Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:6]=[C:5]([NH:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]2)[CH:4]=1.C1C(=O)N([I:36])C(=O)C1>C(#N)C>[I:36][C:4]1[C:5]([NH:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]2)=[N:6][C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:8][C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1I
Reactant: COc1cc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)nc(N2CCOCC2)n1
Solvent: CC#N
Product: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1I

Procedure:
Compound 20 (113 mg, 0.287 mmol) was dissolved in acetonitrile (3 mL) and NIS (129 mg, 0.574 mmol) was added. The solution was heated to reflux for 1 h. The solvent was evaporated and the residue dissolved in EtOAc, washed with sat. NaHCO3, NaS2O3, water, and brine. The organics were dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc/hexane to give the title compound as a colorless foam. 1H NMR (CDCl3) δ 5.07 (d, J=6.8 Hz, 1H), 3.99 (br s, 1H), 3.88 (s, 3H), 3.86-3.73 (m, 8H), 3.43 (br s, 3H), 1.90-1.86 (m, 1H), 1.70-1.63 (m, 2H), 1.56-1.55 (m, 1H), 1.42 (s, 9H); LCMS 2.95 min, 520 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])/[C:11](=[CH:14]\N(C)C)/[CH:10]2[CH2:18][C:19]3[C:24]([CH:9]12)=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[O:26]1CCCC1>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])/[C:11](=[CH:14]\[OH:26])/[CH:10]2[CH2:18][C:19]3[C:24]([CH:9]12)=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)/C=C1\C(=O)N(C(=O)OC(C)(C)C)C2c3ccccc3CC12
Reactant: C1CCOC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C(=O)/C(=C\O)C2Cc3ccccc3C21
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
To a solution of 3-[1-dimethylamino-meth-(Z)-ylidene]-2-oxo-3,3a,4,8b-tetrahydro-2H-indeno[1,2-b]pyrrole-1-carboxylic acid tert-butyl ester E1 (190 mg, 0.579 mmol) in tetrahydrofurane (2 mL) was added hydrogen chloride (1M, 0.87 mL). The solution was stirred at room temperature for 3 h. The solution was diluted with ethyl acetate and washed with water, brine, dried and concentrated. The residue was triturated with ethyl acetate to give 3-[1-Hydroxy-meth-(Z)-ylidene]-2-oxo-3,3a,4,8b-tetrahydro-2H-indeno[1,2-b]pyrrole-1-carboxylic acid tert-butyl ester D1 (White powder, 140 mg, 80%). C17H19NO4; MW: 301.35; LCMS (method A) RT 1.72 min; ES: 302 (MK), 246; 1H NMR (400 MHz, DMSO-d6) δ 11.04 (1H, s), 7.54 (1H, d), 7.42 (1H, d), 7.13-7.31 (3H, m), 5.59 (1H, d), 3.70 (1H, m), 3.22 (1H, dd), 3.15 (1H, dd), 1.53 (10H, s) ppm.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[C:10]1[N:15]=[CH:14][NH:13][C:12]2=[N:16][CH:17]=[CH:18][C:11]=12.[CH3:19][CH:20]([N:22]1[C:26]([C:27]([NH:29][C:30]2[C:31]3[C:35]([CH:36]=[C:37](B4OC(C)(C)CC(C)(C)O4)[CH:38]=2)=[N:34][N:33](C2CCCCO2)[CH:32]=3)=[O:28])=[CH:25][CH:24]=[N:23]1)[CH3:21].O>O1CCOCC1.CO>[CH3:21][CH:20]([N:22]1[C:26]([C:27]([NH:29][C:30]2[CH:38]=[C:37]([C:10]3[C:11]4[CH:18]=[CH:17][NH:16][C:12]=4[N:13]=[CH:14][N:15]=3)[CH:36]=[C:35]3[C:31]=2[CH:32]=[N:33][NH:34]3)=[O:28])=[CH:25][CH:24]=[N:23]1)[CH3:19]
Reactant: Clc1nc[nH]c2nccc1-2
Reactant: CC(C)n1nccc1C(=O)Nc1cc(B2OC(C)(C)CC(C)(C)O2)cc2nn(C3CCCCO3)cc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1nccc1C(=O)Nc1cc(-c2ncnc3[nH]ccc23)cc2[nH]ncc12
Temperature: 120 °C

Procedure:
A microwave vial was charged with Solvias catalyst (8 mg), tripotassium phosphate (90 mg) and 4-chloro-1H-pyrrolo[2,3-d]pyrimidine (available from ABCR, 24 mg). 1-(1-Methylethyl)-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1H-pyrazole-5-carboxamide (70 mg) in 1,4-dioxane (0.5 ml) was added followed by water (0.1 ml). The reaction was heated under microwave irradiation at 120° C. for 10 min. Solvias catalyst (8 mg) was added and the reaction heated under microwave irradiation at 120° C. for 10 min. Further Solvias catalyst (8 mg) and tripotassium phosphate (30 mg) were added and the reaction was heated under microwave irradiation at 120° C. for 30 min. Again further Solvias catalyst (8 mg) and tripotassium phosphate (90 mg) were added and the reaction was heated under microwave irradiation at 120° C. for 30 min. 4-Chloro-1H-pyrrolo[2,3-d]pyrimidine (12 mg) was added and the reaction was heated under microwave irradiation at 120° C. for 30 min. Addition of catalyst and base was repeated and the reaction was heated under microwave irradiation at 120° C. for 30 min. The reaction was passed through a silica cartridge preconditioned with methanol, washing with methanol, then dried under a stream of nitrogen. The residue was subjected to a DCM/water wash and then dried under a stream of nitrogen. The residue was dissolved in DMSO:methanol (1 ml, 1:1, v/v) and purified by MDAP (method A). The appropriate fraction was evaporated under a stream of nitrogen. The residue was dissolved in methanol, a few drops of 2M HCl (aq) were added and the mixture was left to stand briefly at room temperature, then evaporated under a stream of nitrogen. Sequential purification was carried out using the following system and the two gradients shown:
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19][CH:18]([CH3:20])[N:17]([CH3:21])[C:16]2=O)[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:29]([Li])[CH3:30]>C1(C)C=CC=CC=1.C(=O)=O>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19][CH:18]([CH3:20])[N:17]([CH3:21])[C:16]2=[CH:29][CH3:30])[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: [Li]CC
Reactant: CC1CC(c2ccccc2)(c2cccc(O[Si](C)(C)C(C)(C)C)c2)C(=O)N1C
Agent: O=C=O
Solvent: Cc1ccccc1
Product: CC=C1N(C)C(C)CC1(c1ccccc1)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Product of Step 7 (2.5 g) was dissolved in toluene (150 mL). The solution was cooled by surrounding the flask with dry ice and the contents were stirred under argon purging for 30 min. To this was added a dispersion of ethyl lithium (25 mL, 1.7 M in butyl ether). The reaction mixture was stirred in dry ice under argon purging for 1 hr and allowed to warm to 25° C. The reaction mixture was stirred for 3 hr at 25° C. under argon purging. Then, the reaction mixture was poured in a beaker and cooled to 0° C. using an ice bath. The reaction was quenched by slow addition of water (5 mL) to the stirring toluene solution. After the evolution of gases ceased, the reaction mixture was extracted with water (three times at 50 mL each). The organic layer was diluted with ethyl acetate (500 mL) and dried over anhydrous magnesium sulfate. The organic layer was filtered and concentrated under vacuum to obtain Step 8 product as a red-brown viscous oil (3 mL). Mass spectrometry: m/z=408 (M+H). The product was carried forward without further purification.
Reaction SMILES: [OH:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([I:13])=[CH:8][CH:9]=2)[O:4][C:3]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:34](Cl)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CC(C)=O>[CH2:34]([O:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([I:13])=[CH:8][CH:9]=2)[O:4][C:3]=1[C:14]1[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COc1cc(-c2oc3cc(I)ccc3c(=O)c2O)cc(OC)c1OC
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(-c2oc3cc(I)ccc3c(=O)c2OCc2ccccc2)cc(OC)c1OC
Yield: 82.7 %

Procedure:
A stirring suspension of 3-hydroxy-7-iodo-2-(3,4,5-trimethoxyphenyl)-chromen-4-one (0.257 g, 0.6mmol), potassium carbonate (1.48 g, 11 mmol, 19 equ), potassium iodide (0.06 g, 0.3 mmol, 0.6 equ) and benzyl chloride (0.16 ml, 1.3 mmol, 2.3 equ) in acetone (12 ml) under nitrogen was heated to reflux for one hour. The reaction was filtered and the filtrate concentrated in vacuo to give an orange solid. This solid was recrystallised from isopropanol to give 34 (0.270 g, 88%) as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:28]=[CH:27][C:9]3[N:10]=[C:11]([C:13]4[N:18]=[CH:17][C:16]([C:19]#[C:20][C@@H:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])=[CH:15][CH:14]=4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.CO>[Pd].C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:28]=[CH:27][C:9]3[N:10]=[C:11]([C:13]4[N:18]=[CH:17][C:16]([CH2:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])=[CH:15][CH:14]=4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)N[C@@H](C)C#Cc1ccc(-c2nc3ccc(OCC4CC4)cc3o2)nc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](C)CCc1ccc(-c2nc3ccc(OCC4CC4)cc3o2)nc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 37.4 %

Procedure:
Under a hydrogen atmosphere, a mixture of N-[(1S)-3-{6-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]pyridin-3-yl}-1-methylprop-2-yn-1-yl]acetamide (98.0 mg), 10% palladium/carbon (containing water (50%), 19.6 mg), methanol (5 mL) and THF (1 mL) was stirred at 50° C. for 4 hr. The catalyst was removed by filtration, and the obtained filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate/methanol) to give the title compound as yellow crystals (37.0 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][N:5]2[N:4]=1)[CH3:2].[Br:12]Br>CCO>[Br:12][C:11]1[C:3]([CH2:1][CH3:2])=[N:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=12
Reactant: BrBr
Reactant: CCc1cc2n(n1)CCCC2
Solvent: CCO
Product: CCc1nn2c(c1Br)CCCC2
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (4.12 g, from Step B) in EtOH (25 mL) was added Br2 (1.42 mL) dropwise at 0° C. The reaction was stirred at 0° C. for 20 min. The reaction mixture was partitioned between EtOAc and aqueous NaHCO3 (saturated). Aqueous layer was extracted with EtOAc (3×). Combined organic phase was washed with brine and dried over anhydrous MgSO4. After concentration, the residue was purified by flash chromatography with 10% EtOAc in hexanes followed by 20% EtOAc in hexanes to give the title compound as a viscous oil. 1H NMR (500 MHz, CDCl3) δ 1.25 (t, 3H, J=7.5 Hz), 1.80–1.90 (m, 2H), 1.95–2.05 (m, 2H), 2.55–2.70 (m, 4H), 4.07 (t, 2H, J=6.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][C:6]([C:7]([NH:9][NH:10][C:11]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[C:18]([C:22]4[C:27]([CH3:28])=[CH:26][C:25]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:24][C:23]=4[CH3:35])[NH:19]3)=[CH:15][CH:14]=2)=O)=[O:8])=[CH:5][CH:4]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]2[O:8][C:11]([C:13]3[CH:21]=[C:20]4[C:16]([CH:17]=[C:18]([C:22]5[C:27]([CH3:28])=[CH:26][C:25]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:24][C:23]=5[CH3:35])[NH:19]4)=[CH:15][CH:14]=3)=[N:10][N:9]=2)=[CH:36][CH:37]=1
Reactant: COC(=O)CCc1cc(C)c(-c2cc3ccc(C(=O)NNC(=O)c4ccc(OC)cc4)cc3[nH]2)c(C)c1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: COC(=O)CCc1cc(C)c(-c2cc3ccc(-c4nnc(-c5ccc(OC)cc5)o4)cc3[nH]2)c(C)c1
Temperature: 150 °C

Procedure:
A mixture of methyl 3-(4-{6-[N′-(4-methoxybenzoyl) -hydrazinocarbonyl]-1H-indol-2-yl}-3,5-dimethyl-phenyl)-propionate (220 mg, 440 μmol) and Burgess reagent (210 mg, 880 μmol) in THF (10 mL) was heated in a microwave apparatus at 150° C. for 30 min. The solvent was removed under reduced pressure, and the residue chromatographed using a 30-70% gradient of heptane/ethyl acetate to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:24]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[O:25])=[N:4][C:5]([C:18]#[C:19][Si](C)(C)C)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CCO.C1COCC1>[C:18]([C:5]1[N:4]=[C:3]([C:24]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[O:25])[C:2]([CH3:1])=[CH:7][C:6]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:17])[F:15])[CH:9]=1)#[CH:19]
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C#C[Si](C)(C)C)nc1C(=O)N1CCC(N2CCCC2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Product: C#Cc1nc(C(=O)N2CCC(N3CCCC3)CC2)c(C)cc1-c1cccc(C(F)(F)F)c1
Reaction time: 4 h
Yield: 78.3 %

Procedure:
A solution of 0.65 g (1.27 mmol) of [3-methyl-5-(3-trifluoromethyl-phenyl)-6-trimethylsilanylethynyl-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (intermediate 12) in 12 ml of EtOH/THF (5:1) was treated at RT with 0.35 g (2.53 mmol) of potassium carbonate. After 4 hours, the reaction mixture was poured into crashed ice, the pH was adjusted to 3-4 with hydrochloric acid (2 molar) and the mixture was extracted three times with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 9:1) to give 0.439 g (79%) of the title compound as brown solid. MS: 442.3 (MH+).
Reaction SMILES: [CH2:1]([N:5]([C:7]1[C:12]([C:13]([NH:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:23])=O)=[CH:11][N:10]=[C:9]([Cl:24])[N:8]=1)[NH2:6])[CH2:2][CH:3]=[CH2:4].P(Cl)(Cl)(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[C:7]2=[N:8][C:9]([Cl:24])=[N:10][CH:11]=[C:12]2[C:13]([NH:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:23])=[N:6]1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCN(N)c1nc(Cl)ncc1C(=O)Nc1c(C)cccc1C
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: C=CCCn1nc(Nc2c(C)cccc2C)c2cnc(Cl)nc21
Temperature: 100 °C

Procedure:
A mixture of 3.42 g (9.9 mmol) of 4-(1-(but-3-enyl)hydrazinyl)-2-chloro-N-(2,6-dimethylphenyl)pyrimidine-5-carboxamide 31 (Example 1, Step C) in 100 mL of toluene was treated with 2.16 g (95%, 9.9 mmol) of phosphorus pentachloride. The resulting orange slurry was heated at 100° C. for 1.75 h, and then was concentrated. The residue was dissolved in CH2Cl2 (250 mL) and washed with saturated aqueous sodium bicarbonate (150 mL). The aqueous layer was extracted with more CH2Cl2 (100 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was purified by chromatography on silica gel (hexanes:EtOAc, 4:1) to give the title compound 32. 1H-NMR (CDCl3) δ 2.24 (s, 6H), 2.62-2.68 (m, 2H), 4.31 (t, J=7.2 Hz, 2H), 4.99 (dd, J=10.2 Hz, 1.6 Hz, 1H), 5.05 (dd, J=17.1 Hz, 1.6 Hz, 1H), 5.72-5.83 (m, 1H), 6.06 (s, 1H), 7.13-7.22 (m, 3H), 7.58 (s, 1H). Mass Spectrum (ESI) m/e=328.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[Cs+].[Cs+].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.C>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:3][C:4]=1[N+:16]([O-:18])=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1OCc1ccccc1
Reactant: C1CNCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cc(N2CCNCC2)ccc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-2-nitro-1-[(phenylmethyl)oxy]benzene (3.08 g, 10 mmol) in dioxane (60 ml) was added piperazine (2.58 g, 30 mmol) followed by cesium carbonate (4.8 g, 15 mmol), rac-2,2′ bis(diphenylphosphino)-1,1′-binapthyl (0.311 g, 0.5 mmol) and palladium acetate (0.112 g, 0.5 mmol). The resulting mixture was heated at 100° C. under an atmosphere of argon overnight. The mixture was allowed to cool, charcoal was added and the mixture stirred at room temperature for 30 minutes. The solids were then removed by filtration through celite and the residue washed with ethyl acetate. The filtrate was then reduced in vacuo and the residue was purified by flash column chromatography gave 1-(4-(benzyloxy)-3-nitrophenyl)piperazine which was used for next step without further purification.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][CH2:5][CH2:6][N:7]=1.[CH3:8][S:9](Cl)(=[O:11])=[O:10]>>[CH3:8][S:9]([N:7]1[CH2:6][CH2:5][N:4]=[C:3]1[S:2][CH3:1])(=[O:11])=[O:10]
Reactant: CSC1=NCCN1
Reactant: CS(=O)(=O)Cl
Product: CSC1=NCCN1S(C)(=O)=O

Procedure:
Starting from 2-(methylthio)-4,5-dihydro-1H-imidazole and methanesulphonyl chloride, the expected product is obtained according to the procedure described in Step C of Example 3.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=O.[CH:17]1([C:20](=O)[CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:19][CH2:18]1.S(=O)(=O)(O)O>CO>[CH:17]1([C:20]2[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:4]([C:6]3[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=3)[C:3]3[C:2](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:1]=2)[CH2:19][CH2:18]1
Reactant: Nc1ccccc1C(=O)c1ccc(F)cc1
Reactant: COC(=O)CC(=O)C1CC1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To the solution of 2-amino-4′-fluorobenzophenone (100 g) in methanol (500 ml) added Methyl 3-cyclopropyl-3-oxopropanoate (132 g), sulfuric acid (5 ml) and stirred for 15 minutes at 25° C. Heated the reaction mixture to 65° C. for 22 hrs. Distilled off the methanol completely under reduced pressure. Cooled the reaction mixture to 25° C., added water (500 ml) and stirred for 30 minutes. Cooled the reaction mixture to 0° C. and pH adjusted to 6.0 with sodium carbonate solution. Stirred the reaction mixture for 45 minutes at 25° C. Filtered the cake and washed with water. Spin dry the compound for 60 minutes. To this compound added methanol (150 ml) and stirred for 1 hr at 25° C. Filtered the solid and washed with methanol (50 ml). Dried the obtained solid to get the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[O:12][N:11]=[C:10]([CH3:13])[CH:9]=1)[O:6][CH3:7].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[OH:37]>CCOCC>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[O:37][CH2:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[O:12][N:11]=[C:10]([CH3:13])[CH:9]=1)[O:6][CH3:7]
Reactant: Oc1cc(Cl)ccc1Cl
Reactant: COC(c1cc(C)no1)c1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(c1cc(C)no1)c1ccccc1COc1cc(Cl)ccc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
To 0.25 g (1 mmol) of 5-(2-chloromethyl-α-methoxybenzyl)-3-methylisoxazole, 2 ml of N,N-dimethylformamide, 0.28 g (2 mmol) of potassium carbonate and 0.33 g (2 mmol) of 2,5-dichlorophenol were added and stirred at 80° C. for 3 hours. After completion of the reaction, 100 ml of ether was added and washed twice with 80 ml of brine. The ether layer was dried over anhydrous magnesium and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) and recrystallized from ether/n-hexane to give 5-[2-(2,5-dichlorophenoxymethyl)-α-methoxybenzyl]-3-methylisoxazole (0.28 g, 74.0%) as colorless crystals. mp. 78.5-79.5° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]3[CH2:16][C:17]4[S:18][C:19]([C:22]5[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=5)=[CH:20][C:21]=4[C:14]=3[NH:13][N:12]=2)=[CH:7][CH:6]=1.[CH3:29][Si:30]([CH2:33][CH2:34][O:35][CH2:36]Cl)([CH3:32])[CH3:31]>C1COCC1>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]3[CH2:16][C:17]4[S:18][C:19]([C:22]5[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=5)=[CH:20][C:21]=4[C:14]=3[N:13]([CH2:36][O:35][CH2:34][CH2:33][Si:30]([CH3:32])([CH3:31])[CH3:29])[N:12]=2)=[CH:7][CH:6]=1
Reactant: COc1ccc(-c2n[nH]c3c2Cc2sc(-c4ccc(N)nc4)cc2-3)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4ccc(N)nc4)cc2-3)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
At 0° C., NaH (60 percent, 0.15 g, 3.0 mmol) was added to a THF solution (15 mL) containing 5-[6-(4-Methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-pyridin-2-ylamine (3.1 g, 2.0 mmol). Then SEM-Cl (90% pure, 0.42 mL, 2 mmol) was added to the reaction mixture and the resulting mixture was stirred at 0° C. for 30 min, warmed up to 80° C. and stirred for 2 hr. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and washed with saturated aqueous NH4Cl, dried over MgSO4(s), and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to give 5-[6-(4-Methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-pyridin-2-ylamine (0.7 g, 1.44 mmol) as brown solid in 72% yield.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[C:31]([C:33]([OH:36])([CH3:35])[CH3:34])[CH:30]=[C:29]([F:37])[C:28]=1[C:38]1[N:43]=[C:42]([C:44](O)=[O:45])[CH:41]=[CH:40][C:39]=1[F:47]>>[NH2:9][C@H:8]1[C@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:44](=[O:45])[C:42]2[CH:41]=[CH:40][C:39]([F:47])=[C:38]([C:28]3[C:29]([F:37])=[CH:30][C:31]([C:33]([OH:36])([CH3:35])[CH3:34])=[CH:32][C:27]=3[F:26])[N:43]=2)[CH2:6][CH2:7]1
Reactant: CC(C)(O)c1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2ccc(F)c(-c3c(F)cc(C(C)(C)O)cc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(2,6-difluoro-4-(2-hydroxypropan-2-yl)phenyl)-5-fluoropicolinic acid (see US2012/225062) gave 200. 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.28 (dd, J=8.7, 4.0 Hz, 1H), 8.14 (t, J=8.9 Hz, 1H), 7.89 (s, 1H), 7.34 (d, J=9.8 Hz, 2H), 5.36 (br, 1H), 4.80 (dd, J=10.4, 3.7 Hz, 1H), 4.37-4.06 (m, 1H), 4.02-3.87 (m, 2H), 3.75 (s, 3H), 3.13-3.00 (m, 1H), 2.10-1.99 (m, 1H), 1.85-1.57 (m, 3H), 1.47 (s, 6H). LCMS (ES+) m/z 522 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([OH:13])[CH:7]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>CC(C)=O.O>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([O:13][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(O)c(O)c1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)Cc1ccc(O)c(OCc2ccccc2)c1
Yield: 45 %

Procedure:
To a solution of 5.79 g of 3,4-dihydroxylphenyl acetic acid ethyl ester dissolved in dry acetone were added 4.48 g of potassium carbonate and 4.15 ml of benzyl bromide. The mixture was heated to reflux until the starting materials were exhausted; and then the solvent was distilled off under reduced pressure. To the residues thus obtained was added 50 ml of water; and the mixture was acidified with concentrated hydrochloric acid and extracted with dichloromethane. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to obtain residues, which were purified by chromatography to provide 3.80 g (yield 45%) of 3-benzyloxy-4-hydroxyphenylacetic acid ethyl ester, having the characteristics of: NMR(CDCl3, 200 MHz) δ1.24(t, J=7 Hz, 3H, CH3), 3.45(s, 2H, CH2CO), 4.12(q, J=7 Hz, 2H, OCH2), 5.05(s, 2H, CH2Ph), 6.77-7.35(m, 6H, ArH).