Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH2:22])[NH:20][N:21]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.[CH2:23]1[CH:28]2[CH2:29][CH2:30][CH2:31][N:27]2[CH2:26][CH2:25][N:24]1[C:32]1[N:37]=[CH:36][C:35]([C:38](OC)=[O:39])=[CH:34][N:33]=1>C1(C)C=CC=CC=1>[CH2:23]1[CH:28]2[CH2:29][CH2:30][CH2:31][N:27]2[CH2:26][CH2:25][N:24]1[C:32]1[N:37]=[CH:36][C:35]([C:38]([NH:22][C:19]2[NH:20][N:21]=[C:17]([CH2:16][CH2:15][C:9]3[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=3)[CH:18]=2)=[O:39])=[CH:34][N:33]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: COC(=O)c1cnc(N2CCN3CCCC3C2)nc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCN5CCCC5C4)nc3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.6 %

Procedure:
Trimethylaluminium (2M in toluene, 2.55 ml, 5.10 mmol) was added dropwise to a stirred suspension of 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (504 mg, 2.04 mmol) and methyl 2-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)pyrimidine-5-carboxylate (535 mg, 2.04 mmol) in toluene (10.20 ml) at 25° C. The resulting solution was stirred at ambient temperature for 18 h and then at 60° C. for 2 h. The reaction mixture was quenched with methanol (20 mL) and treated with HCl (2N aqueous solution, until a freely stirred solution was obtained). The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford impure product. The impure material was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 0.1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (288 mg, 30%) as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.N1C=CN=C1.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>CCOCC>[Si:28]([O:13][C@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:14]([O:16][CH3:17])=[O:15])[CH2:10]1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl (2S,4R)—N-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinecarboxylate (5.00 g, 0.0198 mol) was dissolved in anhydrous DMF (30 mL, 0.4 mol) under an atmosphere of nitrogen. To this solution was added 1H-imidazole (3.2 g, 0.046 mol) followed by tert-butyldimethylsilyl chloride (3.92 g, 0.0260 mol). The resulting mixture became translucent. After stirring for 16 h at RT, the reaction mixture was diluted with ether (100 mL) and washed with water (3×20 mL), and brine (2×10 mL), then dried (Na2SO4), filtered, concentrated and purified by CombiFlash chromatography (120 g column, eluting with 0-25% EtOAc/hexanes). LC/MS: 260.2 (M−Boc+2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:12][CH:11]=2)[N:3]=1.[CH3:24]I.O>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].C1C=CC=CC=1>[CH3:8][C:6]1[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([S:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]([CH3:24])[C:17](=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:12][CH:11]=2)[N:5]=1
Reactant: CCCCCC(=O)Nc1ccc(Sc2nc(C)cc(C)n2)cc1
Reactant: CI
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCCCCC(=O)N(C)c1ccc(Sc2nc(C)cc(C)n2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 83.9 %

Procedure:
Four grams N-[4-[(4,6-dimethylpyrimidin-2-yl)thio]phenyl]hexanamide, 3.4 g methyl iodide and 0.4 g tetrabutylphosphonium bromide was dissolved in a mixture of 10 ml 50% NaOH and 50 ml benzene. This was stirred vigorously at room temperature for 72 hours. Fifty milliliters water was then added and the benzene layer was separated off. The benzene solution was washed with 4×100 ml water then dried over Na2SO4. The solvent was evaporated giving 3.5 g dark brown oil. The oil was chromatographed on silica gel eluted with 50% ethyl acetate/hexanes giving 2.5 g yellow oil which slowly crystallized. Melting point of the resulting pale yellow wolid was 61°-63° C. The structure was confirmed by infrared, nuclear magnetic resonance and mass spectral analysis as that of the desired product, N-[4[(4,6-dimethylpyrimidin-2-yl)thio]phenyl]-N-methylhexanamide.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][N:14]1[C:18]2[CH:19]=[C:20]([C:23]3[N:30]4[C:26]([S:27][CH:28]=[CH:29]4)=[N:25][C:24]=3[C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[NH2:38])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:37][C:34]1[CH:35]=[CH:36][C:31]([C:24]2[N:25]=[C:26]3[N:30]([C:23]=2[C:20]2[CH:21]=[CH:22][C:17]4[N:16]=[C:15]([NH2:38])[N:14]([CH2:13][CH:9]5[CH2:10][CH2:11][CH2:12][NH:8]5)[C:18]=4[CH:19]=2)[CH:29]=[CH:28][S:27]3)=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1Cn1c(N)nc2ccc(-c3c(-c4ccc(F)cc4)nc4sccn34)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc2ccc(-c3c(-c4ccc(F)cc4)nc4sccn34)cc2n1CC1CCCN1
Reaction time: 18 h
Yield: 68.3 %

Procedure:
To a solution of 2-{2-amino-6-[6-(4-fluorophenyl)-imidazo[2,1-b]thiazol-5-yl]benzimidazol-1-ylmethyl}pyrrolidine-1-carboxylic acid tert-butyl ester (0.12 g, 0.22 mmol; Example #G.1.16) in DCM (2.7 mL) was added TFA (0.30 mL). After about 18 h, the reaction was concentrated under reduced pressure then saturated aqueous NaHCO3 was added and extracted with DCM/MeOH (9:1, 3×30 mL). The combined organic layers were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude material was purified by silica gel chromatography using DCM/MeOH/NH4OH (stepwise gradient 980:18:2 to 950:45:5). After concentration of the column fractions, the residue was dissolved in DCM and heptane was added until a precipitate formed. The mixture was then concentrated under reduced pressure to give the title compound (0.065 g, 67%): LC/MS (Table 1, Method b) Rt, =1.47 min; MS m/z: 433.1 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:27][C:18]4([CH2:26][C:20]5([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH2:19]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:29]1[N:34]=[CH:33][C:32]([CH:35]2[CH2:37][CH2:36]2)=[CH:31][N:30]=1>>[CH:35]1([C:32]2[CH:31]=[N:30][C:29]([N:23]3[CH2:22][CH2:21][C:20]4([CH2:19][C:18]5([O:17][C:14]6=[CH:15][N:16]=[C:11]([C:8]7[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH:7]=7)[CH:12]=[C:13]6[CH2:27]5)[CH2:26]4)[CH2:25][CH2:24]3)=[N:34][CH:33]=2)[CH2:37][CH2:36]1
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCNCC3)C2)CC1
Reactant: Clc1ncc(C2CC2)cn1
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCN(c4ncc(C5CC5)cn4)CC3)C2)CC1

Procedure:
The title compound is prepared from 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (HCl salt) and 2-chloro-5-cyclopropyl-pyrimidine following a procedure analogous to that described for Example 15. LC (method 3): tR=0.85 min; Mass spectrum (ESI+): m/z=508 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[N:11](COCC[Si](C)(C)C)[N:10]=2)=[N:6][C:7]=1F.Cl.[NH:33]1[CH2:37][CH2:36][C@@H:35]([OH:38])[CH2:34]1>>[Br:1][C:2]1[C:7]([N:33]2[CH2:37][CH2:36][C@@H:35]([OH:38])[CH2:34]2)=[N:6][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[NH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)c(F)n2)c2cc(-c3cccnc3)ncc21
Reactant: O[C@@H]1CCNC1
Agent: Cl
Product: O[C@@H]1CCN(c2nc(-c3n[nH]c4cnc(-c5cccnc5)cc34)ccc2Br)C1
Yield: 9.6 %

Procedure:
Following the procedures as described in Example 241 and starting with 3-(5-bromo-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and (R)-pyrrolidin-3-ol hydrochloride, 293 was obtained as an off-white solid (3.50 mg, 9.60%) over two steps. ESI MS m/z=437.1 (M+1)
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:17][N:18]([CH2:29][C:30]([O:32][CH3:33])=[O:31])S(C1C=CC(C)=CC=1)(=O)=O.C[O-].[Na+]>CO>[CH3:33][O:32][C:30]([C:29]1[N:18]=[CH:17][C:5]2[C:4]([C:3]=1[OH:2])=[C:9]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:8]=[CH:7][CH:6]=2)=[O:31]
Reactant: COC(=O)CN(Cc1cccc(Oc2ccccc2)c1C(=O)OC)S(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ncc2cccc(Oc3ccccc3)c2c1O
Yield: 26.7 %

Procedure:
To a solution of crude 2-{[Methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino]-methyl}-6-phenoxy-benzoic acid methyl ester (3.87 g) in methanol (24 mL) was added a solution of NaOMe (30 wt %) in methanol (4 mL) with stirring. After stirring for 3 days at ambient temperature the mixture was concentrated in vacuo. To the residue was added 1 N hydrochloric acid (20 mL) and the mixture was extracted with ethyl acetate (1×100 mL). The organic phase was then washed with concentrated aqueous NaHCO3 solution (3×100 mL), dried over MgSO4 and concentrated in vacuo. The residue was recrystallized from ethyl acetate to give the title compound as a yellowish solid (630 mg); MS-(+)-ion: M+1=295.8.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]4[CH:22]=[N:23][NH:24][C:17]=34)[C:12]([CH3:25])=[CH:11][N:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[N:26]([CH2:29][CH3:30])=[C:27]=[O:28]>N1C=CC=CC=1.C(#N)C>[CH2:29]([NH:26][C:27]([N:24]1[C:17]2[C:18](=[N:19][CH:20]=[CH:21][C:16]=2[NH:15][C:13]2[C:12]([CH3:25])=[CH:11][N:10]=[C:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[C:5]([CH3:8])[N:4]=3)[CH:14]=2)[CH:22]=[N:23]1)=[O:28])[CH3:30]
Reactant: Cc1ccc(F)c(-c2cc(Nc3ccnc4cn[nH]c34)c(C)cn2)n1
Reactant: CCN=C=O
Solvent: c1ccncc1
Solvent: CC#N
Product: CCNC(=O)n1ncc2nccc(Nc3cc(-c4nc(C)ccc4F)ncc3C)c21
Temperature: 75 °C

Procedure:
N-(3′-Fluoro-5,6′-dimethyl-2,2′-bipyridin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine (81 mg, 0.242 mmol) was combined with acetonitrile (2.4 mL) and isocyanatoethane (23.78 μl, 0.303 mmol) along with 1 drop of pyridine. The mixture was heated at 75° C. The reaction was then cooled to give a solid which was collected by filtration, rinsed with acetonitrile to give the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.35 (3H, t, J=7.20 Hz) 2.47 (3H, s) 2.64 (3H, s) 3.51-3.63 (2H, m) 7.17-7.23 (1H, m) 7.33 (1H, d, J=4.55 Hz) 7.43 (1H, dd, J=10.48, 8.46 Hz) 7.51-7.59 (1H, m) 8.08 (1H, br. s.) 8.27 (1H, s) 8.41 (1H, d, J=5.31 Hz) 8.65 (1H, br. s.) 11.00 (1H, br. s.). MS [M+H] found 406.4.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9]C)=[O:8])[CH2:5][NH:4][C:3]1=[O:11].[OH-].[Li+].Cl>O1CCCC1.O>[CH3:1][N:2]1[CH:6]([C:7]([OH:9])=[O:8])[CH2:5][NH:4][C:3]1=[O:11]
Reactant: COC(=O)C1CNC(=O)N1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1C(=O)NCC1C(=O)O
Temperature: 0 °C
Yield: 190.3 %

Procedure:
A solution of 5-methyl 1-(phenylmethyl)2-oxo-1,5-imidazolidinedicarboxylate (5 g, 18 mmol) (prepared as described in step (i) of Example 1, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) in dimethylformamide (27 ml) was added dropwise to a suspension of sodium hydride (60% in oil, 0.72 g, 18 mmol) in dimethylformamide (45 ml) at 0° C. under an argon atmosphere. The cooling bath was removed and the mixture stirred under argon for 1 hr then treated with methyl iodide (5.6 ml). The mixture was stirred at 22° C. for a further 18 hrs and then reduced in vacuo to give a residue which was partitioned between ethyl acetate (250 ml) and brine (75 ml). The organic layer was separated, using a hydrophobic frit, and then reduced in vacuo to give an orange oil. The oil was purified flash-silica gel column chromatography, eluting with 30% ethyl acetate in hexanes (3 column volumes) and then with a 30-70% gradient of ethyl acetate in hexanes (10 column volumes), to give 4-methyl 1-(phenylmethyl)3-methyl-2-oxo-1,4-imidazolidinedicarboxylate (3.65 g) as a colourless oil. (ii) 4-Methyl 1-(phenylmethyl)3-methyl-2-oxo-1,4-imidazolidinedicarboxylate (3.65 g, 12.5 mmol) was dissolved in methanol (300 ml) and hydrogenated in the presence of 10% palladium on carbon (0.5 g). The mixture was stirred for 18 hrs at 22° C., then filtered and reduced in vacuo to give methyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (1.90 g) as a white solid which was used in the next step without further purification. (iii) Methyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (0.150 g, 0.948 mmol) was dissolved in a 3:2 mixture of tetrahydrofuran and water respectively (2.5 ml) and cooled to 0° C. The mixture was then treated with lithium hydroxide (0.068 g, 2.84 mmol) and stirred with ice/water cooling for a further 5 hrs. The mixture was acidified to pH1 by addition of 2N hydrochloric acid (3 ml) and the resulting mixture was then reduced in vacuo to give 3-methyl-2-oxo-4-imidazolidinecarboxylic acid as a white solid (0.260 g) which was used without any further purification.
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.[H-].[Na+].Br[C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][N:18]=1>O>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([O:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([F:6])[CH:8]=2)=[N:18][CH:19]=1
Reactant: Brc1ccc(Br)nc1
Reactant: Oc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cccc(Oc2ccc(Br)cn2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 110.6 %

Procedure:
To an N,N-dimethylformamide (100 mL) solution of 3-fluorophenol (3.30 g, 29.4 mmol) was added sodium hydride (1.41 g, 29.4 mmol, 50% in oil), which was stirred for 10 minutes at 0° C. 2,5-Dibromopyridine (4.64 g, 19.6 mmol) was then added to this mixture at 0° C., followed by 7 hours and 45 minutes of stirring at 110° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=3:1) to obtain the title compound (5.81 g, quant.).
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:8][CH2:9][O:10][C:11]([C:13]2[C:14]([CH3:30])=[N:15][C:16]([CH3:29])=[C:17]([C:26]([OH:28])=O)[C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.CCN=C=NCCCN(C)C.Cl.CN(C=O)C>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[C:31]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][O:10][C:11](=[O:12])[C:13]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)=[C:17]([C:26]([N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[O:28])[C:16]([CH3:29])=[N:15][C:14]=2[CH3:30])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: C1CCNC1
Reactant: Cc1nc(C)c(C(=O)OCCC(c2ccccc2)c2ccccc2)c(-c2cccc(Cl)c2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1nc(C)c(C(=O)N2CCCC2)c(-c2cccc(Cl)c2)c1C(=O)OCCC(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
100 mg (0.200 mmol) of 4-(3-chlorophenyl)-2,6-dimethylpyridine-3,5-dicarboxylic acid mono (3,3-diphenylpropyl) ester, 21.3 mg (0.300 mmol) of pyrrolidine, 46.0 mg (0.240 mmol) of WSC hydrochloride and 3.00 mg (0.0250 mmol) of 4-dimethylaminopyridine were stirred in 1.5 ml of dichloromethane at room temperature overnight. 3.7 mg (0.160 mmol) of WSC hydrochloride and 1 ml of DMF were added and further stirred at 60° C. overnight. After adding ethyl acetate and being washed with water, the organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the thin layer silica gel chromatography (hexane/ethyl acetate=1/3) to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C([Li])CCC.[B:30](OC(C)C)([O:35]C(C)C)[O:31]C(C)C.Cl>CCOCC.CCCCCC.C1(C)C=CC=CC=1>[C:15]1([N:8]([C:5]2[CH:4]=[CH:3][C:2]([B:30]([OH:35])[OH:31])=[CH:7][CH:6]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Brc1ccc(N(c2ccccc2)c2cccc3ccccc23)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: OB(O)c1ccc(N(c2ccccc2)c2cccc3ccccc23)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
Under an ambient atmosphere of argon gas, cooling a solution prepared by mixing 18.7 g of N-(4-bromophenyl)-N-phenyl-1-naphthylamine, 100 milliliter of dried ethyl ether and 100 milliliter of dried toluene down to a temperature of −78° C., a hexane solution of 1.6M normal butyllithium in an amount 32.8 milliliter was dripped into the cooled solution. The reacted solution was stirred for 1 hour while warming up to a temperature of 0° C. Cooling the reacted solution down to the temperature of −78° C. again, a solution prepared by dissolving 23.5 g of boric acid triisopropyl into dried ether in an amount of 50 milliliter was dripped down to the cooled solution. The resultant solution was further stirred at a room temperature for 5 hours. Adding 100 milliliter of 1 N hydrochloric acid and after stirring the resultant solution for 1 hour, a water layer was removed. After drying an organic layer with a use of magnesium sulfate, the solvent was distillated away under a reduced pressure. Refining a resultant solid by means of a silicagel column chromatography, 10.2 g of 4-(N-1-naphthyl-N-phenylamino)phenylboronic acid was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]([NH2:14])([CH3:13])[CH3:12])[CH:5]=1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C@@H:30]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:31]Br)=[CH:26][C:25]=1[CH2:41][OH:42])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[I-].[Na+].C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]([NH:14][CH2:31][C@@H:30]([C:27]2[CH:28]=[CH:29][C:24]([O:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:25]([CH2:41][OH:42])[CH:26]=2)[O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])([CH3:12])[CH3:13])[CH:5]=1
Reactant: COC(=O)c1cccc(CC(C)(C)N)c1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(CO)c1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(CC(C)(C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c(CO)c2)c1

Procedure:
3-(2-amino-2-methylpropyl)benzoic acid methyl ester (Preparation 34) (1.36 g, 6.60 mmol), [2-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]methanol (Preparation 23) (2.96 g, 6.60 mmol), sodium iodide (980 mg, 6.60 mmol) and diisopropylethylamine (3.44 ml, 19.7 mmol) in acetonitrile (10 ml) were heated to reflux for 48 hours under a nitrogen atmosphere. The solvent was then removed in vacuo and saturated aqueous sodium hydrogen carbonate solution (20 ml) added and the product extracted with ethyl acetate (3×30 ml). The combined organics were washed with brine (3×20 ml), dried (sodium sulfate) and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 by volume) to furnish the title compound, the purified product was dissolved in diethylether and evaporated (×3) to yield a white foam (1.70 g).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH3:18])[N:10]=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH2:15]([C:11]1[N:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCc1cccc(OCc2ccccc2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCc1cccc(O)n1

Procedure:
To a pressure reaction bottle were added 1.6 g 2-(benzyloxy)-6-butylpyridine, 0.2 g 5% palladium on carbon and 50 ml ethanol. The mixture was hydrogenated at 22 C and 40 psi hydrogen for 16 hours. Following filtration through celite and solvent removal, an oil was obtained that crystallized on standing to give 0.9 g.
Reaction SMILES: [N:1]1([C:6]2([CH2:9][OH:10])[CH2:8][CH2:7]2)[CH:5]=[CH:4][N:3]=[CH:2]1.I(C1C=CC=CC=1C(O)=O)(=O)=O>C(OCC)(=O)C>[N:1]1([C:6]2([CH:9]=[O:10])[CH2:8][CH2:7]2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: OCC1(n2ccnc2)CC1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CCOC(C)=O
Product: O=CC1(n2ccnc2)CC1

Procedure:
To a solution of (1-(1H-imidazol-1-yl)cyclopropyl)methanol (42.39 mg, 0.307 mmol) in anhydrous ethyl acetate (10 mL) was added 2-iodoxybenzoic acid (IBX) (129 mg, 0.461 mmol). The reaction mixture was heated at reflux for 2 h. The mixture was filtered and the filtrate was concentrated to afford the title compound which was used for the next step without further purification.
Reaction SMILES: ClC1C=CC(O)=C(C2C=NN3C=CC=NC=23)C=1.[NH2:18][C:19]1[C:23]2[CH:24]=[C:25]([C:28]3[C:29]([O:34][C:35]4[C:40]([F:41])=[CH:39][C:38]([S:42]([N:45](CC5C=CC(OC)=CC=5OC)[C:46]5[S:50][N:49]=[CH:48][N:47]=5)(=[O:44])=[O:43])=[C:37]([F:62])[CH:36]=4)=[N:30][CH:31]=[CH:32][CH:33]=3)[CH:26]=[CH:27][C:22]=2[O:21][N:20]=1>>[NH2:18][C:19]1[C:23]2[CH:24]=[C:25]([C:28]3[C:29]([O:34][C:35]4[C:40]([F:41])=[CH:39][C:38]([S:42]([NH:45][C:46]5[S:50][N:49]=[CH:48][N:47]=5)(=[O:44])=[O:43])=[C:37]([F:62])[CH:36]=4)=[N:30][CH:31]=[CH:32][CH:33]=3)[CH:26]=[CH:27][C:22]=2[O:21][N:20]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ncccc3-c3ccc4onc(N)c4c3)cc2F)c(OC)c1
Agent: Oc1ccc(Cl)cc1-c1cnn2cccnc12
Product: Nc1noc2ccc(-c3cccnc3Oc3cc(F)c(S(=O)(=O)Nc4ncns4)cc3F)cc12
Yield: 7 %

Procedure:
Following the procedure as described in EXAMPLE 44, making non-critical variations to replace 4-chloro-2-(pyrazolo[1,5-a]pyrimidin-3-yl)phenol with 4-((3-(3-aminobenzo[d]isoxazol-5-yl)pyridin-2-yl)oxy)-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide, 4-((3-(3-aminobenzo[d]isoxazol-5-yl)pyridin-2-yl)oxy)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide was obtained as a colorless solid in 7% yield (0.01 g): 1H NMR (300 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.18-8.10 (m, 2H), 8.02 (dd, J=7.5, 1.8 Hz, 1H), 7.87-7.77 (m, 2H), 7.69 (dd, J=10.0, 6.0 Hz, 1H), 7.57 (d, J=8.7 Hz, 1H), 7.36 (dd, J=7.4, 4.9 Hz, 1H), 6.51 (br s, 2H); MS (ES+) m/z 502.6 (M+1).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.Cl[C:18]1[NH:22][C:21]2[CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=[CH:26][C:20]=2[N:19]=1>>[F:30][C:27]([F:28])([F:29])[C:24]1[CH:25]=[CH:26][C:20]2[N:19]=[C:18]([N:12]3[CH2:11][CH2:10][N:9]([C:4]4[C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=[CH:6][N:5]=4)[CH2:14][CH2:13]3)[NH:22][C:21]=2[CH:23]=1
Reactant: FC(F)(F)c1ccc2nc(Cl)[nH]c2c1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Product: FC(F)(F)c1ccc2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1

Procedure:
The title compound was prepared from 1-(3-trifluoromethylpyridin-2-yl)piperazine (Maybridge) and 2-chloro-6-trifluoromethyl-1H-benzoimidazole (Example 1c) under the conditions of Example 3c. MS (ESI, pos. ion) m/z: 416 (M+1). M.p. 221-224° C.