Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](O)=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:7]=1.[O:37]1C2C=CC(C(=O)C)=CC=2[CH2:39][CH2:38]1.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][C:3]4[O:37][CH2:38][CH2:39][C:2]=4[CH:7]=2)[CH:17]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)c1ccc2c(c1)CCO2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccc5c(c4)CCO5)ccc3c1)n2C1CCCCC1
Yield: 28 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(2,3-dihydro-benzofuran-5-yl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in Ethanol (506 μL, 0.64 mmol) to produce the title compound (34 mg, 28% yield). MS: 490.19 (M+H+); HPLC Procedure A, retention time=11.50 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([C:10]2[S:11][CH2:12]CN=2)[N:3]=1.[CH3:15][O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([N:28]=[C:29]=[O:30])(=[O:27])=[O:26])=[O:18]>C(#N)C>[CH3:15][O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([NH:28][C:29]([NH:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH2:10][S:11][C:12]2[S:11][CH2:10][CH2:4][N:3]=2)[N:3]=1)=[O:30])(=[O:26])=[O:27])=[O:18]
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: COc1cc(C2=NCCS2)nc(N)n1
Solvent: CC#N
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(CSC2=NCCS2)cc(OC)n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
7.0 g of 2-amino-4-methoxy-6-(4,5-dihydrothiazol-2-yl)-pyrimidine are suspended in 50 ml of abs. acetonitrile, and 6.6 g of 2-methoxycarbonylphenylsulfonylisocyanate are added. There is formed a clear solution with heating, and the product subsequently precipitates in crystalline form. After the reaction mixture has been stirred for 3 hours at 20°-25° C., it is cooled to 0° C. and the solid substance is separated. There is thus obtained N-(2-methoxycarbonylphenyl-sulfonyl)-N'-[4-methoxy-6-(4,5-dihydrothiazol-2-yl)-thiomethyl-pyrimidin-2-yl]-urea, m.p. 135°-145° C. (decomp.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][O-:22].[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16]([O:22][CH3:21])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cncc(Cl)n2)CC1
Agent: [Na+]
Product: COc1cncc(N2CCN(C(=O)OC(C)(C)C)CC2)n1

Procedure:
1 mmol of 6′-Chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester [example 4.9(a)] was dissolved in a solution of sodium methanolate (prepared by dissolving 1 mmol of sodium in 10 ml of methanol). The mixture was heated overnight to 70°, concentrated and the product purified by chromatography (SiO2; dichloromethane/methanol 99:1) to yield the title compound as a colorless foam. MS (m/e): 295.3 (MH+, 100%)
Reaction SMILES: O=[C:2]1[C:7]2[CH:8]=[C:9]([CH3:12])[CH:10]=[CH:11][C:6]=2[S:5][CH2:4][CH:3]1[CH2:13][C:14]([OH:16])=O.O.[NH2:18][NH2:19]>C(O)C>[CH3:12][C:9]1[CH:10]=[CH:11][C:6]2[S:5][CH2:4][CH:3]3[C:2](=[N:18][NH:19][C:14](=[O:16])[CH2:13]3)[C:7]=2[CH:8]=1
Reactant: NN
Reactant: Cc1ccc2c(c1)C(=O)C(CC(=O)O)CS2
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(c1)C1=NNC(=O)CC1CS2
Yield: 50.9 %

Procedure:
A mixture of 2 g of α-(2,3-dihydro-4-oxo-6-methyl-4H-1-benzothiopyran-3-yl)acetic acid and 0.8 g of 100% hydrazine hydrate in 50 ml of ethanol is refluxed under heating for 8 hours. After about half the volume of ethanol is distilled off under reduced pressure and the residue is allowed to cool, the precipitated crystals are collected by filtration and recrystallized from acetic acid to give 1 g of 9-methyl- 2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin 3-one, melting at 217°-219° C., as colorless prisms.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[F:18][C:19]1[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)=[CH:21][CH:20]=1
Reactant: Fc1ccc(S)cc1
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Product: O=C1CCc2cc(OCCCCSc3ccc(F)cc3)ccc2N1

Procedure:
Prepared analogous to Example 1 from 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril (m.p. 142°-147° C.) and 4-fluorothiophenol.
Reaction SMILES: O1CCCC1.C1(C)C=CC=CC=1.[C:13]1([Mg]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:21][C:22](=[O:26])[C:23](=[O:25])[CH3:24]>C1COCC1.C1(C)C=CC=CC=1>[OH:26][C:22]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:21])[C:23](=[O:25])[CH3:24]
Reactant: Br[Mg]c1ccccc1
Reactant: CC(=O)C(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)C(C)(O)c1ccccc1
Yield: 68 %

Procedure:
The process can also be run in mixtures of tetrahydrofuran and toluene, thereby making the process more economical. When 1.1 equivalent of phenylmagnesium bromide (1.9M in 50% THF/PhMe) was added to 2,3-butanedione in 50% THF/PhMe, crude product was isolated in 82.4% yield (Run 10, Table IV) after work-up. Short path vacuum distillation gave 3-hydroxy-3-phenylbutan-2-one in 68% yield. Alternatively, preparation of phenylmagnesium bromide in 38% THF/PhMe, followed by reaction with 2,3-butanedione in 38% THF/PhMe afforded 3-hydroxy-3-phenylbutan-2-one in 66.4% yield (Run 11, Table IV) after work-up and distillation. Similarly phenylmagnessium bromide in 25% THR/PheMe reacted with 2,3-butanedione in 25% THF/PheMe yielded 3-hydroxy-3-phenylbutan-2-one in 56.9% yield after work-up and distillation.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH3:3].S(Cl)([Cl:23])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([Cl:23])=[O:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH3:3]
Reactant: CCCOC[C@H]1CC[C@H](c2ccc(C(=O)O)cc2)CC1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCOC[C@H]1CC[C@H](c2ccc(C(=O)Cl)cc2)CC1

Procedure:
4-(Trans-4-(propoxymethyl)cyclohexyl)benzoic acid (2.0 g, 7.2 mmol) was mixed with thionyl chloride (1.3 g, 10.9 mmol), pyridine (0.1 ml) and toluene (4 ml), followed by reacting them at 80° C. for 2 hours, and distilling off superfluous thionyl chloride and toluene under reduced pressure, to obtain raw 4-(trans-4-(propoxymethyl)cyclohexyl) benzoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[O:43]([C@:51]([C@@H:59]([CH:61]([O:63][Si:64]([C:67]([CH3:70])([CH3:69])[CH3:68])([CH3:66])[CH3:65])[OH:62])[OH:60])([OH:58])[C:52]([F:57])([F:56])[C:53](O)=[O:54])[Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45]>O1CCCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C:53]([C:52]([F:57])([F:56])[C@@:51]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])([C@@H:59]([CH:61]([O:63][Si:64]([C:67]([CH3:70])([CH3:69])[CH3:68])([CH3:66])[CH3:65])[OH:62])[OH:60])[OH:58])=[O:54])=[C:4]([Cl:11])[N:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC(O)[C@@H](O)[C@](O)(O[Si](C)(C)C(C)(C)C)C(F)(F)C(=O)O
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC(O)[C@@H](O)[C@](O)(O[Si](C)(C)C(C)(C)C)C(F)(F)C(=O)n1cnc2c(Cl)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.5 %

Procedure:
To a solution of 1.89 g (10.0 mmol) of 2,6-dichloropurine in 100 ml of tetrahydrofuran was added 2.62 g (10.0 mmol) of triphenylphosphine and 1.74 g (10.0 mmol) of diethyl azodicarboxylate. To this mixture was added a solution of 3.98 g (10.0 mmol) of 3,5-bis(t-butyldimethylsiloxy)-1-hydroxy-2-desoxy-2,2-difluororibose in 25 ml of tetrahydrofuran and the mixture was stirred at room temperature overnight. The precipitated solid was removed by vacuum filtration and the filtrate was concentrated under vacuum. The residue was dissolved in 100 ml of diethyl ether and the solution was stirred at room temperature overnight. The mixture was filtered and the filtrate was evaporated to dryness under vacuum. The residue was dissolved in 25 ml of ethyl acetate, and the mixture was set in the refrigerator. The mixture was filtered and the filtrate was chromatographed by HPLC while eluting with hexane/ethyl acetate (4/1, v/v). The first chromaphore containing fractions were combined and the solvent was evaporated therefrom to provide 2.5 g of 1-(2,6-dichloro-9H-purin-9-yl)-3,5-bis(t-butyldimethylsiloxy)-2-desoxy-2,2-difluororibose. m/e=[568-(t-butyl)]=511
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:9]=[C:10]([C:11]([O-:13])=[O:12])[C:4]=2[N:3]=1.[OH-].[Li+].O1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:23][C:24]1[CH:4]=[C:10]([CH2:11][N:6]2[C:5]3[CH:7]=[C:8]([N:14]4[CH2:15][CH2:16][O:17][CH2:18][CH2:19]4)[CH:9]=[C:10]([C:11]([OH:13])=[O:12])[C:4]=3[N:3]=[C:2]2[CH3:1])[CH:9]=[CH:8][C:25]=1[CH3:26]
Reactant: C1CCOC1
Reactant: Cc1nc2c(C(=O)[O-])cc(N3CCOCC3)cc2[nH]1
Agent: [Li+]
Agent: [OH-]
Product: Cc1ccc(Cn2c(C)nc3c(C(=O)O)cc(N4CCOCC4)cc32)cc1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To a mixture of methyl 1-[3,4-dimethylphenyl)methyl]-2-methyl-6-(4-morpholinyl)-1H-benzimidazole-4-carboxylate (0.24 g, 0.61 mmol) in Tetrahydrofuran (THF) (10 mL) was added in lithium hydroxide (5.99 mL, 11.99 mmol). The reaction was stirred at 50° C. for 2 h. The reaction was cooled to room temperature. The organic solvent was removed in-vacuo. The precipitate was collected by filtration. Water (20 mL) was added in. The mixture was acidified with 1 N HCl. The resulting solid was filtered and washed with water and dried to give the product (0.16 g, 66%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.18 (s, 6H), 2.58-2.75 (s, 3H), 3.06-3.22 (m, 4H), 3.71-3.82 (m, 4H), 5.55 (s, 2H), 6.94 (m, 1H), 7.04 (s, 1H), 7.11 (d, 1H, J=7.83 Hz), 7.52 (m, 2H). MS (ES+) m/e 380.2[M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4](Br)[CH:3]=1.[C:23]1([S:29]([O-:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Na+]>>[Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([S:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:31])=[O:30])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(Br)cc3c2C1
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(S(=O)(=O)c4ccccc4)cc3c2C1
Yield: 43 %

Procedure:
The product of step B was coupled with sodium benzenesulfinate using the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 3:2 hexane/ethyl acetate) provided tert-butyl 6-chloro-8-phenylsulfonyl-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (750 mg, 43%) as an off-white solid: 1H NMR (CDCl3, 300 MHz) δ 7.98-7.94 (m, 3H), 7.84 (d, J=1.2 Hz, 1H), 7.58-7.49 (m, 3H), 4.56 (s, 2H), 3.83 (t, J=5.7 Hz, 2H), 2.90 (br s, 2H), 1.49 (s, 9H).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][C@@:14]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([OH:17])[C@H:13]([OH:25])[CH2:12]1)=O)C1C=CC=CC=1>CCO.[Pd]>[CH2:18]([C@@:14]1([OH:17])[CH2:15][CH2:16][NH:11][CH2:12][C@H:13]1[OH:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(OCc1ccccc1)N1CC[C@](O)(Cc2ccccc2)[C@H](O)C1
Agent: [Pd]
Solvent: CCO
Product: O[C@@H]1CNCC[C@]1(O)Cc1ccccc1
Reaction time: 16 h
Yield: 100 %

Procedure:
(3R,4R)-4-benzyl-3,4-dihydroxy-piperidine-1-carboxylic acid benzyl ester 11.0 g (32 mmol) was dissolved in 250 ml EtOH and hydrogenated in the presence of 1.1 g Pd/C (10%) under atmospheric pressure of H2 at r.t. After 16 hours the reaction was complete and the catalyst was filtered off and the solvent was removed under reduced pressure to give 6.6 g (32 mmol, 100%) (3R,4R)-4-benzyl-3,4-dihydroxy-piperidine as an oil.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=O)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:25]=1[NH2:26]>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:25]=1[N:26]=[C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:1](=[N:26][C:25]2[C:24]([F:23])=[CH:30][CH:29]=[CH:28][C:27]=2[F:31])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:10]=1
Reactant: O=C(c1ccccc1)c1cccc(C(=O)c2ccccc2)n1
Reactant: Nc1c(F)cccc1F
Solvent: Cc1ccccc1
Product: Fc1cccc(F)c1N=C(c1ccccc1)c1cccc(C(=Nc2c(F)cccc2F)c2ccccc2)n1
Reaction time: 72 h

Procedure:
2,6-Dibenzoylpyridine (464 mg, 1.61 mmol) and 2,6-difluoroaniline (7.33 mg, 5.67 mmol) were dissolved in 30 ml of toluene. To this solution molecular sieves (4 Å) were added. After standing for 3 days at room temperature (with addition of more molecular sieves after 2 days) the mixture was filtered. The solvent was removed in vacuo. The residue was crystallised from ethanol. Yield 250 mg (30%) of 2,6-bis[(2,6-difluorophenylimino) (phenyl) methyl]pyridine 8 as a mixture of 3 isomers.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([NH2:19])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4].[CH3:29][S:30](Cl)(=[O:32])=[O:31].CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([NH:19][S:30]([CH3:29])(=[O:32])=[O:31])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](N)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](NS(C)(=O)=O)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Yield: 575.9 %

Procedure:
A solution of 39 (0.10 g, 0.26 mmol), methanesulfonyl chloride (0.08 mL, 1.03 mmol), NEt3 (0.04 mL, 0.28 mmol) and a catalytic amount of DMAP in CH2Cl2 (50 mL) was stirred at room temperature for 2 h. The mixture was washed with 2N HCl (30 mL), 2N NaOH (30 mL), and H2O (30 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure afforded a crude solid. The crude solid was purified by column chromatography (eluent: 2% MeOH/CH2Cl2) to afford 0.7 g (56%) of 42 as a white crystalline solid, mp 262-265° C. (EtOAc/n-hexanes); 1H NMR (CDCl3); δ 1.09 (3H, s); 1.46 (3H, s); 1.60 (3H, m); 1.79 (1H, dd, J=2.7, 9.6); 2.07 (2H, m); 2.18 (1H, m); 2.21 (1H, s); 2.50 (2H, m); 2.75 (1H, dd, J=3.6, 13.2); 2.99 (3H, s); 3.72 (3H, s); 4.15 (1H, m); 5.34 (1H, d, J=5.4); 5.55 (1H, dd, J=5.1, 11.4); 6.38 (1H, dd, J=0.9, 1.2); 7.41 (1H, dd, J=1.5, 1.8); 7.43 (1H, dd, J=0.9, 1.5).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[C:17]1([C:23](=[O:28])[CH2:24][C:25](=O)[CH3:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:25]([CH3:26])[C:24]([C:23]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:28])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Reactant: CC(=O)CC(=O)c1ccccc1
Product: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1C(=O)c1ccccc1
Yield: 61 %

Procedure:
The title compound was prepared from (2-Amino-5-bromo-phenyl)-phenyl-methanone [example A16] and 1-phenyl-1,3-butanedione, except that the residue was purified by spontaneous crystallization from the reaction mixture. Yield: 61%; MS: m/z=402 (M+H).
Reaction SMILES: [H-].[Na+].[NH2:3][CH:4]=[CH:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8].CO[CH:14]=[CH:15][C:16]#[N:17].Cl>CN(C)C=O.O>[F:8][C:7]([F:10])([F:9])[C:6](=[O:11])[CH:5]=[CH:4][NH:3][CH:14]=[CH:15][C:16]#[N:17]
Reactant: COC=CC#N
Reactant: NC=CC(=O)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC=CNC=CC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.1 %

Procedure:
Sodium hydride (60% dispersion in mineral oil suspension, 4.00 g, 100 mmol) was added and washed with hexane twice. Into this flask, N,N-dimethylformamide (100 ml) was added and then a solution prepared by dissolving 4-amino-1,1,1-trifluoro-3-buten-2-one (13.9 g, 100 mmol) and 3-methoxyacrylonitrile (8.30 g, 100 mmol) in N,N-dimethylformamide (50 ml) was added dropwise under ice-cooling. After stirring the mixture at room temperature for 3 hours, the reaction mixture was poured into water (500 ml). This mixture was acidified with concentrated hydrochloric acid under ice-cooling, the precipitate was collected by filtration and then washed with cold water. The obtained precipitate was dried under reduced pressure to obtain 8.20 g (yield 43.1%) of a mixture of compounds (IIa) and (IIb).
Reaction SMILES: [CH2:1]([S:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]2[OH:32])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:34][C:35]1[CH:36]=[C:37]([O:47][CH3:48])[C:38]2[C:43]([CH:44]=1)=[C:42]([O:45][CH3:46])[CH:41]=[CH:40][CH:39]=2>>[CH2:1]([S:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:21][CH:20]2[O:32][CH2:34][C:35]2[CH:36]=[C:37]([O:47][CH3:48])[C:38]3[C:43](=[C:42]([O:45][CH3:46])[CH:41]=[CH:40][CH:39]=3)[CH:44]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCSCc3ccccc3)cc2)C(O)C1
Reactant: COc1cc(CCl)cc2c(OC)cccc12
Product: COc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCSCc3ccccc3)cc2)cc2c(OC)cccc12

Procedure:
(ee) In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-4-[4-(3-benzylsulphanyl-propoxy)-phenyl]-3-hydroxy-piperidine-1-carboxylate [Example 123d)] with 3-chloromethyl-1,5-dimethoxy-naphthalene [Example 123r)] there was obtained tert-butyl (3RS,4RS)-4-[4-(3-benzylsulphanyl-propoxy)-phenyl]-3-(4,8-dimethoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a yellow, viscous oil; MS: 658 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]([C:8]([CH3:12])([CH3:11])[C:9]#N)[CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C.C(OCC)(=[O:26])C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]([C:8]([CH3:12])([CH3:11])[CH:9]=[O:26])[CH:7]=1
Reactant: Cc1ccc(F)cc1C(C)(C)C#N
Reactant: CCOC(C)=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1C(C)(C)C=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6.1 g of 2-(5-fluoro-2-methylphenyl)-2-methylpropionitrile, dissolved in 60 ml of toluene, is mixed at −70° C. for 45 minutes with 44 ml of 1.2 M diisobutylaluminum hydride solution in toluene. After 4 hours at −78° C., 120 ml of ethyl acetate is added in drops. It is heated to room temperature and washed three times with 2N sulfuric acid and once with water. The ethyl acetate phase is dried (Na2SO4) and concentrated by evaporation. After distillation, 5.3 g of 2-(5-fluoro-2-methylphenyl)-2-methylpropionaldehyde of boiling point 120° C./0.031 hPa is obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([C:21]#[C:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]4)=[C:19]([O:38][CH3:39])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([C:21]#[C:22][CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]4)=[C:19]([O:38][CH3:39])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1C#CCCN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc2c(c1C#CCCN1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
A solution of tert-butyl (Z)-4-(4-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}but-3-ynyl)piperazine-1-carboxylate (0.0315 g, 0.0596 mmol) in methylene chloride (2 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-[4-(piperazin-1-yl)but-1-ynyl]benzofuran-3(2H)-one (0.0120 g, 47%).
Reaction SMILES: N[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.[Br:16]Br>CC(O)=O>[Br:16][C:5]1[C:6](=[O:9])[N:7]([CH3:8])[CH:2]=[N:3][C:4]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrBr
Reactant: Cn1c(N)nc(-c2ccccc2)cc1=O
Solvent: CC(=O)O
Product: Cn1cnc(-c2ccccc2)c(Br)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.2 %

Procedure:
To 1.8 g (8.95 mM) of 2-amino-3-N-methyl-6-phenyl-4-pyrimidinone was added 40 ml CH3COOH and 0.535 ml Br2 (1.64 g≈10.3 mM). The reaction mixture was allowed to stir at ambient temperature for 18 hours. The solution was evaporated to dryness and the residual solid azeotroped from EtOH (2X). The solids were heated to reflux with 100 ml of H2O, cooled to 5° and filtered. This procedure was repeated, filtered hot, and allowed to crystallize at room temperature for 18 hours. The crystals were filtered and washed well with H2O to yield 1.0 g (40%) of title compound. Cooling of mother liquors gave an additional 0.6 g (24%) of title compound.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:18][CH:17]([CH2:19][N:20]([CH3:26])[CH:21]2[CH2:25][CH2:24][O:23][CH2:22]2)[CH2:16]1)=O)(C)(C)C>ClCCl>[NH:15]1[CH2:18][CH:17]([CH2:19][N:20]([CH3:26])[CH:21]2[CH2:25][CH2:24][O:23][CH2:22]2)[CH2:16]1
Reactant: CN(CC1CN(C(=O)OC(C)(C)C)C1)C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CC1CNC1)C1CCOC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.6 %

Procedure:
Trifluoroacetic acid (3 mL) was added to a solution of 3-{[methyl(tetrahydrofuran-3-yl)amino]methyl}azetidine-1-carboxylic acid tert-butyl ester (257 mg, 0.95 mmol) in dichloromethane (12 mL). The resulting reaction mixture was stirred at RT for 1.5 h. The solvents were reduced in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge (5 g). The cartridge was washed with DCM/MeOH, the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM to afford (Azetidin-3-ylmethyl)methyl(tetrahydrofuran-3-yl)amine as colourless oil (140 mg, 86%). 1H NMR (400 MHz, CDCl3): δ 3.94 (1 H, td, J=8.62, 4.35 Hz), 3.84 (1 H, dd, J=8.76, 6.50 Hz), 3.76-3.65 (3 H, m), 3.62 (1 H, dd, J=8.76, 6.50 Hz), 3.38 (2 H, t, J=7.31 Hz), 3.09-3.07 (1 H, m), 2.99-2.88 (1 H, m), 2.64 (1 H, dd, J=12.50, 7.22 Hz), 2.53 (1 H, dd, J=12.50, 7.22 Hz), 2.15 (3 H, s), 2.01 (1 H, dtd, J=12.34, 7.72, 3.21 Hz), 1.83 (1 H, dtd, J=12.35, 8.40, 6.96 Hz)