Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14]CC)=O)[N:3]=1.[F:17][C:18]1[CH:19]=[C:20]([Mg]Br)[CH:21]=[CH:22][C:23]=1[F:24].C1COCC1.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([C:21]2[CH:20]=[CH:19][C:18]([F:17])=[C:23]([F:24])[CH:22]=2)=[O:14])[N:3]=1
Reactant: CCOC(=O)c1nc(Cl)c2ccccc2n1
Reactant: Fc1ccc([Mg]Br)cc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(c1ccc(F)c(F)c1)c1nc(Cl)c2ccccc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 25.8 %

Procedure:
A mixture of ethyl 4-chloroquinazoline-2-carboxylate (1 g, 4.2 mmol) in THF (50 mL) was filtered, and to the filtrate at −30° C. under Ar was added 0.5M (3,4-difluorophenyl)magnesium bromide/THF (10.4 mL, 5.2 mmol). The mixture was stirred at −30° C. for 1.5 h., at which time additional 0.5M (3,4-difluorophenyl)magnesium bromide/THF (3 mL) was added. After a further 1.5 h, additional 0.5M (3,4-difluorophenyl)magnesium bromide/THF (3 mL) was added. To the mixture was added saturated aq ammonium chloride and the mixture was allowed to warm to rt. The mixture was extracted with EtOAc (2×) and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford (4-chloroquinazolin-2-yl)(3,4-difluorophenyl)methanone (330 mg, 26%), which was used directly in the next step.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:14]1[CH:26]=[CH:25][C:17]([C:18]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O>[O:19]=[C:18]([C:17]1[CH:25]=[CH:26][C:14]([N:10]2[CH2:9][CH2:8][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11]2)=[CH:15][CH:16]=1)[CH2:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)CCC(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1
Temperature: 120 °C
Yield: 53.5 %

Procedure:
A stirred mixture of 4-phenyl-piperidine (10.4 g, 0.064 mol), 3-(4-fluorobenzoyl)-propionic acid (12.1 g, 0.062 mol), and potassium carbonate (17.5 g, 0.13 mol) in DMSO (15 mL) was heated under an atmosphere of nitrogen at 120° C. for 18 hours. The mixture was allowed to cool, diluted with water (100 mL), and brought to pH 2 dropwise with 1 M HCl. The resulting solid was filtered, washed with water, and dried in vacuo to yield a pale orange solid as the title compound (11.2 g, %C,H,N found: 74.54, 6.98, 4.07).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].Cl[CH2:25][C:26]1[N:27]=[C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[S:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:25][C:26]3[N:27]=[C:28]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[S:29][CH:30]=3)=[CH:21][CH:22]=2)[N:5]=1)[CH3:2]
Reactant: ClCc1csc(-c2ccccc2)n1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1nn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]propionate (1.50 g), 4-chloromethyl-2-phenylthiazole (1.05 g), potassium carbonate (1.30 g), and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). A mixture of the obtained oily substance, 1 N aqueous sodium hydroxide solution (10 ml), tetrahydrofuran (10 ml), and ethanol (10 ml) was stirred at room temperature for two hours, diluted with 1 N hydrochloric acid (10 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration and 3-[3-ethoxy-1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (1.60 g, yield: 73%) was obtained. This was recrystallized from acetone-hexane. Melting point: 114–115° C.
Reaction SMILES: [CH3:1][N:2]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)=[CH:11][C:10]=2[S:9](=[O:26])[C:8]2[C:3]1=[CH:4][CH:5]=[C:6]([C:27]1[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=1)[CH:7]=2.ClC1C=CC=C(C(OO)=[O:45])C=1>>[CH3:1][N:2]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)=[CH:11][C:10]=2[S:9](=[O:45])(=[O:26])[C:8]2[C:3]1=[CH:4][CH:5]=[C:6]([C:27]1[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=1)[CH:7]=2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN1c2ccc(-c3cccc4ccccc34)cc2S(=O)c2cc(-c3cccc4ccccc34)ccc21
Product: CN1c2ccc(-c3cccc4ccccc34)cc2S(=O)(=O)c2cc(-c3cccc4ccccc34)ccc21

Procedure:
For the preparation as a by-product in the synthesis of 10-methyl-3,7-bis(1-naphthyl)phenothiazine 5-oxide, see under Example 5. For a selective preparation of the sulfone, at least two molar equivalents of m-chloroperbenzoic acid are used.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:4]=1[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][C:12]2[CH2:13][NH:14][CH2:15][CH2:16][C:17]=2[N:18]=1)=[NH:8].[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:4]=1[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][C:12]2[CH2:13][N:14]([S:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:33])=[O:32])[CH2:15][CH2:16][C:17]=2[N:18]=1)=[NH:8]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1cccc(OC)c1CNC(=N)Nc1nc2c(s1)CNCC2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cccc(OC)c1CNC(=N)Nc1nc2c(s1)CN(S(=O)(=O)c1ccccc1)CC2
Yield: 34.2 %

Procedure:
Reaction of 30 mg N-(2,6-dimethoxybenzyl)-N′-(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-yl)guanidine (0.09 mmol, Example 221.3) with 18 mg phenylsulfonic acid chloride and 40 mg polymer-bound DMAP (Argonaut; 1.06 mmol/g) in 5 ml dichloromethane followed by chromatographic purification (dichloromethane/methanol 2-4%) yielded 15 mg of the target product; ESI-MS [M+H+]=488.15.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:23][C:24]1[S:25][C:26]([C:30]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[C:27]([CH3:29])[N:28]=1>O1CCCC1>[CH2:33]([NH:32][C:30]([C:26]1[S:25][C:24]([NH:23][C:5](=[O:7])[CH2:4][CH2:3][CH2:2][Br:1])=[N:28][C:27]=1[CH3:29])=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(O)CCCBr
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1nc(NC(=O)CCCBr)sc1C(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a solution of 4-bromobutyric acid (0.94 g, 5.50 mmol) and 4-methylmorpholine (0.70 mL, 6.20 mmol) in tetrahydrofuran (40 mL) was added isobutyl chloroformate (0.75 mL, 5.60 mmol) at 0° C. The resulting reaction mixture was stirred at 0° C. for 2 hours and then 2-amino-N-benzyl-4-methylthiazole-5-carboxamide (1.24 g, 5.00 mmol) was added. After 14 hours at ambient temperature, the solvent was removed in vacuo, and the residue was dissolved in ethyl acetate (200 mL), washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the residue was purified by column chromatography to yield the title compound (1.80 g, 90%): 1H NMR (300 MHz, CDCl3) δ 7.30-7.23 (m, 5H), 5.99 (s, 1H), 4.57-4.55 (m, 2H), 4.34-4.27 (m, 2H), 3.38-3.44 (m, 2H), 2.64-2.18 (m, 5H); MS (ES+) m/z 396.3 (M+1) and 398.3 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH3:8])[C:6]2[C:9]([O:17][CH3:18])=[C:10]([O:15][CH3:16])[C:11]([O:13][CH3:14])=[CH:12][C:5]=2[N:4]=1.[NH:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:8][N:7]1[C:6]2[C:9]([O:17][CH3:18])=[C:10]([O:15][CH3:16])[C:11]([O:13][CH3:14])=[CH:12][C:5]=2[N:4]=[C:3]1[CH2:2][N:19]1[CH2:25][CH2:24][CH2:23][N:22]([CH2:2][C:3]2[N:7]([CH3:8])[C:6]3[C:9]([O:17][CH3:18])=[C:10]([O:15][CH3:16])[C:11]([O:13][CH3:14])=[CH:12][C:5]=3[N:4]=2)[CH2:21][CH2:20]1
Reactant: C1CNCCNC1
Reactant: COc1cc2nc(CCl)n(C)c2c(OC)c1OC
Product: COc1cc2nc(CN3CCCN(Cc4nc5cc(OC)c(OC)c(OC)c5n4C)CC3)n(C)c2c(OC)c1OC

Procedure:
2-Chloromethyl-1-methyl-5,6,7-trimethoxy-benzimidazole (39 mg) and homopiperazine (7 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:28][C:29](=O)[CH2:30][C:31](=[O:43])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH:42]=[N:41][N:40]=[CH:39]2)[CH:33]=1)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:11]([C:20]([F:21])([F:22])[F:23])=[CH:10][C:9]=1[NH:24][C:29](=[O:28])[CH2:30][C:31](=[O:43])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH:39]=[N:40][N:41]=[CH:42]2)[CH:33]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1N
Reactant: CCOC(=O)CC(=O)c1cccc(-n2cnnc2)c1
Product: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2cnnc2)c1

Procedure:
The title compound was prepared from (2-amino-5-morpholin-4-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J1) (434 mg, 1.2 mmol) and 3-oxo-3-(3-[1,2,4]triazol-4-yl-phenyl)-propionic acid ethyl ester [CAS-No. 335255-97-5] (259 mg, 1.0 mmol) according to the general procedure M. Obtained as an off-white solid (372 mg).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])=[N:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:15][C:16]2[CH:21]=[N:20][C:19]([O:22][CH2:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])=[CH:18][CH:17]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)C(F)(F)COc1ccc(CCl)cn1
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)n1ncc(SCc2ccc(OCC(F)(F)C(F)F)nc2)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
In 40 ml of acetonitrile were dissolved 2.2 g of 2-t-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone and 2.7 g of 5-chloromethyl-2-(2,2,3,3-tetrafluoropropyloxy)-pyridine, and thereto was added 1.5 g of potassium carbonate. The reaction mixture was stirred overnight at room temperature, poured into water and extracted with benzene. The organic layer was washed with a 5% aqueous solution of sodium hydroxide and then with water, and dried over anhydrous sodium sulfate. Solvent was distilled off under reduced pressure and the resulting crystals were washed with n-hexane to obtain 4.0 g of 2-t-butyl-4-chloro-5-[{6-(2,2,3,3-tetrafluoropropyloxy)-3-pyridyl}-methylthio]-3(2H)-pyridazinone, m.p. 113.0°~114.0° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14]I)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][N:3]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Na+].O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:14])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][N:3]=1
Reactant: Fc1ccc(C2(CI)CCOCC2)cn1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(c2ccc(F)nc2)CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
To a solution of (2-fluoro-5-(4-(iodomethyl)tetrahydro-2H-pyran-4-yl)pyridine (330 mg, 1.03 mmol) in THF (5 mL) at −15° C., was added N-selectride (2.26 mL, 2.26 mmol) dropwise. The solution was stirred at ambient temperature for 16 h. The solution was recooled in an ice bath, and 0.3 mL of water was added. The resulting solution was stirred for 10 min. The solvent was removed under vacuum, and the residue was dissolved in DCM. Insoluble solid was filtered, and the filtrate was purified by flash column chromatography on silica gel (ISCO) eluting with 0-80% ethyl acetate in heptane to give to 2-fluoro-5-(4-methyltetrahydro-2H-pyran-4-yl)pyridine (110 mg, 0.56 mmol, 54.8% yield) as colorless oil with >90% purity. LCMS (m/z): 196 (MH+), 0.64 min.
Reaction SMILES: FC(O[C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:12])=O.[FH:13]>>[CH3:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=1[F:13]
Reactant: Cc1cccc(C)c1OC(=O)F
Reactant: F
Product: Cc1cccc(C)c1F
Temperature: 140 °C
Yield: 75 %

Procedure:
200 ml of anhydrous hydrogen fluoride were placed at 0° C. in a stainless steel laboratory autoclave and 100 g of 2,6-dimethylphenyl fluoroformate were added dropwise. The autoclave was sealed and heated at a maximum temperature of 140° C. for 1.5 hours. The reaction mixture was worked up as described in Example 9. 2,6-Dimethylfluorobenzene was obtained in a yield of 75%.
Reaction SMILES: [BrH:1].[F:2][C:3]([F:16])([F:15])[C:4]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:5]=1N.N([O-])=O.[Na+]>O.[Cu]>[F:2][C:3]([F:16])([F:15])[C:4]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:5]=1[Br:1]
Reactant: Br
Reactant: Nc1cc(C(F)(F)F)ccc1C(F)(F)F
Agent: [Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: FC(F)(F)c1ccc(C(F)(F)F)c(Br)c1

Procedure:
A suspension of the HBr salt of 2,5-bis-trifluoromethylaniline (1.0 gm, 4.4 mmol) was prepared by addition of 48% HBr (3 gm, 17.5 mmol) and 5 mL of water. This was cooled in an ice bath while a solution of sodium nitrite (335 mg, 4.8 mmol) in 1 mL of water was added dropwise. The reaction was stirred a farther 0.5 hr at which time copper powder (1 gm) and another 3 gm portion of 48% HBr were added. The reaction was heated to reflux and after 10 min the distillate was collected until no organic material was evident with the water. The distillate was extracted twice with ether and the ether layers were washed with brine, dried over sodium sulfate, combined and evaporated. The residue was purified by flash chromatography (5% ethyl acetate/hexanes) to afford the title compound as an oil. NMR (CDCl3): δ 7.68 (d, 1H, J=8 Hz), 7.81 (d, 1H, J=8 Hz), 7.96 (s, 1H).
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].[OH-].[K+].[CH2:16](Br)[CH2:17][CH3:18]>CN(C)C=O>[CH3:2][N:1]1[C:12](=[O:13])[C:11]2[N:10]([CH2:16][CH2:17][CH3:18])[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4]
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: CCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCn1cnc2c1c(=O)n(C)c(=O)n2C
Temperature: 90 °C
Yield: 88.8 %

Procedure:
600 g of theophylline (a product of Katayama Kagaku Kogyo K.K.) was dissolved in 180 ml of an aqueous solution containing 263.4 g of potassium hydroxide, and the solution was evaporated to dryness under reduced pressure to prepare a potassium salt of theophylline. The resulting salt was suspended in 3600 ml of dimethylformamide, and 436.5 ml of propyl bromide was added thereto, followed by heating at 90° C. for 8 hours while stirring. Dimethylformamide was removed by distillation under reduced pressure, and to the residue was added 1800 ml of dichloromethane. The mixture was washed three times with 300 ml portions of a 1N potassium hydroxide aqueous solution and then once with 300 ml of water and dried over 54 g of anhydrous magnesium sulfate. The desiccant was removed by filtration, and the mother liquor was dried under reduced pressure and then in vacuo (85° C., 5 hours) to obtain 657 g (yield: 88.8%) of 1,3-dimethyl-7-propylxanthine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1.[C:16]([N:24]=[C:25]=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[C:16]([NH:24][C:25]([NH:15][C:5]1[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1cc(N)cc(-c2ccccc2)c1
Solvent: CC(C)=O
Product: COc1cc(NC(=S)NC(=O)c2ccccc2)cc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.2 %

Procedure:
5-Methoxy-biphenyl-3-ylamine (129 mg, 0.65 mmol) are dissolved in acetone (5 ml) and slowly treated with a solution of benzoyl isothiocyanate (0.096 ml, 0.71 mmol) in acetone (2 ml). After stirring at ambient temperature for 18 h, the solvent is removed in vacuo and the residue crystallized from hexane. The product (203 mg, 86%) is obtained as colorless crystalls. Mp 149° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13](=[CH:23][N:24](C)C)[C:14](=O)[CH:15]3[CH2:20][CH3:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[NH2:28]N>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13]2[CH:23]=[N:24][NH:28][C:14]=2[CH:15]3[CH2:20][CH3:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCC1C(=O)C(=CN(C)C)C2CCCC1N2S(=O)(=O)c1ccc(Cl)cc1
Solvent: O
Solvent: CC(=O)O
Product: CCC1c2[nH]ncc2C2CCCC1N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 9-(4-chloro-benzenesulfonyl)-2-dimethylaminomethylene-4-ethyl-9-aza-bicyclo[3.3.1]nonan-3-one crude mixture in glacial acetic acid (1 mL) followed by hydrazine monohydrate (0.5 mL). The reaction mixture was stirred at 100° C. for 1 h after which the solution was cooled to room temperature and quenched by the addition of a saturated aqueous NaHCO3 solution (until pH>7). The resulting solution was extracted with EtOAc (3×20 mL), the organic extracts were combined, dried (Na2SO4), filtered, concentrated and purified by silica gel column chromatography and preparative HPLC to give 12-(4-chloro-benzenesulfonyl)-7-ethyl-4,5,12-triaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene as a white solid. Retention time (min)=1.896, Method [1], MS (ESI) 366.1 (M+H); 1H-NMR (300 MHz, CDCl3) δ 7.81-7.78 (m, 2H), 7.47-7.43 (m, 2H), 7.25 (s, 1H), 5.15 (b s, 1H), 4.27 (d, J=4.95 Hz, 1H), 2.56 (dd, J=9.34, 5.49 Hz, 1H), 2.10-1.22 (m, 8H), 1.02 (t, J=7.14 Hz, 3H) (major diastereomer); 1H-NMR (300 MHz, CDCl3) δ 7.68-7.66 (m, 2H), 7.35-7.32 (m, 2H), 7.22 (s, 1H), 5.28 (b s, 1H), 4.31 (d, J=5.5 Hz, 1H), 2.80-2.73 (m, 1H), 2.05-1.21 (m, 8H), 1.06 (t, J=7.69 Hz, 3H) (minor diastereomer).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:19]([CH2:34][CH3:35])[CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH:32]=O)=[CH:26]2)[CH3:18].N1CCCCC1>C(O)C>[CH2:34]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH:32]=[C:10]1[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[NH:12][C:11]1=[O:16])=[CH:26]2)[CH3:35]
Reactant: O=C1Cc2cc(-c3ccccc3)ccc2N1
Reactant: CCN(CC)CCCc1ccc2[nH]c(C=O)cc2c1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCCc1ccc2[nH]c(C=C3C(=O)Nc4ccc(-c5ccccc5)cc43)cc2c1
Temperature: 95 °C
Yield: 11.7 %

Procedure:
A mixture of 5-phenyl-2-oxindole (41 mg, 0.19 mmol), 5-(3-diethylamino-propyl)-1H-indole-2-carbaldehyde (50 mg, 0.19 mmol) and piperidine(0.1 mL) in ethanol (1 mL) was heated in a sealed tube at 95° C. for 20 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 10 mg (11 %) of the title compound as an orange crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(N2CCNCC2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CCN(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
1-(4-Bromo-phenyl)-piperazine (1 g, 4.1 mmol) and potassium carbonate (1.8 g, 3 eq) in DMF (15 ml) treated with methyl iodide (250 μl, 1.1 equivalents), solution stirred at room temperature overnight. Reaction quenched with deionised water (10 ml), extracted with ethyl acetate. Organic phase washed with sodium hydrogen carbonate to remove any dimethylated impurity, dried and solvent removed to give 1-(4-Bromo-phenyl)-4-methyl-piperazine in 73% yield.
Reaction SMILES: [C:1]1([C@H:7]([N:9]2[CH:17]3[CH:13]([CH2:14][O:15][CH2:16]3)[O:12][CH2:11][C:10]2=O)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO>O1CCCC1>[C:1]1([C@H:7]([N:9]2[C@H:17]3[C@@H:13]([CH2:14][O:15][CH2:16]3)[O:12][CH2:11][CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](c1ccccc1)N1C(=O)COC2COCC21
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](c1ccccc1)N1CCO[C@@H]2COC[C@H]21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a 0° C. solution of (3aRS,7aSR)-7-((1R)-1-phenyl-ethyl)-tetrahydro-2,4-dioxa-7-aza-inden-6-one (1.46 g, 5.9 mmol) in tetrahydrofuran (20 ml), a 1 M-solution of boran tetrahydrofuran complex in tetrahydrofuran (18 ml, 18 mmol) was added dropwise under nitrogen atmosphere and the resulting mixture was warmed to room temperature. After the reaction mixture was stirred for 15 hours, methanol was added until disappearance of bubbles. The mixture was concentrated under reduced pressure and methanol (10 ml) and 1 N aqueous solution of sodium hydroxide (10 ml) were added to the obtained residue at room temperature. The white slurry was refluxed for 2 hours and cooled to room temperature. After evaporation of methanol, water (30 ml) was added to the residue and extractive workup with ethyl acetate was performed. The organic layer was dried over sodium sulfate and concentrated. (3aS,7aR)-7-((1R)-1-phenyl-ethyl)-hexahydro-2,4-dioxa-7-aza-indene was isolated as a diastereomerically enriched colorless crystalline by silica gel column chromatography (eluent; hexane/ethyl acetate=100/0 to 1/1) of the residue and subsequent recrystallization from ethanol (1.0 g, 4.9 mmol, 73%, 96% de determined by NMR analysis).
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)[CH2:12][N:11]([C:25](OC4C=CC([N+]([O-])=O)=CC=4)=[O:26])[CH2:10]3)[O:6][N:5]=2)[CH2:3][CH2:2]1.Cl.Cl.[NH2:39][CH:40]1[CH2:44][CH2:43][NH:42][CH2:41]1>>[NH2:39][CH:40]1[CH2:44][CH2:43][N:42]([C:25]([N:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][CH:16]=3)[CH2:14][CH:9]([C:7]3[O:6][N:5]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[N:8]=3)[CH2:10]2)=[O:26])[CH2:41]1
Reactant: NC1CCNC1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1
Agent: Cl
Product: NC1CCN(C(=O)N2CC(c3ccc(C(F)(F)F)cc3)CC(c3nc(C4CC4)no3)C2)C1

Procedure:
100 mg (0.20 mmol) of the compound from Example 184A and 95 mg (0.60 mmol) of 3-aminopyrrolidine dihydrochloride were reacted according to the General Method 6. Yield: 25 mg (27% of theory)