([CH:13]([C:18]3[CH:19]=[C:20]([CH:26]=[C:27]([F:29])[CH:28]=3)[C:21]([O:23]CC)=O)[C:14]([F:17])([CH3:16])[CH3:15])[CH2:10]2)=[CH:4][CH:3]=1.[NH2:38][NH2:39]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[CH:31]=2)[N:9]2[CH2:10][CH:11]([C@@H:13]([C:18]3[CH:19]=[C:20]([CH:26]=[C:27]([F:29])[CH:28]=3)[C:21]([NH:38][NH2:39])=[O:23])[C:14]([F:17])([CH3:16])[CH3:15])[CH2:12]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(F)cc(C(C2CN(C(c3ccc(Cl)cc3)c3cccc(C#N)c3)C2)C(C)(C)F)c1
Reactant: NN
Solvent: CCO
Product: CC(C)(F)[C@H](c1cc(F)cc(C(=O)NN)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Reaction time: 8 h

Procedure:
A mixture of 523 mg (0.41 mmol) of ethyl 3-(1-{l-[(4-chlorophenyl)(3-cyanophenyl)methyl] azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzoate (Preparation 17), 0.6 mL(1 6.36 mmol) of hydrazine, and 4 mL of EtOH was heated to reflux. After 8 h, the mixture was concentrated to remove solvents to afford the of title compound as an white solid. 1H-NMR(CDCl3) δ 1.20(d, 3H, J=21 Hz), 1.29(d, 3H, J=21 Hz), 2.32 (t, 3H, J=7.1 Hz), 2.85 (t, 1H, J=8 Hz), 2.94 (m, 1H), 3.06 (m, 1H), 3.20 (m, 1H), 3.51 (s, 2H), 3.63 (t, 1H, J=5 Hz), 4.26 (s, 1H), 7.06-7.71 (m, 11H); Mass Spectrum: m/e=509 (M+1, 35Cl), 511 (M+1, 37Cl).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][N:3]=1.C[O-].[Na+].[CH:19]([C:21]([CH3:23])=[O:22])=[CH2:20]>C1C=CC=CC=1.CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:9]([CH2:20][CH2:19][C:21](=[O:22])[CH3:23])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:15])=[CH:4][N:3]=1
Reactant: C=CC(C)=O
Reactant: CCOC(=O)CC(=O)c1ccc(C)nc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: CCOC(=O)C(CCC(C)=O)C(=O)c1ccc(C)nc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a stirred solution containing 48 g. of ethyl 3-(2-methyl-5-pyridinyl)-3-oxopropanoate in a mixture of 300 ml. of dry benzene and 100 ml. of dry methanol, said solution kept under nitrogen, was added 0.1 g. of sodium methoxide followed by the dropwise addition over a period of about one hour of the solution containing 16 g. of freshly distilled methyl vinyl ketone in a mixture of 60 ml. of benzene and 10 ml. of methanol. After the reaction had proceeded slowly at room temperature overnight, an additional 0.1 g. of sodium methoxide plus 4 ml. of additional methyl vinyl ketone were added and the reaction mixture was heated with stirring at 40° C. for eight hours. The solvent was distilled-off in vacuo; 300 ml. of benzene was added; the benzene solution was washed once with brine, dried over anhydrous sodium sulfate and heated in vacuo to remove the benzene thereby yielding a quantative yield (63.5 g.) of ethyl 2-(2-methyl-5-pyridinylcarbonyl)-5-oxohexanoate which was added to a mixture containing 95 ml. of concentrated sulfuric acid and 185 ml. of water. The acidic reaction mixture was slowly heated. After about thirty minutes, the temperature reached 55° C. and the evolution of carbon dioxide became noticeable. The temperature of the reaction mixture was maintained at 65° C. for about one hour and then heated to 80° C. and held there for several minutes. By this time the evolution of carbon dioxide appeared to be over. The reaction mixture was cooled and poured into a solution of 305 g. of potassium carbonate in 1 liter of ice water. Chloroform was added; the mixture was shaken well and filtered to remove the precipitated potassium sulfate; and, the layers were separated. The aqueous layer was extracted further with chloroform; the combined chloroform extracts were dried over anhydrous sodium sulfate and filtered; the dried filtrate was heated in vacuo to remove the chloroform to yield, after air-drying, 27.4 g. (80%) of 1-(2-methyl-5-pyridinyl)hexan-1,5-dione, a tan solid melting at 85°-87° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH3:10].O=S(Cl)[Cl:13]>C(Cl)Cl>[Cl:13][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CSc1ccccc1CO
Solvent: ClCCl
Product: CSc1ccccc1CCl

Procedure:
2-Hydroxymethyl-1-methylthiobenzene (3.3 g, 21 mmol) is dissolved in 20 ml of absolute CH2Cl2 under an argon atmosphere. A solution of SOCl2 (2.6 g, 21 mmol) in 10 ml of absolute CH2Cl2 is added dropwise with stirring to this initial mixture in the course of 15 min, first under reflux, then at an internal temperature of 30° C. The reaction mixture is stirred under reflux for 2.25 h. The reaction mixture is concentrated and the oily crude product is purified by bulb tube distillation (7.9×10−2 mbar, 125-140° C.): colorless oil; yield: 3.3 g (88%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:11]3[CH:13]([C:14](=[O:17])[NH:15][N:16]=2)[CH2:12]3)[CH:7]=[CH:8][CH:9]=1)([O-])=O.C1CCCCC=1>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]3[CH:13]([C:14](=[O:17])[NH:15][N:16]=2)[CH2:12]3)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C1NN=C(c2cccc([N+](=O)[O-])c2)C2CC12
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: Nc1cccc(C2=NNC(=O)C3CC23)c1
Yield: 47.9 %

Procedure:
20.4 g (88.2 millimoles) of 2-(m-nitrophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one (see Example 32b), 300 ml of ethanol, 150 ml of cyclohexene and 4.2 g of 10% strength palladium on charcoal are refluxed for 12 hours. The catalyst is filtered off, the filtrate is concentrated and the residue is recrystallized from ethyl acetate/methanol. 8.5 g (48% of theory) of 2-(m-aminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one are obtained as beige crystals, of melting point 192°-193° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+]([O-])=O)[CH:3]=1.[C:14]1([CH:21]=[CH:20][C:18]([OH:19])=[CH:17][CH:16]=1)[OH:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1)[O:15][C:14]1[CH:21]=[CH:20][C:18]([OH:19])=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1cc(Cl)cc([N+](=O)[O-])c1
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)cc(Oc2ccc(O)cc2)c1
Temperature: 25 °C

Procedure:
The product from Example 193a (1.00 g, 5.0 mmol), hydroquinone (0.50 g, 4.5 mmol) and K2CO3 (0.78 g, 5.6 mmol) in DMF (10 ml) was heated at 110° C. for 3.5 hours. The reaction mixture was cooled to room temperature, diluted with H2O and then extracted with EtOAc. The extract was washed with H2O and brine, dried over MgSO4, filtered and concentrated under vacuum giving the title compound. The residue was treated with i-Pr2O and insoluble material was filtered off. The filtrate was evaporated and purified by silica gel column chromatography eluting with 5:2 EtOAc/hexane to give the title product as pale yellow oil (0.51 g, 43%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:12][CH3:13])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:14]([O:18][C:19]([N:21]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].CC([O-])(C)C.[K+].CCOC(C)=O>COCCOC>[C:14]([O:18][C:19]([N:21]1[CH2:27][CH2:26][CH2:25][N:24]([C:2]2[CH:3]=[C:4]([CH2:12][CH3:13])[CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CCc1cc(Br)c2ncccc2c1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCc1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)c2ncccc2c1
Temperature: 60 °C
Yield: 53.2 %

Procedure:
A mixture of 8-bromo-6-ethylquinoline (1.3 g, 5.51 mmol, 1.04 equiv) and 1-(tert-butoxycarbonyl)homopiperazine (1.06 g, 1.0 equiv) in 5.5 mL of DME was degassed with compressed nitrogen gas for 5 minutes. To the mixture was added t-BuOK (0.83 g, 1.4 equiv). After degassing for another 2 minutes, allylchloro[1,3-(2,6-di-isopropylphenyl)imidazol-2-ylidene]palladium (II) (61 mg, 0.02 equiv) was added and the resulting mixture was heated at 60° C. overnight and cooled down to room temperature. EtOAc (˜70 mL) was added and the mixture was filtered through celite. The filtrate was washed with saturated aqueous NaHCO3 (70 mL) and brine (70 mL), dried over magnesium sulfate and concentrated. The residue was purified by silica gel flash column chromatography using 5% to 20% EtOAc in hexane to afford the title compound (1.0 g). MS (ES) m/z 356.2 (M+H+).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[C:9]([CH:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH3:18])[CH:10]=[N:11][CH:12]=1)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CO>[C:6]([C:7]1[CH:8]=[C:9]([CH:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH3:18])[CH:10]=[N:11][CH:12]=1)#[CH:5]
Reactant: CN1CCCC1c1cncc(C#C[Si](C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: C#Cc1cncc(C2CCCN2C)c1

Procedure:
Repeating the procedure of Example 16, but using trimethylsilylacetylene in place of phenylacetylene, 5-ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine and the fumarate derivative thereof were obtained as follows. 5-Trimethylsilylethynyl-3-(1-methyl-2-pyrrolidinyl) pyridine (516 mg, 2 mmol) and cesium carbonate (200 mg, 0.6 mmol) were dissolved in methanol (10 mL) and heated under reflux for 5 h. After cooling the solvents were removed in vacuo and the residue dissolved in ethyl acetate (40 mL) and washed with water (10 mL). The aqueous layer was extracted with ethyl acetate (40mL) and the combined organic extracts washed with brine (10 mL), dried (Na2SO4) and concentrated in vacuo. The crude product was chromatographed on "flash" silica gel with ethyl acetate: hexane (1:9, 1:4, 1:3) to afford 5-ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine as an oil, 218 mg, 59%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([F:18])[C:12]=2[Cl:19])[CH:9]=1)[C:5]#[N:6].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:27][C:28]1[C:36]2[C:31](=[N:32][C:33]([F:37])=[CH:34][CH:35]=2)[N:30]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[N:29]=1>CN1C(=O)CCC1.CCOC(C)=O>[C:41]([O:40][C:38]([N:30]1[C:31]2=[N:32][C:33]([F:37])=[CH:34][CH:35]=[C:36]2[C:28]([CH2:27][O:17][C:15]2[CH:14]=[C:13]([F:18])[C:12]([Cl:19])=[C:11]([O:10][C:8]3[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=[C:2]([Cl:1])[CH:9]=3)[CH:16]=2)=[N:29]1)=[O:39])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccc(F)nc21
Reactant: N#Cc1cc(Cl)cc(Oc2cc(O)cc(F)c2Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1nc(COc2cc(F)c(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2)c2ccc(F)nc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
Under a nitrogen atmosphere, 3-chloro-5-(2-chloro-3-fluoro-5-hydroxyphenoxy)benzonitrile (50-5) (150 mg, 0.503 mmol) was dissolved in NMP (4 mL, 0.1 M). Next, Cs2CO3 (164 mg, 0.503 mmol) was added and the reaction was allowed to stir at room temperature for 15 minutes. Then, tert-butyl-3-(bromomethyl)-6-fluoro-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (37-5) (166 mg, 0.503 mmol, prepared using the procedure set forth in Example 37) was added to the reaction. The reaction was stirred at room temperature for 2 hours. It was then diluted with EtOAc (4 mL). It was partitioned with water (3 mL) and then extracted with EtOAc (3×4 mL). The organic extracts were then washed with water (3×4 mL) and brine (1×4 mL), dried over sodium sulfate and concentrated. Silica gel chromatography (1%-20% EtOAc/Hexanes) gave tert-butyl3-{[4-chloro-3-(3-chloro-5-cyanophenoxy)-5-fluorophenoxy]-methyl}-6-fluoro-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (50-6) (230 mg, 85%). LCMS (ES) m/z 446.9 (M-BOC)+.
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23]([N:25]2[CH2:28][CH:27]([C:29]([O:31][CH3:32])=[O:30])[CH2:26]2)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([N:25]3[CH2:26][CH:27]([C:29]([O:31][CH3:32])=[O:30])[CH2:28]3)=[O:24])[N:19]=2)[CH2:7][C:6]([OH:33])=[O:5])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COC(=O)C1CN(C(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)O)n2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 102.3 %

Procedure:
A solution of methyl 1-[(5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazol-3-yl)carbonyl]-3-azetidinecarboxylate (Preparation 42) (225 mg, 0.48 mmol) in dichloromethane (8 ml) was treated with trifluoroacetic acid (4 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 5 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene (×2). The residue was dissolved in ethyl acetate and washed sequentially with a saturated aqueous solution of sodium citrate and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure to afford the title compound as an oil (200 mg).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([S:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:33][OH:34])=O)(C)(C)C.[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([O:34][CH2:33][C@@H:9]1[CH2:10][C@@H:11]([S:13][C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:12][NH:8]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Product: c1ccc(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2)cc1

Procedure:
In analogy: The reaction of (2S,4R)-2-hydroxymethyl-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ester with benzylbromide gave (2S,4R)-2-benzyloxymethyl-4-tritylsulfanyl-pyrrolidine, MS: 466 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[CH3:12][N:13](C)[CH:14]=[O:15]>>[CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:14]([NH:13][CH2:12][CH2:9][S:8][CH2:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[CH3:1])=[O:15]
Reactant: CN(C)C=O
Reactant: Cc1nc[nH]c1CSCCN
Product: Cc1nc[nH]c1CSCCNC(=O)NCCSCc1[nH]cnc1C

Procedure:
A mixture of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (1.6 g.) and 1,1-carbonyl di-imidazole (0.5 g.) in dimethyl formamide (12 ml.) was heated to reflux temperature whereupon the mixture solidified. After cooling, a small quantity of dimethyl formamide was added and the slurry was filtered to give the solid product which was washed with water, ethanol and ether and finally recrystallised from dimethyl formamide. Yield 0.5 g., m.p. 230°-234°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[C:7]=1[C:19]#[N:20].[N:24]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=1)=[C:25]=[O:26]>CN(C)C=O.C(OCC)(=O)C>[C:33]([C:30]1[CH:31]=[CH:32][C:27]([NH:24][C:25]([NH:1][C:2]2[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=2)[O:5][C:6]2[CH:18]=[CH:17][C:9]3[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=3[C:7]=2[C:19]#[N:20])=[O:26])=[CH:28][CH:29]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)c(C#N)c2s1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)Nc4ccc(C(C)(C)C)cc4)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 39.6 %

Procedure:
N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]acetamide (120 mg, 0.369 mmol) produced in Example 12(ii) was dissolved in N,N-dimethylformamide (1.5 mL), 1-isocyanato-4-(tert-butyl)benzene (85 μL, 0.48 mmol) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (10 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 ml), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=60/40→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from acetone/n-hexane to give the title compound (73 mg, 40%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:10]=2)=[CH:5][CH:4]=1>[Pd].CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2=CC(NCCCCc3ccccc3)CCC2)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(C2CCCC(NCCCCc3ccccc3)C2)cc1
Reaction time: 3 h

Procedure:
A mixture of (RS)-[3-(4-methoxy-phenyl)-cyclohex-2-enyl]-(4-phenyl-butyl)-amine (2.4 g, 7.15 mmol), 10% Pd/C (0.48 g) and MeOH (50 ml) was hydrogenated for 3 h. Removal of the catalyst, evaporation of the solvent and separation of the isomers by flash-chromatography over SiO2 (Biotage 40, 90 g) eluting with AcOEt gave (1RS,3SR)-[3-(4-methoxy-phenyl)-cyclohexyl]-(4-phenyl-butyl)-amine (1.2 g, 50%, light yellow oil, MS: m/e=338.3 (M+H+)) and (1RS,3RS)-[3-(4-methoxy-phenyl)-cyclohexl]-4-phenyl-butyl)-amine (0.43 g, 18%, light yellow oil, MS: m/e=338.3 (M+H+)).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C@H:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[C:1]([O:5][C:6](=[O:33])[NH:7][C@H:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][S:42]([CH3:41])(=[O:44])=[O:43])=[CH:28][CH:27]=1)[CH2:9][N:10]1[CH2:11][CH2:12][CH:13]([C:16](=[O:24])[C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[CH2:14][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(N)cc1)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(NS(C)(=O)=O)cc1)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ((R)-1-(4-amino-benzyl)-2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-ethyl)-carbamic acid tert-butyl ester (1.19 g, 2.61 mmol) in dichloromethane (15 ml) cooled to 0° C. is added triethylamine (0.37 ml, 2.65 mmol) and methanesulfonylchloride (0.192 ml, 2.49mmol). The reaction mixture is allowed to warm to ambient temperature with stirring for 1 hour, then washed with water and saturated brine solution, dried over magnesium sulphate and evaporated. The crude product is purified by flash silica chromatography (ethylacetate:hexane gradient 6:4 to 1:0 elution) to afford [(R)-2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-1-(4-methanesulfonylamino-benzyl)-ethyl]-carbamic acid tert-butyl ester. [MH]+534.7.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH3:27][N:28]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1)[CH3:29].N>CN(C)C=O>[C:13]([C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[NH:4][C:5](=[O:26])[C:6]2=[C:16]([NH:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:28]([CH3:27])[CH3:29])=[CH:36][CH:35]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:15])[CH3:14]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc(C(C)=O)cc21)c1ccccc1
Reactant: CN(C)Cc1ccc(N)cc1
Agent: N
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)C(=C(Nc1ccc(CN(C)C)cc1)c1ccccc1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 mg (0.57 mmol) 1,5-diacetyl-3-[ethoxy-phenyl-methylidene]-2-indolinone (Ex. III) are suspended in 5 ml of dimethylformamide and stirred with 86 mg 0.57 mmol) 4-dimethylaminomethyl-phenylamine at an ambient temperature of 80° C. for about 5 h. The acetyl-protected intermediate product is combined with 2 ml of conc. ammonia without being purified and stirred overnight at ambient temperature. Then the mixture is evaporated down and the residue is chromatographed through a silica gel column with methylene chloride/methanol 9:1 as eluant.