Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][C:11](F)=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1.[CH3:18][NH2:19]>O>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][C:11]([NH:19][CH3:18])=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1
Reactant: O=C1CCCCN1c1ccc(F)c([N+](=O)[O-])c1
Reactant: CN
Solvent: O
Product: CNc1ccc(N2CCCCC2=O)cc1[N+](=O)[O-]

Procedure:
4.1 g (0.017 mol) of 4-(2-oxo-piperidin-1-yl)-2-nitro-fluoro-benzene are stirred in 50 ml methylamine solution (40% in H2O) in a sealed vessel for 1 hour at ambient temperature. Then the mixture is diluted with water, suction filtered and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[CH3:19][C:20]1[C:24]([C:25]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[O:26])=[CH:23][NH:22][C:21]=1[CH:34]=O>C(O)C.N1CCCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[C:11](=[CH:34][C:21]2[NH:22][CH:23]=[C:24]([C:25]([N:27]4[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]4)=[O:26])[C:20]=2[CH3:19])[C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1
Reactant: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=O
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(-c2cccc3c2C(=Cc2[nH]cc(C(=O)N4CCN(C)CC4)c2C)C(=O)N3)cc1
Reaction time: 72 h
Yield: 82.4 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stiffed at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(4-methoxy-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (94 mg, 82%).
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([CH:11]1[C:16]2=[C:17]3[CH2:23][CH2:22][CH2:21][CH2:20][C:18]3=[N:19][C:15]2=[C:14]([CH2:24][C:25]2[O:29][C:28]([CH:30]=[O:31])=[CH:27][CH:26]=2)[CH:13]=[CH:12]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>O.[N+]([O-])([O-])=O.[Ag+]>[CH2:3]([CH:11]1[C:16]2=[C:17]3[CH2:23][CH2:22][CH2:21][CH2:20][C:18]3=[N:19][C:15]2=[C:14]([CH2:24][C:25]2[O:29][C:28]([C:30]([OH:1])=[O:31])=[CH:27][CH:26]=2)[CH:13]=[CH:12]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: [OH-]
Reactant: CCCCCCCCC1C=CC(Cc2ccc(C=O)o2)=C2N=C3CCCCC3=C21
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCC1C=CC(Cc2ccc(C(=O)O)o2)=C2N=C3CCCCC3=C21
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.9 %

Procedure:
To freshly prepared silver oxide obtained by treating 1.9 g of silver nitrate with 0.9 g of sodium hydroxide in 8 mL of water was added at 0°-5° C. a solution of 1.4 g of aldehyde from Example 159. After 2 hours of stirring at room temperature the reaction mixture was filtered on celite. The filtrate was acidified with 2N-HCl and the product extracted with ethyl acetate. Repeated crystallizations of the crude material (1.3 g) from ethyl acetate-hexane gave 0.8 g (54.7%) of 5-[(1,2,3,4-tetra-hydro-9-octyl-9H-dibenzo[b,d]pyrrol-6-yl)-methyl]-2-furancarboxylic acid as a pale yellow solid, mp 152.5°-155.0° C.
Reaction SMILES: [C:1]1([C@@H:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)([O-:31])=[O:30].COCCOC(N=NC(OCCOC)=O)=O>C1COCC1.O>[N+:29]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([O:9][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])=[O:37])=[CH:39][CH:40]=1)([O-:31])=[O:30].[C:1]1([C@@H:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: C[C@H](O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](OC(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Reaction time: 4 h

Procedure:
After (S)-1-phenylethyl alcohol (300 mg, 2.46 mmol), triphenylphosphine (771 mg, 2.95 mmol), 4-nitrobenzoic acid (494 mg, 2.95 mmol), and THF (12 ml) were added to a 50 ml flask, azodicarboxylic acid bis(2-methoxyethyl) ester (691 mg, 2.95 mmol) dissolved in THF (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for four hours. Water (0.5 mL) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using diethyl ether (10 ml,×2). Then, the organic layer was washed with water (10 mL) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 5% ethyl acetate-hexane solution) to give (R)-1-(4-nitrobenzoyloxy)-1-phenylethane as a pale yellow liquid substance (559 mg, yield: 84%/(S)-1-phenylethyl alcohol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:25](=[CH:26][CH:27]=1)[CH2:24][C@:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:8](COCC[Si](C)(C)C)[C:7]1=[O:23])[CH2:5]2.FC(F)(F)C(OC(=O)C(F)(F)F)=O.NC1C=CC=CC=1.FC(F)(F)C(NC1C=CC=CC=1)=O.[N+:61]([O-])([OH:63])=[O:62].FC(F)(F)C(O)=O.C(N)CN>ClCl.O>[NH2:1][C:2]1[CH:3]=[C:4]2[C:25](=[CH:26][C:27]=1[N+:61]([O-:63])=[O:62])[CH2:24][C@:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:23])[CH2:5]2
Reactant: O=[N+]([O-])O
Reactant: C[Si](C)(C)CCOCN1C(=O)[C@@]2(Cc3ccc(N)cc3C2)c2cccnc21
Agent: ClCl
Agent: O=C(Nc1ccccc1)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: Nc1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Nc1cc2c(cc1[N+](=O)[O-])C[C@]1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of (R)-5-amino-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (28.7 g, 75.2 mmol, described in Intermediate 3) in CH2 Cl2 (100 mL) was added trifluoroacetic anhydride (106 mL, 752 mmol). The mixture was stirred for 10 min, after which time the aniline had been converted to the corresponding trifluoroacetanilide. The resulting mixture was cooled in an ice-salt bath and 15.8 M nitric acid (5.0 mL, 79 mmol) was added dropwise over 15 min, keeping the reaction temperature at 10-12° C. After the addition, the reaction mixture was stirred for 30 min, then H2O (12 mL) was carefully added, followed by trifluoroacetic acid (100 mL) and CH2 Cl2 (100 mL). The mixture was allowed to warm to ambient temperature and stirring was continued for 2 h, followed by concentration to dryness in vacuo. The residue was dissolved in MeOH (200 mL) and the solution was adjusted to pH 10 by addition of 10 N NaOH. Ethylene diamine (5 mL, 75 mmol) was added and the mixture was stirred at ambient temperature for 18 h, then diluted with H2O (200 mL). The resulting solid was isolated by filtration, washed with H2O, and dried in vacuo to give the title compound. MS: m/z=297 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:24]3[CH:25]=[N:26][CH:27]=[C:28]([CH2:30][O:31][Si](C(C)(C)C)(C)C)[CH:29]=3)=[CH:5][C:4]=2[N:3]=1.O>C(O)(=O)C.O1CCCC1>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:17])([OH:18])[CH3:19])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:24]3[CH:25]=[N:26][CH:27]=[C:28]([CH2:30][OH:31])[CH:29]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(-c4cncc(CO[Si](C)(C)C(C)(C)C)c4)cnc3c2n1CC(C)(C)O
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCOCc1nc2c(N)nc3cc(-c4cncc(CO)c4)cnc3c2n1CC(C)(C)O
Temperature: 25 °C
Yield: 49.2 %

Procedure:
A solution of 1-{4-amino-7-[5-(tert-butyldimethylsilanyloxymethyl)pyridin-3-yl]-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol (1.37 g, 2.55 mmol) in acetic acid (10 mL), tetrahydrofuran (10 mL), and water (10 mL) was stirred at 60° C. for 18.5 hours and allowed to cool to room temperature. The solvent was removed under reduced pressure, and the residue was diluted with saturated aqueous sodium bicarbonate (30 mL). Dichloromethane was added, but an oil was present that remained insoluble in both phases. Both phases were decanted away from the oil, which was dissolved in methanol. The aqueous phase was then separated and extracted with dichloromethane (30 mL) and ethyl acetate (2×30 mL). Silica gel was added to the combined dichloromethane, ethyl acetate, and methanol fractions, and the solvent was removed under reduced pressure. The residue was purified by automated flash chromatography (FLASH 40+M silica cartridge, eluting with 5% to 20% methanol in dichloromethane). The resulting material was concentrated from acetonitrile to form a solid, which was triturated with acetonitrile (30 mL), isolated by filtration, washed with acetonitrile, and dried overnight in a vacuum oven to provide 530 mg of 1-{4-amino-2-(ethoxymethyl)-7-[5-(hydroxymethyl)pyridin-3-yl]-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl}-2-methylpropan-2-ol as a light yellow solid, mp 212-214° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].C(N(CC)CC)C.[C:14]1([N:20]=[C:21]=[S:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[C:14]1([NH:20][C:21](=[S:22])[NH:2][CH2:3][C:4]([NH2:6])=[O:5])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: S=C=Nc1ccccc1
Reactant: NCC(N)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)CNC(=S)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.1 %

Procedure:
A mixture of glycinamide hydrochloride (8.25 g), triethyl amine (10.0 g), phenyl-isothiocyanate (10.1 g), and methylene chloride (300 mL) was heated at reflux for 1 hour. The mixture was stirred at ambient temperature for 2 hours. The precipitate was collected by filtration, washed with methylene chloride, then with diethyl ether and air dried to give 2-(3-phenyl-thioureido)-acetamide (9.7 g), m.p. 150°-152° C. Anal. Calcd. for. C9H11N3O S: C, 51.66; H, 5.30; N, 20.08. Found: C, 51.41; H, 5.04; N, 20.02. Mass spectrum (El, M.+) m/z 209. 1H-NMR (DMSO-d6 ; 400 MHz) δ9.88 (s, 1H), 7.70 (t, 1H), 7.52 (s, 1H), 7.47 (d, 2H), 7.31 (t, 2H), 7.15 (s, 1H), 7.09 (t, 1H), and 4.08 ppm (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].C(=O)(O)[O-].[Na+].Cl[CH2:19][C:20](Cl)=[O:21]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)(Cl)Cl>[O:12]1[C:11]2[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=2[NH:1][C:20](=[O:21])[CH2:19]1
Reactant: O=C(Cl)CCl
Reactant: COC(=O)c1ccc(O)c(N)c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In a 250 ml three-necked round-bottomed flask were placed methyl 3-amino-4-hydroxybenzoate (5 g, 30 mmole), benzyltriethylammonium chloride (6.8 g, 30 mmole), chloroform (75 ml) and powdered sodium bicarbonate (10.1 g, 120 mmole). The resulting mixture was cooled down to 0° C. and a solution of chloroacetyl chloride (4.1 g, 36 mmole) in chloroform (20 ml) was added dropwise at such a rate as to keep the reaction temperature between 0° C. to 3° C. After the addition was complete the reaction mixture was stirred at 0° C. for another 90 minutes, followed by slow heating to 55° C., kept at that temperature for 8 hours, and finally stirred at room temperature overnight. The solvent was removed in a rotary evaporator, the resulting crude product was taken up in water, shaken and filtered yielding, after drying in a vacuum oven, 5.8 g of the expected methyl 1,4-benzoxazine-3-one-6-carboxylate which was used in the next step without further purification.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]1([S:13]([O-:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Na+].Br[CH2:18][CH:19]=[C:20]([CH2:23][CH3:24])[CH2:21][CH3:22]>CO>[CH2:21]([C:20]([CH2:23][CH3:24])=[CH:19][CH2:18][S:13]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:15])=[O:14])[CH3:22]
Reactant: O=S([O-])c1ccccc1
Reactant: CCC(=CCBr)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CCC(=CCS(=O)(=O)c1ccccc1)CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
1.85 gm of sodium carbonate and 18.5 gm of sodium phenyl sulfinate were introduced into 60 cc of methanol. Then 20 gm of 1-bromo-3-ethyl-2-pentene were added within the space of about 30 minutes at room temperature to the resulting suspension, which then was agitated for 1 hour and 30 minutes at room temperature. Then the reaction mixture was poured into ice-water and the organic phase was was separated by decanting. The aqueous phase was extracted with ethyl ether and the ether extracts were combined with the principal organic solution. The solution thus obtained was dried over magnesium sulfate and the solvent was removed under reduced pressure to obtain 21.665 gm of (3-ethyl-2-pentenyl)-phenylsulfone. A sample of this product was rectified under reduced pressure and the boiling point was 125° C. under 0.02 mm pressure of mercury and its refractive index nD23 =1.530.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:12](=[CH:13][CH:14]=1)[CH:11]1[O:15][CH:7]2[CH2:8][NH:9][CH2:10]1)([O-:3])=[O:2].[CH2:16](Cl)[C:17]#[CH:18].C(=O)([O-])[O-].[K+].[K+].C1COCC1>C([O-])(O)=O.[Na+]>[N+:1]([C:4]1[CH:5]=[C:6]2[C:12](=[CH:13][CH:14]=1)[CH:11]1[O:15][CH:7]2[CH2:8][N:9]([CH2:18][C:17]#[CH:16])[CH2:10]1)([O-:3])=[O:2]
Reactant: C#CCCl
Reactant: O=[N+]([O-])c1ccc2c(c1)C1CNCC2O1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C#CCN1CC2OC(C1)c1cc([N+](=O)[O-])ccc12
Yield: 50.7 %

Procedure:
4-Nitro-12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene (200 mg, 0.97 mmol), propargyl chloride (0.085 mL, 1.2 mmol), potassium carbonate (276 mg, 2.0 mmol) and THF (5 mL) were stirred together at 70° C. for 18 h. The reaction was then diluted with saturated aqueous NaHCO3 (10 mL), extracted with CH2Cl2 (2×10 mL), dried over MgSO4, filtered, and concentrated. The remaining residue was purified with silica gel chromatography (0-100% EtOAc in hexanes) to give 4-Nitro-10-prop-2-ynyl-12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene as a brown oil (120 mg, 51%). MS (m/e) 245 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[CH2:7][CH:8]1[CH2:12][C:11](=[O:13])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:15]1([SH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C>CN(C)C=O.C1COCC1.O>[C:1]([O:5][C:6](=[O:14])[CH2:7][CH:8]([CH2:9][S:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:12][C:11]([OH:10])=[O:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: Sc1ccccc1
Reactant: CC(C)(C)OC(=O)CC1COC(=O)C1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(CSc1ccccc1)CC(=O)O
Temperature: 80 °C
Yield: 34.8 %

Procedure:
The product from step 1 (200 mg, 1.0 mmoles) and thio phenol (110 mg, 1 mmoles) were combined in dimethyl formamide (1.5 mL) at room temperature. Lithium(bis trimethyl silyl)amide (1.25 mL of a 1M solution in THF) was added and the reaction heated at 80° C. for 18 h. Reaction was diluted with water, made acidic with acetic acid and extracted with dichloromethane 2×40 mL. The combined extracts were washed with water 2×50 mL, brine 1×50 mL, dried and the solvent removed under pressure. The crude was chromatographed to give the product 108 mg (35%). MS (ESI+) for C16H22O4S m/z 333 (M+Na)+.
Reaction SMILES: [CH:1]1[C:10]2[C:11]3[CH2:16][NH:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.[BH3-]C#N.[Na+].[OH-].[Na+].O>C(O)(C(F)(F)F)=O>[CH:1]1[C:10]2[C@H:11]3[CH2:16][NH:15][CH2:14][CH2:13][C@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1
Reactant: c1cc2c3c(c1)c1c(n3CCC2)CCNC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: c1cc2c3c(c1)[C@H]1CNCC[C@H]1N3CCC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
5,6,8,9,10,11-Hexahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (2.84 g, 11.4 mmol) was dissolved in TFA (35 mL). The reaction was cooled to 0° C. NaCNBH3 (2.15 g, 34.27 mmol) was added in small portions over 30 min, keeping the temperature less than 5° C. The reaction was stirred at 0° C. for 2 h. Ice was added to the reaction flask, and the reaction was basified with 50% NaOH until pH=14. Water (20 mL) was added to dissolve the precipitate. The reaction was extracted with CHCl3 (3×20 mL). The combined organic layers were washed with brine, dried, and concentrated to afford the title compound (1.67 g, 68%) as a pale-brown, amorphous solid. 1H NMR (CDCl3, 300 MHz) δ 6.80-7.00 (m, 2H), 6.55-6.6.70 (m, 1H), 3.20-3.40 (m, 2H), 2.95-3.20 (m, 2H), 2.75-2.95 (m, 2H), 2.50-2.75 (m, 4H), 2.00-2.20 (m, 2H), 1.85-2.00 (m, 1H), 1.70-1.85 (m, 1H) ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10](F)=[CH:9][C:8]=1[N:14]([C@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])([CH3:4])([CH3:3])[CH3:2].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>O1CCCC1>[C:1]([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([N:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)=[CH:9][C:8]=1[N:14]([C@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: COC[C@@H](C)N(C(=O)C(F)(F)F)c1cc(F)ccc1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: COC[C@@H](C)N(C(=O)C(F)(F)F)c1cc(N2CCN(C)CC2)ccc1C(=O)OC(C)(C)C
Yield: 84.1 %

Procedure:
A solution of 4-fluoro-2-[((R)-2-methoxy-1-methyl-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-benzoic acid tert-butyl ester (2 g, 5.28 mmol) and N-methylpiperazine (5.86 mL, 52.8 mmol) in tetrahydrofuran (20 mL) was stirred at 60° C. for 7 days. The solution was then evaporated, NaHCO3 satured solution was added and the mixture extracted with dichloromethane (3 times). The organic layer was washed with water, brine, dried over sodium sulfate filtered and evaporated to obtain a crude, which was purified by column chromatography on silica gel (dichloromethane-methanol 93:7). The title compound (2.04 g, 84%) was obtained as yellowish solid.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>O.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][N:8]3[CH2:11][CH3:12])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: CCn1ccc2ccc(Br)cc21
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCn1ccc2ccc(-c3ccc(C(F)(F)F)cc3)cc21
Yield: 56.1 %

Procedure:
Following the procedure described in Step 2 of Example 2, 6-bromo-1-ethyl-1H-indole (0.400 g , 1.78 mmol), was coupled to 4-trifluoromethylbenzene boronic acid (0.348 g, 1.83 mmol), using tetrakis(triphenylphosphine)palladium (0.0668 g, 0.0578 mmol), and sodium carbonate (0.769 g, 7.26 mmol) in water (3.6 mL), ethanol (1.5 mL), and toluene (8 mL). Purification by flash chromatography using hexane as an eluant yielded the title compound as a yellow oil (0.289 g, 56%). 1HNMR (300 MHz, DMSO-d6): δ 7.95 (d, 2H, J=7.7 Hz), 7.9 (s, 1H), 7.8 (d, 2H, J=7.7 Hz), 7.65 (d, 1H, J=7.7 Hz), 7.5 (d, 1H, J=1.5 Hz), 7.45 (d, 1H, J=7.7 Hz), 6.45 (d, 1H, J=2.3 Hz), 4.3 (q, 2H, J=6.9 Hz) and 1.4 ppm (t, 3H, J=6.9 Hz).
Reaction SMILES: [Cl-].[NH4+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.C(OCC)(=O)C>O.CO.O1CCCC1.[Fe]>[F:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Sc2ccc(F)cc2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: Nc1ccc(Sc2ccc(F)cc2)cc1
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
To a solution of ammonium chloride (16.63 g, 311 mmol) in water (300 mL) are added iron (17.39 g, 311 mmol) and a solution of 1-fluoro-4-(4-nitrophenyl)sulfanyl-benzene (19.40 g, 78 mmol) in a mixture of methanol (100 mL) and tetrahydrofuran (100 mL). The resulting mixture is heated to 75° C. for 2.5 h and then cooled to room temperature. After addition of ethyl acetate (1 L), the mixture is stirred for 10 min the organic layer is decanted and collected. This procedure is repeated twice. The combined organic layers are dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude residue is first triturated twice with diethyl ether and then purified via column chromatography on silica gel (heptane/ethyl acetate 0 to 30% as eluent) to afford the desired product as a yellow solid (14.45 g, 66 mmol, 85% yield) (HPLC-MS Method 2: retention time: 1.939 min, m/z 261.0).
Reaction SMILES: Cl.[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](Cl)=[O:13])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:35][C@H:36]([CH3:46])[C:37]([N:39]1[CH2:43][CH2:42][CH2:41][C@H:40]1[C:44]#[N:45])=[O:38]>C(Cl)Cl>[C:44]([C@@H:40]1[CH2:41][CH2:42][CH2:43][N:39]1[C:37](=[O:38])[C@H:36]([NH:35][C:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:2]=[CH:3][CH:4]=1)=[O:13])[CH3:46])#[N:45]
Reactant: C[C@@H](N)C(=O)N1CCC[C@H]1C#N
Reactant: O=C(Cl)c1ccnc2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1ccnc2ccccc12)C(=O)N1CCC[C@H]1C#N

Procedure:
Quinoline-4-carbonyl chloride hydrochloride (0.067 g, 0.295 mmol) was added to a mixture of DIPEA (0.160 ml, 0.913 mmol) and (S)-1-((R)-2-aminopropanoyl)pyrrolidine-2-carbonitrile 4-methylbenzenesulfonate (0.100 g, 0.295 mmol) in DCM. After 3 h the mixture was washed with 1N citric acid and saturated sodium bicarbonate and brine. The organic layer was dried sodium sulfate, filtered and purified by column chromatography using a mixture of ethylacetate and methanol as eluents.
Reaction SMILES: [Cl:1][C:2]1(Cl)[CH:5]([O:6][CH2:7][CH:8]([CH3:10])[CH3:9])[C:4]([Cl:12])([Cl:11])[C:3]1=[O:13].C(N(CC)CC)C.CCCCCC.C(OCC)(=O)C>COC(C)(C)C>[Cl:1][C:2]1[C:3](=[O:13])[C:4]([Cl:12])([Cl:11])[C:5]=1[O:6][CH2:7][CH:8]([CH3:9])[CH3:10]
Reactant: CC(C)COC1C(Cl)(Cl)C(=O)C1(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC(C)COC1=C(Cl)C(=O)C1(Cl)Cl
Temperature: 25 °C
Yield: 77 %

Procedure:
A solution formed by dissolving 5.0 g of 2,2,4,4-tetrachloro-3-isobutoxycyclobutanone (compound (I)) and 3.6 g of triethylamine in 50 ml of tert-butyl methyl ether was refluxed for four hours. After cooling to room temperature, the solution was washed using 50 ml of 1 mol/L hydrochloric acid, and the organic layer was concentrated. The concentrated residues were separated by means of silica gel column chromatography (the composition of the developing solvent: n-hexane / ethyl acetate=100/1), to yield 3.3 g of the compound (II), 2,4,4-trichloro-3-isobutoxy-2-cyclobutene-1-one (yield=77%).