Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Mg].C(Br)C.[NH2:9][C:10]1[N:14]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=2[Cl:26])[N:13]=[C:12]([C:27]([F:30])([F:29])[F:28])[C:11]=1[S:31]C#N>C(OCC)C.O>[NH2:9][C:10]1[N:14]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:23])([F:24])[F:25])=[CH:17][C:16]=2[Cl:26])[N:13]=[C:12]([C:27]([F:28])([F:30])[F:29])[C:11]=1[S:31][CH2:1][CH3:2]
Reactant: N#CSc1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: CC[Mg]Br
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Solvent: CCBr
Product: CCSc1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of ethyl magnesium bromide, prepared from magnesium (0.57 g) and ethyl bromide (2.6 g) in dry diethyl ether (25 ml), was added dropwise to a stirred solution of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-thiocyanato-3-trifluoromethylpyrazole (5.0 g) in dry ether (50 ml) at -20° C. After stirring for a further 2 hours at room temperature, water (130 ml) was carefully added, and stirring maintained for 0.25 hour. The ether layer was separated, dried over anhydrous magnesium sulphate, and evaporated in vacuo to give a yellow gum. Purification by chromatography on silica (Merck, 200-400 mesh, 0.7 kg cm-2) eluting with dichloromethane-petroleum ether (1:1) gave a product, which recrystallized from hexane to furnish 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-ethylthio-3-trifluoromethylpyrazole, in the form of white needles, m.p. 116°-116.5° C.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9][CH3:10])=[CH:7][C:6]([NH2:11])=[C:5]([NH2:12])[CH:4]=1)[CH3:2].O.O.[C:15](O)(=[O:19])[C:16](O)=[O:17]>Cl>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][C:8]=1[CH2:9][CH3:10])[NH:11][C:16](=[O:17])[C:15](=[O:19])[NH:12]2)[CH3:2]
Reactant: CCc1cc(N)c(N)cc1CC
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: O
Product: CCc1cc2[nH]c(=O)c(=O)[nH]c2cc1CC
Yield: 88 %

Procedure:
4,5-Diethyl-1,2-diaminobenzene 24 (459 mg, 2.80 mmol) was dissolved in 4N hydrochloric acid (12 mL) at 90° C. Oxalic acid dihydrate (983 mg, 6.47 mmoL) was added to this solution in one portion with stirring under N2. The mixture was refluxed at 130°-5° C. (oil bath) for 3 h. A yellow solid precipitated, which was collected by suction filtration and dried in vacuo overnight, giving 538 mg (88%) of the title compound 25 as a brown solid; mp>360° C.; 1H NMR (DMSO-d6, 300 MHz) δ1.092 (t, 6H, J=7.5 Hz), 2.510 (q, 4H, J=7.5 Hz), 6.867 (s, 2H), 11.742 (s, 2H). EIMS m/e 218 (95, M+), 203 (100, M+ -CH3). (HPLC purity 100%)
Reaction SMILES: OC[C@@H](NC(C1C=NC(N2CCCC2)=C(OCCC)N=1)=O)CC(C)C.[CH2:26]([NH:30][C:31]1[N:32]=[CH:33][C:34]([C:43]([OH:45])=O)=[N:35][C:36]=1[O:37][CH2:38][C:39]([F:42])([F:41])[F:40])[CH2:27][CH2:28][CH3:29].[CH3:46][O:47][C:48](=[O:55])[C:49]([NH2:54])([CH2:52][CH3:53])[CH2:50][CH3:51]>>[CH3:46][O:47][C:48](=[O:55])[C:49]([NH:54][C:43]([C:34]1[CH:33]=[N:32][C:31]([NH:30][CH2:26][CH2:27][CH2:28][CH3:29])=[C:36]([O:37][CH2:38][C:39]([F:40])([F:41])[F:42])[N:35]=1)=[O:45])([CH2:52][CH3:53])[CH2:50][CH3:51]
Reactant: CCC(N)(CC)C(=O)OC
Reactant: CCCCNc1ncc(C(=O)O)nc1OCC(F)(F)F
Agent: CCCOc1nc(C(=O)N[C@H](CO)CC(C)C)cnc1N1CCCC1
Product: CCCCNc1ncc(C(=O)NC(CC)(CC)C(=O)OC)nc1OCC(F)(F)F

Procedure:
In analogy to the procedure described for the synthesis of 6-propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide (example 10, step d) the title compounds was prepared from 5-butylamino-6-(2,2,2-trifluoro-ethoxy)-pyrazine-2-carboxylic acid and 2-amino-2-ethyl-butyric acid methyl ester (European Journal of Medicinal Chemistry 1984, 19, 261). m/z (ES+): 421.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=O.[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH2:25]2.N1CCCCC1>C(O)C>[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[C:25]2=[CH:19][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[C:7](=[O:18])[C:6]=2[C:2]=1[CH3:1]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C=C2C(=O)Nc3ccc(F)cc32)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.4 %

Procedure:
A stirred solution of 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (81 mg, 0.79 mmol), 5-fluoro-1,3-dihydro-indol-2-one (44 mg, 0.79 mmol) in 0.48 ml of ethanol was added dropwise with anhydrous piperidine (0.06 ml). The mixture was stirred at room temperature overnight. The precipitate was filtered under reduced pressure, washed with anhydrous ethanol (0.2 ml×5) and purified by silica gel column chromatography with triethylamine:methanol:dichloromethane (1:20:500) as eluents to give 2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (24 mg, 7.4%) as a brown solid
Reaction SMILES: [NH2:1][C@:2]1([C:14]([O:16][CH3:17])=[O:15])[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[CH2:3]1.[CH2:18]([O:25][C:26](ON1C(=O)CCC1=O)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH2:18]([O:25][C:26]([NH:1][C@:2]1([C:14]([O:16][CH3:17])=[O:15])[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[CH2:3]1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)[C@@]1(N)CC[C@@H](c2ccc(Br)cc2)C1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)[C@@]1(NC(=O)OCc2ccccc2)CC[C@@H](c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To (1R,3R)-methyl 1-amino-3-(4-bromophenyl)cyclopentanecarboxylate (1.5 g, 5.03 mmol) in acetonitrile (7.2 ml) and water (1.800 ml) was added N-(Benzyloxycarbonyloxy)succinimide (1.254 g, 5.03 mmol) followed by potassium carbonate (0.695 g, 5.03 mmol). The reaction mixture was stirred for 1 hour at room temperature. The solvent was removed and the remaining aqueous slurry was taken up in water and ethyl acetate. The organic layer was removed and washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by flash chromatography to yield (1R,3R)-methyl 1-(benzyloxycarbonylamino)-3-(4-bromophenyl)cyclopentanecarboxylate (1.4 g, 3.24 mmol, 64.4% yield) as an off white gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[CH3:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([CH3:30])[CH:29]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[CH:27]=[C:28]([CH3:30])[CH:29]=[C:24]([CH3:23])[CH:25]=3)[CH2:32][CH2:33]2)=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: COc1cc2ccccc2cc1NC(=O)Oc1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc2ccccc2cc1NC(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
Phenyl N-(2-methoxynaphth-3-yl)carbamate (375 mg, 1.28 mmol) and 1-(3,5-dimethylphenyl)piperazine (208 mg, 1.28 mmol) were dissolved in anhydrous tetrahydrofuran (25 ml) and thereto DBU (195 mg, 1.28 mmol) was added, and then stirred at room temperature for 2 hours, concentrated under the reduced pressure to remove the solvent and purified by column chromatography to obtain the titled compound.
Reaction SMILES: [N+:1](=[C:3]([C:11](=[O:13])[CH3:12])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[N-].[C:14](N)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCCl.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Rh+3].[Rh+3]>[C:14]([NH:1][CH:3]([C:11](=[O:13])[CH3:12])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NC(=O)c1ccccc1
Reactant: CC(=O)C(=[N+]=[N-])C(=O)OC(C)(C)C
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Product: CC(=O)C(NC(=O)c1ccccc1)C(=O)OC(C)(C)C
Yield: 49.5 %

Procedure:
A solution of tert-butyl 2-diazo-3-oxobutanoate (13.1 g, 71.7 mmol) in 1,2-dichloroethane was added over 12 h to a refluxing solution of benzamide (6.16 g, 50.8 mmol) and dirhodium tetraacetate (786 mg, 1.78 mmol) in 1,2-dichloroethane (75 ml). The mixture was evaporated in vacuo and purified by flash chromatography to give tert-butyl 2-benzamido-3-oxobutanoate as a white solid (6.97 g, 51% yield).
Reaction SMILES: [NH:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H]>[Pd]>[NH2:1][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:1]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[N:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: c1ccc(NNc2ccccc2)cc1
Agent: [Pd]
Product: Nc1ccccc1
Product: c1ccc(N=Nc2ccccc2)cc1

Procedure:
It has now been found that the abovementioned disadvantages are avoided when the aryldiazosulfonates are catalytically hydrogenated. There is apparently a prejudice against this means of reduction, since even though a large number of reducing agents have been proposed for this purpose (Houben-Weyl, loc. cit. 180 to 223), catalytic hydrogenation has not been considered, presumably because reducing agents which can convert a nitro group into the amino group cleave aromatic hydrazo compounds to give the amines (Houben-Weyl, 11/1, 522). Thus hydrazobenzene in the presence of palladium black, even in the absence of hydrogen, disproportionates to give aniline and azobenzene. Hydrogenation in the presence of nickel produces aniline in virtually quantitative yield. Under the same conditions, phenylhydrazine readily decomposes to give aniline and ammonia (Houben-Weyl, loc.cit. 538).
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][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([O:23][CH3:24])[CH:17]=1.ClC(Cl)(O[C:29](=[O:35])[O:30][C:31](Cl)(Cl)Cl)Cl.[Cl:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1CO.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[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][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:30][CH2:31][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[Cl:37])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: OCc1ccccc1Cl
Reactant: COc1cc(Oc2ncnc3cc(OC)c(OC)cc23)ccc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc(Oc2ncnc3cc(OC)c(OC)cc23)ccc1NC(=O)OCc1ccccc1Cl
Yield: 97 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-methoxyaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, (2-chlorophenyl)methanol (67 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (147 mg, yield 96%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.S(=O)(=O)=O.N1C=CC=CC=1>CS(C)=O>[O:1]=[CH:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=2)=[CH:19][CH:20]=1
Reactant: NC(=O)c1ccc(Oc2ccc(CCCO)cc2)nc1
Agent: O=S(=O)=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: NC(=O)c1ccc(Oc2ccc(CCC=O)cc2)nc1
Temperature: 0 °C
Yield: 35.5 %

Procedure:
Add 6-[4-(3-hydroxy-propyl)-phenoxy]-nicotinamide (0.4051 g, 1.488 mmol) to a stirred solution of triethylamine (0.620 mL, 4.45 mmol) and anhydrous dimethylsulfoxide (4.5 mL). Dissolve pyridine sulfur trioxide (0.7023 g, 4.413 mmol) in anhydrous dimethylsulfoxide (4.5 mL) and add this solution via a cannula to the above stirred solution under nitrogen. Stir the reaction at room temperature for 1 h under nitrogen. Pour the reaction into ice water (50 mL), extract with ethyl acetate (3×50 mL), dry the ethyl acetate extracts over magnesium sulfate, filter, and concentrate on a rotary evaporator to give the crude product. The crude product is purified by flash chromatography on silica gel eluting with 100% ethyl acetate to yield 0.1428 g (36%) of 6-[4-(3-oxo-propyl)-phenoxy]-nicotinamide: mass spectrum (ion spray): m/z=271.2 (M+1); 1H NMR (CDCl3): 9.84 (t, 1H), 8.58 (d, 1H), 8.16 (dd, 1H), 7.26-7.23 (m, 2H), 7.09-7.05 (m, 2H), 6.95 (d, 1H), 6.02 (br s, 2H), 2.98 (t, 2H), 2.82 (t, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C@:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:31]([N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1)[CH3:32].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(OCC)(=O)C>[Si:24]([O:23][CH2:22][C@:19]1([CH3:21])[S:18][CH2:17][CH2:16][N:15]2[C:11]([C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:36]5[CH:35]=[N:34][N:33]([CH2:31][CH3:32])[CH:37]=5)=[CH:3][CH:4]=4)[CH2:10][CH2:9]3)=[N:12][N:13]=[C:14]2[CH2:20]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@]1(C)Cc2nnc(C3(c4ccc(Br)cc4)CC3)n2CCS1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCn1cc(-c2ccc(C3(c4nnc5n4CCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)cn1
Temperature: 90 °C
Reaction time: 5 h
Yield: 89.1 %

Procedure:
The compound (600 mg, 1.18 mmol) obtained in Example 52-1), 1-ethyl-1H-pyrazole-4-boronic acid pinacol ester (314 mg, 1.42 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex (93 mg, 0.12 mmol), and potassium carbonate (489 mg, 3.54 mmol) were dissolved in a mixed solvent of 1,4-dioxane (4 mL) and water (2 mL), and the mixture was stirred at 90° C. for 5 h. The reaction mixture was cooled to room temperature and then diluted with ethyl acetate (200 mL). The organic layer was washed with saturated aqueous sodium hydrogencarbonate and saturated sodium chloride solution and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=40:60 to 100:0) to obtain the title compound (551 mg, 89%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:22])(=[O:21])[NH:19][CH3:20])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[CH2:31](O)[CH3:32]>>[CH2:23]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:22])(=[O:21])[NH:19][CH3:20])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([O:7][CH2:31][CH3:32])=[O:6])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCO
Reactant: CNS(=O)(=O)c1cc(C(=O)O)cc(N)c1Oc1ccccc1
Reactant: BrCc1ccccc1
Product: CCOC(=O)c1cc(NCc2ccccc2)c(Oc2ccccc2)c(S(=O)(=O)NC)c1
Reaction time: 3 h

Procedure:
A mixture of 3-amino-5-methylsulphamyl-4-phenoxy-benzoic acid (1 g), benzyl bromide (1.25 g), and dry ethanol (15 ml) was refluxed for 9 hours. After 3 hours and after 6 hours more benzyl bromide (0.6 g) was added. After cooling, the precipitated ethyl 3-benzylamino-5-methylsulphamyl-4-phenoxy-benzoate was collected by suction, recrystallized from ethanol, and dried in vacuo. The melting point of the compound was 162.5°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.[C:13]1([C:19]2[C:23]([CH:24]=O)=[C:22]([CH3:26])[O:21][N:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>CCO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7](=[CH:24][C:23]1[C:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:20][O:21][C:22]=1[CH3:26])[CH2:6]2
Reactant: Cc1onc(-c2ccccc2)c1C=O
Reactant: COc1ccc2c(c1)CCC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)CC(=Cc1c(-c3ccccc3)noc1C)C2=O
Yield: 48.7 %

Procedure:
5-Methoxy-1-indanone (1 g, 6.2 mmol) and 3-phenyl-5-methyl-4-isoxazolecarbaldehyde (1.14 g, 6.2 mmol) were dissolved in EtOH (30 ml) and NaOH(4 drops of a 4M solution in water) was added. The reaction mixture was heated to reflux for 17 h. The reaction mixture was cooled and filtered to obtain the title compound as a yellow solid (1.0 g, 49%).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[CH:8]=2)[NH:3]1.N1C=CC=CC=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CCOCC>[C:25]([N:3]1[C:4]2[C:9](=[CH:8][C:7]([CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])=[CH:6][CH:5]=2)[CH2:10][CH2:11][C:2]1([CH3:18])[CH3:1])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)C(C)c1ccc2c(c1)CCC(C)(C)N2
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: COC(=O)C(C)c1ccc2c(c1)CCC(C)(C)N2C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.5 %

Procedure:
3.0 g of methyl 2-(1,2,3,4-tetrahydro-2,2-dimethylquinolin-6-yl)propionate (Compound 11) were added to 30 ml of pyridine, and 2.6 g of benzoyl chloride was further added to the solution. The mixture was stirred at room temperature for 15 hours, followed by addition of ice-water and extraction with ether. The ethereal solution was washed with 10% hydrochloric acid, water and saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. Ether was distilled off to give 3.9 g of methyl 2-(1-benzoyl-1,2,3,4-tetrahydro-2,2-dimethylquinolin-6-yl)propionate (Compound 17).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[NH2:23][CH2:24][CH2:25][CH2:26][OH:27]>O>[ClH:1].[Cl:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])[CH:11]=[CH:10]2
Reactant: NCCCO
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Solvent: O
Product: Cl
Product: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(NCCCO)ccc12
Yield: 40.1 %

Procedure:
Prepared according to the method of example 2, using N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1 (a)) (200 mg) and 3-amino-1-propanol (540 mg). Water was added to the residue and the product was collected by filtration. The product was converted to its hydrochloride salt by treatment with hydrochloric acid (4M in 1,4-dioxane). Recrystallisation (methanol/ethyl acetate) afforded the title compound as a solid (98 mg).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]2[C:22]([CH:25]([CH3:27])[CH3:26])=[N:23][CH:24]=[C:18]2[CH:17]1[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>C(Cl)(Cl)Cl.C(Cl)Cl>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]2[C:22]([CH:25]([CH3:27])[CH3:26])=[N:23][C:24]([Cl:1])=[C:18]2[CH:17]1[CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]([F:37])([F:38])[F:39])=[CH:34][CH:35]=1)=[O:15])([CH3:11])([CH3:12])[CH3:10]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)c1ncc2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)c1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Temperature: 70 °C

Procedure:
To a solution of N-chlorosuccinimide (87.3 mg; 0.628 mmol) in chloroform (1 ml) was added a solution of 3-isopropyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (229 mg; 0.523 mmol) in chloroform (2 ml) and the resulting solution was heated to 70° C. for 5 h30. The reaction mixture was allowed to cool to rt, diluted with DCM (20 ml) and washed with water (3×10 ml). The organic layer was dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by preparative HPLC gave the pure product 1-chloro-3-isopropyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow solid (97 mg; 39%). LC-MS: tR=1.04 min.; [M+H]+=472.51 g/mol.
Reaction SMILES: [NH:1]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:16][C:17]([CH3:23])([CH3:22])[CH2:18][C:19](Cl)=[O:20]>>[CH3:16][C:17]([CH3:23])([CH3:22])[CH2:18][C:19]([N:1]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:20]
Reactant: C1COCCOCCOCCOCCN1
Reactant: CC(C)(C)CC(=O)Cl
Product: CC(C)(C)CC(=O)N1CCOCCOCCOCCOCC1

Procedure:
Analogously to Example 14 from 1-aza-4,7,10,13-tetraoxacyclopentadecane and 3,3-dimethylbutyryl chloride.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]#[CH:17])=[N:13][C:12]=1[CH3:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[N:28]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)=[N+:29]=[N-:30]>O1CCCC1.[Cu]I>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[N:30]=[N:29][N:28]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH:17]=2)=[N:13][C:12]=1[CH3:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#Cc1nc(C)c(C(=O)NCc2ccccc2)s1
Reactant: [N-]=[N+]=NCCc1ccc(F)cc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2cn(CCc3ccc(F)cc3)nn2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 54.8 %

Procedure:
To a solution of N-benzyl-2-ethynyl-4-methylthiazole-5-carboxamide (0.10 g, 0.39 mmol) in tetrahydrofuran (5 mL) was added copper(I) iodide (0.002 g, 0.008 mmol), N,N-diisopropylethylamine (0.082 mL, 0.47 mmol) and 1-(2-azidoethyl)-4-fluorobenzene (0.077 g, 0.47 mmol). The reaction mixture was stirred at ambient temperature for 17 hours then concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate:hexanes, 1:1) to afford the title compound as a white solid (0.090 g, 55%): mp 181-182° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.84 (s, 1H), 7.38-7.24 (m, 5H), 7.09-6.99 (m, 2H), 6.95-6.85 (m, 2H), 6.23 (t, J=5.6 Hz, 1H), 4.61-4.56 (m, 4H), 3.20 (t, J=7.1 Hz, 2H), 2.67 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.9, 161.6, 157.9, 156.7, 142.5, 137.8, 132.2, 130.1, 128.8, 127.8, 127.7, 124.8, 121.8, 115.9, 52.0, 44.2, 35.7, 17.3; MS (ES+) m/z 422.3 (M+1).