Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH2:10][CH:11]([O:14][CH3:15])[O:12][CH3:13])[CH:5]=[CH:4][C:3]=1[C:16](=[O:18])[CH3:17].Br.[CH:20]([NH:23][C:24]1[S:25][CH:26]=[C:27]([C:29](O)=[O:30])[N:28]=1)([CH3:22])[CH3:21].P(Cl)(Cl)(Cl)=O.O>N1C=CC=CC=1>[C:16]([C:3]1[C:2]([NH:1][C:29]([C:27]2[N:28]=[C:24]([NH:23][CH:20]([CH3:22])[CH3:21])[S:25][CH:26]=2)=[O:30])=[C:7]([Cl:8])[C:6]([O:9][CH2:10][CH:11]([O:12][CH3:13])[O:14][CH3:15])=[CH:5][CH:4]=1)(=[O:18])[CH3:17]
Reactant: COC(COc1ccc(C(C)=O)c(N)c1Cl)OC
Reactant: CC(C)Nc1nc(C(=O)O)cs1
Agent: Br
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: COC(COc1ccc(C(C)=O)c(NC(=O)c2csc(NC(C)C)n2)c1Cl)OC
Temperature: 0 °C
Reaction time: 4 h
Yield: 85.7 %

Procedure:
To a mixture of 1-[2-amino-3-chloro-4-(2,2-dimethoxyethoxy)phenyl]ethanone (13 g, 47.5 mmol) and isopropylaminothiazole-4-carboxylic acid hydrobromide (prepared as described in Ivanov, V., et. al.; EP1881001A1, p. 62-63; 12.6 g, 47.5 mmol) in pyridine (150 ml) was slowly added phosphorus oxychloride (9.47 g, 61.8 mmol) at −40° C. The mixture was then stirred at 0° C. for 4 h. Upon completion of the reaction, H2O (30 ml) was added dropwise to the mixture. The mixture was then stirred at 0° C. for another 15 min. The mixture was concentrated in vacuo. The residue was diluted with EtOAc, washed with a sat. NaHCO3 aqueous solution. The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in CH2Cl2, hexanes was added slowly to the solution, and a yellow solid started to crash out. More hexanes were added precipitation was complete to afford 2-isopropylaminothiazole-4-carboxylic acid [6-acetyl-2-chloro-3-(2,2-dimethoxyethoxy)phenyl]amide (18 g, 85% yield).
Reaction SMILES: [CH:1](NC(C)C)(C)C.[CH3:8][N:9]1[CH2:14][C:13]([N+:21]([O-:23])=[O:22])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH2:11][C:10]1=[O:24].CI>C1COCC1.CCCCCC>[CH3:8][N:9]1[CH2:14][C:13]([N+:21]([O-:23])=[O:22])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH:11]([CH3:1])[C:10]1=[O:24]
Reactant: CN1CC(c2ccccc2)([N+](=O)[O-])CCC1=O
Reactant: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC1CC(c2ccccc2)([N+](=O)[O-])CN(C)C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81.1 %

Procedure:
To a solution of 1.6 ml (11.1 mmol) diisopropylamine in 40 ml THF were added 7 ml (11.1 mmol) of a 1.6M n-Buli solution in hexane at −5° C. The solution was stirred for 15 minutes at 0° C. and then cooled to −70° C. A solution of 2 g (8.538 mmol) rac-1-methyl-5-nitro-5-phenyl-piperidin-2-one (example A9, step 1) in 20 ml THF was added dropwise. The brown solution was stirred at −70° C. for 45 minutes. 639 ul (10.25 mmol) methyliodide in THF (8 ml) were added dropwise at −70° C. The mixture was stirred at −70° C. for 1 hour and then allowed to warm to 0° C. After 30 minutes at 0° C., the mixture was quenched with 30 ml of a 20% NH4Cl solution. Water and ethyl acetate were added. The aqueous layer was extracted once with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 100%) to provide 1.72 g (81%) of the title compound as a yellow oil. MS (m/e): 249.2 (M+H)
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH2:35]([O:37][C:38](Cl)=[O:39])[CH3:36]>ClCCl>[CH2:35]([O:37][C:38](=[O:39])[NH:2][C@H:3]1[CH2:8][CH2:7][C@@H:6]([NH:9][C:10]([C:11]2[C:12]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=3)=[N:13][CH:14]=[C:15]([F:17])[CH:16]=2)=[O:27])[CH2:5][CH2:4]1)[CH3:36]
Reactant: CCOC(=O)Cl
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N[C@H]1CC[C@@H](NC(=O)c2cc(F)cnc2Oc2cccc(SC)c2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 39.3 %

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (150 mg, 0.364 mmol) was suspended in dichloromethane (2 ml) under nitrogen at room temperature and triethylamine (153 μl, 1.09 mmol) was added followed by ethylchloroformate (39 μl, 0.4 mmol). The reaction was stirred at room temperature for 1.5 h and the mixture was quenched with sat. sodium bicarbonate solution (3 ml). The organic phase was separated and the aqueous phase was washed with dichloromethane (2×3 ml). The combined organic extracts were dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol (98:2, by volume) and the product was triturated with diethylether (3 ml) to give (cis-4-{[5-Fluoro-2-(3-methylsulfanyl-phenoxy)-pyridine-3-carbonyl]-amino}-cyclohexyl)-carbamic acid ethyl ester (64 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:23])=[N:11][C:12]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][CH2:35][O:36][CH3:37].[Li]CCCC>C1COCC1.CCCCC>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][CH2:35][O:36][CH3:37])=[N:13][C:12]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])=[N:11][C:10]=1[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Reactant: COCOCCCCCCCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: COCOCCCCCCCCCCc1nc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution at −78° C. containing 486 mg (1.58 mmol) of 5-(benzyloxy)-2-(2,5-dimethyl-1H-pyrrol-1-yl)-4,6-dimethylpyrimidine and 281 mg (1.05 mmol) of 1-bromo-9-(methoxymethoxy)nonane in 10 mL of anhydrous THF was added 987 μL (1.58 mmol) of a 1.6 M solution of n-BuLi in pentane. The reaction mixture was stirred under argon atmosphere at 23° C. for 30 min. The reaction was quenched with saturated aqueous ammonium chloride and then poured into 50 mL of water. The mixture was then extracted with two 50-mL portions of ethyl acetate. The combined organic layer was washed with 80 mL of brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (15×3 cm). Elution with 5:1 hexanes-ethyl acetate afforded the expected product as a light yellow oil: yield 289 mg (56%); silica gel TLC Rf 0.55 (5:1 hexanes-ethyl acetate); 1H NMR (CDCl381.33 (m, 12H), 1.60 (m, 2H), 1.82 (m, 2H), 2.33 (s, 6H), 2.49 (s, 3H), 2.79 (dd, 2H, J=7.6, 7.6 Hz), 3.36 (s, 3H), 3.52 (t, 2H, J=6.4 Hz), 4.62 (s, 2H), 4.90 (s, 2H), 5.87 (s, 2H) and 7.37-7.48 (m, 5H); 13C NMR (CDCl3) δ14.4, 14.4, 19.3, 26.2, 27.7, 29.4, 29.4, 29.5, 29.5, 29.6, 29.8, 31.6, 55.1, 67.9, 75.7, 96.4, 108.0, 108.0, 128.0, 128.58, 128.62, 128.7, 129.3, 136.2, 147.4, 147.4, 152.6, 161.6, 161.6 and 165.1; mass spectrum (APCI), m/z 494.3395 (M+H)1 (C30H44N3O3 requires 494.3383).
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:18](CC)CC)C.[Cl:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)(Cl)Cl>[Cl:23][CH2:24][C:25]([NH:18][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:8])=[O:26]
Reactant: CCN(CC)CC
Reactant: O=C(Cl)CCl
Reactant: NCC(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(NC(=O)CCl)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a stirred solution of 2,2-diphenylethylamine (100.0 g, 0.5 m) and triethylamine (123.0 g, 1.2 m) in chloroform (2 liters) maintained under nitrogen at ambient temperature was added dropwise chloroacetylchloride (124.2 g, 1.1 m) and the mixture stirred for 2 hours. Thin layer chromatography (TLC) analysis showed the reaction to be complete. The mixture was transferred to a separatory funnel and washed with 10% HCl (3 ×1 liter) and water (1 liter) and the organic phase dried over MgSO4. The solvent was evaporated to a dark oil which was treated with cyclohexane (1 liter) and, upon standing, a solid crystallized which was collected by filtration, washed with cyclohexane and air dried to give 122.0 g of N-chloroacetyl-1,1-diphenylethylamine as a tan solid, m.p. 73°-74°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:25]2[C:26]([CH3:40])=[CH:27][C:28]([O:31][CH2:32][C:33]3([C:37]([OH:39])=[O:38])[CH2:36][CH2:35][CH2:34]3)=[N:29][CH:30]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[N:9](COCC[Si](C)(C)C)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=1>FC(F)(F)C(O)=O.O>[F:1][C:2]1[CH:3]=[C:4]([C:25]2[C:26]([CH3:40])=[CH:27][C:28]([O:31][CH2:32][C:33]3([C:37]([OH:39])=[O:38])[CH2:36][CH2:35][CH2:34]3)=[N:29][CH:30]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[NH:12][C:11]([C:13]([F:14])([F:16])[F:15])=[CH:10][N:9]=1
Reactant: Cc1cc(OCC2(C(=O)O)CCC2)ncc1-c1ccc(-c2nc(C(F)(F)F)cn2COCC[Si](C)(C)C)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc(OCC2(C(=O)O)CCC2)ncc1-c1ccc(-c2ncc(C(F)(F)F)[nH]2)c(F)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 86.3 %

Procedure:
In trifluoroacetic acid (3.0 mL) and water (0.3 mL) was dissolved 1-{[(5-{3-fluoro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarboxylic acid (299 mg), and the solution was stirred at 50° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, the residue was made a pH=4 with a saturated aqueous sodium hydrogen carbonate solution and 1N hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with a saturated brine. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and isopropyl ether was added to the obtained residue. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 1-{[(5-{3-fluoro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarboxylic acid (200 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH3:13])=[C:7]([CH3:14])[C:6]=1[Br:15])(=[O:3])[CH3:2].C(N(C1C=C(C)[C:26](OC)=[C:25]([CH3:32])[C:24]=1Br)C(=O)C)C=C.C(Br)C=C>>[CH3:26][C:25](=[CH2:24])[CH2:32][N:4]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH3:13])=[C:7]([CH3:14])[C:6]=1[Br:15])[C:1](=[O:3])[CH3:2]
Reactant: COc1c(C)cc(NC(C)=O)c(Br)c1C
Reactant: C=CCN(C(C)=O)c1cc(C)c(OC)c(C)c1Br
Solvent: C=CCBr
Product: C=C(C)CN(C(C)=O)c1cc(C)c(OC)c(C)c1Br
Yield: 86 %

Procedure:
Treatment of 4-acetamido-3-bromo-2,6-dimethylanisole (2.7 g, 10 mmol) according to a procedure similar to the one used for making compound 8, substituting methallylbromide for allyl bromide, afforded 14 (2.8 g, 86% yield) as a viscous liquid. Spectral data: 1H NMR (250 MHz): δ 1.71 (s, 3H), 1.75 (s, 3H), 2.18 (s, 3H), 2.33 (s, 3H), 3.26 (d, 1H, J=15 Hz), 3.66 (s, 3H), 4.62 (s, 1H), 4.75 (s, 1H), 4.82 (d, 1H, J=15 Hz), 6.82 (s, 1H).
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[O:10][C:9]([C:25]2[N:26]=[CH:27][C:28]3[C:33]([CH:34]=2)=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].O1CCCC1.CO>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[O:10][C:9]([C:25]2[N:26]=[CH:27][C:28]3[C:33]([CH:34]=2)=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(C#Cc3ccccc3)ccc12
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(CCc3ccccc3)ccc12
Yield: 60 %

Procedure:
A solution of 2-isoquinolin-3-yl-7-phenylethynyl-chromen-4-one O-tert-butyl oxime (60 mg, 0.13 mmol) (prepared using the procedure described in example 20 starting from example 2B) and Lindlar's catalyst (22.5 mg) in tetrahydrofuran (9.2 ml) and methanol (1.8 ml) was stirred at room temperature under 1 atmosphere of hydrogen for 18 h. The catalyst was removed by filtration and the solvent evaporated under reduce pressure to yield the title compound in 60% yield.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][C:8]#[N:9])=[CH:5][CH:4]=[N:3]1.[C:10](Cl)(=O)[CH3:11].Cl.Cl.N[C:17]1[CH:18]=[CH:19][C:20]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([C:30]([N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:31])[CH2:25]2)=[N:21][C:22]=1[NH2:23].C(N(CC)CC)C.C(O)(=O)C>C(O)C>[CH3:1][N:2]1[C:6]([C:7]2([C:8]3[NH:23][C:22]4=[N:21][C:20]([N:24]5[CH2:29][CH2:28][CH2:27][C@@H:26]([C:30]([N:32]6[CH2:36][CH2:35][CH2:34][CH2:33]6)=[O:31])[CH2:25]5)=[CH:19][CH:18]=[C:17]4[N:9]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1CC#N
Reactant: CC(=O)Cl
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cn1nccc1C1(c2nc3ccc(N4CCC[C@@H](C(=O)N5CCCC5)C4)nc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(1-methyl-1H-pyrazol-5-yl)acetonitrile (14.5 mg, 0.10 mmol) in ethanol (150 μL, 2.6 mmol) was added acetyl chloride (110 μL, 1.5 mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under a stream of nitrogen. Ethanol (0.5 mL) was added to the residue followed by a solution of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (36 mg, 0.01 mmol) and triethylamine (70 μL, 0.50 mmol) in ethanol (1 mL). Acetic acid (100 μL, 1.75 mmol) was added and the reaction mixture was heated in the microwave for 45 min at 130° C. The solvent was removed under a stream of nitrogen. Ethyl acetate (10 mL) was added to the residue. The solution was washed with aqueous sodium hydroxide (1N, 3 mL), washed with water (3 mL), washed with brine (3 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via HPLC to afford the title compound. MS (ESI+) (M+H) 420.3; HPLC retention time 1.88 min (Method B).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[S:16][C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH3:27])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[NH2:29][OH:30].C(N(CC)CC)C>O1CCCC1.CO>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[S:16][C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH3:27])[CH:7]=[CH:6][C:3]=1[C:4]([NH:29][OH:30])=[NH:5]
Reactant: NO
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C#N)c(F)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C(=N)NO)c(F)c1
Temperature: 60 °C
Yield: 83.2 %

Procedure:
153 mg of 2-Fluoro-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-ylmethoxy]-benzonitrile were dissolved in a mixture of 1 ml tetrahydrofuran and 2 ml methanol. 265 mg hydroxylamine hydrochloride was added followed by the addition of 0.5 ml triethylamine. The reaction mixture was stirred at 60° C. for twenty hours. The solvents were removed in vacuo and the resulting residue poured into water and extracted five times with ethylacetate. The combined organic extracts were washed with brine, dried over MgSO4 and the solvent was evaporated in vacuo to obtain 138 mg of 2-Fluoro-N-hydroxy-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-ylmethoxy]-benzamidine as crude material.
Reaction SMILES: [CH3:1][C:2]([CH3:6])(O)[C:3]#[N:4].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>CC(C)=O>[CH3:1][C:2]([N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)([CH3:6])[C:3]#[N:4]
Reactant: C1COCCN1
Reactant: CC(C)(O)C#N
Solvent: CC(C)=O
Product: CC(C)(C#N)N1CCOCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Acetone cyanohydrin (4.3 g, 50 mmol) was dissolved into acetone (5 mL). Morpholine (4.3 g, 50 mmol) was added and the solution was stirred at rt for 24 h. The volatile solvents were removed in vacuo to give the title compound as a clear liquid in quantitative yield. MS ESI 155.0 [M+H]+, calcd for [C8H14N2O+H]+ 155.1.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[N:8][CH:9]=1)(=[O:3])[CH3:2].[Br:15][Si](C)(C)C.O.BrN1C(=O)CCC1=O>ClCCl.C(N(CC)CC)C>[Br:15][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[N:8][CH:9]=1)=[O:3]
Reactant: C[Si](C)(C)Br
Reactant: CC(=O)c1ccc(-n2cncn2)nc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(CBr)c1ccc(-n2cncn2)nc1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
480 mg (corresponding to 2.55 mmol) of 5-acetyl-2-(1H-1,2,4-triazole-1-yl)pyridine was dissolved in 10 mL of dichloromethane and 1.07 mL of triethylamine, and then 662 μL (corresponding to 5.10 mmol) of bromotrimethylsilane was dropped under ice cooling. The resulting solution was stirred over night at room temperature under argon gas atmosphere, and then supplemented with water and extracted 3 times with dichloromethane. The combined dichloromethane layer was washed with water and a saturated saline solution, and dried over magnesium sulfate. The solvent was distilled off, the resulting residue was dissolved in 10 mL of tetrahydrofuran, and 454 mg (corresponding to 2.55 mmol) of N-bromosuccinimide was added thereto under ice cooling. The resulting solution was stirred at room temperature for 30 minutes. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by flash silica gel column chromatography (elution solvent: dichloromethane/ethyl acetate=2/1), to obtain 657 mg (corresponding to 2.46 mmol) of 5-(2-bromoacetyl)-2-(1H-1,2,4-triazole-1-yl)pyridine (FIG. 4, step 2).
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][C:14]3([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[N:13]([CH:22]3[CH2:24][CH2:23]3)[C:12]2=[O:25])=[CH:7][CH:6]=1)C.[Li+].[OH-]>C1COCC1.CO.CCOC(C)=O>[CH:22]1([N:13]2[C:14]3([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)[CH2:15][N:11]([C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:26])=[O:3])=[CH:6][CH:7]=3)[C:12]2=[O:25])[CH2:24][CH2:23]1
Reactant: CCOC(=O)c1ccc(N2CC3(CCCCCC3)N(C3CC3)C2=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(N2CC3(CCCCCC3)N(C3CC3)C2=O)cc1
Reaction time: 3 h
Yield: 9.5 %

Procedure:
A solution of 76 mg (2.1 mmol) 4-(1-Cyclopropyl-2-oxo-1,3-diaza-spiro[4.6]undec-3-yl)-benzoic acid ethyl ester in 2 ml THF/Methanol 1.1 was treated with 0.5 ml of 1N LiOH. After stirring for 3 h the reaction mixture was acidified with 1N HCL, taken up in EtOAc and washed with water to give 65.5 mg of pure 4-(1-cyclopropyl-2-oxo-1,3-diaza-spiro[4.6]undec-3-yl)-benzoic acid MS (API): 327.5 (M−H). A solution of 47 mg (1.3 mmol) 4-(1-cyclopropyl-2-oxo-1,3-diaza-spiro[4.6]undec-3-yl)-benzoic acid and 27 mg (0.16 mmol) of 1,1-carbonyl diimidazole in 1 ml of THF was stirred under reflux for 1 h, then 32 mg (0.4 mmol) of Ammonium acetate was added and the stirring under reflux was continued for another 2 h. The reaction mixture was taken up in EtOAc and washed with 1N HCL and water. The crude product was crystallized in Ether/Heptan to give 25 mg of pure 4-(1-Cyclopropyl-2-oxo-1,3-diaza-spiro[4.6]undec-3-yl)-benzamide. MS (ESI): 328.4 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.[N+](N[C:18]1[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]2[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[CH:20][N:19]=1)([O-])=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH2:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:18]2[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]3[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=3)=[CH:20][N:19]=2)=[N:6][CH:7]=1
Reactant: NCCCCc1ncc(Br)cc1N
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Solvent: c1ccncc1
Product: Cc1ccc(Cc2cnc(NCCCCc3ncc(Br)cc3N)[nH]c2=O)cn1
Yield: 57.3 %

Procedure:
5-Bromo-2-(4-aminobutyl)-3-aminopyridine (0.5 g) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone (0.59 g) were refluxed in pyridine (2 ml) under nitrogen for 9 hours. The pyridine was removed in vacuo and the residual pyridine removed by azeotroping with n-propanol. After chromatography on silica in ethylacetate/ethanol/0.880 ammonia (15:10:2), the residue was crystallised from ethanol-ether and water (2 drops) to give 2-[4-(5-bromo-3-aminopyrid-2-yl)butylamino]-5-(6-methylpyrid-3-ylmethyl) 4-pyrimidone (0.52 g), m.p. 196°-197° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([CH2:21]O)=[CH:19][N:18]=[C:17]3[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[CH:25][C:16]=23)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(=O)[NH:38]C(=O)C2=CC=CC=C12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O.NN>O1CCCC1>[NH2:38][CH2:21][C:20]1[CH:19]=[N:18][C:17]2[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:33])[CH3:31])[CH:24]=[CH:25][C:16]=2[C:15]=1[NH:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(NC3CCN(Cc4ccccc4)CC3)c(CO)cnc21
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: NN
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(NC3CCN(Cc4ccccc4)CC3)c(CN)cnc21
Yield: 24.2 %

Procedure:
{4-[(1-Benzylpiperidin-4-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl}methanol (212 mg, 0.454 mmol), phthalimide (134 mg, 0.909 mmol) and triphenylphosphine (238 mg, 0.909 mmol) in tetrahydrofuran was stirred at room temperature for 30 minutes and with diisopropyl azodicarboxylate (184 mg, 0.909 mmol) for one day. The reaction mixture was concentrated under reduced pressure and, after addition of water, extracted with ethyl acetate. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1/(v/v)) to remove triphenylphosphine oxide. The residue was dissolved in ethanol (10 mL) and stirred with hydrazine monohydrate (1.00 mL, 11.6 mmol) at 80° C. for 1 hour. The reaction mixture was concentrated under reduced pressure and, after addition of water, extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 (v/v)) to give the title compound (51.1 mg, yield 24%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]([CH2:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[Cl:28])(=[O:20])=[O:19])[CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:5][CH:4]=1)#[N:2].CNC=[O:32].[S].[CH2:34]([NH2:37])[CH2:35]N>>[Cl:28][C:22]1[C:23]([Cl:27])=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([CH2:17][NH:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16]1)(=[O:19])=[O:20].[NH:37]1[CH2:34][CH2:35][N:2]=[C:1]1[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][N:11]([CH3:12])[CH:17]=[O:32])=[CH:7][CH:8]=1
Reactant: NCCN
Reactant: CNC=O
Reactant: N#Cc1ccc(CCN(CS(=O)(=O)c2cccc(Cl)c2Cl)C2CCCC2)cc1
Agent: [S]
Product: CN(C=O)CCc1ccc(C2=NCCN2)cc1
Product: O=S(=O)(CNC1CCCC1)c1cccc(Cl)c1Cl

Procedure:
Analogously to 13b), 3-[(2,3-dichlorobenzenesulphonyl)methylamino]cyclopentane-N-{2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]ethyl}-N-methylcarboxamide was prepared from 0.185 g (0.374 mmol) of N-[2-(4-cyanophenyl)ethyl]-3-[(2,3-dichlorobenzenesulphonyl)methylamino]cyclopentane-N-methylcarboxamide, 6.0 mg (0.187 mmol) of sulphur and 1 ml of ethylenediamine.