Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:36])([O:5][C:6]([CH3:35])([CH3:34])[CH2:7][NH:8][C:9]([NH:11][C@H:12]([CH:31]([CH3:33])[CH3:32])[C:13]([N:15]1[CH2:20][CH2:19][C@@:18]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([OH:21])[C:17]([CH3:30])([CH3:29])[CH2:16]1)=[O:14])=[O:10])[O:2][CH2:3]Cl.C(N(CC)CC)C.[C:44]([OH:51])(=[O:50])/[CH:45]=[CH:46]/[C:47]([OH:49])=[O:48].C(O)(C(F)(F)F)=O>CN(C=O)C.O.CC#N>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C@@:18]2([OH:21])[CH2:19][CH2:20][N:15]([C:13]([C@H:12]([NH:11][C:9](=[O:10])[NH:8][CH2:7][C:6]([CH3:35])([CH3:34])[O:5][C:1](=[O:36])[O:2][CH2:3][O:51][C:44](=[O:50])/[CH:45]=[CH:46]/[C:47]([OH:49])=[O:48])[CH:31]([CH3:33])[CH3:32])=[O:14])[CH2:16][C:17]2([CH3:29])[CH3:30])=[CH:23][CH:24]=1
Reactant: CC(C)[C@@H](NC(=O)NCC(C)(C)OC(=O)OCCl)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Reactant: O=C(O)/C=C/C(=O)O
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@@H](NC(=O)NCC(C)(C)OC(=O)OCOC(=O)/C=C/C(=O)O)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 70 °C
Yield: 20.1 %

Procedure:
To chloromethyl 1-(3-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)ureido)-2-methylpropan-2-yl carbonate (0.19 g, 0.348 mmol) in DMF (2 mL) are sequentially added triethylamine (0.048 mL, 0.348 mmol) and fumaric acid (0.020 g, 0.174 mmol) at RT. Contents heated at 70° C. (oil bath temp.) for 20 h. The reaction mixture was cooled to rt and subjected to prep. HPLC (Phenomex Luna AXIA 30×100 mm; 10 min. gradient; solvent A=10% CH3CN, 90% H2O, 0.1% TFA, solvent B=90% CH3CN, 10% H2O, 0.1% TFA). The desired fractions are collected and concentrated. The residue is partitioned between DCM (20 mL) and brine (10 mL). The DCM layer is dried over sodium sulfate and concentrated to yield (R,E)-3-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidine-1-carbonyl)-2,8,8-trimethyl-5,10,14-trioxo-9,11,13-trioxa-4,6-diazaheptadec-15-en-17-oic acid (0.022 g, 0.035 mmol, 10.11% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]=[C:6]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[F:16])[CH3:7])[CH3:2].[Br:18]N1C(=O)CCC1=O>ClCCl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:17])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[F:16])\[CH2:7][Br:18])[CH3:2]
Reactant: CCOC(=O)C=C(C)Oc1cc(C)ccc1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)/C=C(\CBr)Oc1cc(C)ccc1F
Temperature: 75 °C
Yield: 88.8 %

Procedure:
A solution of 3-(2-fluoro-5-methyl-phenoxy)-but-2-enoic acid ethyl ester (1.11 g, 4.65 mmol) in dichloromethane (18.9 mL) was treated with N-bromosuccinimide (0.87 g, 4.89 mmol) and benzoyl peroxide (90 mg, 0.37 mmol). The reaction was then heated to 75° C. overnight. At this time, the reaction was cooled to 25° C. and then concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 2% ethyl acetate/hexanes) afforded (E)-4-bromo-3-(2-fluoro-5-methyl-phenoxy)-but-2-enoic acid ethyl ester (1.31 g, 89%) as a light yellow oil: HR-ES-MS m/z calculated for C13H14O3FBr [M+H]+ 317.0183, observed 317.0182; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.15 (t, J=7.2 Hz, 3H), 2.31 (s, 3H), 4.07 (q, J=7.2 Hz, 2H), 4.78 (s, 2H), 4.81 (s, 1H), 7.11 (dd, J=7.8, 1.8 Hz, 1H), 7.14-7.22 (m, 1H), 7.33 (dd, J=10.6, 8.5 Hz, 1H): and (Z)-4-bromo-3-(2-fluoro-5-methyl-phenoxy)-but-2-enoic acid ethyl ester (0.13 g, 9%) as a golden yellow oil: HR-ES-MS m/z calculated for C13H14O3FBr [M+H]+ 317.0183, observed 317.0182; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.09 (t, J=7.1 Hz, 3H), 2.26 (s, 3H), 3.97 (q, J=7.1 Hz, 2H), 4.29 (s, 2H), 5.98 (s, 1H), 6.97 (m, 2H), 7.20 (dd, J=10.7, 8.9 Hz, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[F:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][CH:34]=[CH:33]2>>[F:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]3[C:10]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=3)=[CH:5][CH:4]=1)[CH:34]=[CH:33]2
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Reactant: Fc1ccc2[nH]ccc2c1
Product: O=S(=O)(Nc1nccnc1-c1ccc(Cn2ccc3cc(F)ccc32)cc1)c1ccccc1C(F)(F)F
Yield: 69 %

Procedure:
Following the general method as outlined in Example 1 (Method A), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzene sulfonamide (Intermediate 9), and 5-fluoro-indole, the title compound was isolated as a yellow solid in 69% yield (99% purity by HPLC).
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][Si](C)(C)C.N[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.N>S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O>[CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1
Reactant: Cc1ccc(N)cc1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: N
Agent: O=C1NS(=O)(=O)c2ccccc21
Product: Cc1ccc(N[Si](C)(C)C)cc1
Temperature: 130 °C
Yield: 111.5 %

Procedure:
25 ml of hexamethyldisilazane (0.12 mole) were added in 5 minutes to a mixture of 17.25 g (0.16 mole) of p-toluidine and 0.15 g (0.8 mmole) of saccharin which was heated to 130° C. in an oil bath. By titrating the ammonia evolved during the reaction, it was found that the calculated amount was evolved after refluxing for 2 hours and refluxing was continued for half an hour. The reaction mixture was vacuum distilled to yield 24.0 g (83%) of N-trimethylsilyl-p-toluidine with a boiling point of 98°-102° C. at 12-13 mm Hg.
Reaction SMILES: C[Si]([O:5][CH2:6][C:7]#[CH:8])(C)C.C([Mg]Br)C.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][C:22](=[O:26])[C@@H:21]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl-].[NH4+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][C@:22]([C:8]#[C:7][CH2:6][OH:5])([OH:26])[C@@H:21]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)[C@@H]1c1ccccc1
Reactant: C#CCO[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CC[Mg]Br
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@](O)(C#CCO)[C@@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 63.2 %

Procedure:
O-Trimethylsilylpropargyl alcohol (24.51 ml, 20.47 g, 160 ml) was added slowly to a cooled (-10° C.) solution of ethylmagnesium bromide (1M in tetrahydrofuran, 160 ml, 160 mmol). The mixture was stirred at 0° C. for 20 minutes, then at room temperature for 2 hours. The mixture was cooled to -10° C. and a solution of (2S)-1-tert-butoxycarbonyl-2-phenylpiperidin-3-one (Preparation 1; 42.3 g) in tetrahydrofuran (200 ml) was added dropwise over 30 minutes. (Internal temperature below -5° C.). The mixture was stirred at room temperature for 14 hours, poured into water (300 ml) and saturated aqueous ammonium chloride (300 ml) and extracted with ethyl acetate (2×300 ml). The combined organic fractions were washed with brine (300 ml), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (500 ml) and a solution of tetrabutylammonium fluoride (1M in THF, 160 ml, 160 mmol) was added dropwise. The mixture was stirred at room temperature for 30 minutes, water (300 ml) was added, and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×300 ml) and the combined organic fractions were washed with water (300 ml) and brine (300 ml), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the crude title compound as an orange oil (45 g). The crude material was purified by flash column chromatography on silica gel, eluting with hexane/ethyl acetate (90:10 increasing to 25:75) to give the title compound as an amber oil (32.2 g). 1H NMR (CDCl3) δ 7.53-7.55 (2H, m), 7.19-7.35 (3H, m), 5.56 (1H, s), 4.27 (2H, s), 3.99-4.03 (1H, m), 3.25 (1H, br s), 2.77-2.81 (1H, m), 2.77 (1H, br s), 2.12-2.20 (1H, m), 1.91-1.99 (2H, m), 1.77-1.83 (1H, m), and 1.39 (9H, s).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:14])[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9][CH2:8]1)[CH3:3].Cl.[N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([C:26]([Cl:28])=[O:27])=[CH:18][CH:17]=1.C(N(CC)CC)C.CCCCCCC.CCOC(C)=O>ClCCl.CCOC(C)=O>[ClH:28].[CH2:2]([O:4][C:5](=[O:14])[CH2:6][C@H:7]1[CH2:8][CH2:9][C@H:10]([NH:13][C:26]([C:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:16]=[CH:17][CH:18]=2)=[O:27])[CH2:11][CH2:12]1)[CH3:3]
Reactant: O=C(Cl)c1ccnc2ccccc12
Reactant: CCOC(=O)C[C@H]1CC[C@H](N)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Product: CCOC(=O)C[C@H]1CC[C@H](NC(=O)c2ccnc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of Trans-(4-Amino-cyclohexyl)-acetic acid ethyl ester hydrochloride (3.63 g, 17 mmol) is solved in dichloromethane (115 mL) and quinoline-4-carbonyl chloride hydrochloride is added (4.184 g, 18 mmol) followed by the slow addition of triethylamine (11.3 mL, 81 mmol) at 0° C. The mixture is stirred at room temperature overnight and the salts obtained are removed by filtration and the filtrate is extracted. The organic layer is washed with NaHCO3 and brine. The organic phases are dried and concentrated to obtain 3.8 g of a crude. After a flash chromatography with heptane/AcOEt 4:1 to AcOEt a solid was obtained that was recrystallized with EtOAc and n-heptane to obtain the title compound as a pink solid (2.72 g, 42% yield). MS (m/e): 341.3 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[N:17]=[C:18]2[C:23](Br)=[CH:22][CH:21]=[CH:20][N:19]2[CH:25]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1(B(O)O)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>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>[C:34]1([C:23]2[C:18]3[N:19]([CH:25]=[C:16]([C@@H:12]4[CH2:13][CH2:14][CH2:15][N:11]4[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])[N:17]=3)[CH:20]=[CH:21][CH:22]=2)[C:35]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1c1cn2cccc(Br)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(OCc1ccccc1)N1CCC[C@H]1c1cn2cccc(-c3cccc4ccccc34)c2n1
Yield: 66.1 %

Procedure:
Following the procedures of example 14, (S)-benzyl-2-(8-bromoimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate (0.250 g, 0.62 mmol), 1-napthyl boronic acid (0.1405 g, 0.82 mmol), potassium carbonate (0.1340 g, 0.97 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.0430 g, 0.04 mmol) produced the crude material which was adsorbed onto silica gel and purified by flash chromatography (4 g SiO2, 0-50% ethyl acetate in hexanes) to give (2S)-benzyl 2-(8-(naphthalen-1-yl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate (0.183 g, 0.41 mmol, 66%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH3:21].[C:22](Cl)(=[O:26])[CH:23]([CH3:25])[CH3:24]>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH3:21])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CC(C)C(=O)Cl
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: CCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)C(C)C
Yield: 27.5 %

Procedure:
Using the general method of Example 197, 1-(4-aminobutyl)-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.5 mmol) was reacted with isobutyryl chloride (0.41 mL, 3.9 mmol) to provide 0.34 g of N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-methylpropanamide as an off white solid, m.p. 155.4-156.3° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@@H:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:29])[F:28])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:8])=[CH:4][C:3]=1[C:31]1[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=1.[Cl:37]N1C(=O)CCC1=O>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@@H:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:28])[F:29])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:8])=[CH:4][C:3]=1[C:31]1[N:35]([CH3:36])[N:34]=[CH:33][C:32]=1[Cl:37]
Reactant: Cn1nccc1-c1cc(C(=O)N[C@H](CNC(=O)OC(C)(C)C)Cc2ccccc2C(F)(F)F)sc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@H](CNC(=O)OC(C)(C)C)Cc2ccccc2C(F)(F)F)sc1Cl
Reaction time: 1 h

Procedure:
A solution of 1,1-dimethylethyl {(2S)-2-({[5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-[2-(trifluoromethyl)phenyl]propyl}carbamate (110 mg, 0.202 mmol)[prepared in Example 25] and N-chlorosuccinimide (35 mg, 0.263 mmol) in THF (2 mL) was stirred in a sealed tube at 70° C. After 1 h, the solution was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification: LCMS (ES) m/z=578 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[C:16](=[O:18])[CH3:17]
Reactant: CN(C)CCNc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N(CCN(C)C)c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 50 g (0.239 mol) N,N-dimethyl-N′-(4-nitro-phenyl)-ethane-1,2-diamine in 500 mL acetic anhydride was stirred for 3.5 h at 130° C., then evaporated down i. vac. and neutralised with saturated aqueous sodium bicarbonate. The residue was exhaustively extracted with EtOAc, the combined org. phases were dried over sodium sulphate and evaporated down i. vac.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:12](=[O:23])[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[O:21]C.C[S-].[Na+].[Br-].[Li+]>CN(C=O)C>[NH2:1][C:2]1[C:6]2[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:12](=[O:23])[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[OH:21]
Reactant: COc1ccc(OC)c(C(=O)c2oc3ccc(Cl)cc3c2N)c1
Agent: C[S-]
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COc1ccc(O)c(C(=O)c2oc3ccc(Cl)cc3c2N)c1

Procedure:
A solution of 3-amino-5-chloro-2-(2,5-dimethoxybenzoyl)-benzofuran (0.83 g, 2.5 mmol), sodium thiomethoxide (0.44 g, 6.25 mmol) and lithium bromide (0.22 g, 2.5 mmol) in anhydrous DMF (30 ml) is heated at 80° C. for 72 h. The solvent is removed under high vacuum and the residue is dissolved in a mixture of aqueous ammonium chloride and ethyl acetate. The organic phase is washed with brine, dried and evaporated under reduced pressure. Purification of the product on silicagel yields the title compound of m.p. 202-205° C. 1H-NMR (d6-DMSO, 300 MHz): 11.81 (s, 1H); 8.21-8.20 (m, 1H); 7.82-7.80 (m, 1H); 7.66-7.63 (m, 3H); 7.11 (dd, 1H); 6.87 (d, 2H); 3.79 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:36]=[CH:35][C:11]3[N:12]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)=[C:19]([O:33][CH3:34])[CH:18]=4)[C:13]([NH2:15])=[N:14][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[CH3:37][PH:38](=[O:40])[CH3:39].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:15][C:13]1[N:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)=[C:19]([O:33][CH3:34])[CH:18]=2)[C:11]2[CH:35]=[CH:36][C:8]([C:5]3[CH:4]=[CH:3][C:2]([P:38](=[O:40])([CH3:39])[CH3:37])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:14]=1
Reactant: C[PH](C)=O
Reactant: COc1ccc(COc2ccc(Cn3c(N)nc4cc(-c5ccc(Cl)nc5)ccc43)cc2OC)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(COc2ccc(Cn3c(N)nc4cc(-c5ccc(P(C)(C)=O)nc5)ccc43)cc2OC)cc1
Temperature: 150 °C
Reaction time: 0.75 h
Yield: 147.4 %

Procedure:
To a stirred suspension of 5-(6-chloropyridin-3-yl)-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazol-2-amine (0.15 g, 0.30 mmol) in 1,4-dioxane (4 mL) was added dimethylphosphine oxide (0.029 g, 0.37 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.035 g, 0.060 mmol), palladium(II) acetate (0.007 g, 0.030 mmol), and cesium carbonate (0.20 g, 0.60 mmol). The reaction mixture was heated to 150° C. in a microwave reactor. After 45 min, additional portions of dimethylphosphine oxide (0.029 g, 0.37 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.035 g, 0.060 mmol), and palladium(II) acetate (0.007 g, 0.030 mmol) were added. The reaction mixture was subjected to a second round of heating in the microwave reactor (45 min, 150° C.). After the second heating cycle, the reaction mixture was diluted with water and was extracted with chloroform (×3). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to provide 0.24 g of a bright yellow solid. Chromatographic purification (Combi-Flash, 12 g SiO2 gold column, 5-10% 2M ammonia in methanol/dichloromethane elute) afforded 0.052 g (32%) of the product as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO) δ 9.03 (d, J=1.9 Hz, 1H), 8.22-8.14 (m, 1H), 7.95 (dd, J=8.2, 4.9 Hz, 1H), 7.52 (s, 1H), 7.32 (d, J=8.6 Hz, 2H), 7.28-7.19 (m, 2H), 7.02 (d, J=1.9 Hz, 1H), 6.96 (d, J=8.2 Hz, 1H), 6.91 (d, J=8.6 Hz, 2H), 6.71-6.64 (m, 3H), 5.20 (s, 2H), 4.93 (s, 2H), 3.74 (s, 3H), 3.72 (s, 3H), 1.68 (d, J=13.5 Hz, 6H) ppm; (M+1)=543.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([C:16]3[N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([F:30])([F:29])[F:28])[N:19]=[C:18]([C:31]([OH:34])([CH3:33])[CH3:32])[CH:17]=3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[Br:35]N1C(=O)CCC1=O>CC#N>[Br:35][C:17]1[C:18]([C:31]([OH:34])([CH3:32])[CH3:33])=[N:19][N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:28])[F:29])[C:16]=1[C:14]1[S:15][C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=2)=[CH:12][CH:13]=1
Reactant: CC(C)(O)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2C(F)(F)F)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(C)(O)c1nn(-c2ccccc2C(F)(F)F)c(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)c1Br
Temperature: 20 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a stirred solution of 2-[5-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-1-(2-trifluoromethyl-phenyl)-1H-pyrazol-3-yl]-propan-2-ol (254 mg, 0.5 mmol) in dry MeCN was added N-bromosuccinimide (94 mg, 0.53 mmol) at 20° C. and the reaction mixture was stirred at 20° C. overnight. Evaporation of solvent gave a residue, which was purified by flash chromatography on silica gel eluted with EtOAC-hexane (0-60%) to afford the title compound as a white solid (286 mg, 98%). 1H-NMR (CDCl3): δ 8.05 (m, 1H), 7.85-7.81 (m, 2H), 7.76 (m, 1H), 7.63-7.61 (m, 2H), 7.56 (t, 1H), 7.39 (m, 1H), 7.25 (d, 1H), 6.98 (d, 1H), 3.09 (s, 1H), 3.07 (s, 3H), 1.74 (s, 6H).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([C:15]#[C:16][Si](C)(C)C)[C:11]([NH2:14])=[N:12][CH:13]=1>CN1CCCC1=O.[Cl-].[Na+].O>[Cl:7][C:8]1[CH:9]=[C:10]2[CH:15]=[CH:16][NH:14][C:11]2=[N:12][CH:13]=1
Reactant: C[Si](C)(C)C#Cc1cc(Cl)cnc1N
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Clc1cnc2[nH]ccc2c1
Temperature: 80 °C
Yield: 41 %

Procedure:
A solution of potassium tert-butoxide (36 g, 320 mmol) in N-methylpyrrolidone (70 ml) was heated to 80° C. under nitrogen. A solution of 5-chloro-3-(trimethyl-silanylethynyl)-pyridin-2-ylamine (2) (36 g, 160 mmol) in NMP (200 ml) was added dropwise via a dropping funnel. The reaction mixture was stirred at 80° C. for a further fifty minutes. The reaction mixture was allowed to cool to room temperature. Brine (500 ml) was added to the reaction mixture and extracted with diethyl ether (5×200 ml). The combined organics were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography, using as eluent pentane/EtOAc 0% to 40%, and further recrystallised from cyclohexane to afford the title compound (10 g, 41%). 1H NMR (CDCl3) 6.5 (1H, s), 7.4 (1H, s), 8.0 (1H, s), 8.2 (1H, s), 10.4-10.6 (1H, brs). MS (ES+) 153.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[O:10][N:9]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]1[C:15]#[N:16])=[O:5])[CH3:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]([CH3:13])([CH3:12])[CH3:14])[C:7]=1[C:15]#[N:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1ON=C(C(C)(C)C)C1C#N
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1onc(C(C)(C)C)c1C#N
Temperature: 110 °C

Procedure:
3-tert-Butyl-4-cyano-4,5-dihydro-isoxazole-5-carboxylic acid ethyl ester (1.51 g, 2.56 mmol corrected for the measured purity, prepared as described in the previous step) was dissolved in toluene (10 mL) and DDQ (2.41 g, 10.6 mmol) was added as a solid. The resulting mixture was heated to 110° C. for 16 h and then cooled to room temperature and diluted with hexanes (2 mL). The resulting suspension was filtered and the precipitate was washed once with toluene (4 mL). The filtrates were combined and concentrated under reduced pressure. The resulting residue was chromatographed on a 24-g SiO2 pre-packed column eluting with 0:1-1:4 EtOAc-hexanes to yield 3-tert-butyl-4-cyano-isoxazole-5-carboxylic acid ethyl ester. 1H-NMR (400 MHz, CDCl3) δ: 4.52 (q, J=7.1 Hz, 2H), 1.49 (s, 9H), 1.43-1.48 (t, J=7.1 Hz, 3H).
Reaction SMILES: C(C1C=C(NC(=O)C[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([B:25]([OH:27])[OH:26])=[CH:21][CH:20]=2)C=CC=1S(CC)(=O)=O)#N.BrC1C=CC(C[CH2:35][N:36](C)[C:37]([NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]#[N:47])[CH:41]=2)=[O:38])=CC=1>>[C:46]([C:42]1[CH:41]=[C:40]([NH:39][C:37](=[O:38])[N:36]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([B:25]([OH:26])[OH:27])=[CH:23][CH:24]=2)[CH3:35])[CH:45]=[CH:44][CH:43]=1)#[N:47]
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Reactant: CN(CCc1ccc(Br)cc1)C(=O)Nc1cccc(C#N)c1
Product: CN(CCc1ccc(B(O)O)cc1)C(=O)Nc1cccc(C#N)c1
Yield: 91 %

Procedure:
Using a procedure analogous to that used to prepare 6D, 23C (200 mg, 0.70 mmol) was reacted with 5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 23D (165 mg, 91%) as a yellow oil. MS (ESI) m/z 324.03 (M+H)+.