Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:15][CH2:16][C:17]2([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:6]([NH:8][C:9](=O)[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:15]([CH2:16][C:17]3([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:9]([C:10]([CH3:13])([CH3:12])[CH3:11])=[N:8][C:6]=2[CH:7]=1
Reactant: CC(C)(C)C(=O)Nc1cc(Br)ccc1NCC1(O)CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1nc2cc(Br)ccc2n1CC1(O)CCCC1
Temperature: 140 °C
Reaction time: 23 h
Yield: 37.8 %

Procedure:
To a solution of N-(5-bromo-2-{[(1-hydroxycyclopentyl)methyl]amino}phenyl)-2,2-dimethylpropanamide (Step C, 1.3 g, 3.41 mmol) in toluene (100 mL) was added p-toluenesulfonic acid monohydrate (130 mg, 0.68 mmol) at room temperature and the mixture was stirred at 140° C. for 23 h. After cooling to room temperature, p-toluenesulfonic acid monohydrate (130 mg, 0.68 mmol) was added, and the mixture was heated at 140° C. After stirring for 26 h at 140° C., the mixture was quenched with saturated sodium hydrogen carbonate aqueous solution. The mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate:dichloromethane=5.5:1:0.5 as eluent) to afford the title compound (453 mg, 38%) as a beige amorphous.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:38])([CH2:32][N:33]1[CH:37]=[N:36][CH:35]=[N:34]1)[C@H:10]([S:12][C@@H:13]1[CH2:18][O:17][C@@H:16](/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[F:31])[O:15][CH2:14]1)[CH3:11].[H-].[Na+].[CH2:41]([O:44][C:45]([O:47][CH2:48][CH2:49][CH2:50][C:51](Cl)=[O:52])=[O:46])[CH:42]=[CH2:43].[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C>[CH2:41]([O:44][C:45]([O:47][CH2:48][CH2:49][CH2:50][C:51]([O:38][C@:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([CH2:32][N:33]1[CH:37]=[N:36][CH:35]=[N:34]1)[C@H:10]([S:12][C@@H:13]1[CH2:18][O:17][C@@H:16](/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[F:31])[O:15][CH2:14]1)[CH3:11])=[O:52])=[O:46])[CH:42]=[CH2:43]
Reactant: C=CCOC(=O)OCCCC(=O)Cl
Reactant: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC(=O)OCCCC(=O)O[C@@](Cn1cncn1)(c1ccc(F)cc1F)[C@@H](C)S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1
Reaction time: 1 h
Yield: 75.1 %

Procedure:
4-[(1E,3E)-4-[trans-5-[[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-1,3-butadienyl]-3-fluorobenzonitrile (570 mg, 1.05 mmol) obtained from Example Reference example 1 was dissolved in N,N-dimethylformamide (3 ml), and sodium hydride (ca. 30 mg, 1.3 mmol) was added thereto at room temperature. The mixture was stirred for 1 hour, then 4-(allyloxycarbonyloxy)butyryl chloride (250 mg, 1.21 mmol) obtained from Example 11-(2) was added thereto, and the mixture was stirred further for 1 hour. The mixture was diluted with ethyl acetate, and a saturated aqueous solution of ammonium chloride was poured thereinto. The organic layer was separated, washed with an aqueous solution of sodium hydrogen carbonate and then with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by recycle preparative HPLC [LC-908; Japan Analytical Industry Co., Ltd.; GPC column JAIGEL-1H (20 mm i.d.×600 mm) and JAIGEL-2H (20 mm i.d.×600 mm) connected in series for use; solvent, chloroform] to afford the title compound (562 mg, 75% yield) as a colorless amorphous solid.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH2:21][C:22]#[N:23])[C:17]=3[CH:24]=2)[C:3]1=[O:25].I[CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[CH3:1][N:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH:21]([CH2:27][CH3:28])[C:22]#[N:23])[C:17]=3[CH:24]=2)[C:3]1=[O:25]
Reactant: CCI
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CC#N)c3c2)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCC(C#N)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Yield: 28 %

Procedure:
To a solution of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-acetonitrile (0.730 g, 0.00199 mol) in dimethyl sulfoxide is added iodoethane (0.170 ml, 0.00210 mol) followed by potassium carbonate (0.750 g, 0.00543 mol). The resultant mixture is stirred overnight at room temperature and poured onto a mixture of ice and 5% aqueous hydrochloric acid. The resultant solid is filtered, dried and taken up in a minimal amount of methylene chloride. Flash column chromatography using silica gel and 100% to 99:1 methylene chloride/diethyl ether gives the title compound as a white solid (0.220 g, 28.0%, mp 107-109° C.) which is identified by NMR spectral analysis.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:14]=[CH:13][C:9]2[N:10]=[CH:11][S:12][C:8]=2[CH:7]=1.N.[BrH:16]>O.Cl.[Cu]Br>[Br:16][C:6]1[CH:14]=[CH:13][C:9]2[N:10]=[CH:11][S:12][C:8]=2[CH:7]=1
Reactant: Br
Reactant: Nc1ccc2ncsc2c1
Agent: [Cu]Br
Agent: Cl
Agent: N
Solvent: O
Product: Brc1ccc2ncsc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium nitrite (0.147 g, 2.1 mmol) in water (1.0 mL) was slowly added to a suspension of 6-aminobenzothiazole (0.30 g, 2.0 mmol) in HBr (48% in water, 3 mL) at 0° C. and then the mixture was stirred at room temperature for 30 min. The formed solution was then slowly added to a solution of copper (I) bromide (0.435 g, 3.0 mmol) in HCl (conc., 5 mL) at 0° C. After the addition, the mixture was stirred at 60° C. for 1.5 h. Cooled down, and the reaction mixture was basified with excess ammonia and extracted with diethyl ether. The combined extract was washed with water, brine, dried and concentrated. The 6-bromobenzothiazole (0.26 g) was obtained by Combiflash and then converted to the final compound using procedures analogous to those for example 1, MS(ESI): (M+H)+=413.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[C:4]([F:10])[CH:3]=1>C(OCC)(=O)C.[Pd]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([F:10])[CH:3]=1
Reactant: C=Cc1ccc(Br)cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1ccc(Br)cc1F

Procedure:
4-Bromo-2-fluoro-1-vinyl-benzene (1.80 g, 8.96 mmol) was dissolved in ethyl acetate (50 mL) and palladium-on-carbon (10%, 70 mg) was added and the mixture was hydrogenated under 1 atmosphere overnight. The mixture was filtered and the filtrate was concentrated to give the crude, 1.80 g, which was used directly for the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.CCN(C(C)C)C(C)C>CS(C)=O>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([N:14]2[CH2:13][CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a sealed tube were added 5-bromo-2-nitropyridine 125-1 (5.1 g, 25.2 mmol), tert-butyl piperazine-1-carboxylate 125-2 (4.7 g, 25.2 mmol), DIEA (12 mL, 75 mmol) and DMSO (20 mL). The reaction was heated to 120° C. and stirred for 16 hours. The reaction was cooled down to room temperature. Triethylamine was removed by rotary evaporation. The residue was triturated in 15 mL ethyl acetate. The solid was collected by filtration and washed with small amount of ethyl acetate to give tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate 125-3 as light yellow solid. MS m/z 309.2 (M+1).
Reaction SMILES: [CH2:1]1[O:20][C:4]2([CH2:9][CH2:8][CH:7]([NH:10][C:11]3[C:16]([Cl:17])=[C:15]([CH2:18][CH3:19])[N:14]=[CH:13][N:12]=3)[CH2:6][CH2:5]2)[O:3][CH2:2]1.[CH2:21]([O:23][CH2:24]C(O)CO)[CH3:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:17][C:16]1[C:11]([NH:10][CH:7]2[CH2:6][CH2:5][C:4]3([O:20][CH:1]([CH2:24][O:23][CH2:21][CH3:22])[CH2:2][O:3]3)[CH2:9][CH2:8]2)=[N:12][CH:13]=[N:14][C:15]=1[CH2:18][CH3:19]
Reactant: CCc1ncnc(NC2CCC3(CC2)OCCO3)c1Cl
Reactant: CCOCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOCC1COC2(CCC(Nc3ncnc(CC)c3Cl)CC2)O1

Procedure:
3.0 g (10 mmol) of 4-(5-chloro-6-ethylpyrimidin-4-ylamino)-cyclohexanone ethylene ketal and 10 ml of 3-ethoxypropane-1,2-diol together with 100 mg of p-toluenesulfonic acid hydrate were refluxed for 8 hours in 10 ml of toluene. The reaction mixture was extracted by stirring with dilute sodium hydroxide solution and water, the organic phase was dried, and the solvent was stripped off in vacuo. The crude product was purified by silica gel chromatography (eluent petroleum ether/ethyl acetate 3:2). This gave 2.0 g (56.3% of theory) of a colorless oil (diastereomer mixture).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([C:18]2[C:19]([F:30])=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[C:25]([O:28][CH3:29])[CH:24]=[CH:23]3)[CH2:16][OH:17])[CH2:10][CH2:9]1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([C:18]2[C:19]([F:30])=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[C:25]([O:28][CH3:29])[CH:24]=[CH:23]3)[CH2:16][OH:17])[CH2:10][CH2:9]1
Reactant: COc1ccc2ccc(F)c(C(CO)CN3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2ccc(F)c(C(CO)CN3CCC(N)CC3)c2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100.6 %

Procedure:
A solution of rac-{1-[2-(7-fluoro-2-methoxy-quinolin-8-yl) -3-hydroxy-propyl]-piperidin-4-yl}-carbamic acid tert-butyl ester (WO 2007/081597, 1.42 g, 3.28 mmol) in a mixture of TFA (15 mL) and DCM (9 mL) was stirred at rt for 20 min. The solvent was removed in vacuo and the residue was diluted in sat. NaHCO3 (20 mL). The pH was adjusted to 12 adding 6M NaOH. The aq. layer was extracted 3 times with DCM-MeOH (9-1, 3×25 mL). The combined org. layers were washed once with brine (20 mL), dried over Na2SO4, filtered and concentrated to dryness to afford the title amine as a yellowish gum (1.1 g, 100% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13]Cl.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: ClCCBr
Reactant: N#CCc1ccc(Br)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: N#CC1(c2ccc(Br)cc2)CC1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
A mixture of (4-bromo-phenyl)-acetonitrile (1.0 eq.), 1-bromo-2-chloro-ethane (1.6 eq.), triethylbenzyl ammonium chloride (0.03 eq.) and aqueous NaOH 50% (6 eq.) was stirred for 12 h at 60° C. The resulting mixture was poured in water and extracted with Et2O (2×). The combined organic extracts were washed with HCl 5%, brine, dried over MgSO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 95:5) afforded the title compound as a foam.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)O1.Br[C:21]1[CH:22]=[N:23][N:24]2[C:29]=1[CH:28]=[CH:27][CH:26]=[N:25]2.C(=O)([O-])[O-].[K+].[K+]>CC#N.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>[N:23]1[N:24]2[N:25]=[CH:26][CH:27]=[CH:28][C:29]2=[C:21]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:13][CH:14]=2)[CH:22]=1
Reactant: CC1(C)OB(c2ccc(CC(=O)O)cc2)OC1(C)C
Reactant: Brc1cnn2ncccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CC#N
Product: O=C(O)Cc1ccc(-c2cnn3ncccc23)cc1
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
To a solution of 1.00 g (3.82 mmol) [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetic acid in 5.70 ml CH3CN and 3.80 ml water was added 0.76 g (3.82 mmol) 3-bromopyrazolo[1,5-b]pyridazine, 8.57 mg (0.038 mmol) palladium acetate, 1.21 g (8.77 mmol) potassium carbonate, and 0.031 g (0.076 mmol) SPhos. The resulting suspension was degassed for 5 minutes. After 30 min in the microwave at 150° C., the reaction mixture was cooled, acidified with 1N HCl, extracted with ethyl acetate, and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (silica gel, linear gradient 50-100% EtOAc in hexanes) afforded 0.69 g (72%) (4-pyrazolo[1,5-b]pyridazin-3-ylphenyl)acetic acid. 1H NMR (CD3OD, 400 MHz) 8.40 (dd, J=1.83, 15.75 Hz, 1H); 8.40 (m, 1H); 8.28 (s, 1H); 7.62 (d, J=8.05 Hz, 2H); 7.41 (d, J=7.97 Hz, 2H); 7.22 (dd, J=4.4, 9.1 Hz, 1H); 3.66 (s, 2H). ES-MS M+1=254.1.
Reaction SMILES: N1C=CN=C1.[OH:6][CH:7]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH3:15])[CH2:9][CH2:8]1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C)C=O.CCOCC>[Si:16]([O:6][CH:7]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH3:15])[CH2:9][CH2:8]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC1CCC(O)CCC1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC1CCC(O[Si](C)(C)C(C)(C)C)CCC1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 100.9 %

Procedure:
Imidazole (2.45 g, 31.6 mmol) is added to a solution of (±) 5-hydroxy-2-methylcycloheptanone (2.03 g, 14.3 mmol) in dimethylformamide (35 ml) at 0° C. followed by t-butyldimethylsilyl chloride (2.38 g, 15.7 mmol) under nitrogen. The mixture is stirred at room temperature for 17 hours and then diluted with ether (100 ml) and washed three times with water. After drying (Na2SO4), the ether is removed in vacuo to afford (±) 5-t-butyldimethylsilyloxy-2-methylcycloheptanone (3.7 g, 100%). IR (neat)μ: 5.88 (C=O); NMR (CDCl3)δ: 0.1 (s, 6H, Si(CH3)0.93 [s, 9H, Si(CH3)2 --C(CH3)3 ], 1.1 (d, J=2--CH3), 3.6-4.2 (m, 1H, 5-H).
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH2:11][CH2:10][N:9]([C:14]4[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=4)[C:17]([OH:19])=O)[CH2:8][C:7]=3[CH:6]=[N:5][C:4]=2[CH:3]=[CH:2]1.C(N(CC)C(C)C)(C)C.CCCP(=O)=O.[CH2:38]([C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43])[CH3:39]>CN(C1C=CN=CC=1)C.ClCCCl>[S:1]1[C:13]2[C:12]3[CH2:11][CH2:10][N:9]([C:14]4[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=4)[C:17]([NH:43][C:42]4[CH:44]=[CH:45][CH:46]=[C:40]([CH2:38][CH3:39])[CH:41]=4)=[O:19])[CH2:8][C:7]=3[CH:6]=[N:5][C:4]=2[CH:3]=[CH:2]1
Reactant: CCc1cccc(N)c1
Reactant: O=C(O)c1cccc(N2CCc3c(cnc4ccsc34)C2)c1
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cccc(NC(=O)c2cccc(N3CCc4c(cnc5ccsc45)C3)c2)c1
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 68.5 %

Procedure:
To a mixture of 3-(8,9-dihydrothieno[3,2-c]-2,7-naphthyridin-7(6H)-yl)benzoic acid (0.113 mmol, 35 mg), N, N-diisopropylethylamine (0.339 mmol, 0.059 mL), and catalytic DMAP in 1.2 mL 1,2-dichloroethane at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.136 mmol, 0.081 mL). After 7 min at rt, 3-ethylaniline (0.17 mmol, 0.021 mL) was added and the reaction stirred at rt for 5 hours. The reaction was quenched into dilute aqueous NaHCO3 solution, extracted with EtOAc, the EtOAc layer washed with H2O, dilute aqueous NaHCO3 solution, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting oil was chromatographed eluting with EtOAc/CDCl3 to give the title compound as a light yellow solid (32 mg, 69%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:3]=1.[CH3:25][N:26]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[N:27]1.C([O-])(=O)C.[K+].O>C(=O)([O-])[O-].[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[CH3:25][N:26]1[CH:30]=[CH:29][C:28]([C:2]2[C:10]3[C:5](=[CH:6][N:7]=[C:8]([C:11]4[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=4)[CH:9]=3)[N:4]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:3]=2)=[N:27]1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc(-c3cccnc3)ncc21
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: Cn1ccc(-c2nn(COCC[Si](C)(C)C)c3cnc(-c4cccnc4)cc23)n1
Temperature: 150 °C

Procedure:
In a microwave reaction vials was charged with 3-iodo-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (49.10 mg, 0.11 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (33.19 mg, 0.16 mmol), 1,1′-Bis(diphenylphosphino)ferrocenepalladium (II) chloride (8.68 mg, 0.011 mmol), 1.00 M of Potassium acetate in Water (0.16 mL, 0.16 mmol), 1.00 M of Sodium carbonate in Water (0.16 mL, 0.16 mmol), and Acetonitrile (3 mL). The reaction mixture was heated under microwave at 150° C. for 5 minutes. The mixture was concentrated to afford 3-(1-methyl-1H-pyrazol-3-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine, which was used without purification.
Reaction SMILES: [CH2:1]1[O:19][C:4]2([CH2:9][CH2:8][N:7]([C:10](=[O:18])[C:11]3[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=3)[CH2:6][CH2:5]2)[O:3][CH2:2]1.C[Sn](C)(C)[C:22]1[S:23][CH:24]=[CH:25][N:26]=1>C1(C)C=CC=CC=1.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>[CH2:1]1[O:19][C:4]2([CH2:9][CH2:8][N:7]([C:10](=[O:18])[C:11]3[CH:16]=[CH:15][C:14]([C:22]4[S:23][CH:24]=[CH:25][N:26]=4)=[CH:13][CH:12]=3)[CH2:6][CH2:5]2)[O:3][CH2:2]1
Reactant: C[Sn](C)(C)c1nccs1
Reactant: O=C(c1ccc(Br)cc1)N1CCC2(CC1)OCCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(c1ccc(-c2nccs2)cc1)N1CCC2(CC1)OCCO2
Yield: 72.6 %

Procedure:
A solution of 1-(4-bromobenzoyl)-4-piperidone ethylene ketal (652 mg, 2 mmol) and trimethyl-2-thiazolylstannane (595 mg, 2.4 mmol) in degassed toluene was heated at reflux with tetrakis(triphenylphosphine)palladium(0) (200 mg, 0.17 mmol) for 16 h. The mixture was cooled, filtered through celite and evaporated. The residue was purified by flash chromatography on silica eluting with 50% ethyl acetate/hexane to yield a white solid (480 mg), MS (+CI) 331 [(M+H)+].
Reaction SMILES: [H-].[Na+].O1CCCC1.[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:14].Br[CH2:16][CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CCCCCC.O.CN(C)C=O>[Si:20]([O:19][CH2:18][CH2:17][CH2:16][N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:14])([C:23]([CH3:24])([CH3:25])[CH3:26])([CH3:22])[CH3:21]
Reactant: O=C1CCCCN1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCN1CCCCC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.1 %

Procedure:
At 0° C., sodium hydride (60% in oil, 2.22 g, 55.6 mmol) was added in portions to a tetrahydrofuran solution (200 ml) of piperidin-2-one (5.00 g, 50.5 mmol). The reaction mixture was then stirred at room temperature for 3 hours. After addition of (3-bromopropoxy)-t-butyldimethylsilane (14.1 ml, 60.6 mmol) and N,N-dimethylformamide (20 ml) to the reaction mixture, the resulting mixture was stirred at room temperature for 4 days. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and concentrated. The residue thus obtained was subjected to silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=2:1 eluate was concentrated to give the title compound (6.44 g, 23.8 mmol, 47%) as a colorless oil.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)O.[CH3:9]/[C:10](=C\C)/[C:11](O)=[O:12]>>[O:5]1[C:4]2[CH:3]=[CH:1][CH:8]=[CH:7][C:6]=2[C:11](=[O:12])[CH:10]=[CH:9]1
Reactant: C/C=C(\C)C(=O)O
Reactant: Oc1cccc(O)c1
Product: O=c1ccoc2ccccc12

Procedure:
Alternatively, the resorcinol can be reacted with methyl crotonic acid according to the method of Fahrenholtz [J. Am. Chem. Soc. 89 5934 (1967)] to give the benzopyran-4-one which in turn is reacted with a Grignard or other organometallic compound to give the desired benzopyran.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[F:26][C:27]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>CN(C=O)C>[F:26][C:27]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Reactant: OB(O)c1cccc(F)c1F
Solvent: CN(C)C=O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1cccc(F)c1F

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2,3-difluorophenylboronic acid (CAS RN 121219-16-7) and using DMF as reaction solvent. Off-white solid (14%). MS (ESI): m/z=461.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:12]Br)[C:5]([C:8]([O:10]C)=O)=[N:6][CH:7]=1.[NH2:14][C@@H:15]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1)[CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27].C(N(CC)C(C)C)(C)C>C(O)CCC>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][N:14]([C@@H:15]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)[CH2:16][N:17]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:27])[C:8](=[O:10])[C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)c1ncc(Br)cc1CBr
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: O=C1c2ccccc2C(=O)N1C[C@H](Cc1cccc(F)c1)N1Cc2cc(Br)cnc2C1=O
Temperature: 120 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
A mixture of methyl 5-bromo-3-(bromomethyl)pyridine-2-carboxylate (500.0 mg, 1.618 mmol), 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (482.8 mg, 1.618 mmol) and N,N-diisopropylethylamine (0.564 mL, 3.24 mmol) in 1-butanol (10.0 mL) was stirred at 120° C. for 2 h under microwave. Purification by combi-flash chromatography gave 0.48 g (61% yield) of the desired product. LC-MS found: 494.1 (M+H)+.