Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:31]=[C:32]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:33]=1)[C:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:15]=1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:44]([C:48]1[CH:55]=[CH:54][C:51]([CH2:52]Cl)=[CH:50][CH:49]=1)[CH:45]([CH3:47])[CH3:46].Cl>CN(C)C=O.C(OCC)(=O)C>[CH2:44]([C:48]1[CH:55]=[CH:54][C:51]([CH2:52][N:34]([C:32]2[CH:31]=[C:11]([CH:10]=[C:9]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:52][C:51]3[CH:54]=[CH:55][C:48]([CH2:44][CH:45]([CH3:47])[CH3:46])=[CH:49][CH:50]=3)[CH:33]=2)[C:12]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:15]=2)=[O:13])[C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])=[CH:50][CH:49]=1)[CH:45]([CH3:47])[CH3:46]
Reactant: CCOC(=O)CCCn1cc(C(=O)c2cc(NC(=O)OC(C)(C)C)cc(NC(=O)OC(C)(C)C)c2)c2ccccc21
Reactant: CC(C)Cc1ccc(CCl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCn1cc(C(=O)c2cc(N(Cc3ccc(CC(C)C)cc3)C(=O)OC(C)(C)C)cc(N(Cc3ccc(CC(C)C)cc3)C(=O)OC(C)(C)C)c2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34.1 %

Procedure:
A solution of ethyl 4-[3-[3,5-bis[tertbutoxycarbonylamino)benzoyl]indol-1-yl]butyrate (300 mg) in N,N-dimethylformamide (5 ml) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 54 mg) in N,N-dimethylformamide (5 ml) at 0° C. The mixture was stirred at 0° C. for 30 minutes, and a solution of 4-isobutylbenzyl chloride (388 mg) in N,N-dimethylformamide (5 ml) was added at 0° C. The reaction mixture was stirred at 0° C. for 3 hours, and poured into a mixture of 0.1N hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water, aqueous solution of sodium bicarbonate and brine in successively. After dryness over magnesium sulfate and evaporation of the solvent, the residue was chromatographed on silica gel (25 g) eluting with a mixture of ethyl acetate and hexane (1:4) to give ethyl 4-[3-[3,5-bis[N-(4-isobutylbenzyl)-N-tert-butoxycarbonyl- amino]benzoyl]indol-1-yl]butyrate (155 mg) as an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([O:4][C:5]([NH:7][C@H:8]([C:16]([OH:18])=[O:17])[CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:6])[CH3:3].[CH2:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C1C=CN=CC=1.CN(C)C=O.ClCCl>[C:21]1([CH2:20][O:17][C:16](=[O:18])[C@H:8]([CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[NH:7][C:5]([O:4][C:2]([CH3:19])([CH3:1])[CH3:3])=[O:6])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)OCc1ccccc1
Temperature: 5 °C
Reaction time: 8 h
Yield: 103.3 %

Procedure:
A stirred, milky solution of 25.6 g (94.5 mmole) of N-[(1,1-dimethylethoxy)carbonyl]-3-cyclohexyl-(L)-alanine, 11.2 g (104 mmole) of benzyl alcohol, and 1.15 g (9.45 mmole) of 4-dimethylaminopyridine in a mixture of 210 mL of dimethyl formamide and 150 mL of dichloromethane is cooled to 5° C., and 19.2 g of 3-N,N-dimethylaminopropylethylcarbodiimide hydrochloride is added over 5 minutes. The mixture is then warmed to ambient temperature and is stirred overnight. The reaction mixture is filtered to remove a fine precipitate, and the filtrate is concentrated in vacuo. The residue is taken up in water and extracted with ethyl acetate (3×). The combined organic solutions are washed with 0.5N aqueous citric acid and twice with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil is subjected to high vacuum to minimize volatiles to give N-[(1,1-dimethylethoxy)carbonyl]-3-cyclohexyl-(L)-alanine phenylmethyl ester (35.3 g). MS (ion spray) m/z 362 (M+H)+.
Reaction SMILES: [Cl-].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:3]=1.C([Li])CCC.[CH3:33][C:34]([CH3:56])([CH2:39][CH:40]([CH2:53][CH:54]=O)[CH2:41][CH2:42][CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[C:35]([O:37][CH3:38])=[O:36]>O1CCCC1.CCCCCC>[CH3:33][C:34]([CH3:56])([CH2:39][CH:40]([CH2:53][CH:54]=[CH:8][C:4]1[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=1)[CH2:41][CH2:42][CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[C:35]([O:37][CH3:38])=[O:36]
Reactant: COC(=O)C(C)(C)CC(CC=O)CCCCO[Si](C)(C)C(C)(C)C
Reactant: c1ccc([P+](Cc2cccnc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)CC(CC=Cc1cccnc1)CCCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8.8 g (22.6 mmol) 3-pyridylmethyltriphenylphosphonium chloride in 40 ml dry tetrahydrofuran at 0° is added slowly 9.0 ml (22.5 mmol) of 2.5M n-butyllithium in hexane. After stirring the resulting deep red solution at room temperature for 0.5 h, a solution of 3.23 g (9 mmol) of methyl 2,2-dimethyl-4-formylmethyl-8-(t-butyldimethylsilyloxy)-octanoate in 10 ml dry tetrahydrofuran is added slowly and then stirred for 16 h. The reaction is quenched by addition of saturated ammonium chloride solution and then extracted thrice with ether. The combined organic extracts are washed with water and brine, dried, filtered and concentrated. The residue is taken up in ether and the resulting precipitate is removed by filtration. The filtrate is evaporated and the residue is purified by silica gel chromatography using 1:1 hexane/ether to give methyl 2,2-dimethyl-4-[3-(3-pyridyl)-2-propenyl]-8-(t-butyldimethylsilyloxy)-octanoate; NMR (CDCl3): delta 5.7-6.4 (m,2H), 3.63 and 3.60 (two s,3H), 1.2 and 1.15 (two s,6H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13]O[C:11](=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1(=[O:31])[C:29]2[C:20](=[CH:21][C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19](=[O:30])[CH:18]=C1>C1C(Cl)=CC=C(Cl)C=1.O=[Mn]=O>[CH2:1]([S:8][C:9]1[CH:14]=[CH:13][C:18]2[C:19](=[O:30])[C:20]3[C:29](=[CH:28][C:27]4[C:22]([CH:21]=3)=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:16](=[O:31])[C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=CC(=O)c2cc3ccccc3cc21
Reactant: O=c1cc(SCc2ccccc2)cco1
Agent: O=[Mn]=O
Solvent: Clc1ccc(Cl)cc1
Product: O=C1c2ccc(SCc3ccccc3)cc2C(=O)c2cc3ccccc3cc21
Temperature: 180 °C

Procedure:
A mixture of 0.27 g (0.0012 mol) of 4-benzylthio-2-oxo-2H-pyrane, 0.25 g (0.0012 mol) of 1,4-anthraquinone and 0.10 g (0.0012 mol) of MnO2 in 5 ml of dichlorobenzene is heated for 24 hours under reflux (180° C.), then cooled and chromatographed over silica gel. Using cyclohexane as eluant, dichlorbenzene is first extracted, then the crude product is chromatographed with CH2Cl2. The pre-purified product is chromatographed once more, using CH2Cl2 as eluant, and the solvent is removed by evaporation. Yield: 0.09 g (20%). Melting point: 200°-203° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]2=[O:14].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(C(CC)=O)C>[CH2:21]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:12])([CH3:13])[CH2:6][C:5]2=[O:14])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)CC(=O)c2cc(O)ccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(=O)CC
Product: CC1(C)CC(=O)c2cc(OCc3ccccc3)ccc2O1
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
At RT, 25.2 g (131.2 mmol) of 6-hydroxy-2,2-dimethylchroman-4-one were introduced with stirring into 350 ml of diethyl ketone and, after addition of 18.0 g (131 mmol) of powdered potassium carbonate, stirred at 75° C. for 30 min. After cooling to 60° C., 15.7 ml (131 mmol) of benzyl bromide were added dropwise, and after 2 h the mixure was concentrated i. vac., the residue was treated with water and the solid was filtered off with suction, 37 g, m.p. 109-110° C.
Reaction SMILES: [CH2:1]([N:5]([CH2:33][CH2:34][CH2:35][CH3:36])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[NH:11][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].Cl.Cl[CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>>[CH2:33]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[N:11]([CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[CH:12]=1)=[O:7])[CH2:34][CH2:35][CH3:36]
Reactant: CCCCN(CCCC)C(=O)c1c[nH]c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Reactant: ClCCN1CCOCC1
Agent: Cl
Product: CCCCN(CCCC)C(=O)c1cn(CCN2CCOCC2)c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Yield: 69.6 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 274A, 3-benzyl 1-methyl 4-(4-(dibutylcarbamoyl)-1H-imidazol-2-yl)isophthalate (280 mg, 0.57 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (106 mg, 0.57 mmol) were converted to the title compound (240 mg, 70%). 1H NMR (CDCl3) δ 8.68 (d, J=1.6 Hz, 1H), 8.23 (dd, J=8.0, 1.6 Hz, 1H), 7.62 (s, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.36-7.32 (m, 3H), 7.25-7.23 (m, 2H), 5.14 (s, 2H), 3.97 (s, 3H), 3.92 (br s, 2H), 3.60-3.54 (m, 6H), 3.45 (br s, 2H), 2.37 (t, J=6.4 Hz, 2H), 2.20-2.18 (m, 4H), 1.63-1.56 (m, 4H), 1.38-1.22 (m, 4H), 0.95-0.82 (m, 6H); MS(ESI+) m/z 605.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:11][C:10]([O:12][C@H:13]3[CH2:18][O:17][C@H:16]([CH2:19][OH:20])[C@@H:15]([OH:21])[CH2:14]3)=[N:9][C:5]2=[N:6][C:7]=1I.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=1)#[CH:23].C(N(C(C)C)CC)(C)C>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:11][C:10]([O:12][C@H:13]3[CH2:18][O:17][C@H:16]([CH2:19][OH:20])[C@@H:15]([OH:21])[CH2:14]3)=[N:9][C:5]2=[N:6][C:7]=1[C:23]#[C:22][C:24]1[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:31])[CH3:32])=[CH:26][CH:25]=1
Reactant: OC[C@H]1OC[C@H](Oc2nc3nc(I)c(Cl)cc3[nH]2)C[C@@H]1O
Reactant: C#Cc1ccc(C(C)(C)O)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(O)c1ccc(C#Cc2nc3nc(O[C@H]4CO[C@H](CO)[C@@H](O)C4)[nH]c3cc2Cl)cc1

Procedure:
A mixture of (2R,3 S,5R)-5-((6-chloro-5-iodo-1H-imidazo[4,5-b]pyridin-2-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3-ol (50 mg, 0.120 mmol), 2-(4-ethynylphenyl)propan-2-ol (28.2 mg, 0.176 mmol), Pd(Ph3P)4 (13.58 mg, 0.012 mmol), copper(I) iodide (2.237 mg, 0.012 mmol) and diisopropylethylamine (0.062 ml, 0.360 mmol) in dioxane (2 ml) was charged in a reaction tube. Then the tube was sealed and N2 was bubbled through for 5 min. The mixture was heated at 80 C for 2 h, and then concentrated. The resulting residue was purified on reverse phase HPLC eluting with 10-70% CH3CN/H2O with TFA as an additive to give the title compound. LC-MS m/e=458.35 (M+H)+ (Rt 1.70/4.0 min); 1H NMR δ (ppm) (CD3OD): 7.83 (s, 1H), 7.58-7.54 (m, 4H), 5.13 (septet, 1H, J=5 Hz)), 4.34 (ddd 1H, J=12, 5, 2 Hz), 3.89 (dd, 1H, J=12, 2 Hz), 3.64 (dd, 1H, J=12, 6 Hz)), 3.61 (dd, 1H, J=12, 5 Hz), 3.37 (t, 1H, J=11 Hz), 3.19-3.15 (m, 1H), 2.77-2.73 (m, 1H), 1.70 (dd, 1H, J=23, 12 Hz), 1.55 (s, 6H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[CH3:30][S:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[O:37])=[CH:34][C:33]=1[C:40]([F:43])([F:42])[F:41]>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[CH:36]([C:35]2[CH:38]=[CH:39][C:32]([S:31][CH3:30])=[C:33]([C:40]([F:43])([F:42])[F:41])[CH:34]=2)[OH:37])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Reactant: CSc1ccc(C=O)cc1C(F)(F)F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSc1ccc(C(O)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
To a −78° C. suspension of 1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridine (2.84 g, 11 mmol) in dry tetrahydrofuran (50 mL) was added n-butyllithium in n-hexane (1.6 M, 6.9 mL, 11 mmol) dropwise. The mixture was stirred at −78° C. for 30 min before adding 4-methylsulfanyl-3-trifluoromethyl-benzaldehyde (2.65 g, 12 mmol) dropwise. The resulting mixture was stirred at −78° C. for 1 h and quenched by adding brine (20 mL). The mixture was extracted with ethyl acetate (300 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (20% ethyl acetate/hexanes) afforded (1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-methanol as colorless oil (4.78 g, 91%): LC/MS m/e calcd for C23H20F3N2O4S2 [M+H]+ 479.06, observed 479.0;
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]=[CH:3][CH:2]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([N:21]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C>[N:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:7]([C:5]1[CH:6]=[CH:1][CH:2]=[CH:3][N:4]=1)[C:15]1[CH:16]=[CH:17][C:18]([N:21]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)=[CH:19][CH:20]=1
Reactant: Brc1ccc(N(c2ccncc2)c2ccncc2)cc1
Reactant: c1ccc(Nc2ccccn2)nc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(N(c2ccc(N(c3ccncc3)c3ccncc3)cc2)c2ccccn2)nc1
Temperature: 145 °C
Reaction time: 30 h
Yield: 41.2 %

Procedure:
A mixture of 2,2′-dipyridylamine (5.27 g, 30.76 mmol), (4-bromophenyl)-di(4-pyridyl)amine (2.50 g, 7.69 mmol), anhydrous potassium carbonate (2.66 g, 19.23 mmol), bronze powder (4.93 g, 77.64 mmol), 18-crown-6 (200 mg, 0.76 mmol), and DMF (125 mL) was heated at 145 degrees C. under nitrogen for 30 hours. The reaction was cooled and worked up by a procedure similar to that for L1. A yellowish solid was collected from a silica gel column, and was further purified by recrystallization from dichloromethane and petroleum ether, to afford a white solid of N,N-di(2-pyridyl)-N′,N′-di(4-pyridyl)-1,4-phenylenediamine (L2, 1.32 g, yield: 41%). 1H NMR (CDCl3, Bruker 400 MHz): 8.43 (d, J=4.4 Hz, 4H, pyridyl-H), 8.37 (d, J=3.6 Hz, 2H, pyridyl-H), 7.60-7.65 (m, 2H, pyridyl-H), 7.21 (d, J=8.8 Hz, 2H, phenylene-H), 7.14 (d, J=8.8 Hz, 2H, phenylene-H), 6.98-7.09 (m, 8H, pyridyl-H). Anal. Calcd (%) for C26H20N6: C, 74.98; H, 4.84; N, 20.18. Found: C, 74.53; H, 4.72; N, 19.89. IR (KBr pellet, cm−1): 1575(vs), 1505(s), 1490(s), 1467(s), 1431(vs), 1324(s), 1305.13 (s), 1276(s), 1218(m), 1163(w), 1103(w), 991(m), 811(m), 777(m), 737(w), 654(w), 622(m), 530(m).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])=[CH:9][CH:10]=2)[NH:5][CH:4]=1.[Br:20][C:21]1[CH:22]=[N:23][C:24](Cl)=[N:25][CH:26]=1.BrC1C=NC(N2C3C(=CC=C(C(N4CCOCC4)=O)C=3)C(SC)=C2)=NC=1>>[Br:20][C:21]1[CH:22]=[N:23][C:24]([N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[C:8]([C:12]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)=[O:13])[CH:7]=3)[C:3]([CH2:2][OH:1])=[CH:4]2)=[N:25][CH:26]=1
Reactant: Clc1ncc(Br)cn1
Reactant: O=C(c1ccc2c(CO)c[nH]c2c1)N1CCOCC1
Agent: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Product: O=C(c1ccc2c(CO)cn(-c3ncc(Br)cn3)c2c1)N1CCOCC1

Procedure:
Prepared from 27b) (700 mg, 2.69 mmol, 1.0 eq) and 5-bromo-2-chloropyrimidine (520 mg, 2.69 mmol, 1.0 eq) in an analogous manner to the procedure of 1c). The raw product was purified by column chromatography [100-200 mesh; ethyl acetate/petrolether=7:3]. White solid. Yield: 400 mg (35% of theory).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].[C:22]([Si:26]([O:39][CH2:40][CH2:41]I)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:25])([CH3:24])[CH3:23].O>CN(C=O)C>[C:22]([Si:26]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[O:39][CH2:40][CH2:41][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][OH:1])[S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])([CH3:23])([CH3:24])[CH3:25]
Reactant: O=S(=O)(NCCCCO)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)[Si](OCCI)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCN(CCCCO)S(=O)(=O)c1ccc(-c2ccccc2)cc1)(c1ccccc1)c1ccccc1

Procedure:
Biphenyl-4-sulfonic acid-(4-hydroxybutyl)-amide (1 g) and tert-butyl-(2-iodo-ethoxy) diphenyl silane (2 g) were heated in DMF (30 mL) for 3 hours at 60° C. The resultant mixture was poured into water and extracted with dichloromethane. Evaporation and column chromatography (petrol/ethyl acetate) gave the title compound as an amorphous solid. δC (CDCl3, 62.9 MHz): 19.2, 25.1, 26.8, 29.5, 49.3, 49.8, 62.4, 62.9, 127.3, 127.6, 127.7, 127.8, 128.5, 129.1, 129.9, 133.2, 135.6, 138.4, 139.4 and 145.3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[N:26][N:27](C(OC(C)(C)C)=O)[CH:28]=1>CO.O>[NH:26]1[CH:25]=[C:24]([NH:23][C:2]2[N:7]=[C:6]([CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:16]3([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]3)[C:5]([Cl:22])=[CH:4][N:3]=2)[CH:28]=[N:27]1
Reactant: CC(C)(C)OC(=O)n1cc(N)cn1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Solvent: CO
Solvent: O
Product: NC(=O)C1(c2ccccc2CCc2nc(Nc3cn[nH]c3)ncc2Cl)CC1
Reaction time: 16 h
Yield: 19 %

Procedure:
A solution of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.070 g, 0.21 mmol) and tert-butyl 4-amino-1H-pyrazole-1-carboxylate (0.11 g, 0.63 mmol) was stirred in MeOH:water (10:1 ratio, 4 mL) at 70° C. for 2 hours and then at 90° C. for 16 hours. The volatiles were removed in vacuo and the residue was purified by silica gel column chromatography (Combiflash Rf, 0-15% MeOH in DCM) to give the title compound 19 as a light yellow solid (0.015 g, 19%). 1H NMR (300 MHz, d6-DMSO) δ 0.93-1.02 (m, 2H), 1.38-1.49 (m, 2H), 3.04-3.16 (m, 4H), 6.03 (brs, 1H), 6.98 (brs, 1H), 7.18-7.39 (m, 4H), 7.48-7.72 (m, 1H), 7.79-8.00 (m, 1H), 8.37 (s, 1H), 9.62 (s, 1H). LCMS-C: rt 4.92 min; m/z 383 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])=[C:9]([O:23][CH3:24])[C:8]([Cl:25])=[C:7]([CH3:26])[C:6]=1[C:27](=[O:29])[CH3:28].Cl.[F:31][C:32]1([F:38])[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]1>>[Cl:25][C:8]1[C:7]([CH3:26])=[C:6]([C:27](=[O:29])[CH3:28])[C:5]([O:4][CH2:3][CH2:2][N:34]2[CH2:35][CH2:36][CH2:37][C:32]([F:38])([F:31])[CH2:33]2)=[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])[C:9]=1[O:23][CH3:24]
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCC(C)c1ccc(F)cc1
Reactant: FC1(F)CCCNC1
Agent: Cl
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCN2CCCC(F)(F)C2)c1OCCC(C)c1ccc(F)cc1
Yield: 33 %

Procedure:
Example 8a (101 mg, 0.21 mmol) was reacted with 3,3-difluoropiperidine hydrochloride (2.5 eq.) as described under General Procedure K to afford the title compound (37 mg, 33%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 7.20-7.15 (m, 2H), 7.01-6.95 (m, 2H), 4.07 (t, J=5.4 Hz, 2H), 3.97 (td, J=6.9, 1.5 Hz, 2H), 3.83 (s, 3H), 3.05-2.83 (m, 1H), 2.75-2.68 (m, 4H), 2.50-2.46 (m, 5H), 2.18 (s, 3H), 2.13-1.94 (m, 2H), 1.90-1.74 (m, 4H), 1.29 (d, J=6.9 Hz, 3H). MS (ES+) m/z 528 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH3:10])[C:3]=1[F:11].C([Li])CCC.CN([CH:20]=[O:21])C>C(OCC)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([CH:20]=[O:21])=[C:3]([F:11])[C:4]=1[O:9][CH3:10]
Reactant: CN(C)C=O
Reactant: COc1c(Cl)ccc(Br)c1F
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1c(Cl)ccc(C=O)c1F
Temperature: -78 °C
Yield: 61 %

Procedure:
1-Bromo-4-chloro-2-fluoro-3-methoxybenzene (23.7 g, 99 mmol, see U.S. Pat. No. 7,300,907 for preparation) was dissolved in dry diethyl ether and cooled to −78° C. 2.5M n-Butyllithium in hexanes (44 mL, 110 mmol) was added in portions, keeping the temperature below −70° C. during the addition. DMF (15.5 mL, 200 mmol) was then added in portions, keeping the temperature below −60° C. The reaction mixture was then allowed to warm to ambient temperature and quenched with water. The organic phase was dried and concentrated. The product was purified by flash chromatography on silica gel (hexane/ethyl acetate gradient) to yield the title compound in sufficient purity for subsequent reactions (11.4 g, 61% yield): 1H NMR (CDCl3) δ 10.32 (s, 1H), 7.55 (m, 1H), 7.3 (m, 1H), 4.05 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]2[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=2[F:20])=[C:10](Cl)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH:22]([NH2:25])([CH3:24])[CH3:23].C(N(C(C)C)C(C)C)C>CN(C=O)C>[Cl:1][C:2]1[C:11]([C:12]2[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=2[F:20])=[C:10]([NH:25][CH:22]([CH3:24])[CH3:23])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(C)N
Reactant: Fc1cc(F)c(-c2c(Cl)nc3ncccc3c2Cl)c(F)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1c(-c2c(F)cc(F)cc2F)c(Cl)nc2ncccc12
Yield: 46 %

Procedure:
The product from Step 3 (0.12 g), isopropylamine (0.3 ml) and N-ethyl-diisopropylamine (0.10 g) were refluxed in DMF (8 ml) in a sealed tube at 50° C. for 17 hours. The dark coloured reaction mixture was evaporated to give an oil, which was purified by flash column chromatography on silica gel (40-60, ethyl acetate/hexane 1/3) to give [2-chloro-3-(2,4,6-trifluorophenyl)-[1,8]naphthyridin-4-yl]-isopropylamine as white crystals (0.059 g, 46%), m.p. 193° C.