Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([F:13])([F:12])[CH2:3][C@@H:4]1[CH2:8][N:7]([CH2:9]O)[C:6](=[O:11])[CH2:5]1.S(Cl)([Cl:16])=O>ClCCl>[Cl:1][C:2]([F:13])([F:12])[CH2:3][C@@H:4]1[CH2:8][N:7]([CH2:9][Cl:16])[C:6](=[O:11])[CH2:5]1
Reactant: O=C1C[C@H](CC(F)(F)Cl)CN1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C1C[C@H](CC(F)(F)Cl)CN1CCl
Temperature: 22 °C
Reaction time: 1 h

Procedure:
A solution of (4R)-4-(2-chloro-2,2-difluoroethyl)-1-(hydroxymethyl)pyrrolidin-2-one a12R (0.281 g, 1.32 mmol, 1.5 eq) in dichloromethane (25 ml) is treated with thionyl chloride (382 μl, 5.27 mmol, 6 eq). The mixture is stirred for 1 h at 22° C. and concentrated in vacuo to obtain (4R)-4-(2-chloro-2,2-difluoroethyl)-1-(chloromethyl)pyrrolidin-2-one a18R. The resulting liquid is then added to a solution of anhydrous zinc chloride (0.239 g, 1.76 mmol, 2 eq) and 2-[methoxy(2H2)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole a44 (0.210 g, 0.88 mmol, 1 eq) in dioxane. The mixture is stirred at 80° C. for 4 days. Some more (4R)-4-(2-chloro-2,2-difluoroethyl)-1-(hydroxymethyl)pyrrolidin-2-one a12R (1.5 eq) are then added and the mixture is stirred for another 24 h. (4R)-4-(2-chloro-2,2-difluoroethyl)-1-(hydroxymethyl)pyrrolidin-2-one a12R (2 eq) is added again and the mixture stirred for another 3 days. The mixture is then diluted with dichloromethane and washed with water (2×25 ml). The organic layer is dried over magnesium sulphate and concentrated under reduced pressure to afford 1.28 g of a brown oil. The mixture is purified by reverse phase HPLC (X-bridge C18, eluent: MeCN/H2O/NH3) to afford (4R)-4-(2-chloro-2,2-difluoroethyl)-1-({2-[methoxy(2H2)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl}methyl)pyrrolidin-2-one 31 as a yellow oil.
Reaction SMILES: [OH:1][C@@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][C:33]=1[NH:34][C:35](=[O:40])[C:36]([OH:39])([CH3:38])[CH3:37])[NH:30][C:29](=[O:41])[CH2:28]2.N1CCCCC1>C(O)C>[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][C:33]=1[NH:34][C:35](=[O:40])[C:36]([OH:39])([CH3:38])[CH3:37])[NH:30][C:29](=[O:41])/[C:28]/2=[CH:14]\[C:11]1[NH:10][C:7]2[CH2:8][CH2:9][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:5](=[O:16])[C:6]=2[C:12]=1[CH3:13]
Reactant: CC(C)(O)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(/C=C2\C(=O)Nc3cc(NC(=O)C(C)(C)O)c(F)cc32)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Temperature: 25 °C
Yield: 73.9 %

Procedure:
(S)-5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 5f (40 mg, 0.125 mmol), N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-2-methyl-propionamide 11b (28.3 mg, 0.112 mmol) and piperidine (50 μL, 0.5 mmol) were dissolved in 2 mL of ethanol under stirring at room temperature. The reaction system was stirred at 80° C. in an oil bath in dark for 2 hours. The reaction was completed until TLC showed the disappearance of starting materials, and the oil bath was removed. The reaction system was naturally cooled down to room temperature to precipitate solids. The resulting solids were filtered to give the title compound (S,Z)-N-{5-fluoro-3-[5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-2-methyl-propionamide 11 (46 mg, 74%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:17][NH:16][CH2:15]2)[C:10]([F:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:25]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[C:29]#[N:30]>C(#N)C>[Cl:40][C:37]1[CH:36]=[CH:35][C:34]([C@H:25]([N:16]2[CH2:15][CH:14]([C@@H:9]([C:4]3[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=3)[C:10]([F:13])([CH3:12])[CH3:11])[CH2:17]2)[C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[C:29]#[N:30])=[CH:39][CH:38]=1
Reactant: N#Cc1cccc(C(Br)c2ccc(Cl)cc2)c1
Reactant: CC(C)(F)[C@H](c1cc(F)cc(F)c1)C1CNC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(F)[C@H](c1cc(F)cc(F)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A solution of the crude amine from Step 3 and 6.51 g (20 mmole) of Cs2CO3 in 30 mL dry acetonitrile was stirred at rt in a flask fitted with a small Dean-Stark trap. After 15 minutes, 4.6 g (15 mmole) of 3-[bromo(4-chlorophenyl)methyl]benzonitrile was added and the mixture was heated at 60° C. After 18 h, the solution was filtered through CELITE and the residue was washed with acetonitrile. The combined filtrates were concentrated and the residue was purified by flash chromatography using a step gradient of 5 to 20 % ethyl acetate-hexane. Fractions containing the faster product diastereomer were pooled and concentrated to afford the title compound; 1H-NMR(CDCl3) δ 1.25 (t, J=22 Hz, 6H), 2.33 (t, J=6.5 Hz, 1H), 2.83-2.89 (m, 2H), 3.09-3.11 (m, 2H), 3.60 (m, 1H), 4.24 (s, 1H), 6.68-6.71 (m, 3H), 7.21-7.8 (m, 8H); Mass Spectrum: m/e=469 (M+1, 35Cl) and 471 (M+1, 37Cl).
Reaction SMILES: [OH:1][C@@H:2]([C:6]([O:19][CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O-:5])=[O:4].Cl[C@H](C1C=CC(Cl)=CC=1)C[NH3+].CC(C)([O-])C.[K+].[CH3:38][C:39]1[CH:44]=[C:43]([CH3:45])[N:42]=[C:41](S(C)(=O)=O)[N:40]=1.O>CN(C=O)C>[CH3:45][C:43]1[CH:44]=[C:39]([CH3:38])[N:40]=[C:41]([O:1][C@@H:2]([C:6]([O:19][CH3:20])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]([OH:5])=[O:4])[N:42]=1
Reactant: Cc1cc(C)nc(S(C)(=O)=O)n1
Reactant: COC(c1ccccc1)(c1ccccc1)[C@H](O)C(=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [NH3+]C[C@H](Cl)c1ccc(Cl)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(c1ccccc1)(c1ccccc1)[C@H](Oc1nc(C)cc(C)n1)C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In a 25 mL three neck flask with stirring arrangement, (1 gm) (R)-2,4-dichlorophenylethyl ammonium (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionate and (0.726 gm) potassium tertiary butoxide (6.488 mmol) in 10 ml DMF at 25° C. were taken and stirred for 5 min. (0.604 gm) 4,6-dimethyl-2-(methylsulfonyl)pyrimidine (3.244 mmol) was added to the reaction mixture in one lot. The reaction mixture was stirred at room temperature for 6 hours and subsequently dumped into cold water and washed the aqueous layer with toluene. Aqueous layer was collected and acidified with HCl to pH 2. The solid was extracted with ethyl acetate, and wash the ethyl acetate layer with water followed by brine. Dry over sodium sulphate and concentrated on Buchi Rotavapor.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([OH:15])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].F[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[C:18]=1[N+:25]([O-:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[C:18]=1[N+:25]([O-:27])=[O:26])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Reactant: CCOC(=O)c1cc2c(O)cccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Oc3cc(F)cc(F)c3[N+](=O)[O-])cccc2[nH]1
Temperature: 25 °C

Procedure:
4-Hydroxy-1H-indole-2-carboxylic acid ethyl ester (1 g, 4.87 mmol) and 1,3,5-Trifluoro-2-nitro-benzene (0.57 ml, 4.87 mmol) are dissolved in 10 ml of dimethylformamide. After addition of potassium carbonate (1.3 g, 9.74 mmol) the mixture is stirred over night at room temperature. Then the reaction mixture is evaporated under reduced pressure, dissolved with ethyl acetate and washed with water. The organic layers are dried over sodium sulfate and evaporated.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8].[Na].[H][H]>O.[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)C1CCC=CO1
Reactant: [H][H]
Agent: [Pd]
Agent: [Na]
Solvent: O
Product: O=C(O)C1CCCCO1

Procedure:
3,4-Dihydro-2 H-pyran-2-carboxylic acid, sodium salt (5.0 g) in water (30 ml) was treated with 10% Palladium on carbon catalyst (0.2 g) and the mixture hydrogenated until there was no further uptake of hydrogen. The mixture was filtered through Kieselguhr, the filtrate passed through a column of 'Amberlite IR120(H+), evaporated in vacuo and the residue dissolved in dichloromethane, dried and evaporated to give the title compound as colourless oil. (3.3 g, 76%); (Found: M+, 130.0631. C6H10O3 requires M, 130.0630; νmax (CH2Cl) 3500-2750 (v.br), 1772, 1725 cm-1 ; δH (CDCl3), 1.5-1.7 (4 H, m), 1.8-2.1 (2 H, m), 3.50-3.59 (1 H, m), 3.99-4.14 (2 H, m) and 7.28 (1 H, br.s).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=[N:3]1.[F:24][C:25]([F:29])([F:28])[CH2:26][NH2:27]>>[CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:27][CH2:26][C:25]([F:29])([F:28])[F:24])=[O:15])=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=[N:3]1
Reactant: NCC(F)(F)F
Reactant: Cn1nnc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cn1nnc(-c2ccccc2)c1COc1ccc(C(=O)NCC(F)(F)F)cn1
Yield: 58 %

Procedure:
As described for example 2b, 6-(3-methyl-5-phenyl-3H-[1,2,3]triazol-4-ylmethoxy)-nicotinic acid (155 mg, 0.5 mmol) was converted, using 2,2,2-trifluoroethylamine instead of 4-aminotetrahydropyran, to the title compound (127 mg, 58%) which was obtained as a white solid after a further recrystallisation from ethyl acetate. MS: m/e=392.1 [M+H]+.
Reaction SMILES: [Na].[CH:2]([O:5][C:6]1[N:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)([CH3:4])[CH3:3].C([O:18][C:19]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)=O)C.Cl>C(O)C>[CH:2]([O:5][C:6]1[N:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH:9]2[C:19](=[O:18])[C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)([CH3:4])[CH3:3]
Reactant: CC(C)Oc1ccc2c(n1)CC(=O)N2
Reactant: CCOC(=O)c1cccs1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CC(C)Oc1ccc2c(n1)C(C(=O)c1cccs1)C(=O)N2
Temperature: 25 °C
Yield: 44.7 %

Procedure:
Pellets of sodium metal (250 mg, 11 mmole) were added to dry ethanol (10 mL) in a dry round-bottomed flask. When dissolution of the sodium was complete, solid 5-isopropoxy-4-azaoxindole (419 mg, 2.22 mmol) was added followed by ethyl-2-thiophene carboxylate (0.59 mL, 688 mg). The mixture was heated at reflux overnight and then cooled to room temperature. After pouring into ice/water, the mixture was acidified using 1N HCl solution and extracted with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was subjected to flash chromatography on silica gel eluting successively with chloroform and 49:1 chlorform/methanol. All fractions containing the desired product were combined and concentrated. The residue was again subjected to flash chromatography on silica gel eluting with chloroform. Fractions containing only the desired product were combined and concentrated to give 5-isopropoxy-3-(2-thenoyl)-4-azaoxindole as a yellow gum (300 mg, 45%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][C:17]([C:20]1[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=1)([F:19])[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:27]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:28]=[O:29].CO>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][C:17]([C:20]1[CH:21]=[C:22]([NH:26][C:28]([NH:27][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:29])[CH:23]=[CH:24][CH:25]=1)([F:19])[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(C(F)(F)COCCCCCCOCc2ccccc2)c1
Reactant: CCOC(=O)CN=C=O
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CNC(=O)Nc1cccc(C(F)(F)COCCCCCCOCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.8 %

Procedure:
To a solution of Intermediate 58 (3.9 g, 10.7 mmol) in methylene chloride (35 mL) was added ethyl isocyanatoacetate (1.38 mL, 12.3 mmol). The mixture was stirred at room temperature for 5 hours. The crude reaction was cooled to 0° C. and then methanol (2.3 mL) was added. The mixture was stirred at room temperature for 0.5 hours and the solvent was removed under reduced pressure. Purification by column cromatography using methylene chloride/methanol (from pure methylene chloride to 98:2) as eluent gave the title compound (5.1 g, 95%) as oil.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=1[NH:14][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)#[N:2].C(=O)([O-])[O-:21].[K+].[K+].OO.O>CS(C)=O>[NH2:2][C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=1[NH:14][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:21]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1ccc(C#N)c(NC2CCCC2)c1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(C(N)=O)c(NC2CCCC2)c1
Temperature: 25 °C
Yield: 334.7 %

Procedure:
A solution of ethyl 4-cyano-3-(cyclopentylamino)benzoate (363 mg, 1.41 mmol), potassium carbonate (50 mg, 0.36 mmol), and 30% aqueous hydrogen peroxide (0.25 mL) in DMSO (1.5 mL) was stirred at 60° C. for 1 h. After cooling to room temperature, water was added and the resulting mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with water (10 mL) and brine (10 mL), dried over sodium sulfate, filtered and concentrated to give ethyl 4-(aminocarbonyl)-3-(cyclopentylamino)benzoate (333 mg, 86% yield). MS (EI) for C15H20N2O3: 277 (MH+).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH:12]=[C:13]([C:19]#[N:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>C(O)C>[NH2:20][C:19]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[CH:12][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: NNc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccccc2)c1N
Temperature: 0 °C
Reaction time: 48 h
Yield: 55.7 %

Procedure:
A solution of 31.9 g of phenylhydrazine and 50.0 g of ethyl (ethoxymethylene)cyanoacetate (both reactants were obtained from Aldrich Chemical Company, Milwaukee, Wis.) disssolved in 500 ml of ethanol was refluxed for 6 hours. The mixture was allowed to stand for approximately 48 hours and was refluxed for an additional 8 hours. The reaction mixture was poured into ice water and the precipitated solid was collected by filtration. The solid was recrystallized from ethanol to afford 38.0 g of 5-amino-1-phenyl-1H-pyrazole-4-carboxylic acid, ethyl ester. Yield 44%. mp=101°-103° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][CH2:12][N:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][C:17]([N+:23]([O-])=O)=[CH:18][CH:19]=2)[CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[Sn](Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:23][C:17]1[CH:16]=[C:15]2[C:20]([CH2:21][CH2:22][N:13]([CH2:12][CH2:11][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:14]2)=[CH:19][CH:18]=1
Reactant: O=C(CCN1CCc2ccc([N+](=O)[O-])cc2C1)OCc1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)CN(CCC(=O)OCc1ccccc1)CC2
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
1.80 g of 2-(2-benzyloxycarbonylethyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline was dissolved in 10 ml of ethanol, and 4.77 g of tin chloride dihydrate was added to the solution. The solution was heated under reflux with stirring for 30 minutes. The resulting solution was neutralized by adding saturated aqueous solution of sodium bicarbonate, and the solution was extracted with ethyl acetate, washed with water and saturated aqueous solution of sodium chloride, and dried with anhydrous sodium sulfate. After separating the desiccant by filtration, the residue was purified by silica gel column chromatography to obtain 1.52 g of 7-amino-2-(2-benzyloxycarbonylethyl)-1,2,3,4-tetrahydroisoquinoline as an oily product. This product, with no further purification, was dissolved in 10 ml of DMF, and 1.52 g of 1-(tertbutoxycarbonyl)-4-(carboxymethoxy)piperidine and 0.41 g of 1-ethyl-3-(3-dimethylaminopopyl)carbodiimide, which had been separately synthesized, were added to this solution. The solution was stirred overnight at room temperature. The resulting solution was extracted with ethyl acetate, washed with water, saturated aqueous solution of sodium bicarbonate, and saturated aqueous solution of sodium chloride, and dried with anhydrous sodium sulfate. After separating the desiccant by filtration, the residue was purified by silica gel column chromatography to obtain 1.84 g of 2-(2-benzyloxycarbonylethyl)-7-[1-(tert-butoxycarbonyl)piperidine-4-yloxyacetylamino]-1,2,3,4-tetrahydroisoquinoline, which was an oily product (yield: 68%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1.[CH3:28][N:29]([CH3:44])[C:30]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:31]=1[CH:32]=[CH:33][CH:34]=[C:35]2[S:40](Cl)(=[O:42])=[O:41].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][S:40]([C:35]3[C:36]4[C:31](=[C:30]([N:29]([CH3:44])[CH3:28])[CH:39]=[CH:38][CH:37]=4)[CH:32]=[CH:33][CH:34]=3)(=[O:42])=[O:41])=[CH:13][CH:14]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(Nc2ccnc3nc(C)ccc23)c1
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(Sc2ccc(OS(=O)(=O)c3cccc4c(N(C)C)cccc34)cc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 19 (167 mg, 0.94 mmol) was reacted with 5-Dimethylamino-naphthalene-1-sulfonyl chloride (245 mg, 0.94 mmol) in 10 mL of CH2Cl2 with N,N-diisopropylethylamine (0.530 mL, 410 mmol) for 22 h. Washed with water and dried over Na2SO4, filtered and concentrated under vacuum giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (35 mg, 40%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.75 (s, 3 H) 2.86 (s, 6 H) 6.65 (d, J=6.99 Hz, 1 H) 6.76 (d, J=9.19 Hz, 2 H) 6.87 (d, 2 H) 7.16 (d, J=8.82 Hz, 1 H) 7.34 (d, J=7.72 Hz, 1 H) 7.53-7.62 (m, 2 H) 7.69-7.79 (m, 3 H) 7.97 (d, J=7.35 Hz, 1 H) 8.22 (d, J=8.82 Hz, 1 H) 8.50 (d, J=6.99 Hz, 1 H) 8.60 (d, J=8.46 Hz, 1 H) 8.82 (d, J=8.82 Hz, 1 H); MS 1 H) 8.50 (d, J=6.99 Hz, 1 H) 8.60 (d, J=8.46 Hz, 1 H) 8.82 (d, J=8.82 Hz, 1 H); MS (DCI NH3+) m/z 611 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[C:4]([S:6][CH3:7])=[CH2:5].C(OC(=C)C(O)=O)C.[CH2:17]([N:24]([CH2:30]OC)[CH2:25][Si](C)(C)C)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C:4]1([S:6][CH3:7])[CH2:5][CH2:25][N:24]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:30]1)=[O:8]
Reactant: C=C(SC)C(=O)OC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: C=C(OCC)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1(SC)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-ethoxyacrylate 2-Methylsulfanyl-acrylic acid methyl ester 6BP (136 g, 1.03 mol) and benzyl-methoxymethyl-trimethylsilanylmethyl-amine 7BP (290 g, 1.22 mol) in dichloromethane (2.7 L ml) was added at 0° C. a solution of trifluoroacetic acid (26 mL, 0.3 mol). The resulting solution was warmed to room temperature and stirred for one overnight. The crude product was purified by column chromatography on silica gel eluting with a solution of ethyl acetate in hexane (1:4) to give 1-benzyl-3-methylsulfanyl-pyrrolidine-3-carboxylic acid methyl ester 8BP (131 g, 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17]Cl)[C:12]=2[CH2:19][CH3:20])[CH:3]=1.[NH3:21].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>CO>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[NH2:21][CH2:17][C:13]1[C:12]([CH2:19][CH3:20])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7].[NH2:21][CH2:17][C:13]1[C:12]([CH2:19][CH3:20])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N
Reactant: CCc1c(CCl)cccc1Oc1cc(Cl)ccc1C#N
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Product: CCc1c(CN)cccc1Oc1cc(Cl)ccc1C#N
Temperature: 25 °C
Reaction time: 96 h
Yield: 95.2 %

Procedure:
To a solution of 4-chloro-2-(3-chloromethyl-2-ethyl-phenoxy)-benzonitrile (0.16 g, 0.53 mmol) in methanol (10 mL) was added ammonia (7N in methanol, 15 mL, 105 mmol), and the reaction mixture stirred for 4 days at ambient temperature. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and a solution of fumaric acid (60 mg, 0.52 mmol) in methanol (3 mL) was added. After the solvent was removed in vacuo, the residue was triturated with diethyl ether overnight, collected by filtration, and dried to give 2-(3-aminomethyl-2-ethyl-phenoxy)-4-chloro-benzonitrile hemifumarate (174 mg, 83%) as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[OH:11])=[O:3].[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN1C(=O)CCC1.O>[OH:11][C:5]1[CH:6]=[C:7]([S:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:9][C:4]=1[C:2](=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(F)cc1O
Reactant: Sc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(=O)c1ccc(Sc2ccccc2)cc1O
Temperature: 110 °C
Yield: 101.9 %

Procedure:
To a solution of 4-fluoro-2-hydroxyacetophenone (3.083 g, 20 mmol) in NMP (50 mL) were added thiophenol (2.054 ml, 20 mmol) and K2CO3 (8.293 g, 60 mmol). The reaction was heated at 110° C. overnight. Upon cooling the mixture was poured into water, acidified by addition of HCl (diluted) and extracted with Et2O. The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to afford 1-(2-hydroxy-4-phenylsulfanyl-phenyl)-ethanone (4.980 g of oil) that was used for the next step without further purification.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)C=C[CH:4]=[CH:3][CH:2]=1.[NH:21]1C=CC=C1B(O)O>>[NH:21]1[CH:4]=[CH:3][CH:2]=[C:1]1[C:7]1[NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=1[C:14]=23
Reactant: OB(O)c1ccc[nH]1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Product: O=C1NCCc2c(-c3ccc[nH]3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (300 mg, 1.13 mmol) and 1-)t-butoxycarbonyl)pyrrole-2-boronic acid (263 mg, 1.24 mmol) were coupled with concomitant removal of the BOC group to yield 2-(1H-pyrrol-2-yl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 81 mg (28% as a greenish grey solid: m.p. >400° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ 3.02 (m, 2H), 3.42 (m, 2H), 6.22 (m, 1H), 6.44 (m, 1H), 6.97 (m, 1H), 7.14 (t, J=7.5 Hz, 1H), 7.49 (dd, J=8.1, 0.9 Hz, 1H), 7.64 (dd, J=7.5, 0.6 Hz, 1H), 7.98 (br t, 1H), 11.01 (br s, 1H), 11.13 (br s, 1H). MS (electrospray, MH+) 252. Anal. (C15H13N3O.0.4 H2O) C, H, N.
Reaction SMILES: [H][H].[F:3][C:4]([F:15])([F:14])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1>C(O)(C)C.[Rh]>[F:3][C:4]([F:14])([F:15])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1
Reactant: [H][H]
Reactant: Oc1ccc(CCC(F)(F)F)cc1
Agent: [Rh]
Solvent: CC(C)O
Product: OC1CCC(CCC(F)(F)F)CC1

Procedure:
At 50° C. and 150 bar hydrogen pressure, 40.7 g of 4-(3,3,3-trifluoropropyl)phenol in 800 ml of isopropanol were hydrogenated using rhodium on carbon as catalyst for 20 h. The catalyst was filtered off and the reaction solution was concentrated, to give the title product as a colourless solid which was reacted further without any purification.