Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][CH:15]([CH3:21])[CH2:16][CH2:17][C:18](Cl)=[O:19]>>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:18](=[O:19])[CH2:17][CH2:16][CH:15]([CH3:21])[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: CC(C)CCC(=O)Cl
Product: CC(C)CCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1

Procedure:
27.1 g of the crude title compound (yield: quant.) was obtained in the same manner as in Reference Example 5 using (S)-4-benzyl-2-oxazolidinone and 4-methylpentanoyl chloride.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][Si:11]([CH3:16])([CH3:15])[CH2:12][C:13]#[CH:14].[CH2:17]([C:19]1[C:20]([C:27]([O:29][CH3:30])=[O:28])=[C:21]([CH:25]=[O:26])[NH:22][C:23]=1I)[CH3:18]>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].[Cu]I.O1CCOCC1>[CH2:17]([C:19]1[C:20]([C:27]([O:29][CH3:30])=[O:28])=[C:21]([CH:25]=[O:26])[NH:22][C:23]=1[C:14]#[C:13][CH2:12][Si:11]([CH3:16])([CH3:15])[CH3:10])[CH3:18]
Reactant: C#CC[Si](C)(C)C
Reactant: CCc1c(I)[nH]c(C=O)c1C(=O)OC
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCc1c(C#CC[Si](C)(C)C)[nH]c(C=O)c1C(=O)OC
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate was obtained following the procedures described in Example 3. Pd(Pt-Bu3)4 (18.4 mg, 0.040 mmol), Pd2(dba)3 (16.5 mg, 0.020 mmol), and CuI (4.6 mg, 0.020 mmol) were combined in a dry flask under N2 prior to evacuating the flask and refilling with argon. After the flask was charged with dioxane (4.0 mL), i-Pr2NEt (0.0675 mL, 0.48 mmol), trimethyl(prop-2-ynyl)silane (90.0 mg, 0.80 mmol), and methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate (123.0 mg, 0.40 mmol) were added sequentially. The reaction was stirred overnight at 80° C. After the reaction was cooled to ambient temperature, it was filtered through a plug of silica gel and concentrated in vacuo. The resultant residue was dissolved in acetonitrile and purified by reverse phase HPLC. Proton NMR for the product was consistent with the title compound. 1H NMR (500 MHz, CDCl3) δ 10.04 (s, 1H); 3.90 (s, 3H); 2.78 (q, J=7.5 Hz, 2H); 1.77 (s, 2H); 1.16 (t, J=7.5 Hz, 3H); 0.17 (s, 9H). HRMS (ES) exact mass calculated C15H22NO3Si (M+H): 292.1364. Found 292.1364
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]([NH2:10])=[N:8][CH:9]=1)([O-:3])=[O:2].[N:11]1([CH2:16][CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][N:22]=2)=[O:20])[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[Cs+].[Cs+].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>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(Cl)Cl.CO>[N:11]1([CH2:16][CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([NH:10][C:7]3[N:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][N:6]=3)=[CH:23][N:22]=2)=[O:20])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(NCCN1CCCC1)c1ccc(Br)cn1
Reactant: Nc1ncc([N+](=O)[O-])cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: O=C(NCCN1CCCC1)c1ccc(Nc2ncc([N+](=O)[O-])cn2)cn1
Yield: 35 %

Procedure:
In a dry 50 mL round bottom flask 5-nitro-pyrimidin-2-ylamine (0.2 g, 1.36 mmol), intermediate 21 (Example 29) (0.61 g, 2.04 mmol), cesium carbonate (1.33 g, 4.08 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.157 g, 0.272 mmol) and tris(dibenzylideneacetone) dipalladium (0.124 g, 0.136 mmol) were combined. Reactants were flushed with argon, diluted with dioxane (8 mL) and outfitted with reflux condenser. Reaction was heated to reflux for 18 h. Reaction was then filtered hot and solvents were evaporated to provide dark solids. Silica gel chromatography (6:1 DCM/MeOH) provided desired product as a yellow powder (0.17 g, 33% yield). Rf=0.23 (10% MeOH/DCM)
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[O:7])[CH2:4][C:5]#[N:6].[N+](=[CH2:12])=[N-].N(CNC(N)=O)=O.[OH-].[K+]>C(O)(=O)C.C(OCC)C>[CH3:12][O:7][C:3]([C:2]([F:9])([F:8])[F:1])=[CH:4][C:5]#[N:6]
Reactant: N#CCC(=O)C(F)(F)F
Reactant: C=[N+]=[N-]
Agent: NC(=O)NCN=O
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=CC#N)C(F)(F)F
Yield: 35.1 %

Procedure:
Diethylether (300 ml) was added to trifluoroacetoacetonitrile (13.7 g, 0.100 mole) and to this was added an ethereal solution of diazomethane, which was prepared from N-nitrosomethylurea (25.77 g, 0.250 mole), a 50% solution of potassium hydroxide (112.22 g, 1.00 mole) and diethylether (180 ml), with ice cooling. The solution was allowed to stand over night while cooling with ice. Next day, until the pH being 3-4 (by an universal test paper) acetic acid in limited amounts was added to the reaction mixture to decompose an excess of diazomethane and the solution was concentrated to about 200 ml at atmospheric pressure by using a distillation apparatus equipped with a fractionating column. The concentrate was washed with a 8% solution of sodium bicarbonate and water and dried with anhydrous sodium sulfate. Diethyl ether was distilled off by using a distillation apparatus equipped with a fractionating column at atmospheric pressure and the residue was distilled under reduced pressure to give the title compound (5.31 g, 35.1%) as a colorless liquid, b.p. 58.0° C./68 mmHg-64.0° C./70.0 mmHg. The structure of the product was confirmed by IR and NMR.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])[CH2:4][C:5]#[N:6].[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.O=P(Cl)(Cl)Cl>CCOCC>[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:1][CH2:2][C@@H:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])[CH2:4][C:5]#[N:6]
Reactant: C1=COCCC1
Reactant: N#CC[C@@H](CO)c1ccccc1F
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: N#CC[C@@H](COC1CCCCO1)c1ccccc1F
Reaction time: 0.08 h

Procedure:
To a solution of β(R)-(hydroxymethyl)-β-(2-fluorophenyl)-propionitrile (210 g, 1.18 mol) in Et2O (200 ml), is added 3,4-dihydro-2H-pyran (225 ml, 2.68 mol) at ambient temperature. The mixture is stirred for 5 minutes and POCl3 (5 mL) is added dropwise. The reaction mixture is stirred for 30 minutes at ambient temperature and then refluxed for 2 hours. The resulting solution is allowed to cool and the solvent is removed in vacuo. The residue is then chromatographed (EtOAc/hexane, 1:4) to give β(R)-[[(tetrahydropyran-2-yl)oxy]methyl]-β(2- fluorophenyl)-propionitrile as an oil.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH:3]=[CH2:4].[CH3:6][S:7](Cl)(=[O:9])=[O:8].Cl.C(N(CC)CC)C>O1CCCC1.C(N(CC)CC)C>[CH3:6][S:7]([O:5][CH2:1][CH2:2][CH:3]=[CH2:4])(=[O:9])=[O:8]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCCO
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A four-necked flask (11) was charged with 3-buten-1-ol (72 g), dry tetrahydrofuran (400 ml), and methanesulfonyl chloride (126 g), and the mixture was subjected to a nitrogen stream. After sufficiently cooling the flask with ice water, triethylamine (111 g) was slowly added dropwise to the flask from a dropping funnel After the dropwise addition, the mixture was stirred for about 30 minutes while cooling the flask with ice water, and then stirred at room temperature for about 4 hours. After completion of the reaction, 100 ml of tetrahydrofuran was added to the mixture, and salts (triethylamine hydrochloride) produced by the reaction were filtered off Most of the tetrahydrofuran was evaporated from the filtrate using an evaporator. After the addition of 200 ml of diethyl ether to the residue, the mixture was sequentially washed with 5% hydrochloric acid, a saturated sodium bicarbonate aqueous solution, and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and magnesium sulfate was filtered off Diethyl ether was evaporated from the filtrate using an evaporator to obtain 126 g of 4-methanesulfonyloxy-1-butene (hereinafter referred to as “mesylate”) as a yellowish brown oil (yield: 84%).
Reaction SMILES: [C:1](Cl)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[CH3:9][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[C:13]([NH:15][NH2:16])=[O:14].C(N(CC)CC)C.O>O1CCOCC1>[C:1]([NH:16][NH:15][C:13](=[O:14])[C:12]1[CH:17]=[C:18]([CH3:20])[CH:19]=[C:10]([CH3:9])[CH:11]=1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: Cc1cc(C)cc(C(=O)NN)c1
Reactant: CCOC(=O)C(=O)Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)NNC(=O)c1cc(C)cc(C)c1
Yield: 70.2 %

Procedure:
265 g of ethoxalyl chloride are added, in the course of one hour, to 316 g of 3,5-dimethylbenzhydrazide and 195 g of triethylamine in 1.58 liters of anhydrous dioxane, whilst keeping the temperature of the reaction medium at about 10°-12° C. The stirring is continued (sic) for about two hours. whilst allowing the temperature to return to the ambient value. The reaction mixture is then poured into seven liters of water, whilst stirring. The precipitate which has formed is filtered off, washed three times with one liter of water and then dried at 20° C. under a pressure of one millimeter of mercury. 357 g of 1-ethoxalyl-2-(3,5-dimethylbenzoyl)-hydrazine, which melts at 159° C., are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7][CH2:8][CH3:9])=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+].[F:27][C:28]([F:38])([F:37])[CH2:29][CH2:30][S:31][CH2:32][CH2:33][C:34](Cl)=[O:35]>O>[Cl:1][C:2]1[C:6]([N:7]([CH2:8][CH3:9])[C:34](=[O:35])[CH2:33][CH2:32][S:31][CH2:30][CH2:29][C:28]([F:38])([F:37])[F:27])=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1
Reactant: CCNc1cn(-c2cccnc2)nc1Cl
Reactant: O=C(Cl)CCSCCC(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(C(=O)CCSCCC(F)(F)F)c1cn(-c2cccnc2)nc1Cl

Procedure:
A 100 mL three neck round bottom flask was charged with 3-chloro-N-ethyl-1-(pyridine-3-yl)-1H-pyrazol-4-amine (5.00 g, 22.5 mmol) and ethyl acetate (50 mL). Sodium bicarbonate (4.72 g, 56.1 mmol) was added, followed by dropwise addition of 3-((3,3,3-trifluoropropyl)thio)propanoyl chloride (5.95 g, 26.9 mmol) at <20° C. for 2 hours, at which point HPLC analysis indicated that the reaction was complete. The reaction was diluted with water (50 mL) (off-gassing) and the layers were separated. The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic layers were concentrated to dryness to afford a light brown solid (10.1 g, quantitative). A small sample of crude product was purified by flash column chromatography using ethyl acetate as eluent to obtain an analytical sample: mp 79-81° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.11 (d, J=2.7 Hz, 1H), 8.97 (s, 1H), 8.60 (dd, J=4.8, 1.4 Hz, 1H), 8.24 (ddd, J=8.4, 2.8, 1.4 Hz, 1H), 7.60 (ddd, J=8.4, 4.7, 0.8 Hz, 1H), 3.62 (q, J=7.2 Hz, 2H), 2.75 (t, J=7.0 Hz, 2H), 2.66-2.57 (m 2H), 2.57-2.44 (m, 2H), 2.41 (t, J=7.0 Hz, 2H), 1.08 (t, J=7.1 Hz, 3H). EIMS m/z 406 ([M]+).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl[CH2:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1)=[O:36]>[Cu]I.CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[N:6]([CH2:34][C:35]([N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[O:36])[C:5]=2[CH2:4][CH2:3]1
Reactant: O=C(CCl)N1CCCC1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(=O)N2CCCC2)CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 2.7 %

Procedure:
The title compound was prepared by following general procedure 7. 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.46 mmol), was taken into DMF. To the above solution CuI (9 mg, 0.046 mmol), L-proline (11 mg, 0.093 mmol), K3PO4 (198 mg, 0.93 mmol) were added and stirred for 10 min. at RT. 2-Chloro-1-(pyrrolidin-1-yl)ethanone (82 mg, 0.56 mmol) was added dropwise. The reaction mixture was heated at 90° C. for 12 h. After completion of reaction, the reaction mixture was filtered through Celite. DMF was evaporated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure to obtain 4 mg of 2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(pyrrolidin-1-yl)ethanone as the TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][O:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=4)[N:16]=[CH:15][CH:14]=3)=[N:9][N:10]=2)[N:7]=1.[Cl:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:28][C:27]=1[CH:41]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH3:42].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][O:12][C:13]4[C:22]5[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=5)[N:16]=[CH:15][CH:14]=4)=[N:9][N:10]=3)[N:7]=2)[CH:29]=[CH:28][C:27]=1[CH:41]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH3:42]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Reactant: COc1ccc2c(OCc3nnc4ccc(Cl)nn34)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(C)NC(=O)OC(C)(C)C)c(Cl)c5)nn34)ccnc2c1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A suspension of 4-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline (180 mg, 527 μmol), tert-butyl 1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethylcarbamate (302 mg, 790 μmol), dichloro[1,1 bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethane adduct (77.1 mg, 105 μmol), cesium carbonate (686 mg, 2107 μmol) in DMF (2 mL) and water (0.4 mL) was first sparged with argon for 5 min then heated to 100° C. with stirring. 2:20 pm After 10 min, LCMS suggests >95% conversion. Reaction then partitioned between 9:1 CHCl3/IPA (20 mL) and 1M NaOH (5 mL). Organic then dried over MgSO4, concentrated, and purified on silica (40 g) eluting with isocratic 4% of 2M NH3 in MeOH/DCM. MS (ESI pos. ion) m/z: 561 (MH+). Calc'd exact mass for C29H29ClN6O4: 560.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:19][CH2:18][C:10]3([NH:14][C:13](=[O:15])[N:12]([CH3:16])[C:11]3=[O:17])[CH2:9]2)=[CH:4][CH:3]=1.N#N.[CH3:22][N:23]1C(=O)CCC1>[Zn].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.[Fe+2].[C-]#N.[Zn+2].[C-]#N.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]>[CH3:16][N:12]1[C:11](=[O:17])[C:10]2([CH2:18][CH2:19][C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:22]#[N:23])=[CH:3][CH:4]=3)[CH2:9]2)[NH:14][C:13]1=[O:15]
Reactant: CN1C(=O)NC2(CC[C@H](c3ccc(Br)cc3)C2)C1=O
Reactant: CN1CCCC1=O
Agent: [Fe+2]
Agent: [Pd]
Agent: N#N
Product: CN1C(=O)NC2(CC[C@H](c3ccc(C#N)cc3)C2)C1=O
Temperature: 120 °C

Procedure:
A suspension of (7S)-7-(4-bromophenyl)-3-methyl-1,3-diazaspiro[4.4]nonane-2,4-dione (General procedures A, B, C) (0.500 g, 1.547 mmol) in anhydrous NMP (4.00 ml) was degassed by evacuating the reaction vial then refilling with N2 a couple of times. To this suspension was added zinc (1.012 mg, 0.015 mmol), dppf (0.027 g, 0.048 mmol), zinc cyanide (0.145 g, 1.238 mmol), and Pd2(dba)3 (0.021 g, 0.023 mmol) at ambient temperature. The resulting mixture was heated to 120° C. for about 16 hours. The crude material was filtered through Celite®. The filtrate was taken up in water (70 mL) and ethyl acetate (100 mL). The organic phase was washed with water (50 mL×2) and brine (50 mL), dried (MgSO4) and concentrated to yield 4-((7S)-3-methyl-2,4-dioxo-1,3-diazaspiro[4.4]nonan-7-yl)benzonitrile (0.44 g, 0.20 mmol) as light brown solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[I:11].[OH-].[K+].[F:14][C:15]([F:19])([F:18])[CH2:16][OH:17].Cl>CS(C)=O.O>[I:11][C:3]1[C:2]([O:17][CH2:16][C:15]([F:19])([F:18])[F:14])=[N:7][CH:6]=[C:5]([CH:4]=1)[C:8]([OH:10])=[O:9]
Reactant: OCC(F)(F)F
Reactant: O=C(O)c1cnc(Cl)c(I)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cnc(OCC(F)(F)F)c(I)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
6-Chloro-5-iodo-3-pyridinecarboxylic acid (CAN 59782-87-5, 4.7 g, 16.6 mmol) was dissolved in DMSO (49.5 ml). Potassium hydroxide pellets (2.79 g, 49.7 mmol) and 2,2,2-trifluoroethanol (2.16 g, 1.55 ml, 21.6 mmol) were added slowly at room temperature under argon. The reaction mixture was stirred for 2 h at rt; water (35 mL) was added and the mixture was cooled to 0-5° C. Concentrated HCl solution (8 mL) was added drop by drop and the precipitated solid was collected, washed with cold water and dried. The crude material was purified by flash chromatography (silica gel, 150 g, 0% to 20% i-propyl acetate in n-heptane +10% of acetic acid) to give the title compound (1.6 g, 28%) as colorless solid; MS (ESI) 345.7 (M−H)−.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[CH:14]=[CH:15][O:16][C:12]=3[C:11](=[O:17])[C:10]([C:18]3[N:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:21]=[CH:20][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[NH:29]1[CH:33]=[CH:32][CH:31]=[N:30]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.[Cu]=O>[C:23]1([N:22]2[C:18]([C:10]3[C:11](=[O:17])[C:12]4[O:16][CH:15]=[CH:14][C:13]=4[N:8]([C:5]4[CH:6]=[CH:7][C:2]([N:29]5[CH:33]=[CH:32][CH:31]=[N:30]5)=[CH:3][CH:4]=4)[N:9]=3)=[CH:19][CH:20]=[N:21]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1cn[nH]c1
Reactant: O=c1c(-c2ccnn2-c2ccccc2)nn(-c2ccc(I)cc2)c2ccoc12
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c(-c2ccnn2-c2ccccc2)nn(-c2ccc(-n3cccn3)cc2)c2ccoc12
Temperature: 50 °C
Reaction time: 12 h
Yield: 36.6 %

Procedure:
A suspension of 1-(4-iodophenyl)-3-(1-phenyl-1H-pyrazol-5-yl)furo[3,2-c]pyridazin-4(1H)-one (200 mg), pyrazole (57 mg), copper oxide (6 mg), 2-hydroxybenzaldehydeoxime (23 mg) and cesium carbonate (271 mg) in DMF (5 mL) was stirred at 50° C. for 12 hr, and water was added. The reaction mixture was extracted with ethyl acetate, the extract was washed with saturated brine, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (64 mg).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)C=C.Cl[C:20]1[CH:25]=CC=C[C:21]=1Cl>>[CH3:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[C:10]([CH2:25][CH:20]=[CH2:21])[CH:9]=2)=[CH:17][CH:16]=1
Reactant: C=CCOc1ccc(Oc2ccc(C)cc2)cc1
Reactant: Clc1ccccc1Cl
Product: C=CCc1cc(Oc2ccc(C)cc2)ccc1O

Procedure:
4-(4′-Methylphenoxy)phenyl allyl ether (4.00 g, 16.37 mnmol) was taken up in 1,2-dichlorobenzene (50 mL) and refluxed for 20 h. After cooling, the solvent was removed in vacuo and the resulting crude oil was chromatographed on silica gel (15% ethyl acetate/hexane) to afford 4-(4′-methylphenoxy)-2-allylphenol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][OH:6].[H-].[Na+].CS[C:15]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:18]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])=[CH:17][N:16]=1.[Cl-].[NH4+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][O:6][C:15]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:18]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])=[CH:17][N:16]=1
Reactant: CSc1ncc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)n1
Reactant: OCc1ccc(F)c(F)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Fc1ccc(COc2ncc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)n2)cc1F

Procedure:
To a 25 mL round bottom flask fitted with a stirrer bar was added 3 mL DMF, 3,4-difluorobenzyl alcohol (113.3 mg, 0.79 mmol) and sodium hydride (60% in oil, 52.4 mg, 1.31 mmol). The flask was flushed with N2, stoppered with a rubber septum and 2-methylthio-4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)pyrimidine (100 mg, 0.26 mmole) from Reference Example 3 was added via syringe in 500 μL of DMF for 90 min. Aqueous ammonium chloride was added, the mixture extracted with ethyl acetate (3×) and the combined organics dried over anhydrous MgSO4. The solution was filtered and the volume reduced by rotoevaporation. Flash column chromatography on silica gel (eluted with 96/4 hexanes/ethyl acetate) afforded 2-(3,4-difluorobenzyloxy)-4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)pyrimidine (HRf): HPLC/MS: m/e=478 (M++1); Rt=4.85 min; 1H-NMR 400 MHz (CDCl3): 5.49 (s, 2H), 7.1-7.12 (d, J=9 Hz, 2H), 7.14-7.25 (m, 5H), 7.26-7.40 (m, 2H), 7.43 (s, 1H), 8.48 (s, 1H) and 2-(3,4-difluorobenzyloxy)-4-(4-chlorophenyl)-5-(2-chloro-4-thiomethylphenyl)-pyrimidine (LRf): HPLC/MS: m/e=489 (M++1); Rt=4.74 min; 1H-NMR 400 MHz (CDCl3): δ 2.45 (s, 3H), 5.55 (s, 2H), 7.1-7.18 (d, 2H), 7.2-7.6 (m, 8H), 8.42 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:24][C:25]3[CH:30]=[N:29][CH:28]=[CH:27][N:26]=3)[CH:14]=[C:15]([O:16]CC3C=CC=CC=3)[C:7]1=2)[CH3:2]>C1COCC1.CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:24][C:25]3[CH:30]=[N:29][CH:28]=[CH:27][N:26]=3)[CH:14]=[C:15]([OH:16])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(OCc3ccccc3)c21
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(O)c21
Yield: 62.1 %

Procedure:
A solution of [4-benzyloxy-1-hydroxy-6-(pyrazin-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (410 mg, 0.976 mmol) in THF/EtOH (20 mL, 1:1) was degassed 3 times and Pd/C (40 mg) was added. The suspension was degassed 3 times and charged with H2 at room temperature overnight. The reaction was filtered through a pad of Celite and the filtrate was concentrated to dryness. The residue was purified by preparative HPLC to give the title compound (200 mg, 62%). MS calcd for (C15H15BN2O6+H)+: 331.1. MS found: (M+H)+=331.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:45])=[C:4]([S:9]([N:12]([CH2:21][C:22]2[CH:23]=[C:24]([CH:34]=[C:35]([O:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH:36]=2)[CH2:25][NH:26]C(=O)OC(C)(C)C)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:26][CH2:25][C:24]1[CH:23]=[C:22]([CH:36]=[C:35]([O:37][C:38]2[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=2)[CH:34]=1)[CH2:21][N:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)[S:9]([C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[OH:45])(=[O:11])=[O:10]
Reactant: CC(C)(C)OC(=O)NCc1cc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc(Oc2ccc(F)cc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1cc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc(Oc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.3 %

Procedure:
To a solution of tert-butyl 3-((3,5-dichloro-N-(4-fluorobenzyl)-2-hydroxyphenylsulfonamido)methyl)-5-(4-fluorophenoxy)benzylcarbamate (0.65 g, 0.96 mmol) in CH2Cl2 (8 mL) was added TFA (1.10 mL, 14.4 mmol). The reaction mixture was stirred at rt. for 3 h. The reaction mixture was concentrated and to the residue was added saturated NaHCO3 solution and ethyl acetate. The organic layer was washed with brine twice, dried over MgSO4, and concentrated in vacuo to give white solid (0.53 g, 96%). 1H NMR (CD3OD): δ 7.49 (d, J=2.8 Hz, 1H), 7.35 (d, J=2.8 Hz, 1H), 7.21-7.09 (m, 4H), 6.99-6.90 (m, 5H), 6.85 (s, 1H), 6.64 (s, 1H), 4.48 (s, 2H), 4.40 (s, 2H), 3.93 (s, 2H); MS (ESI): (M+H)+=579.0.