Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=5)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][NH:17][CH2:16][CH2:15]4)=[CH:4][CH:3]=1.ClCCl.[F:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1.C(N(C(C)C)CC)(C)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=5)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:39]([C:36]2[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=2)(=[O:41])=[O:40])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: O=C(c1ccccn1)[C@@]12CNCCC1=Cc1c(cnn1-c1ccc(F)cc1)C2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccccn1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(F)cc1)C2
Reaction time: 1.25 h

Procedure:
A solution of (R)-(1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone in dichloromethane (2.5 ml) (2.7 mL, ˜0.2 mmol) containing disiopropylethylamine (174 μL, 1 mmol) was added to 4-fluoro-phenyl sulfonyl chloride (48 mg, 0.25 mmol) and diisopropylethylamine (100 μL, 0.57 mmol) and the mixture stirred for 1.25 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (gradient: 20-30% ethyl acetate in cyclohexane) to afford (R)-(1-(4-fluorophenyl)-6-((4-fluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone as a white solid (72 mg). LCMS (Method D, ESI): RT 5.32 min, m+H=533.0; 1H NMR (400 MHz, CDCl3): δ 8.62-8.63 (m, 1 H); 7.85-7.86 (m, 2 H); 7.69-7.70 (m, 2 H); 7.44-7.45 (m, 3 H); 7.28 (s, 1 H); 7.14 (dt, J=12.9, 8.5 Hz, 4 H); 6.48 (d, J=2.2 Hz, 1 H); 5.51 (dd, J=12.2, 2.1 Hz, 1 H); 4.29 (d, J=16.9 Hz, 1 H); 3.82-3.86 (m, 1 H); 2.84-2.86 (m, 2 H); 2.72 (d, J=12.2 Hz, 1 H); 2.46-2.51 (m, 2 H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:13][C:14](Br)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2.[C:18](=[O:21])([O-])[O-].[K+].[K+].O>N1C=CC=CC=1.[Cu](I)I>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:13][C:14]([O:21][C:18]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2
Reactant: O=C([O-])[O-]
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Br)s1
Agent: I[Cu]I
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Oc2ccccc2)s1
Temperature: 125 °C
Reaction time: 65 h
Yield: 34.7 %

Procedure:
To a solution of (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromothiophene-2-carboxamide) (463 mg) in pyridine (10 mL) phenol (158 mg), copper iodide (32 mg) and potassium carbonate (97 mg) were added. The mixture was stirred at 125° C. for 65 h under nitrogen. Water was added and the aqueous layer was extracted with chloroform. Following evaporation, the residue was purified by flash chromatography using 5-20% 3.5M methanolic ammonia/chloroform mixtures as the eluent and then by reverse phase HPLC on a Waters Bondapak® C18 column using a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. The free base was prepared by basification of the product-containing fractions and extraction into chloroform followed by evaporation to gave the title compound (80 mg); MS (ES+) 329 (MH+).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]([C:14](Cl)=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:3])[CH3:2].[CH3:17][C:18]1[C:19]([CH2:30][S:31]([C:33]2[NH:37][C:36]3[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=3[N:34]=2)=[O:32])=[N:20][CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]([F:29])([F:28])[F:27].C(N(CC)CC)C.C(OCC)(=O)C>O1CCCC1.CN(C)C1C=CN=CC=1>[C:1]([O:4][CH2:5][CH2:6][N:7]([C:14]([N:34]1[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=[C:33]1[S:31]([CH2:30][C:19]1[C:18]([CH3:17])=[C:23]([O:24][CH2:25][C:26]([F:27])([F:28])[F:29])[CH:22]=[CH:21][N:20]=1)=[O:32])=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reactant: CC(=O)OCCN(C(=O)Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCCN(C(=O)n1c(S(=O)Cc2nccc(OCC(F)(F)F)c2C)nc2ccccc21)c1ccccc1
Temperature: 60 °C
Reaction time: 15 h
Yield: 67.8 %

Procedure:
To a solution (10 mL) of 2-[(chlorocarbonyl)(phenyl)amino]ethyl acetate (0.58 g) prepared in the same manner as in Synthetic Example 25 in tetrahydrofuran were added 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (0.739 g), triethylamine (0.558 mL) and 4-dimethylaminopyridine (0.024 g), and the mixture was stirred at 60° C. for 15 hrs. Ethyl acetate (30 mL) was added to the reaction mixture, and the mixture was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (eluted with acetone:hexane=1:4, then 3:2). Crystallization from diethyl ether gave the title compound (0.779 g) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[C:7]1=[O:18])=O)C.[O:19]=[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH:21]1[CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[CH2:52]([O:59][NH2:60])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>C(Cl)Cl.C(N(CC)CC)C>[CH3:17][O:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:18])[CH:6]([CH2:4][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])[CH2:15][CH2:14]2.[CH2:52]([O:59][NH:60][C:34](=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH:21]1[CH2:22][CH2:23][C:24]2[C:29](=[CH:28][CH:27]=[C:26]([O:3][CH3:1])[CH:25]=2)[C:20]1=[O:19])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: O=C(O)CCCCC1CCc2ccccc2C1=O
Reactant: NOCc1ccccc1
Reactant: CCOC(=O)C1CCc2cc(OC)ccc2C1=O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(c1)CCC(CCCCC(=O)NOCc1ccccc1)C2=O
Product: COc1ccc2c(c1)CCC(CCCCC(=O)O)C2=O

Procedure:
5-(6-methoxy-1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl)-pentanoic acid (2b) is prepared from 6-methoxy-1-oxo-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid ethyl ester (2a) (Basu, B., et al., Synth. Commun., 11, 10, 1981, 803-810) in an analogous manner to that described for 1b in example 1. 6.6 g (24.3 mmol) 1b are dissolved in 140 mL of CH2Cl2. To this solution is added sequentially 3.3 mL triethylamine, 6.9 g bis-(2-oxo-3-oxazolidinyl)-phosphorylchlorid, 3.0 g O-benzylhydroxylamine and another 10.2 mL triethylamine. After stirring over night the solution is washed with 2N HCl, then sat. NaCl sol., and evaporated. On treating with diethylether, 8.5 g 5-(6-Methoxy-1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl)-pentanoic acid benzyloxy-amide (2c) is obtained as bright crystalls. Hydrogenation of 0.5 g of 2c in Methanol with Pd/BaCO3/Pb as a catalyst yields, after evaporation and treating with diethylether, 0.3 g of the title compound, MP 118-120° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N:11]1[C:15]2=[N:16][CH:17]=[CH:18][C:19]([I:20])=[C:14]2[C:13]([CH:21]([CH3:23])[CH3:22])=[N:12]1)[C:6]#[N:7])=O.[CH3:24][NH:25][CH3:26]>C(O)(=O)C.CO>[CH3:24][N:25]([CH2:1][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N:11]1[C:15]2=[N:16][CH:17]=[CH:18][C:19]([I:20])=[C:14]2[C:13]([CH:21]([CH3:23])[CH3:22])=[N:12]1)[C:6]#[N:7])[CH3:26]
Reactant: CNC
Reactant: CC(C)c1nn(-c2ccc(C#N)cc2C=O)c2nccc(I)c12
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)c1nn(-c2ccc(C#N)cc2CN(C)C)c2nccc(I)c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 40 %

Procedure:
Compound (125a) (0.500 g), 2-picoline-borane complex (0.166 g), and dimethylamine (0.216 mL) were dissolved in acetic acid (1.0 mL) and methanol (10 mL), followed by stirring at room temperature for 12 hr. The reaction solution was concentrated, and the residue was purified by basic silica gel column chromatography (hexane/ethyl acetate) to obtain 3-{(dimethylamino)methyl}-4-{4-iodo-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile (0.213 g, 40%). This 3-{(dimethylamino)methyl}-4-{4-iodo-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile was dissolved in DMSO (1.6 mL), and a hydrogen peroxide solution (30 wt %) (0.060 mL) and a 4 mol % aqueous sodium hydroxide solution (0.132 mL) were added to the resulting solution, followed by stirring at room temperature for 20 min. Water was added to the reaction solution, and the precipitate was collected by filtration and was dried under reduced pressure to obtain 3-{(dimethylamino)methyl}-4-{4-iodo-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide (0.144 g, 65%). According to Example 97(2), compound (126) (64%) was prepared as a white solid using 3-{(dimethylamino)methyl}-4-{4-iodo-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide instead of compound (97a) and using 4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazole hydrochloride instead of 4-phenyl-1H-imidazole.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6]NC2C3C(=CC=CC=3)N=C(C)C=2C(=O)C)=[CH:4][CH:3]=1.[NH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[C:27]([CH2:35][CH3:36])[C:26]=1[C:37]([O:39][CH3:40])=[O:38].BrC1C=CC(CBr)=CC=1>>[Br:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=[C:27]([CH2:35][CH3:36])[C:26]=2[C:37]([O:39][CH3:40])=[O:38])=[CH:4][CH:3]=1
Reactant: CCc1nc2ccccc2c(N)c1C(=O)OC
Reactant: CC(=O)c1c(C)nc2ccccc2c1NCc1ccc(Br)cc1
Agent: BrCc1ccc(Br)cc1
Product: CCc1nc2ccccc2c(NCc2ccc(Br)cc2)c1C(=O)OC

Procedure:
Methyl 4-(4-bromobenzylamino)-2-ethylquinoline-3-carboxylate was synthesized by the same process as described for 1-(4-(4-bromobenzylamino)-2-methylquinolin-3-yl)ethanone (Example 1, Intermediate 2c) starting from methyl 4-amino-2-ethylquinoline-3-carboxylate and 4-bromobenzyl bromide. MS(ES+): 399/401.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.N1C=CN=C1.C(OCC)C>CN(C)C=O>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.1 %

Procedure:
tert-Butyldimethylsilyl chloride (1.8 g) was added over 30 minutes to a stirred solution of 4-bromo-4'-hydroxybiphenyl (2.49 g) and imidazole (1.63 g) in dimethylformamide (15 ml) whilst keeping the temperature of the reaction mixture below 10° C. The reaction mixture was stirred at room temperature for 18 hours. Diethyl ether (225 ml) was added, the ether washed with saturated sodium hydrogen carbonate solution (3×60 ml) and brine (100 ml), dried (MgSO4) and evaporated to yield, as a colourless oil, 4-bromo-4'-(tert-butyldimethylsilyloxy)biphenyl (3.2 g); NMR (CDCl3): 0.2(6H, s), 1.0(9H, s), 6.8-6.9(2H, d), 7.3-7. 4(4H, m) and 7.45-7.55(2H, d).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1.F[C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[O:22]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:19]2[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=2[CH:21]=[O:22])[CH2:13]1
Reactant: c1ccc2sc(OCC3CCCNC3)nc2c1
Reactant: O=Cc1ccccc1F
Product: O=Cc1ccccc1N1CCCC(COc2nc3ccccc3s2)C1
Yield: 12.2 %

Procedure:
Using 3-[(benzothiazol-2-yl)oxymethyl]piperidine (58.0 mg, 0.234 mmol) and 2-fluorobenzaldehyde (0.0381 mL, 0.351 mmol), the same procedure was followed as in Step 1c of Example 1 to give 10.1 mg (12%) of the desired compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[CH3:11][N:12]([CH3:26])[C:13]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:45]CCCl>>[S:9]1[CH:8]=[CH:7][C:6]2[CH:10]=[C:2]([NH:1][CH:16]3[CH2:15][CH2:14][C:13]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)([N:12]([CH3:26])[CH3:11])[CH2:18][CH2:17]3)[CH:3]=[CH:4][C:5]1=2.[ClH:45].[S:9]1[CH:8]=[CH:7][C:6]2[CH:10]=[C:2]([NH:1][CH:16]3[CH2:15][CH2:14][C:13]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)([N:12]([CH3:26])[CH3:11])[CH2:18][CH2:17]3)[CH:3]=[CH:4][C:5]1=2
Reactant: Nc1ccc2sccc2c1
Reactant: ClCCCl
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(C)C1(c2ccccc2)CCC(Nc2ccc3sccc3c2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
300 mg 5-Aminobenzothiophene and 435 mg 4-dimethylamino-4-phenyl-cyclohexanone were dissolved in dry 1,2-dichloroethane (20 ml) under argon. Glacial acetic acid (2 mmol) and 600 mg sodium triacetoxyborohydride were added to this mixture and the mixture was stirred for 24 hours at RT. For working up, the reaction mixture was concentrated and the residue was adjusted to pH 11 with five molar sodium hydroxide solution. The alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (3×20 ml). The combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product was chromatographed over silica gel with ethyl acetate/ethanol (1:1). 230 mg of the nonpolar diastereomer of N′-benzo[b]thiophen-5-yl-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine were obtained as a white solid, from which the corresponding hydrochloride was precipitated with 1.85 M ethanolic hydrochloric acid (0.54 ml) in 2-butanone (8 ml) (243 mg; m.p. 155-157° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:12](F)(F)F)=[CH:7][CH:8]=2)[N:3]=1.[OH:16]S(O)(=O)=O.[OH-:21].[Na+]>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:12]([OH:16])=[O:21])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccc2ccc(C(F)(F)F)cc2n1
Reactant: O=S(=O)(O)O
Reactant: [OH-]
Agent: [Na+]
Product: Cc1ccc2ccc(C(=O)O)cc2n1
Temperature: 230 °C
Yield: 71.6 %

Procedure:
A mixture of 2-methyl-7-(trifluoromethyl)quinoline (5.2 g, 24.6 mmol) and 80% H2SO4 (18.1 g, 148 mmol) was heated at 230° C. for 20 minutes. After cooling to ambient temperature, the mixture was basified by 6 N NaOH to about pH 12. The resulting solid was removed by filtration. The filtrate was acidified by 2 N HCl to about pH 3, extracted with 3:1 DCM/IPA (2×50 mL), dried (sodium sulfate), filtered and concentrated under reduced pressure to give 2-methylquinoline-7-carboxylic acid (3.3 g, 71.6%) as a solid.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1.CC[N:28]([CH:32]([CH3:34])C)[CH:29](C)C.N1CCC1>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:28]4[CH2:29][CH2:34][CH2:32]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(NCC1(O)CCCC(F)(F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Agent: C1CNC1
Product: O=C(NCC1(O)CCCC(F)(F)C1)c1c(Cl)ccc2nc(N3CCC3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (3,3-difluoro-1-hydroxycyclohexylmethyl)-amide, DIPEA and azetidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.84 (m, 1H), 7.56 (2H), 6.85 (1H), 4.57 (m, 1H), 4.11 (m, 4H), 3.49 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 2H). m/z: 410 [M+H]
Reaction SMILES: NCCC[OH:5].C1C(=O)N(OC(CC[S:18][S:19][C:20]2[N:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=O)C(=O)C1.OP(O)(O)=O>C(Cl)Cl.CC(O)C>[N:25]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:19][S:18][OH:5]
Reactant: NCCCO
Reactant: O=C(CCSSc1ccccn1)ON1C(=O)CCC1=O
Agent: O=P(O)(O)O
Solvent: CC(C)O
Solvent: ClCCl
Product: OSSc1ccccn1
Reaction time: 1.25 h

Procedure:
3-Aminopropanol (0.76 ml, 10 mmol) was dissolved in a mixture of CH2Cl2 (5 ml) and 2-propanol (3 ml) and cooled in an ice bath. A solution of SPDP (1.23 g, 3.9 mmol) in CH2Cl2 (2 ml) was added dropwise in ca. 1 min. The mixture was stirred in the cooling bath for 1.25 h, and a 13% aqueous solution of NaH2PO4 (15 ml) and 85% H3PO4 (0.5 ml) were added. The products were extracted with ethyl acetate (2×30 ml), the organic layers were washed with 13% NaH2PO4, 15% KHCO3 and dried in vacuo. The crude compound 3 (1.14 g) was purified by flash-chromatography on silica-gel, elution with mixtures of CHCl3 and 2-propanol (100:0 to 100:7 by volume). Yield of pure compound 3 was 1.01 g (94%). TLC of compound 3 (CHCl3-2-propanol, 9:1): one spot, Rf ca. 0.3. 1H NMR of compound 3 (CDCl3), 5, ppm: 1.68 (quint., 6 Hz, 2H), 2.60 (t, 7 Hz, 2H), 3.05 (t, 7 Hz, 2H), 3.4 (br., 1H), 3.42 (q, 6 Hz, 2H), 3.62 (br., 2H), 6.99 (br., 1H), 7.10 (m, 1H), 7.58-7.65 (m, 1H).
Reaction SMILES: C[N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[N:3]1.[CH:31](NN)([CH3:33])[CH3:32]>>[CH:31]([N:3]1[C:4]([C:13]2[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:29][CH:30]=2)=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH:6]=[N:2]1)([CH3:33])[CH3:32]
Reactant: CC(C)NN
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Product: CC(C)n1ncc(-c2ccncc2)c1-c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting isopropyl hydrazine provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.33 (bs, 2H), 8.24 (d, J=8.3 Hz, 1H), 8.08 (d, J=8.3 Hz, 1H), 7.86 (s, 1H) 7.83 (m, 1H), 7.72 (m 2H), 7.58 (t, J=7.9 Hz, 1H), 7.20 (d, J=8.7 Hz, 2H), 7.15 (d, J=9.1 Hz, 2H) 7.04 (m, 2H), 5.43 (s, 2H), 4.31 (m, 1H), 1.43 (d, J=6.6 Hz, 6H); MS: (M+H m/z=421.2).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[F:27][C:28]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:29]=1[CH2:30][OH:31]>>[F:27][C:28]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:29]=1[CH2:30][O:31][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: OCc1cc(F)ccc1F
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCc3cc(F)ccc3F)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (70 mg; 0.184 mmol), intermediate 42.1, and 2,5-difluorobenzyl alcohol (107 mg; 0.736 mmol), example 81 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][C:5]1[N:6]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[CH:7]=[C:8]2[C:13]=1[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]2[CH2:17][CH:18]([CH3:20])[CH3:19].S([O-])(O[O-])(=O)=[O:33].[K+].[K+].OOS([O-])=O.[K+]>CO.O>[OH:1][CH2:2][CH2:3][S:4]([C:5]1[N:6]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[CH:7]=[C:8]2[C:13]=1[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]2[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:33]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCO)n(Cc3cccc4ccccc34)cc21
Reactant: O=S(=O)([O-])O[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(S(=O)CCO)n(Cc3cccc4ccccc34)cc21
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-(2-hydroxyethyl)thio-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (100 mg) in methanol (20 ml) was added potassium peroxymonosulphate (commercially sold under the trade mark "OXONE") (300 mg) in water (10 ml). After stirring for 10 minutes the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extracts were dried over magnesium sulphate and concentrated in vacuo. Chromatography on silica gel (ethyl acetate) gave the title compound (70 mg) as a white foam.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:5]=[C:6]([C:10]2[C:15]3[N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:17]=[N:18][C:14]=3[CH:13]=[C:12]([C:25]([F:28])([F:27])[F:26])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:3].[H-].[Na+].[H][H].I[CH3:34]>CN(C=O)C.O>[CH3:34][O:1][CH:2]([C:4]1[CH:5]=[C:6]([C:10]2[C:15]3[N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:17]=[N:18][C:14]=3[CH:13]=[C:12]([C:25]([F:28])([F:27])[F:26])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:3]
Reactant: [H][H]
Reactant: CI
Reactant: CC(O)c1cccc(-c2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(C)c1cccc(-c2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)c1
Reaction time: 0.25 h
Yield: 36.8 %

Procedure:
To a stirred solution of 7-(3-(1-hydroxyethyl)phenyl)-1-phenyl-5-trifluoromethylbenzimidazole (0.9 g, 2.4 mmol) in anhydrous DMF (5 ml) was added sodium hydride (0.15 g 60% dispersion in mineral oil, 3.5 mmol) at ambient temperature. When the evolution of hydrogen had ceased iodomethane (0.25 ml, 2.6 mmol) was added and stirring was continued for 15 min. Four volumes of water was added and the resultant mixture was extracted with ethyl acetate. This extract was washed twice with aqueous calcium chloride (3M), dried over magnesium sulphate and evaporated under reduced pressure. The residue was eluted through silica gel with a mixture of ethyl acetate and petroleum ether (2:3, v/v). Trituration of the concentrated eluate in ligroin afforded the title product (0.35 g, 37%) m/z, 397.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[O:9][C:10]([CH3:15])=[C:11]([CH2:13][OH:14])[N:12]=1.Cl[C:17]1[CH:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][N:18]=1.O1CCC[CH2:28]1>O.CN(C)C=O>[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[O:9][C:10]([CH3:15])=[C:11]([CH2:13][O:14][C:17]2[CH:22]=[C:21]([C:23]([O:25][CH2:26][CH3:28])=[O:24])[CH:20]=[CH:19][N:18]=2)[N:12]=1
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: Cc1oc(-c2ccco2)nc1CO
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccnc(OCc2nc(-c3ccco3)oc2C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15 %

Procedure:
Sodium hydride (60%, oily, 2.88 g) was added to a mixture of 2-(2-furyl)-5-methyl-4-oxazolylmethanol (10.80 g), methyl 2-chloro-4-pyridinecarboxylate (10.30 g), tetrahydrofuran (100 ml) and N,N-dimethylformamide (100 ml) at 0° C., and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 2-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-4-pyridinecarboxylate (2.86 g, yield 15%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 80–81° C.