Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=1)=[O:4].[OH-].[Na+:19]>CO>[Na+:19].[CH3:15][Si:14]([CH3:17])([CH3:16])[CH2:13][CH2:12][O:11][CH2:10][N:8]1[CH:9]=[C:5]([C:3]([O-:4])=[O:2])[N:6]=[CH:7]1
Reactant: COC(=O)c1cn(COCC[Si](C)(C)C)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[Si](C)(C)CCOCn1cnc(C(=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carboxylic acid methyl ester (0.42 g, 1.6 mmol) (as prepared in Example 40, step (a)) in MeOH (3.0 mL) was added 1N NaOH (1.6 mL) and mixture was stirred for 8 h at RT. The reaction was concentrated to give 0.43 g (100%) of the title compound as a white solid. Mass spectrum (ESI, m/z): Calcd. for C10H18N2O3Si, 243.1 (M+H), found 243.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:18])=[CH:12]3)[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[C:22]([CH2:26][S:27]([NH:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=1>>[CH3:34][N:33]([CH3:35])[CH2:32][CH2:31][NH:30][S:27]([CH2:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([NH:19][C:2]2[N:7]=[C:6]([O:8][C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[NH:14][C:13]([CH3:18])=[CH:12]4)[CH:5]=[CH:4][N:3]=2)[CH:21]=1)(=[O:29])=[O:28]
Reactant: CN(C)CCNS(=O)(=O)Cc1cccc(N)c1
Reactant: Cc1cc2cc(Oc3ccnc(Cl)n3)ccc2[nH]1
Product: Cc1cc2cc(Oc3ccnc(Nc4cccc(CS(=O)(=O)NCCN(C)C)c4)n3)ccc2[nH]1

Procedure:
The title compound of Formula A can be synthesized as the crude product of the compound of Formula A by the reaction of Compound 3 with 1-(3-aminophenyl)-N-(2-(dimethylamino)ethyl)methane-sulfonamide (Compound 4) in the presence of an acid, such as but not limited to acetic acid, formic acid, HCl, H2SO4, toluenesulfonic acid, trifluoroacetic acid, or ethanesulfonic acid acidic, and in a solvent, such as but not limited to, N,N-dimethylformamide (DMF), acetonitrile, tetrahydrofuran, ethanol, isopropanol, or toluene. The reaction can be carried out at a suitable temperature, such as a temperature ranging from 40 to 100° C.
Reaction SMILES: [Cl:1][C:2]1([Cl:12])[CH2:4][CH:3]1[C:5]1[CH:11]=[CH:10][C:8](N)=[CH:7][CH:6]=1.N([O-])=[O:14].[Na+].NC(N)=O.N(O)=O.[OH-].[Na+].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>S(=O)(=O)(O)O.O.C(OCC)C>[Cl:1][C:2]1([Cl:12])[CH2:4][CH:3]1[C:5]1[CH:11]=[CH:10][C:8]([OH:14])=[CH:7][CH:6]=1
Reactant: Nc1ccc(C2CC2(Cl)Cl)cc1
Reactant: O=N[O-]
Agent: NC(N)=O
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=NO
Solvent: CCOCC
Solvent: O
Product: Oc1ccc(C2CC2(Cl)Cl)cc1
Reaction time: 0.08 h
Yield: 101.8 %

Procedure:
(+)-4-(2,2-Dichlorocyclopropyl)aniline (3 g, 0.015 mol) from the previous resolution was dissolved in concentrated sulphuric acid (15 ml) to which was added iced water (30 ml). With the reaction temperature maintained below 5° C. a solution of sodium nitrite (1.3 g, 0.019 mol) in distilled water (15 ml) was added. After a further 5 minutes, urea (0.27 g, 0.0045 mol) was added to eliminate excess nitrous acid. The pH of the mixture was then adjusted to 3 by addition of an aqueous solution of sodium hydroxide (10M) whilst the temperature of less than 5° C. was maintained. This mixture was then added slowly to a vigorously stirred mixture of cupric nitrate hemipentahydrate (60 g, 0.26 mol) and sodium ascorbate (2.8 g, 0.014 mol) in distilled water (530 ml) and diethyl ether (200 ml). After 5 minutes the organic phase was removed and the aqueous phase extracted with diethyl ether (3× 100 ml). The combined organic phases were washed with distilled water, dried over anhydrous magnesium sulphate and the solvent removed by evaporation under reduced pressure to afford crude (+)-4-(2,2-dichlorocyclopropyl)phenol (3.1 g) which was used directly in the following reaction.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:30])[CH:25]=[CH:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:30])[CH2:25][CH:26]([N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)[CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: CCCC=CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Reactant: CN1CCNCC1
Product: CCCC(CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1)N1CCN(C)CC1
Yield: 40 %

Procedure:
N-Cyclopropyl-N-{1-[3-(4-methylpiperazin-1-yl)hexanoyl]piperidin-4-yl}-3-trifluoromethylbenzenesulfonamide (31) was prepared by reacting N-cyclopropyl-N-(1-hex-2-enoyl-piperidin-4-yl)-3-trifluoromethyl-benzenesulfonamide (30) (250 mg, 0.56 mmol) and N-methyl-piperazine (2 mL) as described in Example 26 above. The residue was chromatographed over flash silica eluting with ethyl acetate:methanol:ammonia (100:10:1) to give the title compound 31 (120 mg, 40%) as a white solid. LC: 100%. MS: m/z=545.3, 546.3 (M+H). 1H NMR (400 MHz, CDCl3): (1:1 mixture of rotamers) δ 8.14 (1H, s), 8.07 (1H, d, J=7.5 Hz), 7.88 (1H, d, J=7.5 Hz), 7.70 (1H, t, J=7.5 Hz), 4.74 (1H, d, J=13 Hz), 4.09 (1H, t, J=13 Hz), 3.95 (1H, d, J=13 Hz), 3.08 (2H, m), 2.67-2.33 (9H, m), 2.26 (3H, s), 2.15 (1H, dd, J=8.8 Hz), 1.96 (1H, m), 1.85-1.65 (3H, m), 1.52-1.22 (4H, m), 0.98 (1H, m), 0.98-0.70 (6H, m).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:9]([Cl:10])=[N:8][C:7]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:6][C:5]=2[N:19]=1.Cl.[NH2:21][CH2:22][C:23]([NH2:25])=[O:24]>>[Cl:10][C:9]1[C:4]2[S:3][C:2]([NH:21][CH2:22][C:23]([NH2:25])=[O:24])=[N:19][C:5]=2[N:6]=[C:7]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1
Reactant: Clc1nc(SCc2ccccc2)nc2nc(Br)sc12
Reactant: NCC(N)=O
Agent: Cl
Product: NC(=O)CNc1nc2nc(SCc3ccccc3)nc(Cl)c2s1

Procedure:
Prepared by the method of Example 231, using the product of Example 219 and glycinamide hydrochloride.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[Cl:11][C:12]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:13]=1[CH2:14][C@H:15]1[CH2:19][NH:18][C@H:17]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[O:21])[CH2:16]1>>[N:2]1([CH2:7][C:8]([N:18]2[CH2:19][C@H:15]([CH2:14][C:13]3[CH:37]=[CH:38][C:39]([F:41])=[CH:40][C:12]=3[Cl:11])[CH2:16][C@H:17]2[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[CH:25][CH:24]=2)=[O:21])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2Cl)CN1
Reactant: O=C(O)Cn1cncn1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2Cl)CN1C(=O)Cn1cncn1
Yield: 36 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)-4-(2-chloro-4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 9, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(2-chloro-4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (35.4 mg, 36%). Major isomer 1H-NMR (400 MHz, CDCl3): δ 9.08 (s, 1H), 8.27 (s, 1H), 7.98 (s, 1H), 7.37-7.33 (m, 2H), 7.23-7.19 (m, 1H), 7.16-7.12 (m, 1H), 7.02-6.82 (m, 7H), 5.07 (d, 1H), 5.00 (d, 1H), 4.73 (d, 1H), 3.75-3.69 (m, 1H), 3.31 (t, 1H), 3.08-2.98 (m, 1H), 2.88 (d, 2H), 2.46 (dd, 1H), 1.82-1.73 (m, 1H). MS (EI) for C28H24ClF2N5O3 found 552 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([C:9]1[CH:14]=[C:13]([S:15][CH3:16])[CH:12]=[CH:11][C:10]=1[N+:17]([O-])=O)[CH3:8])([CH3:4])([CH3:3])[CH3:2]>CO.O1CCCC1.[Pd]>[C:1]([O:5][C:6](=[O:20])[N:7]([C:9]1[CH:14]=[C:13]([S:15][CH3:16])[CH:12]=[CH:11][C:10]=1[NH2:17])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CSc1ccc(N)c(N(C)C(=O)OC(C)(C)C)c1
Reaction time: 8 h

Procedure:
To a solution of N-(2-nitro-5-methylthiophenyl)-N-methylcarbamic acid t-butyl ester (obtained in Reference Example 3) in anhydrous methanol (120 ml) and anhydrous tetrahydrofuran (30 ml) was added 10% palladium on carbon (3.0 g). The resulting mixture was vigorously stirred under a hydrogen atmosphere. Further 10% palladium on carbon (1.5 g) was added after 2.5 hours and 4.5 hours of the reaction respectively. The resulting mixture was stirred at room temperature for 1.5 hours and allowed to stand overnight. 10% palladium on carbon (0.7 g) was further added to the reaction mixture, which was then stirred under a hydrogen atmosphere for 1 hour. At the end of this time the 10% palladium on carbon was filtered off and the filtrate concentrated in vacuo. The residue was chromatographed on a silica gel column using ethyl acetate/n-hexane (⅓) as the eluant to afford the desired compound (3.61 g). Rf=0.24 (thin-layer chromatography on a silica gel plate using ethyl acetate/n-hexane (⅓) as the eluant).
Reaction SMILES: [CH:1]1[C:14]2[N:13]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:26]([O:28][CH2:29]C)=[O:27])=[CH:20][CH:19]=3)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Mg]>CO>[CH:11]1[C:12]2[N:13]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([O:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=3)[C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[O:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1)Oc1ccccc1
Agent: [Mg]
Solvent: CO
Product: COC(=O)C(Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1)Oc1ccccc1
Yield: 85.3 %

Procedure:
A solution of ethyl diethylphosphino phenoxy acetate in dry THF was added slowly to a stirred ice cooled suspension of sodium hydride in dry THF under nitrogen atmosphere. The mixture was stirred at 0° C. for 30 min. and added a solution of 4-[2-(Phenoxazin-10-yl)ethoxy]benzaldehyde in dry THF dropwise at ice temperature. The mixture was allowed to warm to room temperature and stirred for overnight. The solvent was evaporated under reduced pressure, residue was diluted with water and extracted with ethylacetated. The organic layer was washed with water, brine, dried and concentrated. The residue was chromatographed with 10% ethylacetate in pet, ether as an eluent to afford ethyl 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxypropanoate (59%) as thick liquid. Ethyl 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxypropanoate (3.5 gm) and magnesium turnings in dry methanol was stirred at room temp for 12 h. Methanol was evaporated and the residue was taken into water, acidified with 2N HCl and extracted with ethylacetate. The organic layer was washed with water, brine, evaporated and chromatographed with 10% ethylacetate in per. ether to yield the title compound (2.9 g, 85%). mp: 106-110° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[N:6]2)[CH2:2]1.[NH:28]1[CH:32]=[C:31]([CH2:33][C:34]([O-])=[O:35])[N:30]=[CH:29]1.[Na+].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2N=CC=CC=2N=N1>CN(C)C=O>[NH2:14][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[N:5]([CH:3]3[CH2:2][N:1]([C:34](=[O:35])[CH2:33][C:31]4[N:30]=[CH:29][NH:28][CH:32]=4)[CH2:4]3)[N:6]=[C:7]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)[C:8]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CNC1
Reactant: O=C([O-])Cc1c[nH]cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CN(C(=O)Cc2c[nH]cn2)C1
Temperature: 25 °C
Yield: 28.6 %

Procedure:
A mixture of 1-(3-azetanyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.05 g, 0.00014 mol), sodium 2-(1H-4-imidazolyl)acetate (0.0026 g, 0.000175 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.0034 g, 0.000175 mol), N, N-diisopropylethylamine (0.033 g, 0.00026 mol) and 1-hydroxy-7-azabenzotriazole (0.019 g, 0.00014 mol) in anhydrous N,N-dimethylformamide (6 mL) was stirred for eighteen hours at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (3 mL) and washed with water (2 mL). The solvent was removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield 1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-2-(1H-4-imidazolyl)-1-ethanone (0.018 g, 0.00004 mol).
Reaction SMILES: [ClH:1].C[O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH2:14][CH:15]([NH2:17])[CH3:16].Br>>[ClH:1].[OH:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH2:14][CH:15]([NH2:17])[CH3:16]
Reactant: COc1c(CC(C)N)ccc2ccccc12
Agent: Br
Agent: Cl
Product: CC(N)Cc1ccc2ccccc2c1O

Procedure:
A solution of 2-(1-methoxy-naphthalen-2-yl)-1-methylethylamine hydrochloride (0.1 g, 0.40 mmol) and HBr 48% was refluxed for 3 h. The reaction mixture was concentrated under vacuum, the residue was washed with hexane and ether and then collected by filtration: 1H NMR (DMSO-d) δ 1.14 (d, 3H, CH3), 2.86–3.11 (m, 2H, CH2), 3.47 (m, 1H, CH), 7.25 (d, 1H, Ar—H), 7.47 (m, 2H, Ar—H), 7.83 (m, 4H, 1Ar—H+NH3+); 8.24 (m, 1H, Ar—H), 9.36 (s, OH); MS 202 (M+1). Analysis. Calcd. for C13H15NO.HBr.0.5 H2O: C, 53.62; H, 5.88; N, 4.81. Found: C, 53.53; H, 5.56; N, 4.77.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:28][C:25]=1[CH:26]=O.C[O-].[Li+]>CN(C=O)C.CO>[CH3:22][O:23][C:24]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:28][C:25]=1/[CH:26]=[CH:2]/[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[O:3]
Reactant: COc1cc(OC)c(N2CCCC2)cc1C=O
Reactant: CC(=O)c1ccc(S(=O)(=O)NCCCn2ccnc2)cc1
Agent: C[O-]
Agent: [Li+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(OC)c(N2CCCC2)cc1/C=C/C(=O)c1ccc(S(=O)(=O)NCCCn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 41.3 %

Procedure:
A solution 4-acetyl-N-(3-imidazol-1-ylpropyl)benzenesulfonamide (Ex-23A, 653 mg, 2.13 mmol) and 2,4-dimethoxy-5-pyrrolidin-1-yl-benzaldehyde (Ex-38B, 500 mg, 2.13 mmol) in DMF (9.3 mL) and MeOH (4.0 mL) was treated with lithium methoxide (162 mg, 4.26 mmol) and stirred for 20 h at room temperature under nitrogen atmosphere. The reaction mixture was quenched with water (75 mL) and extracted ethyl acetate (3×50 mL). The organic phase was brined, dried over sodium sulfate, and concentrated to a red solid. Crystallization from hot ethanol (10 mL) and water (12 mL) gave 461 mg (41%) of the title compound as a red solid, mp 140–143° C. 1H-NMR (300 MHz, DMSO-d6) 8.23 (d, 2H, J=8.7 Hz), 8.05 (d, 1H, J=15.3 Hz), 7.88 (d, 2H, J=9.3 Hz), 7.64 (d, 1H, J=15.3 Hz), 7.51 (s, 1H), 7.17 (s, 1H), 7.05 (s, 1H), 6.81 (s, 1H), 6.67 (s, 1H), 3.92 (t, 2H, J=6.9 Hz), 3.86 (s, 6H), 3.15 (m, 4H), 2.68 (t, 2H, J=6.3 Hz), 1.80 (m, 6H). HRMS (ESI) Calcd. for C27H32N4O5S: 525.2172 (M+H)+; Found; 525.2179.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:14][CH2:15][C:16]([C:18]2[S:19][C:20]([CH3:29])=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:22]=2)=[O:17])[CH:5]=[C:6]([CH3:13])[C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][O:11]1.[CH3:30][NH2:31]>CO>[OH:11][CH:10]([CH2:12][NH:31][CH3:30])[CH2:9][O:8][C:7]1[C:6]([CH3:13])=[CH:5][C:4]([CH2:14][CH2:15][C:16]([C:18]2[S:19][C:20]([CH3:29])=[C:21]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:22]=2)=[O:17])=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(CCC(=O)c2cc(-c3ccccc3)c(C)s2)cc(C)c1OCC1CO1
Reactant: CN
Solvent: CO
Product: CNCC(O)COc1c(C)cc(CCC(=O)c2cc(-c3ccccc3)c(C)s2)cc1C

Procedure:
A solution of 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-1-(5-methyl-4-phenyl-thiophen-2-yl)-propan-1-one (33 mg, 82 μmol) and methylamine (0.082 mL, 2 M solution in THF) in methanol (1 mL) is stirred at 65° C. for 4 h and at rt for 18 h. The solvent is removed in vacuo and the residue is purified by prep. HPLC to give 3-[4-(2-hydroxy-3-methylamino-propoxy)-3,5-dimethyl-phenyl]-1-(5-methyl-4-phenyl-thiophen-2-yl)-propan-1-one (4 mg) as a colourless resin; LC-MS: tR=0.88 min, [M+1]+=438.25, 1H NMR (as formate salt) (CDCl3): δ 8.56 (s, 1H), 7.60 (s, 1H), 7.45-7.30 (m, 5H), 6.85 (m, 2H), 4.60 (s br, 2H), 4.37-4.30 (m, 1H), 3.81-3.20 (m, 2H), 3.18-3.10 (m, 4H), 2.96-2.88 (m, 2H), 2.70 (s, 3H), 2.51 (s, 3H), 2.20 (s, 6H).
Reaction SMILES: C(OC(=O)[N:7]([C:10]1[S:14][C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:12][C:11]=1[Cl:21])[CH2:8][CH3:9])(C)(C)C.O1CCOCC1.Cl.O1CCOCC1>CCOCC>[ClH:21].[Cl:21][C:11]1[N:12]=[C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[S:14][C:10]=1[NH:7][CH2:8][CH3:9]
Reactant: CCN(C(=O)OC(C)(C)C)c1sc(-c2cccnc2)nc1Cl
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCNc1sc(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 0 h
Yield: 209 %

Procedure:
Into a 1 L three-necked flask fitted with a J-KEM type-T temperature probe, overhead stirrer, and nitrogen inlet was added (4-chloro-2-pyridin-3-yl-thiazol-5-yl)-ethyl-carbamic acid tert-butyl ester (63.5 g, 187 mmol) and 1,4-dioxane (125 mL). To the solution was added 4 M HCl/dioxane (100 mL, 400 mmol). The mixture exothermed from 31° C. to 49° C. over 10 seconds and slowly turned from an auburn solution to a green-black solution. After 10 minutes the reaction had cooled back to 25° C. After 30 min a green-yellow precipitate began to form in the reaction mixture. The reaction conversion was 31% after 10 min, 32% after 1.5 hours and 67% after 16 hours. Additional 4M HCl/dioxane (75 mL, 300 mmol) was added (note: no exotherm this time) and the reaction stirred at 23° C. for 1.5 hours (no change in reaction progress by HPLC analysis). The reaction was heated to 40° C. for 4 hours which led to complete conversion. The reaction was allowed to cool to 25° C. and ether (200 mL) was added. The green-yellow suspension was stirred for 30 min and the solid collected by vacuum filtration and washed with ether (2×50 mL). This gave a green-yellow filter cake which was allowed to stand in the air for 16 hours. This gave 67.99 g (131%) of a green-yellow wet cake that assayed to >99% purity by HPLC at 254 nm. The sample was placed into a vacuum oven (55° C., 74 mmHg vacuum, 4 hours). This gave 53.96 g (quantitative yield) of a green solid: mp 180-182 C; 1H NMR (400 MHz, DMSO-d6) δ 9.08 (d, J=2.1 Hz, 1H), 8.75 (dd, J=5.5, 0.9 Hz, 1H), 8.66 (ddd, J=8.3, 2.2, 1.3 Hz, 1H), 7.97 (ddd, J=8.3, 5.5, 0.6 Hz, 1H), 3.21 (q, J=7.1 Hz, 2H), 2.51 (dt, J=3.7, 1.8 Hz, 1H), 1.24 (dd, J=9.2, 5.1 Hz, 3H); ESIMS m/z 240 (M+1).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:19][CH2:20]OC)[CH2:11][CH2:10][N:9]([C:12](=[O:18])[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:8][CH2:7]1)=[O:5])C.[Cl-].C[Al+]C.[CH2:27]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)[CH3:28]>CCCCCCC>[CH3:17][C:14]([CH3:15])([CH3:16])[CH2:13][C:12]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:33]([C:32]3[CH:34]=[CH:35][C:29]([CH2:27][CH3:28])=[CH:30][CH:31]=3)[CH2:20][CH2:19]2)[CH2:11][CH2:10]1)=[O:18]
Reactant: CCc1ccc(N)cc1
Reactant: CCOC(=O)C1(CCOC)CCN(C(=O)CC(C)(C)C)CC1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CCCCCCC
Product: CCc1ccc(N2CCC3(CCN(C(=O)CC(C)(C)C)CC3)C2=O)cc1
Yield: 69.2 %

Procedure:
This material was prepared in analogy to example 1 step D) 1-(3,3-Dimethyl-butyryl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.15 g), dimethylaluminium chloride in heptane (1.0 molar, 0.96 ml) and 4-ethylaniline (0.087 g) to give the desired 8-(3,3-dimethyl-butyryl)-2-(4-ethyl-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (0.118 g) as an off-white solid. MS (ESI): 357.25 (MH+).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:27])[C:5]2[C:10]([CH2:11][NH:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)=[CH:9][NH:8][C:6]=2[N:7]=1.NC1NC(=O)C2C(CNC3C=CC(C(O)=O)=CC=3)=CNC=2N=1.C(N(CC1C2C(=O)NC(N[C:77](=[O:85])[CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH3:84])=NC=2NC=1)CC1C=CC=CC=1)C1C=CC=CC=1.C(C1C=CC(N)=CC=1)C1C=CC(N)=CC=1>>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][C:16]2[CH:15]=[CH:14][C:13]([NH:12][CH2:11][C:10]3[C:5]4[C:4](=[O:27])[NH:3][C:2]([NH:1][C:77](=[O:85])[CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH3:84])=[N:7][C:6]=4[NH:8][CH:9]=3)=[CH:18][CH:17]=2)=[CH:21][CH:22]=1
Reactant: Nc1ccc(Cc2ccc(NCc3c[nH]c4nc(N)[nH]c(=O)c34)cc2)cc1
Reactant: CCCCCCCC(=O)Nc1nc2[nH]cc(CN(Cc3ccccc3)Cc3ccccc3)c2c(=O)[nH]1
Agent: Nc1ccc(Cc2ccc(N)cc2)cc1
Agent: Nc1nc2[nH]cc(CNc3ccc(C(=O)O)cc3)c2c(=O)[nH]1
Product: CCCCCCCC(=O)Nc1nc2[nH]cc(CNc3ccc(Cc4ccc(N)cc4)cc3)c2c(=O)[nH]1

Procedure:
The synthesis of 2-amino-5-{[4-(4-amino-benzyl)-phenylamino]-methyl}-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one 24 follows the same steps as the synthesis of 4-[(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-amino]-benzoic acid 21, except that octanoic acid{5-[(dibenzylamino)-methyl]-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl}-amide 18 is reacted with 4,4′-methylene dianiline 22 to form octanoic acid (5-{[4-(4-amino-benzyl)-phenylamino]-methyl}-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-amide 23. Octanoic acid (5-{[4-(4-amino-benzyl)-phenylamino]-methyl}-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-amide 23 is then reacted with 5M KOH to form 2-amino-5-{[4-(4-amino-benzyl)-phenylamino]-methyl}-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one 24.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[N:6][N:5]2[C:9]([C:13]3[S:17][C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[N:15][C:14]=3[CH3:24])=[C:10]([CH3:12])[N:11]=[C:4]2[C:3]=1[CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27].[Li][CH2:31]CCC.CCCCCC.IC>CCOCC>[Br:1][C:2]1([CH3:31])[C:7]([CH3:8])=[N:6][N:5]2[CH:9]([C:13]3[S:17][C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[N:15][C:14]=3[CH3:24])[C:10]([CH3:12])=[N:11][C:4]2=[C:3]1[CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27]
Reactant: [Li]CCCC
Reactant: CCC(CC)c1c(Br)c(C)nn2c(-c3sc(N4CCOCC4)nc3C)c(C)nc12
Solvent: CI
Solvent: CCCCCC
Solvent: CCOCC
Product: CCC(CC)C1=C2N=C(C)C(c3sc(N4CCOCC4)nc3C)N2N=C(C)C1(C)Br
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 69 %

Procedure:
50 mg of N-{5-[7-Bromo-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}-morpholine (0.1 mmol) is dissolved in 4 ml of Et2O and cooled to −78° C. 0.09 ml of n-BuLi 1.6M in hexane (0.15 mmol) is added at −78° C. and stirred at −78° C. for 20 min. 43 mg of iodomethane (0.3 mmol) is added to the mixture and stirred at −78° C. and allowed to come to room temperature overnight. The reaction is quenched with sat. NH4Cl and extracted with Et2O. The separated organic layer is dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt=3:1) to give 29.6 mg of the title compound. Yield 69%. mass spectrum (m/e): 414 (M+1). 1H NMR (CDCl3): δ 3.87 (t, J=4.6 Hz, 4H), 3.56 (t, J=4.6 Hz, 4H), 3.35 (m, 1H), 2.54 (s, 3H), 2.43 (s, 3H), 2.35 (s, 3H), 2.20 (s, 3H), 2.01 (m, 4H), 0.88 (m, 6H).