Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3Br)=[CH:5][CH:4]=1.[F:20][C:21]1[C:26](B(O)O)=[CH:25][CH:24]=[CH:23][N:22]=1.C([O-])(=O)C.[K+]>C(O)CCC.O.CCOCC>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[C:26]2[C:21]([F:20])=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2cnc3c(Br)ncnc32)cc1
Reactant: OB(O)c1cccnc1F
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CCCCO
Product: COc1ccc(Cn2cnc3c(-c4cccnc4F)ncnc32)cc1
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
A mixture of 9-(4-Methoxybenzyl)-6-bromo-9H-purine (2.7 g, 8.5 mmol), 2-fluoropyridin-3-ylboronic acid (1.8 g, 13 mmol) and potassium acetate (2.5 g, 25 mmol) in 1-butanol (50 mL) and water (10 mL) was purged with Ar (vacuum/purge three times) to remove oxygen, then PdCl2(PtBu2Ph)2 (0.063 g, 0.10 mmol) was added. The reaction mixture was stirred in a 100° C. oil bath for 45 min. The reaction mixture was allowed to cool to RT and diluted with Et2O (300 mL). The mixture was washed with water (2×100 mL), brine (50 mL), dried over Na2SO4, and filtered. Some product precipitated before the filtration so the Na2SO4 was washed with 3:1 CHCl3:IPA to dissolve all product. The combined filtrate was concentrated in vacuo to ˜50 mL as a suspension. The suspension was diluted with Et2O (200 mL) and hexane (200 mL) and the solid collected by suction filtration. The solid was washed with hexane (50 mL) and dried under a stream of N2 with vacuum suction for 14 h to afford 2.39 g (crop 1) as a pale orange fine crystalline solid. The mother liquors were concentrated in vacuo to ˜100 mL to afford a second crop of product. The second crop was collected by suction filtration, washed with hexane (100 mL) and dried under a stream of N2 as above to provide 200 mg (crop 2) as a pale orange fine crystalline solid. MS (ESI, pos. ion) m/z: 336.1 [M+H]+.
Reaction SMILES: [O:1]1[CH2:27][CH:2]1[CH2:3][O:4][C:5]1[CH:26]=[CH:25][C:8]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=3[Cl:24])[N:13]=[CH:12][N:11]=2)=[CH:7][CH:6]=1.CC(C)([O-])C.[K+].[CH3:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1.[CH3:44][NH:45][CH3:46]>CN(C=O)C.O>[CH3:44][N:45]([CH2:27][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:26]=[CH:25][C:8]([NH:9][C:10]2[CH:15]=[C:14]([N:16]([CH2:40][C:39]3[CH:42]=[CH:43][C:36]([O:35][CH3:34])=[CH:37][CH:38]=3)[C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=3[Cl:24])[N:13]=[CH:12][N:11]=2)=[CH:7][CH:6]=1)[CH3:46]
Reactant: Clc1ccc(Cl)c(Nc2cc(Nc3ccc(OCC4CO4)cc3)ncn2)c1
Reactant: COc1ccc(CBr)cc1
Reactant: CNC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2cc(Nc3ccc(OCC(O)CN(C)C)cc3)ncn2)c2cc(Cl)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
To a solution of 4-{4-[2,3-epoxypropoxy]anilino}-6-(2,5-dichloroanilino)pyrimidine (Reference Example 9; 316 ma) in DMF (3 ml) was added potassium tert-butoxide (1M solution in tetrahydrofuran. 0.86 ml) at −35° C. and the solution stirred for 30 minutes. 4-Methoxybenzyl bromide (0.32 ml) was then added and the solution allowed to warm to ambient temperature over 2.5 hours. After stirring for 1 hour at ambient temperature, dimethylamine (2M in MeOH, 2 ml) was added and the reaction stirred for a further 18 hours. The solution was then poured into water and extracted with EtOAc. The organic extract was dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with DCM:MeOH:concentrated ammonia; 91:8:1 to give the title compound (220 mg, 49%) as a colourless oil. NMR: 2.19 (6H, s), 2.21-2.40 (2H, m), 3.68-3.92 (6H, m), 4.76 (1H, m), 4.95 (2H, brs), 5.38 (1H, s), 6.81 (4H, m), 7.19 (2H, m), 7.35 (3H, m), 7.42 (1H, dd), 7.61 (1H; d), 8.21 (1H, s), 8.83 (1H, s); m/z 568 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH3:2].[CH:12]([NH:15][OH:16])([CH3:14])[CH3:13]>>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N+:15]([CH:12]([CH3:14])[CH3:13])[O-:16])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C=O)cc1
Reactant: CC(C)NO
Product: CCOc1ccc(C=[N+]([O-])C(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 11 using 4-ethoxybenzaldehyde and N-isopropylhydroxylamine. The title compound was isolated in 41.2% yield as a solid, m.p. 115.1° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][C:10]1[C:11]([CH3:16])=[N:12][N:13]([CH3:15])[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:23]Br>ClCCl>[Br:23][C:14]1[N:13]([CH3:15])[N:12]=[C:11]([CH3:16])[C:10]=1[O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Cl:1]
Reactant: BrBr
Reactant: Cc1nn(C)cc1Oc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nn(C)c(Br)c1Oc1ccc(F)cc1Cl
Temperature: -25 °C

Procedure:
To a mixture of 4-(2-chloro-4-fluorophenyoxy)-1,3-dimethyl-1H-pyrazole (i.e. the product of Step B) (680 mg, 2.82 mmol) and sodium carbonate (389 mg, 3.67 mmol) in dichloromethane (12 mL) at −40° C. was added a solution of bromine (474 mg, 2.96 mmol) in dichloromethane (1 mL). After the addition was complete, the reaction mixture temperature was maintained at about −30 to −20° C. for 5 h. The reaction mixture was diluted with dichloromethane (50 mL) and washed with water (2×10 mL), aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound as a yellow solid (720 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]3OCC[O:16]3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].C1(C)C=CC=CC=1>C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(-c2ccc(C3OCCO3)cc2)cc1F
Solvent: Cc1ccccc1
Solvent: O=CO
Product: O=Cc1ccc(-c2ccc(F)c(F)c2)cc1
Yield: 95.7 %

Procedure:
A mixture of 5.4 g of 2-(3',4'-difluoro-4-biphenylyl)dioxolane; 100 ml of toluene and 20 ml of formic acid was stirred for 16 hours. The formic acid phase was separated and the toluene phase was washed neutral with two 50 ml portions of saturated sodium hydrogen carbonate solution and three 75 ml portions of water, dried over sodium sulphate and concentrated. There were obtained 4.3 g of p-(3,4-difluorophenyl)benzaldehyde.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:43])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[C:37]([CH3:42])=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=1)=O)(C)(C)C>>[CH3:42][C:37]1[C:36]([C:32]2[CH:31]=[C:30]([C:28]3[CH2:27][C:26](=[O:43])[NH:19][C:9]4[CH:10]=[C:11]([N:14]5[CH:18]=[CH:17][CH:16]=[CH:15]5)[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)=[CH:41][CH:40]=[CH:39][N:38]=1
Reactant: Cc1ncccc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1N
Product: Cc1ncccc1-c1cccc(C2=Nc3ccc(-n4cccc4)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from (2-amino-4-pyrrol-1-yl-phenyl)-carbamic acid tert-butyl ester (Example J11) (273 mg, 1 mmol) and 3-[3-(2-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K5) (311 mg, 1 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (146 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[N:18]2[CH2:23][CH2:22][CH:21]([NH:24][CH3:25])CC2)=[CH:4][CH:3]=1.[N:26]#[C:27][NH2:28].[C:29]([OH:32])(=[O:31])[CH3:30]>C(Cl)Cl>[C:29]([OH:32])(=[O:31])[CH3:30].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[N:18]2[CH2:30][CH2:29][CH:21]([N:24]([CH3:25])[C:27]([NH2:28])=[NH:26])[CH2:22][CH2:23]2)=[CH:6][CH:7]=1
Reactant: CNC1CCN(c2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: N#CN
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(C(=N)N)C1CCN(c2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 135 °C

Procedure:
A mixture of 10.1 g (0.03 mole) of 1-[1-[(4-fluorophenyl)methyl]-2(1H)-benzimidazolyl]-N-methyl-4-piperidinamine with 1.4 g (0.032 mole) of cyanamide and 1.8 g (0.03 mole) of acetic acid is heated to 135° C. for 1.5 hours. The mixture is cooled and it is then taken up with methylene chloride under reflux, and the precipitate is filtered off and then dried. N-[1-[1-[(4-fluorophenyl)methyl]-2(1H)-benzimidazolyl]-4-piperidinyl]-N-methylguanidine acetate is thus obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C1(C)C=CC=CC=1>[C:2]1([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccccc1
Reactant: C1CCNCC1
Solvent: Cc1ccccc1
Product: c1ccc(N2CCCCC2)cc1
Temperature: 25 °C
Yield: 43.4 %

Procedure:
A 50 mL of reactor equipped with magnetic stir bar was charged with 340 mg (0.50 mmol) of {[(t-Bu)2P(OH)]PdCl2}2 (from Experiment 8), 1.12 g (10.0 mmol) of chlorobenzene, 1.02 g (12.0 mmol) of piperidine and 1.35 g (14.0 mmol) of NaO(t-Bu) in 20.0 mL of toluene. The resulting mixture was refluxed for 16 h before the reaction was cooled to room temperature and quenched with 50 mL of H2O. The mixture was transferred to a separatory funnel, and diluted with 300 mL of diethyl ether. The layers were separated, and organic layer was washed with H2O (2×30 mL), brine (30 mL), and dried over mgSO4, filtered, and the ether removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel with hexane/ethyl acetate (50:1 volume ratio). The eluate was concentrated by rotary evaporation followed by high vacuum to give 700 mg (43% yield) of 1-phenylpiperidine.
Reaction SMILES: I[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH:8][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:6]2.[O:21]=[S:22]1(=[O:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C1COCC1.O>[O:21]=[S:22]1(=[O:28])[CH2:27][CH2:26][N:25]([CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=2)[NH:8][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6]3)[CH2:24][CH2:23]1
Reactant: O=[N+]([O-])c1cc(CI)cc2cc(-c3ccccc3)[nH]c12
Reactant: O=S1(=O)CCNCC1
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(CN2CCS(=O)(=O)CC2)cc2cc(-c3ccccc3)[nH]c12
Reaction time: 2 h
Yield: 72.1 %

Procedure:
5-Iodomethyl-2-phenyl-7-nitro-1H-indole (850 mg, 2.5 mmol) prepared in Step A was dissolved in THF (10 mL). 1,1-Dioxo-thiomorpholine (405 mg, 2.25 mmol) was added thereto, and the mixture was stirred for 2 h. After completion of the reaction, the reaction mixture was diluted with water, extracted with EtOAc, dried over anhydrous magnesium sulfate, and filtered. The residue was recrystallized from DCM and hexane to give the title compound (625 mg, Yield 65%).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:29])[C:11]([N:14]2[C:19](=[O:20])[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:17]([CH2:27]Br)[O:16][CH2:15]2)([CH3:13])[CH3:12])[CH:6]=[CH:7][CH:8]=1.[C:32]([O-:35])(=[O:34])[CH3:33].[Na+]>CN(C)C=O.CCOCC>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:29])[C:11]([N:14]2[C:19](=[O:20])[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:17]([CH2:27][O:35][C:32](=[O:34])[CH3:33])[O:16][CH2:15]2)([CH3:13])[CH3:12])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C(=O)Nc1cccc(C(F)(F)F)c1)N1COC(CBr)=C(c2ccccc2)C1=O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=O)OCC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)Nc2cccc(C(F)(F)F)c2)CO1
Yield: 77.6 %

Procedure:
A mixture of N-(3-trifluoromethylphenyl)-2-(6-bromomethyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (1.09 g) and sodium acetate (0.36 g) was heated at 80-90° C. in N,N-dimethylformamide for 3 hours. The cooled solution was diluted with ether, washed with water, dried (magnesium sulphate) and evaporated in vacuo to give N-(3-trifluoromethylphenyl)-2-(6-acetoxymethyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (compound 103, 0.81 g) as a white solid, m.p. 76.5-77.5° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[CH:11]1([C:16](Cl)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1.[N+](C)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-]>O>[CH:11]1([C:16]([C:3]2[S:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:2]=2[CH3:1])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(Cl)C1CCCC1
Reactant: Cc1csc2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Product: Cc1c(C(=O)C2CCCC2)sc2ccccc12
Reaction time: 1.5 h
Yield: 93 %

Procedure:
To a mixture of 3-methyl-1-benzothiophene (1.00 g), cyclopentanecarbonyl chloride (903 μL) and nitromethane (10 mL) was added aluminum chloride (1.35 g) at 0° C., and the mixture was stirred for 1.5 hr. Water was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography (ethyl acetate) to give the title object compound (1.54 g, 93%) as a pale-brown oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:32](O)=[O:33])=[C:21]([CH3:31])[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]=23)[CH2:3][CH2:2]1.[NH2:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38][CH2:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:32]([NH:35][C@H:36]4[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:47])([CH3:46])[CH3:48])[CH2:38][CH2:37]4)=[O:33])=[C:21]([CH3:31])[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[C:15]=23)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Product: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c5) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:16]=1.Cl.[CH2:18]([N:20]([CH2:33][CH3:34])[CH2:21][CH2:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27])[CH3:19]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]([C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=3[O:23][CH2:22][CH2:21][N:20]([CH2:33][CH3:34])[CH2:18][CH3:19])[C:6]=2[CH:16]=1
Reactant: CCN(CC)CCOc1ccccc1C(=O)Cl
Reactant: Clc1ccc2oc(-c3ccccc3)cc2c1
Agent: Cl
Product: CCN(CC)CCOc1ccccc1C(=O)c1c(-c2ccccc2)oc2ccc(Cl)cc12

Procedure:
Acylation of 5-chloro-2-phenylbenzofuran with 2-(2-diethylaminoethoxy)benzoyl chloride hydrochloride by the procedure described in Example 6 gives the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]([CH3:24])([CH3:23])[CH2:11][C:12]([OH:22])([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[CH:13]=O.[NH2:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH:28]=[N:29][NH:30][C:31]2=[O:36]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[OH:22][C:12]1([C:15]([F:20])([F:21])[C:16]([F:18])([F:19])[F:17])[CH2:11][C:10]([CH3:23])([CH3:24])[C:4]2[C:5](=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=2[O:2][CH3:1])[CH:13]1[NH:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH:28]=[N:29][NH:30][C:31]2=[O:36]
Reactant: Nc1cccc2c(=O)[nH]ncc12
Reactant: COc1cc(C)ccc1C(C)(C)CC(O)(C=O)C(F)(F)C(F)(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C)cc2c1C(C)(C)CC(O)(C(F)(F)C(F)(F)F)C2Nc1cccc2c(=O)[nH]ncc12
Yield: 2.3 %

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 250 mg of 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)pentanal and 118 mg of 5-amino-phthalazin-1-one. As in Example 3, 65 mg of the imine is reacted by reaction with 0.38 ml of titanium tetrachloride (1 M in dichloromethane) in 6 ml of dichloromethane, and 8 mg of the title compound is obtained.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:3]([NH:5][C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[N:9][N:10]=1)=[O:4].[NH:24]1[CH:28]=[C:27]([CH:29]=O)[N:26]=[CH:25]1.[BH3-][C:32]#N.[Na+]>CO>[CH3:32][N:24]1[CH:28]=[C:27]([CH2:29][NH:1][C@@H:2]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:3]([NH:5][C:6]2[S:7][C:8]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[N:9][N:10]=2)=[O:4])[N:26]=[CH:25]1
Reactant: O=Cc1c[nH]cn1
Reactant: N[C@@H](Cc1ccccc1)C(=O)Nc1nnc(-c2ccncc2)s1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cn1cnc(CN[C@@H](Cc2ccccc2)C(=O)Nc2nnc(-c3ccncc3)s2)c1
Reaction time: 4 h
Yield: 56 %

Procedure:
A solution of (S)-2-amino-3-phenyl-N-(5-(pyridin-4-yl)-1,3,4-thiadiazol-2-yl)propanamide (0.066 g, 0.20 mmol), 1H-imidazole-4-carbaldehyde (0.019 g, 0.20 mmol) in MeOH (2 mL) was heated to 55° C. for 15 min before addition of NaCNBH3 (0.038 g, 0.61 mmol) and let stir for 4 h. The crude mixture was then purified by RPHPLC to afford (S)-2-((1-methyl-1H-imidazol-4-yl)methylamino)-3-phenyl-N-(5-(pyridin-4-yl)-1,3,4-thiadiazol-2-yl)propanamide (47.0 mg, 55%).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Cl:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][CH2:26][CH2:27][OH:28])[CH:20]=3)[CH:16]=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.C1COCC1>[Cl:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:25]4[CH2:26][CH2:27][O:28][C:1]4=[O:2])[CH:20]=3)[CH:16]=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: OCCNc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1OCCN1c1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phosgene in toluene (1.9 ml of a 20% commercial solution, 3.5 mmol) is added within five minutes to a solution of 2-{4-[2-(3-chloro-phenylamino)-pyrimidin-4-yl]-pyridin-2-ylamino}-ethanol (0.88 g, 2.6 mmol) and triethylamine (1.7 ml, 11.7 mmol) in absolute THF (20 ml) at 50° C. After stirring the resulting suspension for one hour at room temperature it is partitioned between ethyl acetate and water. The organic phase is separated, dried over magnesium sulfate, filtered and evaporated under reduced presssure. The residue is purified by silicagel chromatography to give the title compound, m.p. 162–163° C.
Reaction SMILES: [C:1]12([CH2:11][OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C1OCCOCCOCCOCCOC1.[H-].[Na+].[Cl:30][C:31]1[CH:36]=[C:35](Cl)[N:34]=[C:33]([NH2:38])[N:32]=1>C1COCC1>[C:1]12([CH2:11][O:12][C:35]3[CH:36]=[C:31]([Cl:30])[N:32]=[C:33]([NH2:38])[N:34]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: OCC12CC3CC(CC(C3)C1)C2
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc(Cl)cc(OCC23CC4CC(CC(C4)C2)C3)n1
Temperature: 25 °C

Procedure:
A solution of adamantan-1-yl-methanol (100 mg, 0.60 mmol) in THF (5 mL) was cooled 15 to 0° C. 15-Crown-5 ether (99 mg, 0.5 mmol) and NaH (60% in oil, 92 mg, 2.4 mmol) were added sequentially. The reaction was warmed to RT for 1 h, cooled to 0° C., and 4,6-dichloropyrimidin-2-ylamine (247 mg, 1.5 mmol) was added. The reaction was heated to 65° C. for 16 h, cooled to RT, quenched with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase chromatography (EtOAc/heptane) provided 4-(adamantan-1-ylmethoxy)-6-chloro-pyrimidin-2-ylamine as a white solid.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([S:7](O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:18]>O>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([S:7]([Cl:18])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)(O)c1ccc(-c2ccccc2)cc1
Solvent: O
Product: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
4-Biphenyl sulfonic acid (2.4 g, 10 mmol) was heated to 100 C with phosphorus pentachloride (2.1 g, 10 mmol) overnight. The reaction was cooled to RT, diluted with water, filtered and washed with water. The solid was then triturated with EtOAc-ether and the beige solid was used in the next reaction without further purification.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9](Br)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:14](=[O:17])([O-])[O-].[Na+].[Na+].[CH2:20]1[CH2:24]O[CH2:22][CH2:21]1>C(Cl)(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:5][N:4]1[C@H:1]2[C@@:20]([CH3:24])([C:20]3[CH:24]=[CH:8][C:7]([C:9]4[CH:8]=[C:7]5[C:12](=[CH:11][CH:10]=4)[N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]5)=[CH:6][C:21]=3[CH2:22][CH2:2]2)[CH2:21][CH2:22][C:14]1=[O:17]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)N1CCc2cc(Br)ccc21
Reactant: C1CCOC1
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCc2cc(-c3ccc4c(c3)CC[C@H]3N(C)C(=O)CC[C@]43C)ccc21
Yield: 26 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronic acid (178 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium(O) (23 mg, 0.02 mmol), 1-acetyl-5-bromoindoline (156 mg, 0.65 mmol), 0.65 mL of 2M sodium carbonate and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (5% methanol/ethyl acetate eluent) to give 67 mg (26%) of the title compound as a yellow solid. mp 197°-200°. FDMS: m/e =388. α[D]589 =+77.92 (c=0.36, chloroform).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH:6]1[CH2:8][CH2:7]1)=[O:4].[C:9]([OH:14])(=[S:13])[CH:10](C)O.O.Cl>ClCCl>[CH:6]1([NH:5][C:3]([CH2:2][S:13][C:9](=[O:14])[CH3:10])=[O:4])[CH2:8][CH2:7]1
Reactant: O=C(CCl)NC1CC1
Reactant: CC(O)C(O)=S
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(=O)SCC(=O)NC1CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 98.9 %

Procedure:
To a solution of 2-chloro-N-cyclopropyl-acetamide (58.1 g, 0.435 mol) in dichloromethane (700 ml) at 0° C. is added thiolactic acid (49.65 g, 0.652 mol). The mixture is stirred at 0° C. for 5 minutes, then TEA (88.0 g, 0.870 mol) is added very slowly (exothermic reaction). The mixture is stirred at 0° C. for 2 hours, then poured over 700 ml of water with stirring. The aqueous layer is acidified to pH2 with 5 N HCl, and the layers are shaken and separated. The aqueous layer is extracted with dichloromethane (2×400 ml). The combined organic layers are washed with brine, then dried (anhydrous magnesium sulfate), filtered, and concentrated to give the title compound as a yellow-orange solid (74.5 g, 99%). Mass (m/z): 174.1 (M++1).