Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]([CH2:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=1)[CH2:14][CH3:15].Cl[C:32]1[N:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[CH:34][N:33]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.[Cl-].[Na+].O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:30][C:27]([F:28])([F:29])[C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=1)[CH2:16][N:13]([CH2:14][CH3:15])[C:4]1[CH:5]=[CH:6][C:7]([C:9]([F:11])([F:12])[F:10])=[CH:8][C:3]=1[CH2:2][NH:1][C:32]1[N:33]=[CH:34][C:35]([O:38][CH2:39][CH2:40][CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[CH:36][N:37]=1
Reactant: CC(C)(C)OC(=O)CCCOc1cnc(Cl)nc1
Reactant: CCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(C(F)(F)F)cc1CN
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(C(F)(F)F)cc1CNc1ncc(OCCCC(=O)OC(C)(C)C)cn1
Temperature: 80 °C
Reaction time: 5 h
Yield: 28.9 %

Procedure:
(2-Aminomethyl-4-trifluoromethyl-phenyl)-(3,5-bis-trifluoromethyl-benzyl)-ethyl-amine (165 mg) is dissolved in toluene (3 ml) and thereto are added tert-butyl 4-(2-chloro-pyrimidin-5-yloxy)-butyrate (202 mg), tris(dibenzylideneacetone)dipalladium(0) (68 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (92 mg) and sodium tert-butoxide (71 mg), and the mixture is stirred under nitrogen flow at 80° C. for 5 hours. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane:ethyl acetate=7:1) to give tert-butyl 4-(2-{2-[(3,5-bis-trifluoromethyl-benzyl)-ethyl-amino]-5-trifluoromethyl-benzylamino}-pyrimidin-5-yloxy)-butyrate (73 mg). MS (m/z): 681 [M+H]+
Reaction SMILES: C1COCC1.C([O:13][C:14]1[CH:35]=[CH:34][C:17]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[O:26])[CH2:21][CH2:20]2)=[CH:16][CH:15]=1)C1C=CC=CC=1.[H][H]>[C].[Pd].CC(O)C>[OH:13][C:14]1[CH:35]=[CH:34][C:17]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[O:26])[CH2:21][CH2:20]2)=[CH:16][CH:15]=1
Reactant: [H][H]
Reactant: O=C(Oc1cccnc1)N1CCC(Oc2ccc(OCc3ccccc3)cc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: O=C(Oc1cccnc1)N1CCC(Oc2ccc(O)cc2)CC1
Yield: 83.5 %

Procedure:
10% Palladium-carbon (catalytic amount) was added to a THF (75 ml)/2-propanol (75 ml) solution containing 3-pyridyl 4-[4-(benzyloxy)phenoxy]-1-piperidinecarboxylate (3.7 g), and in a hydrogen gas atmosphere, this was stirred at room temperature under normal pressure for 24 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure, and the resulting solid was washed with EtOAc/hexane, and dried under reduced pressure to obtain 3-pyridyl 4-(4-hydroxyphenoxy)-1-piperidinecarboxylate (2.4 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.N1([CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)CCCC1>>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1
Reactant: COC[C@@H]1CCCN1
Reactant: COC(=O)c1ccc(CN2CCCC2)cc1
Product: COC[C@@H]1CCCN1Cc1ccc(C(=O)OC)cc1

Procedure:
The title compound was synthesized from (S)-2-(methoxymethyl)pyrrolidine (0.175 g, 1.52 mmol) according to a procedure similar to that used for compound 56. 1H NMR (400 MHz, CDCl3): δ 7.99 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 4.17 (d, J=13.6 Hz, 1H), 3.92 (s, 3H), 3.45 (m, 2H), 3.35 (m, 4H), 2.92 (m, 1H), 2.74 (m, 1H), 2.21 (m, 1H), 1.95 (m, 1H), 1.69 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([F:25])=[C:13]([NH:15][C:16]([C:18]3[N:22]([CH3:23])[N:21]=[C:20]([CH3:24])[CH:19]=3)=[O:17])[CH:14]=2)=[CH:4][CH:3]=1.[N:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:27]=[S:28]>CS(C)=O.O>[CH3:23][N:22]1[C:18]([C:16]([NH:15][C:13]2[CH:14]=[C:9]([CH:10]=[CH:11][C:12]=2[F:25])[O:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:27]([NH:26][C:29](=[O:30])[O:31][CH2:32][CH3:33])=[S:28])=[N:7][CH:6]=2)=[O:17])=[CH:19][C:20]([CH3:24])=[N:21]1
Reactant: CCOC(=O)N=C=S
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc(N)nc3)ccc2F)n(C)n1
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)NC(=S)Nc1ccc(Oc2ccc(F)c(NC(=O)c3cc(C)nn3C)c2)cn1
Reaction time: 15 h
Yield: 97.8 %

Procedure:
To a solution of N-{5-[(6-aminopyridin-3-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (860 mg, 2.51 mmol) in DMSO (5 mL) was added ethyl isothiocyanatoformate (428 mg, 3.27 mmol), and the mixture was stirred for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was dried to give the title compound (1.16 g, 98%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:13][CH:12]([C:14]([N:16]3[CH2:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)=[O:15])[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:13][CH:12]([C:14]([N:16]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])[CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)N2CC(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)C2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)N2CC(C(=O)N3CCCNCC3)C2)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.4 %

Procedure:
To a stirred solution of tert-butyl 4-({1-[(6-methylpyridin-3-yl)carbonyl]azetidin-3-yl}carbonyl)-1,4-diazepane-1-carboxylate (455 mg, 1.13 mmol) in DCM (10 mL) was added TFA (440 μL, 5.65 mmol) and stirred at room temperature for 24 hours. The reaction was re-charged with TFA (0.5 mL, 6.5 mmol) and the reaction stirred for a further 5 hours until consumption of starting materials seen by TLC. Volatiles were removed at reduced pressure and the crude product shaken with Ambersep 900-OH resin in DCM (20 ml) for 2 hours. The resin was removed by filtration and the washings concentrated at reduced pressure to give the title compound (302 mg, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.FC(F)(F)S(O[C:17]1[CH:22]=[CH:21][C:20]([C@H:23]2[C:28]3=[N:29][S:30](=[O:34])(=[O:33])[CH2:31][CH2:32][N:27]3[CH2:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CCO.O.CN(C=O)C.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>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[CH:19][C:20]([C@H:23]2[C:28]3=[N:29][S:30](=[O:34])(=[O:33])[CH2:31][CH2:32][N:27]3[CH2:26][CH2:25][CH2:24]2)=[CH:21][CH:22]=1
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(OS(=O)(=O)C(F)(F)F)cc3)C2=N1
Reactant: OB(O)c1ccccc1Cl
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: [Na+]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: O=S1(=O)CCN2CCC[C@@H](c3ccc(-c4ccccc4Cl)cc3)C2=N1
Temperature: 50 °C
Reaction time: 19 h
Yield: 42.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (16.0 mg) was added to a mixture of (2-chlorophenyl)boronic acid (76.0 mg), 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenyl trifluoromethanesulfonate (100 mg) and sodium carbonate (51.4 mg) in EtOH (3 mL), water (1.5 mL) and DMF (dry) (2 mL). The mixture was stirred at 50° C. under nitrogen for 19 hr. Silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc), dissolved in MeCN/DMSO (4700/300 μM) and purified by preparative HPLC (C18, eluted with water in acetonitrile containing 0.1% TFA). The desired fractions were neutralized with sat.NaHCO3 aq., extracted with EtOAc and washed with brine. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was crystallized from MeCN-THF/hexane to give the title compound (38.4 mg) as colorless crystals.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:11].[S:13]1[CH:17]=[CH:16][N:15]=[C:14]1[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1>>[CH3:2][O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:22][C:21]1[CH:20]=[CH:19][C:18]([C:14]2[S:13][CH:17]=[CH:16][N:15]=2)=[CH:25][CH:24]=1
Reactant: O=Cc1ccc(-c2nccs2)cc1
Reactant: COC(=O)CCCCCCN
Agent: Cl
Product: COC(=O)CCCCCCNCc1ccc(-c2nccs2)cc1

Procedure:
The title compound was prepared following the procedure described in Step A of Example 1 from 7-amino-heptanoic acid methyl ester hydrochloride, of Preparation 1, and 4-thiazol-2-yl-benzaldehyde, of Preparation 25. 1H NMR (400 MHz, CDCl3) δ 7.91 (d, 2H), 7.84 (d, 1H), 7.38 (d, 2H), 7.30 (d, 1H), 3.82 (s, 2H), 3.65 (s, 3H), 2.62 (t, 2H), 2.29 (t, 2H), 1.61 (m, 2H), 1.51 (m, 2H), 1.33 (m, 4H); MS 333 (M+1).
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[CH3:5][C:6]1[N:7]=[C:8]([C:11](=[O:13])[CH3:12])[S:9][CH:10]=1>O1CCCC1>[CH3:5][C:6]1[N:7]=[C:8]([C:11]([OH:13])([C:1]#[CH:2])[CH3:12])[S:9][CH:10]=1
Reactant: C#C[Mg]Br
Reactant: CC(=O)c1nc(C)cs1
Solvent: C1CCOC1
Product: C#CC(C)(O)c1nc(C)cs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.3 %

Procedure:
To a stirred solution of ethynylmagnesium bromide (0.5 M in THF, 30.6 mL, 15.30 mmol) maintained under nitrogen at −20° C. was added slowly a solution of 1-(4-methyl-1,3-thiazol-2-yl)ethan-1-one (1.8 g, 10.20 mmol, 80%) in tetrahydrofuran (10 mL) over a period of 20 min. The resulting solution was stirred for 3 hr at 20-30° C. and then quenched by the addition of water (20 mL). The resulting mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1/6) to yield 0.5 g (26%) of the title compound as a yellow solid: LC-MS: m/z=+168 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2.[H-].[Na+].FC(F)(F)S(O[CH2:20][C:21]([F:24])([F:23])[F:22])(=O)=O.C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:20][C:21]([F:24])([F:23])[F:22])[CH2:5]2
Reactant: O=C1NCc2cc(Br)ccc21
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccc(Br)cc2CN1CC(F)(F)F
Temperature: 0 °C

Procedure:
5-Bromo-2,3-dihydro-1H-isoindol-1-one (100 mg, 0.47 mmol) was dissolved in DMF (4.7 mL) and stirred at 0° C. NaH (38 mg, 0.94 mmol, 60% dispersion in oil) was carefully added in two portions, and the resulting mixture was allowed to stir at 0° C. for 15 minutes before 2,2,2-trifluoroethyl trifluoromethanesulfonate (110 mg, 0.47 mmol) was added. The mixture was allowed to stir at 0° C. for 30 minutes before saturated aqueous NaHCO3 (10 mL) was carefully added, and the mixture was extracted with EtOAc. The organic layer was washed with water, brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-20% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](=[O:7])[NH:3][CH:2]=1.CC(C)([O-])C.[K+].[C:14]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][C:23]([CH3:26])([CH3:25])[CH:22]3[O:27][CH:21]3[C:20]=2[CH:28]=1)#[N:15].O>CS(C)=O.C(OCC)(=O)C>[C:14]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][C:23]([CH3:26])([CH3:25])[C@@H:22]([OH:27])[C@H:21]([N:3]3[C:4](=[O:7])[CH:5]=[CH:6][N:1]=[CH:2]3)[C:20]=2[CH:28]=1)#[N:15]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: O=c1ccnc[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](n2cnccc2=O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.4 %

Procedure:
4(3H)-Pyrimidone (0.772 g, 8 mmol) was dissolved in dimethylsulphoxide (10 ml) and treated with potassium tert-butoxide (0.440 g, 4 mmol). The mixture was stirred for 30 minutes at ambient temperature and 6-cyano-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran (1.278 g, 6 mmol) added. The resulting mixture was heated at 90° C. for 30 minutes, cooled and poured into water. Extractive work up with ethyl acetate yielded a gum which was purified by chromatography on silica (ethyl acetate) to give trans-6-cyano-3,4-dihydro-2,2-dimethyl-4-(6(1H)-pyrimidinon-1-yl)-2H-1-benzopyran-3-ol 0.703 g, (38%), mpt 202°-3° (ethyl acetate/hexane).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](=O)[NH:10][C:9]([NH2:14])=[N:8][C:7]=2[N:6]([C@@H:15]2[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:32])[CH3:31])[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:16]2[O:17][C:18](=[O:20])[CH3:19])[C:5]1=[O:33])[CH:2]=[CH2:3].P(Cl)(Cl)([Cl:36])=O>>[CH2:1]([N:4]1[C:12]2[C:7](=[N:8][C:9]([NH2:14])=[N:10][C:11]=2[Cl:36])[N:6]([C@@H:15]2[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:32])[CH3:31])[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:16]2[O:17][C:18](=[O:20])[CH3:19])[C:5]1=[O:33])[CH:2]=[CH2:3]
Reactant: C=CCn1c(=O)n([C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]2OC(C)=O)c2nc(N)[nH]c(=O)c21
Reactant: O=P(Cl)(Cl)Cl
Product: C=CCn1c(=O)n([C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]2OC(C)=O)c2nc(N)nc(Cl)c21
Temperature: 75 °C
Yield: 41 %

Procedure:
Compound 40 (0.65 g, 1.39 mmol) was dissolved in phosphorus oxychloride (10 mL) and heated to 75° C. for 16 h. The reaction mixture was concentrated under vacuum and the crude product dissolved in DCM. The mixture was then washed with NaHCO3 solution, brine, dried (MgSO4) and filtered. The filtrate was concentrated under vacuum and purified by flash chromatography using 10 to 50% gradient of ethyl acetate in hexanes. Removal of the solvent afforded 280 mg (41%) of the desired product 41: 1H NMR (400 MHz, CDCl3) δ 6.04 (d, J=4.0 Hz, 1H), 6.03 (t, J=5.6 Hz, 1H), 5.87 (m, 1H), 5.86 (t, J=5.6 Hz, 1H), 5.18 (m, 4H), 4.59 (d, J=8.0 Hz, 2H), 4.45 (d, J=7.6 Hz, 1H), 4.31 (m, 2H), 2.10 (s, 3H), 2.08 (s, 3H), 2.04 (s, 3H); MS (+)-ES [M+H]+ 484.2 m/z.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=4[F:24])[CH:15]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:43]2[CH:44]=[C:45]([NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH:46]=[CH:47][CH:48]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.C(O)C.O>[F:24][C:18]1[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=1[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:43]4[CH:44]=[C:45]([NH:49][S:50]([CH3:53])(=[O:51])=[O:52])[CH:46]=[CH:47][CH:48]=4)[CH:3]=3)[N:8]([S:25]([C:28]3[CH:29]=[CH:30][C:31]([CH3:32])=[CH:33][CH:34]=3)(=[O:27])=[O:26])[CH:9]=2)[CH:12]=[N:13]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)ccc4F)c3)c3cc(Br)cnc32)cc1
Reactant: CC1(C)OB(c2cccc(NS(C)(=O)=O)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)ccc4F)c3)c3cc(-c4cccc(NS(C)(=O)=O)c4)cnc32)cc1
Yield: 85.8 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(2,5-difluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (250 mg, 0.46 mmol) was coupled with N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) methane sulfonamide (intermediate 3) (150 mg, 0.506 mol) in sodium carbonate (146 mg, 1.38 mol), bis(triphenyl phosphine)palladium(ii) dichloride (16 mg, 0.023 mmol) and toluene/ethanol/water (7/7/4 ml) to afford 250.0 mg (85.91% yield) of the pure product after column purification using 40% ethyl acetate in hexane as eluent.
Reaction SMILES: C(Cl)Cl.[CH3:4][O:5][C:6]1[C@@:7]2([CH2:34][CH:35]=[C:36]([CH3:38])[CH3:37])[CH2:13][CH:11]3[O:12][C@@:8]2([O:32][CH3:33])[C@H:9]([C:29](=[O:31])[CH:30]=1)[C@:10]3([CH3:28])[CH2:14][CH2:15][CH2:16][C:17]([CH3:27])([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:18].C(N(CC)CC)C.BrB(C)C.CC[O:52]C(C)=O>CCCCCC>[OH:12][C@@H:11]1[C@@:10]([CH3:28])([CH2:14][CH2:15][CH2:16][C:17]([CH3:18])([O:19][Si:20]([CH2:21][CH3:22])([CH2:23][CH3:24])[CH2:25][CH3:26])[CH3:27])[C@@H:9]2[C@:8]([OH:52])([O:32][CH3:33])[C@@:7]([CH2:34][CH:35]=[C:36]([CH3:37])[CH3:38])([C:6]([O:5][CH3:4])=[CH:30][C:29]2=[O:31])[CH2:13]1
Reactant: CC[Si](CC)(CC)OC(C)(C)CCC[C@]1(C)C2C[C@]3(CC=C(C)C)C(OC)=CC(=O)[C@H]1[C@]3(OC)O2
Reactant: CCOC(C)=O
Agent: CB(C)Br
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: ClCCl
Product: CC[Si](CC)(CC)OC(C)(C)CCC[C@@]1(C)[C@H]2C(=O)C=C(OC)[C@@](CC=C(C)C)(C[C@@H]1O)[C@@]2(O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
A DCM (20 mL) solution of 38 (794 mg, 1.57 mmol, 1 equiv.) and triethylamine (131 μL, 0.940 mmol, 0.6 equiv.) was cooled to −95° C. in a 100-mL recovery flask, and a DCM solution of bromodimethylborane (1.59 M, 5.9 mL, 9.4 mmol, 6 equiv.) was added slowly over 5 min. The resulting bright yellow solution was stirred at −95° C.±3° C. for 10 min, whereupon it was quenched through the sequential addition of NEt3 (6 mL) and saturated aqueous NaHCO3 at −95° C. The mixture was warmed to room temperature and extracted thrice with EtOAc. The organic extracts were combined, washed successively with 2 N HCl, H2O, saturated aqueous NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated in vacuo to a yellow foam. Flash column chromatography (150 mL SiO2, 8:2 to 7:3 hexane:EtOAc) afforded 471 mg (0.897 mmol, 57% yield) of 39 as a white flocculent solid. TLC Rf 0.30 (7:3 hexane:EtOAc). 1H NMR (600 MHz; CDCl3): δ 5.46 (s, 1H), 5.26 (d, J=10.3 Hz, 1H), 3.74 (s, 3H), 3.61 (dd, J=11.8, 5.3 Hz, 1H), 3.55 (s, 1H), 3.25 (s, 3H), 2.87-2.82 (m, 2H), 2.25 (d, J=14.2 Hz, 1H), 1.95 (t, J=12.4 Hz, 1H), 1.73 (s, 3H), 1.70-1.65 (m, 4H), 1.43 (td, J=13.0, 4.2 Hz, 1H), 1.39-1.35 (m, 1H), 1.32-1.27 (m, 3H), 1.21 (s, 3H), 1.20 (s, 3H), 1.09 (s, 3H), 0.93 (t, J=7.9 Hz, 9H), 0.55 (q, J=7.6 Hz, 6H). 13C NMR (126 MHz; CDCl3): δ 198.2, 176.0, 137.4, 122.1, 104.1, 100.6, 73.8, 73.3, 57.6, 56.5, 51.1, 48.5, 45.9, 40.9, 39.4, 37.0, 30.8, 30.0, 29.4, 26.2, 18.0, 17.0, 7.3, 7.0. HRMS-ESI (m/z): [M+Na]+ calculated for C29H52O6Si, 547.3425. found, 547.3404.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][NH:24][CH2:25][CH:26]([CH3:28])[CH3:27]>>[CH2:25]([N:24]([CH3:23])[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:5]=[N:1][NH:2][CH:3]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:20])[CH:26]([CH3:28])[CH3:27]
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: CNCC(C)C
Product: CC(C)CN(C)C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and N,2-dimethylpropan-1-amine to give 254. MS: (ESI+)=369.1
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].O.Cl.[NH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1>>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:18]3[CH2:19][CH2:20][NH:15][CH2:16][CH:17]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CCNCC1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Agent: Cl
Solvent: O
Product: O=[N+]([O-])c1ccc2c(C3=CCNCC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Preparation 30 from 6-nitroindole (6.0 g, 37 mmol) and 4-piperidone hydrochloride hydrate (11.4 g, 74 mmol). The product was isolated as an orange solid. Yield 8.8 g (97%). mp 247°-250° C.(dec.) FDMS m/e=243 (M+ of free base).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([O:11][C:12]([C:14]1[N:15]=[CH:16][S:17][CH:18]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8].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.Br[C:62]1[CH:63]=[N:64][C:65]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)=[N:66][CH:67]=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:68]1([C:65]2[N:64]=[CH:63][C:62]([C:16]3[S:17][CH:18]=[C:14]([C:12]([O:11][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:13])[N:15]=3)=[CH:67][N:66]=2)[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=1
Reactant: Brc1cnc(-c2ccccc2)nc1
Reactant: CC(C)(C)OC(=O)c1cscn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1csc(-c2cnc(-c3ccccc3)nc2)n1
Temperature: 110 °C

Procedure:
In a sealed tube, cesium carbonate (1.95 g, 6.00 mmol), tert-butyl-4-thiazolecarboxylate (556 mg, 3.00 mmol; prepared according to the procedure described in Organic Letters, 2008, 10(13), 2909), palladium(II) acetate (47 mg, 0.21 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (240 mg, 0.42 mmol) were combined with 5-bromo-2-phenylpyrimidine (705 mg, 3.00 mmol) in dry DMF (11 mL) and the mixture heated at 110° C. for 18 hours with stirring. The mixture was cooled to room temperature and filtered through Celite washing with hot ethyl acetate. Solvent was removed under reduced pressure and the residue purified by silica gel flash chromatography (9:1 to 3:2 v/v hexane-ethyl acetate gradient) through a 40-g Silicycle® flash silica cartridge. The title compound was obtained as a white solid (646 mg, 63% yield); Rf 0.75 with 1:1 v/v hexane-ethyl acetate; 1H-NMR (300 MHz; CDCl3) δ 9.37 (s, 2H), 8.52 (dd, 2H), 8.15 (s, 1H), 7.54 (m, 3H), 1.64 (s, 9H); MS (ESI+) m/z 340 (M+1); H-PGDS FPBA IC50: 5.9 μM.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1O.C(N(CC)CC)C.FC(F)(F)[S:22](OS(C(F)(F)F)(=O)=O)(=O)=O.O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[SH:22]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1cc([N+](=O)[O-])ccc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1S
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
2-methoxy-4-nitrophenol (19.2 g) was dissolved in methylene chloride (192 ml), triethylamine (20.5 ml) was added to the mixture, trifluoromethanesulfonic acid anhydride (23.0 ml) was added dropwise to the solution at 0° C., and the mixture was stirred for 1 hour at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was dissolved in ethanol (274 ml) under heat reflux, and an aqueous solution (342 ml) of sodium sulfate nanohydrate (21.1 g) and sulfur (2.8 g) in ethanol was added dropwise thereto for 20 minutes. Aqueous solution of sodium hydroxide (7.02 g, 28.1 ml) was added dropwise to the solution for 20 minutes, and then, the mixture was cooled to room temperature, ice-water was added thereto. The precipitates were filtered, and the pH of the filtrate was adjusted to about pH 5 with 6N hydrochloric acid, and the precipitates were collected by filtration, and washed with water to give 2-methoxy-4-nitrobenzenethiol (15.8 g, 75%).