Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[CH:11]([C:27](=[O:37])[NH:28][CH:29]3[CH:34]4[CH2:35][CH2:36][N:31]([CH2:32][CH2:33]4)[CH2:30]3)[CH2:10]2)=CC=1.FC(F)(F)C(O)=O.[F:47][C:48]([F:54])([F:53])[S:49]([OH:52])(=[O:51])=[O:50]>C1(OC)C=CC=CC=1>[F:47][C:48]([F:54])([F:53])[S:49]([OH:52])(=[O:51])=[O:50].[F:47][C:48]([F:54])([F:53])[S:49]([OH:52])(=[O:51])=[O:50].[SH:8][C@@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[CH:11]([C:27](=[O:37])[NH:28][CH:29]2[CH:34]3[CH2:33][CH2:32][N:31]([CH2:36][CH2:35]3)[CH2:30]2)[CH2:10]1
Reactant: COc1ccc(CS[C@H]2CC(C(=O)NC3CN4CCC3CC4)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(NC1CN2CCC1CC2)C1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
770 mg of (4S)-4-(4-methoxybenzylthio)-2-[(3-quinuclidinyl)carbamoyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (prepared as described in Preparation 6) were suspended in 1.5 ml of anisole, and the suspension was placed on an ice bath. Whilst the suspension was still on the ice bath, 6.5 ml of trifluoroacetic acid and 246 μl of trifluoromethanesulfonic acid were added to it, and the resulting mixture was stirred for 1.5 hours at room temperature. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was washed with hexane; the produce was then precipitated by the addition of diethyl ether, and the mixture was filtered, to give 813 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH2:23]([N:27]=[C:28]=[O:29])[CH2:24][CH2:25][CH3:26]>C1(C)C=CC=CC=1>[CH2:23]([NH:27][C:28]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:29])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCN=C=O
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: CCCCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Yield: 46 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (51 mg) was dissolved in toluene (3 ml) with heat, n-butyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 14 hours. The resulting residue was purified by chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 31 mg of the title compound (yield: 46%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([CH3:13])([CH3:12])[CH2:7][CH:6]=[C:5]([S:14][CH2:15][CH3:16])[C:4]=2[CH:3]=1.[CH:17]([C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1)=[CH2:18].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][C:8]1([CH3:13])[CH2:7][CH:6]=[C:5]([S:14][CH2:15][CH3:16])[C:4]2[CH:3]=[C:2](/[CH:18]=[CH:17]/[C:19]3[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=3)[CH:11]=[CH:10][C:9]1=2
Reactant: C=Cc1ccc(C(=O)OCC)cc1
Reactant: CCSC1=CCC(C)(C)c2ccc(Br)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(/C=C/c2ccc3c(c2)C(SCC)=CCC3(C)C)cc1
Temperature: 90 °C

Procedure:
To a degassed solution of 0.50 g (1.7 mmol) of 2-bromo-5,6-dihydro-5,5-dimethyl-8-(ethylthio)-naphthalene (Compound A36) and 0.45 g (2.5 mmol) of ethyl 4-vinylbenzoate in 4.0 mL of triethylamine, was added 109 mg (0.36 mmol) of tri-o-tolylphosphine and then 35 mg (0.16 mmol) of palladium(II) acetate. The reaction was heated at 90° C. for 2.25 h. The reaction was concentrated in vacuo and purified by flash chromatography (silica, 2% ethyl acetate in hexane) to afford the title compound as a colorless oil.
Reaction SMILES: F[C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:26])[CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:5].[C:31](C1C=CC(C(Cl)=O)=CC=1)#[N:32]>>[C:31]([C:29]1[CH:28]=[CH:27][C:3]([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:12][C:13](=[O:26])[CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[O:5])=[CH:2][CH:30]=1)#[N:32]
Reactant: O=C(CNC(=O)OCc1ccccc1)Nc1ccccc1C(=O)c1ccccc1F
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Product: N#Cc1ccc(C(=O)c2ccccc2NC(=O)CNC(=O)OCc2ccccc2)cc1
Yield: 76 %

Procedure:
According to the method used for the synthesis of the compound 28a, the titled compound (551 mg) is synthesized by using tert-butyl((2-trimethylstannylphenyl)-(2-(3-m-tolylureido)acethyl)amino)acetate (1.0 g) and 4-cyanobenzoylchloride (289 mg). Yield 76%.
Reaction SMILES: C1(S([NH:10][C:11](N)=[O:12])(=O)=O)C=CC=CC=1.C1(C)C=CC=CC=1.[Cl:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[NH2:28]>C(O)(=O)C>[Cl:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[NH:28][C:11](=[O:12])[NH2:10]
Reactant: NC(=O)NS(=O)(=O)c1ccccc1
Reactant: NC1CCCCC1Cl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: NC(=O)NC1CCCCC1Cl

Procedure:
A mixture of 10.3 g of of N-[4-<2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl]-ethyl)-benzenesulfonyl-urea (melting point 171° -173°C), 300 ml of toluene, 30 ml of glycolmonomethyl-ether, 1.65 g of glacial acetic acid and 3.3 g of 2-chloro-cyclohexylamine are heated under reflux for 5 hours. Then the whole is concentrated in vacuo and the residue is treated with alcohol. The N-[4-(β<2-methoxy-5-chlorobenzamido> -ethyl)-benzenesulfonyl]-N'-(2-chlorocyclohexyl)-urea obtained as crude product melts at 194° -195°C after recrystallization from methanol/dimethylformamide.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.C[Si](C=[N+]=[N-])(C)C.[NH2:20][C:21]1[C:26]([CH:27]=O)=[CH:25][CH:24]=[C:23]([CH2:29][O:30][CH3:31])[N:22]=1>O1CCCC1.C(O)(=O)C>[C:27]([C:26]1[C:21]([NH2:20])=[N:22][C:23]([CH2:29][O:30][CH3:31])=[CH:24][CH:25]=1)#[CH:1]
Reactant: COCc1ccc(C=O)c(N)n1
Reactant: CC(C)NC(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C#Cc1ccc(COC)nc1N
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a mixture of diisopropylamine (0.15 mL, 1.1 mmol) and tetrahydrofuran (2 mL) was added dropwise n-butyl lithium (1.6 M n-hexane solution, 0.68 mL, 1.1 mmol) at −78° C., which was stirred for 30 minutes at that temperature. Trimethysilyl diazomethane (2 M n-hexane solution, 0.50 mL, 0.99 mmol) was added to the reaction mixture at −78° C., and stirred for 30 minutes at that temperature. A mixture of 2-amino-6-methoxymethyl-pyridine-3-carbaldehyde (150 mg, 0.90 mmol) is described in Manufacturing Example 26-1-6 and tetrahydrofuran (1.5 mL) was added dropwise to the reaction mixture at −78° C., and stirred for 30 minutes at 0° C. The reaction mixture was cooled to −78° C., and a mixture of acetic acid (0.10 mL) and tetrahydrofuran (1 mL) was added dropwise to the reaction mixture. This reaction mixture was gradually warmed to 0° C., and partitioned into water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=2:3) to obtain the title compound (73 mg, 50%).
Reaction SMILES: [CH3:1][N:2]1[C:13]2[C:5](=[CH:6][CH:7]=[C:8]3[C:12]=2[CH:11]=[N:10][NH:9]3)[C:4]([C:14]([OH:16])=O)=[CH:3]1.C1C=CC2N(O)N=[N:23]C=2C=1.N.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:1][N:2]1[C:13]2[C:12]3[C:8](=[N:9][NH:10][CH:11]=3)[CH:7]=[CH:6][C:5]=2[C:4]([C:14]([NH2:23])=[O:16])=[CH:3]1
Reactant: On1nnc2ccccc21
Reactant: Cn1cc(C(=O)O)c2ccc3[nH]ncc3c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(C(N)=O)c2ccc3n[nH]cc3c21
Temperature: 25 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
To a solution of 1-methyl-1,6-dihydro-1,6,7-triaza-as-indacene-3-carboxylic acid B2 (0.232 mmol) dry DMF (2 mL), HOBT.NH3 (0.464 mmol), TBTU (0.464 mmol) and DIEA (0.08 mL) were added. The mixture was stirred at rt for 24 h. The reaction mixture was concentrated and the residue was chromatographed on silica gel (eluant: DCM/MeOH 20:1). The title compound was obtained in 60% yield.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[N:8]1[C:12]2=[C:13]3[S:19][CH:18]=[CH:17][C:14]3=[N:15][CH:16]=[C:11]2[N:10]=[C:9]1[CH2:20]Cl.[CH3:22][S:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[N:8]1[C:12]2=[C:13]3[S:19][CH:18]=[CH:17][C:14]3=[N:15][CH:16]=[C:11]2[N:10]=[C:9]1[CH2:20][N:26]([S:23]([CH3:22])(=[O:24])=[O:25])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30]
Reactant: ClCc1nc2cnc3ccsc3c2n1[C@H]1CC2CCC1C2
Reactant: CC(C)(C)OC(=O)NS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1nc2cnc3ccsc3c2n1[C@H]1CC2CCC1C2)S(C)(=O)=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[(2S)-bicyclo[2.2.1]hept-2-yl]-2-(chloromethyl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridine (0.10 g, 0.31 mmol) dissolved in N,N-dimethylformamide (1 mL) was added tert-butyl (methylsulfonyl)carbamate (0.092 g, 0.47 mmol) and potassium carbonate (0.087 g, 0.63 mmol). The mixture was stirred at 50° C. overnight, then diluted with water and extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated to give crude tert-butyl ({1-[(2S)-bicyclo[2.2. l]hept-2-yl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}methyl)(methylsulfonyl)carbamate. LCMS calculated for C22H29N4O4S2 (M+H)+: m/z=477.2. Found: 477.1. The crude intermediate was treated with trifluoroacetic acid (0.5 mL, 6 mmol) in methylene chloride (0.5 mL) at room temperature for 30 min, then the solvent was removed in vacuo. The residue was re-dissolved in MeOH and purified on prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (30 mg, 25%). LCMS calculated for C17H21N4O2S2 (M+H)+: m/z=377.1. Found: 377.0.
Reaction SMILES: [C:1]([CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:12]=1)[C:5](OCC)=[O:6])(=O)[CH3:2].O.[NH2:26][NH2:27]>C(O)C>[CH:20]1([O:19][C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=2[O:17][CH3:18])[CH2:10][C:4]2[C:5](=[O:6])[N:26]=[N:27][C:1]=2[CH3:2])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)C(Cc1ccc(OC)c(OC2CCCC2)c1)C(C)=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(CC2=C(C)N=NC2=O)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 65.6 %

Procedure:
To a stirred solution of ethyl 2-acetyl-3-(3-cyclopentyloxy-4-methoxyphenyl)-propanoate (585 mg, 1.74 mmol) in absolute ethanol (10 ml) at 0° C. was added hydrazine monohydrate (87 mg, 1.74 mmol) in one portion. The resulting solution was stirred at 0° C. for 45 minutes and then refluxed at 80° C. for 3 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo and purified by flash chromatography (SiO2 ; methylene chloride/ethanol/ammonia (4:1:0.1)) to afford the title compound as a white solid (343 mg). m.p. 186-187° C.
Reaction SMILES: Br[C:2]1[C:3]([F:8])=[N:4][CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OC([C:17]2[CH2:18][CH2:19][O:20][CH2:21][CH:22]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[F:8][C:3]1[C:2]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Fc1ncccc1Br
Reactant: CC1(C)OC(C2=CCOCC2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Fc1ncccc1C1CCOCC1
Yield: 51.1 %

Procedure:
A mixture of 3-bromo-2-fluoro-pyridine (500 mg, 2.84 mmol), 4-(4,4,5,5-Tetramethyl-[1,3]dioxolan-2-yl)-3,6-dihydro-2H-pyran (656 mg, 3.12 mmol), K3PO4 (1.2 g, 5.68 mmol), and Pd (dppf)Cl2 (208 mg, 0.284 mmol) in 1,4-Dioxane/H2O (5:1) (30 mL) was heated to reflux overnight under N2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated and purification by prep-TLC to give 2-fluoro-3-(tetrahydro-pyran-4-yl)-pyridine (260 mg, 1.45 mmol, 51.2%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=4)[CH:17]=3)=[C:11]([CH3:27])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[CH:26]=[CH:25][C:21]([C:22]([NH:28][N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)=[O:24])=[CH:20][N:19]=4)[CH:17]=3)=[C:11]([CH3:27])[N:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: NN1CCOCC1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Product: Cc1nnn(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)NN3CCOCC3)cn2)cn1
Yield: 61 %

Procedure:
As described for example 36b, 6-(4-(1-(4-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (65 mg, 0.178 mmol) was converted, using 4-aminomorpholine instead of isopropylamine, to the title compound (49 mg, 61%) which was obtained as a white solid after recrystallisation from ethyl acetate in hexane. MS: m/e=449.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)[CH:5]=1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:47](=[O:51])[CH:48]([CH3:50])[CH3:49].O>O1CCCC1>[CH3:1][O:2][C:3]([C:4]1[C:5]2[CH:47]([OH:51])[C:48]([CH3:50])([CH3:49])[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)[NH:11][C:6]=2[CH:7]=[C:8]([F:10])[CH:9]=1)=[O:20]
Reactant: COC(=O)c1cc(F)cc(N=Cc2cccc(Br)c2)c1
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(F)cc2c1C(O)C(C)(C)C(c1cccc(Br)c1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.3 %

Procedure:
To a stirred mixture solution of 3-[(3-bromo-benzylidene)-amino]-5-fluoro-benzoic acid methyl ester (51.7 g, 153.8 mmol) and ytterbium(III) triflate hydrate (14.3 g, 23.1 mmol) in dry tetrahydrofuran (100 mL) at 25° C. was added isobutyraldehyde (14 mL, 153.8 mmol) and water (2.8 mL, 153.8 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-phenyl)-7-fluoro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (63.0 g, quant.) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C19H19BrFNO3 (M+H)+: 409.27, observed: 390.0 & 392.0.
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)C.[CH2:17]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][NH2:32])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][NH:32][C:4]2[C:5](=[O:16])[C:6](=[O:15])[C:7]=2[NH:8][C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOc1c(Nc2ccncc2)c(=O)c1=O
Reactant: NCCC1CCN(Cc2ccccc2)CC1
Product: O=c1c(NCCC2CCN(Cc3ccccc3)CC2)c(Nc2ccncc2)c1=O
Yield: 71 %

Procedure:
The title compound was prepared according to the procedure described in example 37 starting from 3-ethoxy-4-(pyridine-4-yl-amino)-3-cyclobutene-1,2-dione prepared according to example 7A and 2-(1-benzylpiperidin-4-yl)-ethylamine.
Reaction SMILES: FC1C=C(F)C=CC=1N[S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH2:16][CH2:15][CH2:14]1)(=O)=O.[Cl:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[CH2:32]S>>[Cl:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[CH2:32][S:10][CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)C1=CCCCC1S(=O)(=O)Nc1ccc(F)cc1F
Reactant: Fc1ccc(CS)c(Cl)c1
Product: CCOC(=O)C1=CCCCC1SCc1ccc(F)cc1Cl
Yield: 78.6 %

Procedure:
In the same manner as in Reference Example 1, ethyl 6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate (835 mg) and (2-chloro-4-fluorophenyl)-methanethiol (853 mg) were reacted to give ethyl 6-[(2-chloro-4-fluorobenzyl)sulfanyl]-1-cyclohexene-1-carboxylate (625 mg) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([F:40])=[CH:11][C:12]([F:39])=[C:13]([N:15]2[C:24]3[C:19](=[CH:20][C:21]([F:32])=[C:22]([F:31])[C:23]=3[C:25]#[C:26][Si](C)(C)C)[C:18](=[O:33])[C:17]([C:34]([O:36]CC)=[O:35])=[CH:16]2)[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([F:40])=[CH:11][C:12]([F:39])=[C:13]([N:15]2[C:24]3[C:19](=[CH:20][C:21]([F:32])=[C:22]([F:31])[C:23]=3[C:25]#[CH:26])[C:18](=[O:33])[C:17]([C:34]([OH:36])=[O:35])=[CH:16]2)[CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(C#C[Si](C)(C)C)c(F)c(F)cc2c1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C#Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(NC(=O)OC(C)(C)C)c(F)cc3F)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.7 %

Procedure:
Ethyl 1-(5-tert-butoxycarbonylamino-2,4-difluorophenyl)-6,7-difluoro-8-(trimethylsilylethynyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (750 mg) was dissolved in tetrahydrofuran (6 ml). 1N Sodium hydroxide (2 ml) was added to this solution, and the mixture was stirred overnight at room temperature. After the reaction mixture was acidified with citric acid and then extracted with chloroform. An organic layer was dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure to obtain the title compound (240 mg) as a colorless powder.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[NH:25][C:24](=[O:26])[O:23][CH2:22][C:21]=3[CH:27]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH:28]O>>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[NH:25][C:24](=[O:26])[O:23][CH2:22][C:21]=3[CH:27]=2)=[O:28])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(SCCCCOc2ccc3c(c2)COC(=O)N3)cc1
Reactant: OO
Product: CC(=O)Nc1ccc(S(=O)CCCCOc2ccc3c(c2)COC(=O)N3)cc1

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-acetamido-phenylmercapto)-butoxy]-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.O[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:19])[C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[O:4]1[CH2:5][CH2:6][CH:2]([O:1][C:8]2[CH:9]=[CH:10][C:11]([C:14](=[O:19])[C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:13]=2)[CH2:3]1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: OC1CCOC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1ccc(OC2CCOC2)cc1
Reaction time: 2 h
Yield: 88 %

Procedure:
In 30 ml of tetrahydrofuran were dissolved 3 g of 3-hydroxytetrahydrofuran, 6.5 g of methyl 2-(4-hydroxyphenyl)-2-oxoacetate and 9 g of triphenylphosphine. The thus prepared solution was mixed with 6.5 g of diethyl azodicarboxylate, and the mixture was stirred for 2 hours. After distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using dichloromethane as an eluant, thereby obtaining 7.5 g of methyl 2-[4-[(tetrahydro-3-furanyl)oxy]phenyl]-2-oxoacetate in an oily form.
Reaction SMILES: Br[CH2:2][C:3]1[CH:19]=[CH:18][C:6]2[NH:7][C:8](=[O:17])[C:9]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:10]=3[NH:11][C:5]=2[CH:4]=1.[O:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][NH2:28])[CH2:22][CH2:21]1>O1CCOCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:9]2[C:8](=[O:17])[NH:7][C:6]3[CH:18]=[CH:19][C:3]([CH2:2][NH:28][CH2:27][CH2:26][CH:23]4[CH2:24][CH2:25][O:20][CH2:21][CH2:22]4)=[CH:4][C:5]=3[NH:11][C:10]=2[CH:12]=1
Reactant: O=C1Nc2ccc(CBr)cc2Nc2cc(Cl)ccc21
Reactant: NCCC1CCOCC1
Solvent: C1COCCO1
Product: O=C1Nc2ccc(CNCCC3CCOCC3)cc2Nc2cc(Cl)ccc21
Temperature: 25 °C
Yield: 52.3 %

Procedure:
A mixture of Example 512A (50 mg, 0.15 mmol) and 2-(tetrahydro-pyran-4-yl)-ethylamine (38.3 mg, 0.30 mmol) in dioxane (2.0 mL) was heated 11 hours at 50° C., cooled to room temperature, and concentrated under vacuum. The residue was purified by preparative HPLC to give 30.3 mg (53%) of the desired product. 1H NMR (300 MHz, DMSO-d6) □ 10.05 (s, 1H), 8.56 (br s, 1H), 8.16 (s, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.11 (d, J=2.0 Hz, 1H), 7.00-7.08 (m, 3H), 6.97 (dd, J=2.0, 8.5 Hz, 1H), 4.00-4.04 (m, 2H), 3.78-3.86 (m, 2H), 3.20-3.30 (m, 3H), 2.88-3.00 (m, 2H), 1.49-1.58 (m, 4H), 1.11-1.19 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([CH:13]=[CH:14][N:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[F:25][C:26]1[CH:27]=[CH:28][C:29]2[N:33]=[C:32]([CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[NH:31][C:30]=2[CH:40]=1>>[F:25][C:26]1[CH:27]=[CH:28][C:29]2[N:33]=[C:32]([CH:34]3[CH2:35][CH2:36][N:37]([CH2:20][C:19]4[CH:22]=[CH:23][C:16]([C:8]5[C:7]([C:1]6[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=6)=[CH:12][N:11]6[CH:13]=[CH:14][N:15]=[C:10]6[N:9]=5)=[CH:17][CH:18]=4)[CH2:38][CH2:39]3)[NH:31][C:30]=2[CH:40]=1
Reactant: Fc1ccc2nc(C3CCNCC3)[nH]c2c1
Reactant: O=Cc1ccc(-c2nc3nccn3cc2-c2ccccc2)cc1
Agent: Cl
Product: Fc1ccc2nc(C3CCN(Cc4ccc(-c5nc6nccn6cc5-c5ccccc5)cc4)CC3)[nH]c2c1
Yield: 65.7 %

Procedure:
150 mg (0.5 mmol) 4-(6-phenylimidazo[1,2-a]pyrimidin-7-yl)benzaldehyde were reacted with 132 mg (0.6 mmol) 6-fluoro-2-piperidine-4-yl-1H-benzimidazole hydrochloride salt in analogy as described in example 6.0. The desired compound (165 mg) was obtained after purification on silicagel.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][NH:6][C:5](=[O:8])[CH2:4]1.[H-].[Na+].Cl[C:12]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:24]([C:35]([F:38])([F:37])[F:36])[CH:23]=2)[CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2>>[O:32]1[CH2:33][CH2:34][CH:29]([O:28][C:25]2[CH:26]=[CH:27][C:22]([C:20]3[CH:19]=[C:18]4[C:13]([CH:14]=[CH:15][CH:16]=[N:17]4)=[C:12]([O:1][CH2:2][C@H:3]4[CH2:7][NH:6][C:5](=[O:8])[CH2:4]4)[N:21]=3)=[CH:23][C:24]=2[C:35]([F:38])([F:37])[F:36])[CH2:30][CH2:31]1
Reactant: O=C1C[C@@H](CO)CN1
Reactant: FC(F)(F)c1cc(-c2cc3ncccc3c(Cl)n2)ccc1OC1CCOCC1
Agent: [H-]
Agent: [Na+]
Product: O=C1C[C@@H](COc2nc(-c3ccc(OC4CCOCC4)c(C(F)(F)F)c3)cc3ncccc23)CN1
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
50.7 mg (R)-4-Hydroxymethyl-pyrrolidine-2-one (2.2) was placed in 1.5 mL of dimethylacetamaide at ambient temperature under nitrogen before 20.5 mg sodium hydride (60% dispersion in oil) was added. The reaction was stirred for 10 min and then 150 mg 5-chloro-7-[4-(tetrahydro-pyran-4-yloxy)-3-trifluoromethyl-phenyl]-[1,6]naphthyridine (6.23) was introduced and the reaction was heated to 70° C. and stirred overnight. After this time the mixture was cooled to ambient temperature and partitioned between ethyl acetate, water and some saturared sodium chloride solution. The organic layer was separated, dried over sodium sulfate, filtered and the solvent was removed from the filtrate under reduced pressure. Purification by chromatography on silica provided the title compound.