Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:11]([C:21]1([OH:24])[CH2:23][CH2:22]1)([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH2:12][CH3:13].CN1CCOCC1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]([N:6]2[C:7]3[C:3](=[C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:5]2)([C:21]2([OH:24])[CH2:22][CH2:23]2)[CH2:12][CH3:13])=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCC(c1ccc(Cl)cc1)(n1ccc2c(N)cccc21)C1(O)CC1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(c1ccc(Cl)cc1)(n1ccc2c(NS(C)(=O)=O)cccc21)C1(O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of compound from step B (83 mg, 0.22 mmol) and NMM (44 mg, 0.44 mmol) in DCM (5 mL) was added methylsulfonyl chloride (37 mg, 0.3 mmol) dropwise. Then the mixture was stirred at room temperature overnight. The reaction was quenched with saturated ammonium chloride solution, and extracted with ethyl acetate (20 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by Pre-HPLC to afford the title compound as a white solid. LC/MS m/z=419.1[M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17].N1CCCCC1>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:5]=[CH:15][C:16]([OH:18])=[O:17])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C=O)c(OC)c1Cl
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1ccc(C=CC(=O)O)c(OC)c1Cl
Yield: 95 %

Procedure:
A solution of compound (2a) (11.07 g, 55.2 mmol), malonic acid (8.639 g, 83 mmol) and piperidine (2 ml, 1.722 g, 20.2 mmol) in 80 ml of anhydrous pyridine was refluxed (bath temperature 110° C.) for 2 h. Reaction mixture was cooled, concentrated under vacuum and acidified 250 ml of 5% aqueous citric acid to a pH of 3. Resulted heterogeneous mixture was sonicated for a few minutes. The precipitated material was filtered off, washed with water (2×20 ml) and dried in vacuum over KOH to give 12.7 g (52.3 mmol, 95% yield) of pure (HPLC, 1H NMR) desired acid 3a as a white solid. 1H NMR (DMSO-d6): δ 7.77 (d, J=9.0 Hz, 1H), 7.67 (d, J=16.0 Hz, 1H), 7.01 (d, J=9.0 Hz, 1H), 6.51 (d, J=16.0 Hz, 1H), 3.90 (s, 3H), 3.77 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[C:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=3)=[N:11][CH:10]=[N:9]2)[N:5]=[C:4]([CH3:24])[N:3]=1.[C:25]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=1)#[CH:26]>C(#N)C.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>[CH3:23][O:22][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[O:20][CH3:21])[CH2:13][C:12]1[N:8]([C:6]2[CH:7]=[C:2]([C:26]#[C:25][C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=3)[N:3]=[C:4]([CH3:24])[N:5]=2)[N:9]=[CH:10][N:11]=1
Reactant: C#Cc1ccc(C)cn1
Reactant: COc1ccc(Cc2ncnn2-c2cc(Cl)nc(C)n2)cc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(Cc2ncnn2-c2cc(C#Cc3ccc(C)cn3)nc(C)n2)cc1OC
Temperature: 50 °C

Procedure:
A slurry of 4-chloro-6-(5-(3,4-dimethoxybenzyl)-1H-1,2,4-triazol-1-yl)-2-methylpyrimidine (1-3, 100 mg, 0.289 mmol, 1.0 eq), 2-ethynyl-5-methylpyridine (67.8 mg, 0.578 mmol, 2.0 eq), bis(triphenylphosphine)palladium(II) dichloride (10.15 mg, 0.014 mmol. 0.050 eq.) and copper(I) iodide (2.203 mg, 0.012 mmol 0.040 eq.) in a mixture of acetonitrile (1 ml) and triethylamine (1 mL) was heated at 50° C. for 16 h. The solvents were removed by roto-evaporation and the resulting residue was purified by silica gel column chromatography (0-100% ethyl acetate in hexanes) to afford 4-(5-(3,4-dimethoxybenzyl)-1H-1,2,4-triazol-1-yl)-2-methyl-6-((5-methylpyridin-2-yl)ethynyl)pyrimidine (1-4). 1H NMR (500 MHz, CDCl3) δ 8.78 (s, 1H), 7.94 (m, 2H), 7.69 (m, 2H), 6.86 (m, 2H), 6.79 (d, 1H, J=8.2 Hz), 4.79 (s, 2H), 3.84 (s, 6H), 2.82 (s, 3H), 2.54 (s, 3H). HRMS m/z (M+H) 429.2029 found, 429.2034 required.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1.Cl.[CH3:22][O-:23].[Na+]>CN(C)C=O>[CH:22]([NH:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:23]
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCc2ccccc21
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=CNc1cc(C(F)(F)F)ccc1N1CCc2ccccc21
Reaction time: 0.08 h

Procedure:
A stirred solution of 15.7 g of 1-(2-amino-4-trifluoromethylphenyl)indoline.HCl in 75 ml of dry dimethylformamide, kept under N2, is immersed in an oil bath preheated to 100° C. After 5 minutes, 8.1 g of fresh, solid sodium methoxide is added in one portion. The mixture is quickly (15 minutes) brought to reflux, and kept at reflux an additional 45 minutes. The heating bath is then removed and when the internal temperature falls to 100° C., 300 ml of water is added in portions, with vigorous stirring. The product separates first as an oil which then solidifies. This material is filtered, washed with H2O, with alcohol, and dried to afford 1-(2-formamido-4-trifluoromethylphenyl)indoline, m.p. 135°-357° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[C:10]2=[CH:11][CH:12]=[CH:13][N:9]2[CH2:8][C:7]2[CH:14]=[CH:15][CH:16]=[CH:17][C:6]=2[NH:5]1.[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20]>>[CH3:1][N:2]([CH2:3][CH:4]1[C:10]2=[CH:11][CH:12]=[CH:13][N:9]2[CH2:8][C:7]2[CH:14]=[CH:15][CH:16]=[CH:17][C:6]=2[NH:5]1)[CH2:20][CH2:19][C:18]([O:22][CH3:23])=[O:21]
Reactant: CNCC1Nc2ccccc2Cn2cccc21
Reactant: C=CC(=O)OC
Product: COC(=O)CCN(C)CC1Nc2ccccc2Cn2cccc21

Procedure:
The starting material is prepared as follows: The solution of 1.5 g of 11-(N-methylaminomethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (Example 1) in 7.5 ml of methyl acrylate is stirred at room temperature for 24 hours and the excess reagent is evaporated to yield the 11-(N-methyl-N-methoxycarbonylethylamino-methyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine as an oil, which is chromatographed on silica gel and eluted with 2% methanol-methylene chloride.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[N:3]1[CH2:8][CH2:7][C:6]([NH:11][OH:12])([C:9]#[N:10])[CH2:5][CH2:4]1.C(=O)(O)[O-].[Na+].[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:21]=1[CH2:28][C:29](Cl)=[O:30].O>O1CCCC1>[C:9]([C:6]1([N:11]([OH:12])[C:29](=[O:30])[CH2:28][C:21]2[C:20]([CH3:19])=[CH:25][C:24]([CH3:26])=[CH:23][C:22]=2[CH3:27])[CH2:7][CH2:8][N:3]([N:2]([CH3:13])[CH3:1])[CH2:4][CH2:5]1)#[N:10]
Reactant: CN(C)N1CCC(C#N)(NO)CC1
Reactant: Cc1cc(C)c(CC(=O)Cl)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)c(CC(=O)N(O)C2(C#N)CCN(N(C)C)CC2)c(C)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
4.31 g 1-Dimethylamino-4-hydroxyamino-piperidine-4-carbonitrile (from Step 2) is dissolved in 70 ml tetrahydrofuran. 3.34 g sodium bicarbonate is added, and the mixture cooled to 0° C. Then at 0° C., a solution of (2,4,6-trimethyl-phenyl)-acetyl chloride in 30 ml tetrahydrofuran is added slowly. The mixture is allowed to warm to room temperature and stirred for 4 hours. The water is added and three times extracted with ethyl acetate. The organic layer is separated, washed with brine, dried over sodium sulfate, and the solvent is evaporated. The residue is purified by chromatography, with ethyl acetate/cyclohexane (2:1) as a solvent. Thus, 3.9 g N-(4-Cyano-1-dimethylamino-piperidin-4-yl)-N-hydroxy-2-(2,4,6-trimethyl-phenyl)-acetamide is obtained. 1H-NMR (CDCl3): 8.18 ppm (s, broad, 1H), 6.86 ppm (s, 2H), 3.81 ppm (s, 2H), 2.97 ppm (m, 2H), 2.72 ppm (m, 2H), 2.52 ppm (m, 2H), 2.40 ppm (s, 6H), 2.25 ppm (s, 3H), 2.21 ppm (s, 6H), 2.12 ppm (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([CH3:22])[CH:17]=1.O>CN(C)C(=O)C>[CH3:22][C:18]1[CH:17]=[C:16]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:21]=[CH:20][N:19]=1
Reactant: Cc1cc(Cl)ccn1
Reactant: Nc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(Oc2ccc(N)cc2)ccn1
Temperature: 9 °C
Yield: 63.9 %

Procedure:
4-aminophenol (44.9 g, 410 mmol) was added to the 1 L 3-neck flask and dissolved with N,N-dimethylacetamide (600 mL). The stirred mixture was then cooled to 9° C. and potassium t-butoxide (46.18 g, 410 mmol) was added portionwise; the solution turned green and solidified before potassium t-butoxide addition was completed. Stirring was reestablished and a solution containing the 4-chloro-2-picoline (50 g, 390 mmol) in N,N-dimethylacetamide (400 mL) was slowly added and the mixture was heated at 90° C. for 17 h. The mixture was then allowed to cool to 45° C., filtered and concentrated to near dryness in vacuo to leave brown residue. The residue was slowly added to vigorously stirred water (1 L) and the suspension was stirred for 1 hr. The solids were then collected by suction filtration and washed with small amount of isopropanol, ether and dried to afford {4-[(2-Methylpyridin-4-yl) oxy] phenyl} amine (49.9 g, 64%) as light tan solid. 1H NMR (DMSO-d6) δ 8.21 (d, 1H), 6.78 (d, 2H), 6.57-6.63 (m, 4H), 5.10 (s, 2H), 2.35 (s, 3H); MS ES 201 (M+H)+, calcd 201, RT=1.04 min.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH:8]=[CH:9][C:10]([OH:12])=O)=[O:7])=[CH:4][CH:3]=1.C(OC(Cl)=O)C.C(N(CC)CC)C.[CH:28]([NH2:31])([CH3:30])[CH3:29]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:7])[CH:8]=[CH:9][C:10]([NH:31][CH:28]([CH3:30])[CH3:29])=[O:12])=[CH:13][CH:14]=1
Reactant: CC(C)N
Reactant: O=C(O)C=CC(=O)c1ccc(Cl)cc1
Agent: CCOC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)C=CC(=O)c1ccc(Cl)cc1

Procedure:
The precursor 4-(4-chlorophenyl)-N-(1-methylethyl)-4-oxo-2-butenamide (7A) was prepared by the procedure shown in the previous examples by treating 1A with ethylchloroformate and triethylamine in toluene at 0°, then adding at 0° a solution of isopropylamine in toluene. 7A was obtained as a solid, m.p.: 162°-163°. It was converted to 7 by treatment with hydrogen perioxide, by the procedure described in Example 1, 7 being obtained as a solid, m.p.: 128-129°.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:3]=1.[F:22][C:23]1[C:28]([F:29])=[C:27]([F:30])[C:26]([F:31])=[C:25]([F:32])[C:24]=1[OH:33]>>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:6]=[N:7][C:2]([O:33][C:24]3[C:25]([F:32])=[C:26]([F:31])[C:27]([F:30])=[C:28]([F:29])[C:23]=3[F:22])=[CH:3][C:4]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][CH:10]=1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: COc1ccc(-c2nnc(Cl)cc2-c2ccccc2)cc1
Product: COc1ccc(-c2nnc(Oc3c(F)c(F)c(F)c(F)c3F)cc2-c2ccccc2)cc1

Procedure:
In a similar manner as in Example 2, 6-chloro-3-(4-methoxyphenyl)-4-phenylpyridazine (200 mg, 0.675 mmol) and 2,3,4,5,6-pentafluorophenol were reacted as starting materials at 150° C. for 48 hours and post-treatment was then conducted, whereby the title compound was obtained as a colorless crystalline powder (91.2 mg, 30.5%). Melting point: 133.1-133.9° C. (ethyl acetate-hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH:6]=[O:7].[C:13](O)(=[O:16])[CH2:14][SH:15].B(F)(F)F.CCOCC>CCOCC>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH:6]1[S:15][CH2:14][C:13](=[O:16])[O:7]1
Reactant: O=CCOc1ccc(Cl)cc1Cl
Reactant: O=C(O)CS
Agent: FB(F)F
Solvent: CCOCC
Product: O=C1CSC(COc2ccc(Cl)cc2Cl)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.1 %

Procedure:
A solution containing 10.25g (0.05 mole) of 2,4-dichlorophenoxyacetaldehyde, 5.1g (0.055 mole) of thioglycolic acid and 15g (0.15 mole) of boron trifluoride etherate in 250 ml of ether was stirred at ambient temperature for 2 hours, washed with 5% aqueous sodium carbonate, dried, concentrated, and triturated with hexane to give 5.6g of 2-(2,4-dichlorophenoxymethyl)-1,3-oxathiolan-5-one as an off-white crystalline solid melting at 59°-61°.
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([C@@H:10]3[CH2:12][O:11]3)[CH:7]=[CH:6][C:5]=12.[CH:13]1([NH2:16])[CH2:15][CH2:14]1>C(O)C>[CH:13]1([NH:16][CH2:12][C@@H:10]([C:8]2[CH:7]=[CH:6][C:5]3[N:4]([N:3]=[N:2][N:1]=3)[CH:9]=2)[OH:11])[CH2:15][CH2:14]1
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Reactant: NC1CC1
Solvent: CCO
Product: O[C@@H](CNC1CC1)c1ccc2nnnn2c1
Temperature: 100 °C
Yield: 70.3 %

Procedure:
A solution of 375 mg (2.31 mmol) of (R)-2-(tetrazolo[1,5-a]pyrid-6-yl)oxirane and 652 mg (11.4 mmol) of cyclopropyl amine in 0.9 ml of absolute ethanol in a sealed reaction tube was heated at 100° C. for 3 hours. The reaction mixture was concentrated to dryness to yield 452 mg of crude product. Chromatography on silica gel (90:10:1 methylene chloride:methanol:conc. ammonium hydroxide) afforded 356 mg of product, m.p. 137°-39°.
Reaction SMILES: [H-].[Na+].[NH2:3]/[C:4](/[C:11]([F:14])([F:13])[F:12])=[CH:5]\[C:6]([O:8]CC)=O.[Cl:15][C:16]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][C:17]=1[C:18]([O:20][C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:19].Cl>C(OCC)C.CN(C)C=O>[Cl:15][C:16]1[CH:32]=[CH:31][C:30]([N:33]2[C:6](=[O:8])[CH:5]=[C:4]([C:11]([F:12])([F:13])[F:14])[NH:3][C:34]2=[O:35])=[CH:29][C:17]=1[C:18]([O:20][C:21]([CH3:27])([CH3:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:19]
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: CCOC(=O)C(C)(C)OC(=O)c1cc(N=C=O)ccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)OC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)ccc1Cl
Temperature: -5 °C

Procedure:
4.9 g of sodium hydride (50% dispersion in white oil) are added to 120 ml of dimethylformamide while stirring and the mixture is cooled to -5° C. At this temperature a solution of 22.4 g of ethyl 3-amino-4,4,4-trifluorocrotonate in 180 ml of diethyl ether is added dropwise during 30 minutes. The reaction mixture is stirred at room temperature for one hour and thereafter cooled to -65° C. A solution of 28 g of ethyl 2-(2-chloro-5-isocyanato-benzoyloxy)-2-methylpropionate in 100 ml of dimethylformamide is now added dropwise during 30 minutes. The reaction mixture is stirred at -65° C. for 2 hours; thereafter it is left to warm to room temperature. The reaction mixture is introduced into 300 ml of 1N hydrochloric acid at 0° C. The mixture is extracted twice with 300 ml of ethyl acetate each time. The organic phases are back-washed once with 200 ml of water and once with 200 ml of saturated sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue is recrystallized from ethyl acetate/n-hexane. There is obtained ethyl 2-{2-chloro-5-[3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2H)-pyrimidinyl]-benzoyloxy}-2-methylpropionate, m.p. 176°-177° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH2:21]([CH:23]([CH2:27][CH2:28][CH2:29][CH3:30])[C:24]([Cl:26])=[O:25])[CH3:22]>C(Cl)Cl>[ClH:26].[CH2:21]([CH:23]([CH2:27][CH2:28][CH2:29][CH3:30])[C:24]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=[O:25])[CH3:22]
Reactant: CCCCC(CC)C(=O)Cl
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(CC)C(=O)NCCCSc1ccncc1
Yield: 92.8 %

Procedure:
To a solution of 800 mg (3.32 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.22 ml (15.9 mmol) of triethylamine in 30 ml of methylene chloride was added 0.69 ml (3.98 mmol) of 2-ethylhexanoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 1.02 g of the desired compound (free base) (quant., pale yellow oil).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2([C:16]3=[CH:17][C:18]4[O:22][CH2:21][O:20][C:19]=4[CH:23]=[C:15]3[O:14][CH2:13]2)[C:5]1=[O:24].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br.C(N(CC)CC)C>C1COCC1>[N:1]1([CH2:2][CH2:3][N:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]3([C:16]4=[CH:17][C:18]5[O:22][CH2:21][O:20][C:19]=5[CH:23]=[C:15]4[O:14][CH2:13]3)[C:5]2=[O:24])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: BrCCCCCBr
Reactant: NCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1N(CCN2CCCCC2)c2ccccc2C12COc1cc3c(cc12)OCO3

Procedure:
A mixture of 1′-(2-aminoethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.20 g, 0.62 mmol), 1,5-dibromopentane (0.08 mL, 0.62 mmol) and triethyl amine (0.17 mL, 1.23 mmol) in THF (10.0 mL) was refluxed for 15 hrs and concentrated in vacuo to dryness. The residue was subjected to flash chromatography eluting with 10% methanol in ethyl acetate to give 1′-(2-piperidin-1-ylethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, which was treated with 4.0 M HCl in dioxane to give the title compound (28%): mp >240° C.; 1H NMR (300 MHz, CD3OD) δ 7.40 (t, 1H), 7.27-7.11 (m, 3H), 6.51 (s, 1H), 6.17 (s, 1H), 5.86 (s, 2H), 4.91 (d, 1H), 4.71 (d, 1H), 4.40-4.13 (m, 2H), 3.95-3.84 (m, 1H), 3.66-3.37 (m, 3H), 3.14-2.96 (m, 2H), 2.06-1.45 (m, 6H); 13C NMR (75 MHz, CD3OD) δ 180.4, 157.5, 150.5, 143.8, 142.5, 133.9, 130.3, 125.3, 125.1, 120.6, 110.2, 103.9, 102.9, 94.2, 81.4, 59.7, 55.4, 54.9, 53.9, 36.4, 24.2, 22.6; MS (ES+) m/z 393 (M+1).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[C:38]1([CH:44]([NH2:46])[CH3:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH3:35][O:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:46][CH:44]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH3:45])=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Reactant: CC(N)c1ccccc1
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NC(C)c4ccccc4)n3Cc3ccccc32)ccc1-c1ccccc1C

Procedure:
The title compound was prepared in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and (±)-1-phenylethylamine. Purification was performed using HPLC with a normal phase column by eluting with a two phase solvent system (A=hexane, B=dichloromethane/methanol, 4:1) that gave the title compound in 63% yield, m.p. 211° C. MS [(+)ESI, m/z]: 554 [M+H]+ Anal. Calcd for C36H33N3O3: C, 77.81; H, 5.99; N, 7.56. Found: C, 77.65; H, 6.01; N, 7.45.
Reaction SMILES: CO[C:3](=[O:17])[C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:16])=[C:12]([F:15])[CH:13]=2)[NH:8][CH:7]=1)=O.[C:18]1([CH2:30][C:31]([NH2:33])=[O:32])[C:28]2=[C:29]3[C:24](=[CH:25][CH:26]=[CH:27]2)[CH2:23][CH2:22][CH2:21][N:20]3[CH:19]=1>>[C:18]1([C:30]2[C:31](=[O:32])[NH:33][C:3](=[O:17])[C:4]=2[C:6]2[C:14]3[C:9](=[CH:10][C:11]([Cl:16])=[C:12]([F:15])[CH:13]=3)[NH:8][CH:7]=2)[C:28]2=[C:29]3[C:24](=[CH:25][CH:26]=[CH:27]2)[CH2:23][CH2:22][CH2:21][N:20]3[CH:19]=1
Reactant: NC(=O)Cc1cn2c3c(cccc13)CCC2
Reactant: COC(=O)C(=O)c1c[nH]c2cc(Cl)c(F)cc12
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2cc(Cl)c(F)cc12

Procedure:
Beginning with (5-fluoro-6-chloroindol-3-yl)oxoacetic acid methyl ester and 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)acetamide, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:13])[CH2:11][CH3:12])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:13][C:22]3[N:30]=[CH:29][N:28]=[C:27]4[C:23]=3[NH:24][CH:25]=[N:26]4)[CH2:11][CH3:12])[N:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[CH:20]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: CC[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC[C@H](Nc1ncnc2nc[nH]c12)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 21 %

Procedure:
A mixture of (S)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)propylamine from Example 28 (42 mg, 0.16 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (37 mg, 0.16 mmol) and DIPEA (0.14 mL, 0.8 mmol) in n-butanol (1 mL) was stirred in a sealed vial for 16 h at 90° C. After cooling to RT, the crude reaction mixture was loaded into an Isolute® SCX-2 which was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) affording 160 as a white solid (13 mg, 21%). LCMS: RT 3.61 min [M+H]+ 388.1. 1H NMR (DMSO, 400 MHz): δ 8.22-8.03 (2H, m), 7.80 (1H, s), 7.71-7.43 (6H, m), 7.09 (1H, t, J=9.42 Hz), 6.85 (1H, d, J=8.93 Hz), 5.38 (1H, s), 2.08-1.88 (2H, m), 0.83 (3H, t, J=7.34 Hz)
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:8]=2)[C:3]1=[O:15].[CH3:16][NH:17][C:18]([NH:20][CH3:21])=[S:19]>CC(C)=O>[CH3:14][S:11]([C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][CH:2]3[S:19][C:18](=[N:17][CH3:16])[N:20]([CH3:21])[C:3]3([OH:15])[C:4]=2[CH:5]=1)(=[O:13])=[O:12]
Reactant: CNC(=S)NC
Reactant: CS(=O)(=O)c1ccc2c(c1)C(=O)C(Br)C2
Solvent: CC(C)=O
Product: CN=C1SC2Cc3ccc(S(C)(=O)=O)cc3C2(O)N1C
Reaction time: 0.17 h

Procedure:
1.45 g of 2-bromo-6-methanesulfonyl-1-indanone are dissolved in 15 ml of acetone and, while stirring, 0.65 g of N,N′-dimethylthiourea in 10 ml of acetone is added. The solution is initially clear but, after about 10 min, the hydrobromide of 5-methanesulfonyl-3-methyl-2-methylimino-2,3,8,8a-tetrahydroindeno[1,2-d]thiazol-3a-ol crystallizes out. Stirring, at room temperature for 1 h is followed by filtration with suction and washing with a little acetone. 2.1 g of hydrobromide (melting point 265° C.) are suspended in 10 ml of methanol, and 1 ml of triethylamine is added. After 15 min, 150 ml of water is added, and the mixture is stirred while cooling in ice for 1 h. The product which is formed is filtered off with suction and washed with a little cold water. 5-Methanesulfonyl-3-methyl-2-methylimino-2,3,8,8a-tetrahydroindeno[1,2-d]thiazol-3a-ol is obtained with a melting point of 158° C.