Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:12])[C:4]=2[N:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[N:23][N:24]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:25]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.C(OCC)(=O)C>[N:28]1[CH:29]=[CH:30][CH:31]=[C:26]([N:24]2[CH:25]=[C:21]([C:2]3[CH:11]=[CH:10][C:9]4[CH2:8][CH2:7][CH2:6][C:5](=[O:12])[C:4]=4[N:3]=3)[CH:22]=[N:23]2)[CH:27]=1
Reactant: O=C1CCCc2ccc(Cl)nc21
Reactant: CC1(C)OB(c2cnn(-c3cccnc3)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CCCc2ccc(-c3cnn(-c4cccnc4)c3)nc21
Temperature: 80 °C

Procedure:
A mixture of 2-chloro-6,7-dihydro-8(5H)-quinolinone (1.14 g, 6.3 mmol, prepared as described in J. Org. Chem. 1990, 55, 4789) and 3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-pyridine (1.7 g, 6.3 mmol, WO 2012/000896), sodium carbonate (3.15 g, 29.6 mmol) in a mixture of acetonitrile (50 ml) and water (30 ml) was purged with argon for 10 min. To this solution was added Pd[P(Ph)3]4 (270 mg, 0.23 mmol) and the solution was heated at 80° C. overnight. The reaction mixture was diluted with ethyl acetate and the water phase was separated. The organic phase was washed with brine and dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was crystallized in isopropanol/petrol ether (1:1) to give two crops of the title product as a beige solid.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:21]#[N:22])[C:10]([CH3:20])=[C:11]([C:14]4[N:15]=[C:16]([CH3:19])[S:17][CH:18]=4)[C:12]=3F)[N:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:30][N:31]([CH3:37])[C@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1.O>CS(C)=O>[CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:21]#[N:22])[C:10]([CH3:20])=[C:11]([C:14]4[N:15]=[C:16]([CH3:19])[S:17][CH:18]=4)[C:12]=3[N:34]3[CH2:35][CH2:36][C@H:32]([N:31]([CH3:37])[CH3:30])[CH2:33]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1nc(-c2c(C)c(C#N)c3nc(C4CC4)oc3c2F)cs1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1nc(-c2c(C)c(C#N)c3nc(C4CC4)oc3c2N2CC[C@H](N(C)C)C2)cs1
Temperature: 90 °C
Reaction time: 4 h
Yield: 61.3 %

Procedure:
2-Cyclopropyl-7-fluoro-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-1,3-benzoxazole-4-carbonitrile (I-80) (3.96 g, 12.65 mmol) was dissolved in dimethyl sulfoxide (40 ml), then triethylamine (4.27 ml, 30.36 mmol) and (3S)-3-(dimethylamino)pyrrolidine (1.93 ml, 15.18 mmol) were added, followed by stirring at 90° C. for 4 hours under nitrogen atmosphere. After cooling to room temperature, water was added, the precipitated solid was collected by filtration, recrystallized and purified with a mixed solvent of diethyl ether/ethyl acetate/methanol to obtain the entitled compound (3.16 g, 61%) as a white solid.
Reaction SMILES: [Cl-].[Cl-].[Ca+2:3].[P:4](=[O:8])([OH:7])([OH:6])[OH:5].FF.[Na+].[Cl-]>>[P:4]([O-:8])([O-:7])([O-:6])=[O:5].[Ca+2:3].[P:4]([O-:8])([O-:7])([O-:6])=[O:5].[Ca+2:3].[Ca+2:3]
Reactant: O=P(O)(O)O
Agent: FF
Agent: [Ca+2]
Agent: [Cl-]
Product: O=P([O-])([O-])[O-]
Temperature: 160 °C

Procedure:
An aqueous solution of calcium dichloride was mixed with phosphoric acid of high fluorine content to produce a solution having a Ca/P mole ratio of 0.8 and a solution P/F ratio of about 20. The solution was treated with NaCl and chilled to produce a precipitate in accordance with the procedure of Example 1(a). The slurry was filtered yielding a filtrate having a Ca/P mole ratio of 0.8 and a P/F ratio of about 60. The solution was then fed to a conventional spray dryer at a rate of about 125 ml./min., with the exit gas temperature of the dryer being maintained at about 320°F. The dried product had a P/F ratio in excess of 100 and comprised a mixture of CaHPO4, CaClH2PO4.H2O, and Ca(H2PO4)2.
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:16][CH2:15][CH2:14][C:13](=O)[C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]2=3)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[F:23][C:24]([F:38])([F:37])[C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:28][NH2:29].[BH4-].[Na+].[OH-].[Na+]>COCCOCCOC.CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[F:23][C:24]([F:37])([F:38])[C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=1)[CH2:28][NH:29][CH:13]1[CH2:14][CH2:15][CH2:16][N:10]([S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:22])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[C:11]2[CH:21]=[CH:20][CH:19]=[CH:18][C:12]1=2
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1ccc(S(=O)(=O)N2CCCC(=O)c3ccccc32)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: COCCOCCOC
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2CCCC(NCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of (+/−)1-(Toluene-4-sulfonyl)-1,2,3,4-tetrahydro-benzo[b]azepin-5-one (500 mg, 1.58 mmol), 3,5-Bis(trifluoromethyl)benzylamine (423 mg, 1.74 mmol) and titanium(IV) isopropoxide (0.59 ml, 1.97 mmol) in diglyme (2 ml) is stirred at room temperature for 22 hours. The mixture is diluted with methanol (7 ml) and treated with sodium borohydride (90 mg, 2.37 mmol), then stirred at room temperature for 6 hours. The mixture is treated with 0.1N aqueous NaOH (15 ml) and stirred for 10 minutes, then filtered. The filter cake is washed with 1:1 ethanol:diethyl ether. The filtrate is diluted with water (70 ml) and extracted with ethyl acetate (2×30 ml). The combined organic extracts are washed with brine, dried (Na2SO4) and concentrated to an oil. The oil is purified by silica gel column chromatography (eluent, 15% ethyl acetate in hexanes) to give the title compound as a solid. Mass spectrum (ES+): 543 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([O:15]C)=[CH:10][C:9]=2[F:17])=[N:6][CH:7]=1.B(Br)(Br)Br.CO.C([O-])(O)=O.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[C:9]([F:17])=[CH:10][C:11]([OH:15])=[CH:12][C:13]=2[F:14])=[N:4][CH:3]=1
Reactant: COc1cc(F)c(-c2ncc(Br)cn2)c(F)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Oc1cc(F)c(-c2ncc(Br)cn2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a solution of 5-bromo-2-(2,6-difluoro-4-methoxyphenyl)pyrimidine (0.887 g, 2.95 mmol) in DCM at 0° C., was added dropwise a solution of BBr3 (1M in DCM) (22 ml, 22 mmol) and the reaction mixture was stirred overnight at room temperature. This mixture was then poured over cold MeOH and solid NaHCO3 was added slowly until pH=4-5. The suspension obtained was filtered and the filtrate evaporated. The solid obtained was redissolved in ethyl acetate, washed with water and brine, dried and concentrated to give the desired compound as a white solid (0.817 g, 85% of yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH2:8][CH3:9].F[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1.O>CN(C)C(=O)C.C(Cl)Cl>[CH2:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[CH2:8][CH3:9]
Reactant: CCCc1ccc(O)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCCc1ccc(Oc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Yield: 69.1 %

Procedure:
Anhydrous potassium carbonate (14.9 g, 0.12 mol) was added to a mixture of 4-propylphenol (13.6 g, 0.10 mol) and 4-fluorobenzaldehyde (12.4 g, 0.10 mol) in N,N-dimethylacetamide (100 mL) under argon. The heterogeneous mixture was brought to reflux, maintained at that temperature for 5 h, then cooled to RT. Water (100 mL) and CH2Cl2 (100 mL) were added, resulting in a tri-phase system. The bottom layer was removed; the middle layer was dried over MgSO4 ; and, the top layer was extracted with CH2Cl2 (100 mL) and dried over MgSO4. The dried layers were combined and concentrated in vacuo at 50° C. to give an orange oil. The crude product was purified by distillation to give title compound (16.6 g, 69%) as a colorless oil. bp 133°-50° C. (0.2 mm Hg)
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[CH2:12][CH:13]4[NH:17][CH:16]([C:5]=3[C:4]=2[C:3]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH2:14]4.[Na+].[C:26]1([S:32]([O-:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[C:26]1([S:32]([C:2]2[CH:10]=[CH:9][C:8]3[N:7]([CH3:11])[C:6]4[CH2:12][CH:13]5[NH:17][CH:16]([C:5]=4[C:4]=3[C:3]=2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH2:14]5)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=S([O-])c1ccccc1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccccc4)ccc31)C1CCC(C2)N1
Temperature: 25 °C
Yield: 70.2 %

Procedure:
A mixture of product from step B (1.5 g, 3.84 mmol) and benzene sulfinic acid sodium salt (755 mg, 4.6 mmol) were suspended in toluene (30 mL) and N2 was bubbled through the reaction mixture for 10-15 min. Di-palladium-tris(dibenzylideneacetone) (89 mg, 0.096 mmol), cesium carbonate (1.84 g, 5.76 mmol), xantphos (111 mg, 0.192 mmol) and tetrabutylammonium chloride (1.28 g, 4.6 mmol) were then added sequentially, and the reaction was heated to reflux for 12 h. The reaction mixture was cooled to ambient temperature, partitioned between ethyl acetate and sat. ammonium chloride solution and the organics removed. The aqueous was extracted with ethyl acetate (×2) and the combined organics dried over sodium sulfate and concentrated. Purification by flash column chromatography (silica gel, hexanes/EtOAc, 100:0 to 50:50) provided tert-butyl 2-phenylsulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (1.22 g, 71%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.20 (s, 1H), 7.96 (dd, J=7.7, 1.5 Hz, 2H), 7.68 (d, J=9.0 Hz, 1H), 7.47 (m, 3H), 7.30 (d, J=8.7 Hz, 1H), 5.25 (brs, 1H), 4.68 (m, 1H), 3.60 (s, 3H), 3.37 (m, 1H), 2.50 (d, J=16.7 Hz, 1H), 2.26 (m, 2H), 1.94 (t, J=10.3 Hz, 1H), 1.61 (m, 1H, partially masked by H2O peak), 1.36 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:3]=1[CH2:20][CH3:21].[O:22]1[CH2:27][CH2:26][N:25]([C:28]2[C:33]([NH2:34])=[CH:32][C:31]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:30][N:29]=2)[CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[N:25]1([C:28]2[C:33]([NH:34][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=4[F:12])[N:5]=[C:4]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)[C:3]=3[CH2:20][CH3:21])=[CH:32][C:31]([N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)=[CH:30][N:29]=2)[CH2:24][CH2:23][O:22][CH2:27][CH2:26]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: CCc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: CCc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
Prepared according to Procedure H using 4-chloro-3-ethyl-5,7-difluoro-2-(pyridin-2-yl)quinoline (40.0 mg, 0.131 mmol) and 2,5-dimorpholinopyridin-3-amine in toluene to give N-(2,5-di-4-morpholinyl-3-pyridinyl)-3-ethyl-5,7-difluoro-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (CDCl3) δ ppm 8.70 (1H, td, J=2.4, 1.0 Hz), 7.79-8.00 (2H, m), 7.53-7.66 (2H, m), 7.45 (1H, d, J=6.3 Hz), 7.40 (1H, ddd, J=7.3, 4.8, 1.6 Hz), 6.98 (1H, ddd, J=12.8, 8.7, 2.6 Hz), 6.43 (1H, d, J=2.3 Hz), 3.87-4.07 (4H, m), 3.73-3.82 (4H, m), 3.15-3.35 (4H, m), 2.93-3.03 (4H, m), 2.70 (2H, br. s.), 0.98 (3H, t, J=7.5 Hz). Mass Spectrum (ESI) m/e=533.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[C:5]2[Cl:25].[Li]CCCC.[CH3:31][C:32]1[N:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:33]=1[CH:34]=[O:35]>C1COCC1>[Cl:25][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:34]([C:33]3[C:32]([CH3:31])=[N:39][C:38]([CH3:40])=[CH:37][CH:36]=3)[OH:35])[CH:3]=2)[N:8]=[C:7]([O:12][CH3:13])[C:6]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(C=O)c(C)n1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -70 °C
Reaction time: 0.03 h

Procedure:
To a flask containing 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (1.85 g, 4.3 mmol, Intermediate 5: step d) was added THF (45 mL) at room temperature which resulted in a colorless homogeneous solution. The solution was cooled to −70° C. and then n-BuLi (2.5 M in hexanes, 1.75 mL, 4.38 mmol) was added dropwise. After 2 minutes, 2,6-dimethylnicotinaldehyde (755 mg, 5.50 mmol, in 2 mL THF) was introduced and the color of the mixture changed from a reddish-brown to green. The reaction mixture was allowed to warm to −20° C. over 40 minutes at which time the reaction was quenched with aqueous NH4Cl solution. The aqueous portion was extracted with EtOAc (3×50 mL) and the combined organics were washed with brine, dried over MgSO4, filtered and concentrated to dryness. Chromatography on silica gel (10% acetone-hexane increasing to 30% acetone) afforded the title compound.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:19]1([CH3:28])[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1.C([O-])([O-])=O.[Na+].[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>CN(C=O)C.Cl[Pd]Cl.O>[CH3:28][C:19]1[CH:20]=[C:21]([C:2]2[N:11]=[C:10]([NH:12][C:13]3[NH:14][N:15]=[C:16]([CH3:18])[CH:17]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: Cc1cc(Nc2nc(Cl)nc3ccccc23)n[nH]1
Agent: Cl[Pd]Cl
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(-c2nc(Nc3cc(C)n[nH]3)c3ccccc3n2)c1
Temperature: 80 °C
Yield: 101.8 %

Procedure:
A suspension of 1H-quinazoline-2,4-dione (10.0 g, 61.7 mmol) in POCl3 (60 mL, 644 mmol) and N,N-dimethylaniline (8 mL, 63.1 mmol) was heated under reflux for 2 h. The excess POCl3 was removed in vacuo, the residue poured into ice, and the resulting precipitate collected by filtration. The crude solid product 2,4-dichloro-quinazoline (6.5 g, 53% yield) was washed with water and dried under vacuum for next step use without further purification. To a solution of the 2,4-dichloro-quinazoline (3.3 g, 16.6 mmol) in anhydrous ethanol (150 mL) was added 5-methyl-1H-pyrazol-3-yl amine (3.2 g, 32.9 mmol) and the resulting mixture was stirred at room temperature for 4 hours. The resulting precipitate was collected by filtration, washed with ethanol, and dried under vacuum to afford 4.0 g (93% yield) of (2-chloro-quinazolin-4-yl)-(5-methyl-1H-pyrazol-3-yl)-amine which was used in the next step without further purification. To a solution of the (2-chloro-quinazolin-4-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (50 mg, 0.19 mmol) in DMF (1.0 mL) was added m-tolyl boronic acid (0.38 mmol), 2M Na2CO3 (0.96 mmol), and tri-t-butylphosphine (0.19 mmol). The flask was flushed with nitrogen and the catalyst PdCl2 (dppf) (0.011 mmol) added in one portion. The reaction mixture was then heated at 80° C. for 10 hours, cooled to room temperature, and poured into water (2 mL). The resulting precipitate was collected by filtration, washed with water, and purified by HPLC to afford III-50 as a pale yellow solid (61 mg, 75%): 1H NMR (500 MHz, DMSO-d6) δ12.3 (br s, 1H), 10.4 (br s, 1H), 8.75 (d, 1H), 8.30 (s, 1H), 8.25 (d, 1H), 7.78 (s, 2H), 7.55 (m, 1H), 7.45 (m, 1H), 7.35 (m, 1H), 6.80 (s, 1H), 2.47 (s, 3H), 2.30 (s, 3H); MS 316.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[SH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14].CN(C)CC(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.[Cu]I.O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([S:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=[O:14])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(S)c1
Reactant: Nc1ccc(I)cn1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(Sc2cccc(C(=O)O)c2)cn1
Temperature: 120 °C
Yield: 34.1 %

Procedure:
A procedure described in Syn. Lett. 1254, 2004 was followed. To solution of 2-amino-5-iodopyridine (220 mg, 1 mmol) in dimethyl formamide (2 mL) were added sequentially 3-mercaptobenzoic acid (185 mg, 1.2 mmol), CuI (50 mg), N,N-dimethylglycine (50 mg) and K3PO4 (1.06 g). The mixture was heated to 120° C. for 2 h, cooled to RT and water was added. The solid was filtered and the filtrate was treated with 1N HCl to adjust the solution to pH 4. The solid formed was collected by filtration, dissolved in 1N NaOH and the solution was filtered. The filtrate was purified by RP HPLC eluting with a mixture of methanol in water containing 0.1% TFA to obtain 3-(6-aminopyridin-3-ylthio)benzoic acid (84 mg, 34%). LC/MS; (M+H)+=247.
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([NH2:12])=[O:11])[CH2:6][C@@H:5]1[OH:13])=[N+]=[N-]>CO.[Pd]>[NH2:1][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([NH2:12])=[O:11])[CH2:6][C@@H:5]1[OH:13]
Reactant: [N-]=[N+]=N[C@H]1CC[C@H](C(N)=O)C[C@@H]1O
Agent: [Pd]
Solvent: CO
Product: NC(=O)[C@H]1CC[C@H](N)[C@@H](O)C1
Reaction time: 18 h

Procedure:
To (1S,3S,4S)-4-azido-3-hydroxy-cyclohexanecarboxylic acid amide (352c) (760 mg, 4.13 mmol) in MeOH (30 mL) was added Pd/C (10%, 500 mg), and the mixture hydrogenated under atmospheric pressure for 18 h. On completion of reaction the mixture was filtered through Celite®, the filter pad washed with MeOH, and the combined organic solutions concentrated in vacuo to give a white solid in quantitative yield;
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:21][C:22]2[CH:23]=[C:24]([C:28]3[C:33]([CH3:34])=[CH:32][C:31]([OH:35])=[CH:30][C:29]=3[CH3:36])[CH:25]=[CH:26][CH:27]=2)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[CH2:37][CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].[CH2:46]([S:48][CH2:49][CH2:50]O)[CH3:47].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(OCC)C>[CH2:46]([S:48][CH2:49][CH2:50][O:35][C:31]1[CH:32]=[C:33]([CH3:34])[C:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][N:8]([S:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N+:18]([O-:20])=[O:19])(=[O:10])=[O:11])[C:6]3[CH:5]=[CH:4][C:3]([CH2:37][CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[C:2]([F:1])[CH:7]=3)[CH:23]=2)=[C:29]([CH3:36])[CH:30]=1)[CH3:47]
Reactant: CCSCCO
Reactant: Cc1cc(O)cc(C)c1-c1cccc(CN(c2ccc(CCC(=O)OC(C)(C)C)c(F)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCSCCOc1cc(C)c(-c2cccc(CN(c3ccc(CCC(=O)OC(C)(C)C)c(F)c3)S(=O)(=O)c3ccccc3[N+](=O)[O-])c2)c(C)c1
Temperature: 25 °C
Yield: 86.1 %

Procedure:
To a solution of tert-butyl 3-(2-fluoro-4-{[(4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methyl][(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (2.0 g, 3.15 mmol), 2-(ethylthio)ethanol (0.37 mL, 3.47 mmol) and tributylphosphine (1.18 mL, 4.73 mmol) in tetrahydrofuran (40 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.19 g, 4.73 mmol) under stirring at room temperature, and the mixture was stirred for 16 hr. To the reaction mixture were added reagents (2-(ethylthio)ethanol, tributylphosphine and 1,1′-(azodicarbonyl)dipiperidine) in a half amount as above, and the mixture was further stirred for 8 hr. The reaction mixture was diluted with diethyl ether, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=2/1) to give the title compound (1.96 g, yield 86%) as a yellow oil.
Reaction SMILES: [N+](=[CH:3][C:4]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)=[O:5])=[N-].[Cl:11][C:12]1[C:13](=[O:22])[C:14](=[O:21])[C:15]([Cl:20])=[C:16]([Cl:19])[C:17]=1[Cl:18]>C1C=CC=CC=1>[Cl:11][C:12]1[C:13]2[O:22][CH:3]([C:4]([C:6]3[S:7][CH:8]=[CH:9][CH:10]=3)=[O:5])[O:21][C:14]=2[C:15]([Cl:20])=[C:16]([Cl:19])[C:17]=1[Cl:18]
Reactant: [N-]=[N+]=CC(=O)c1cccs1
Reactant: O=C1C(=O)C(Cl)=C(Cl)C(Cl)=C1Cl
Solvent: c1ccccc1
Product: O=C(c1cccs1)C1Oc2c(Cl)c(Cl)c(Cl)c(Cl)c2O1
Yield: 43.7 %

Procedure:
2-diazo-1-(thiophen-2-yl)ethanone (2.3 g, 0.0151 mol) and 3,4,5,6-tetrachlorocyclohexa-3,5-diene-1,2-dione (3.36 g, 0.0136 mol) were then combined in dry benzene (25 mL) and refluxed vigorously for 6 hours. The solvent was then evaporated to dryness, and the crude material was subjected to column chromatography using 100-200 mesh silica gel and 15% ethyl acetate-hexane solvent system. Evaporation of the solvent yielded (4,5,6,7-tetrachlorobenzo[d][1,3]dioxol-2-yl)(thiophen-2-yl)methanone as an orange solid (2.2 g, 43.4%).
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])C.[F:42][C:43]1[CH:44]=[C:45](B(O)O)[CH:46]=[CH:47][C:48]=1[CH3:49]>>[C:36]([CH2:35][CH2:34][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:45]3[CH:46]=[CH:47][C:48]([CH3:49])=[C:43]([F:42])[CH:44]=3)[CH:25]=[C:26]([C:28](=[O:32])[N:29]([CH3:30])[CH3:31])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:41])=[O:3])([OH:38])=[O:37]
Reactant: Cc1ccc(B(O)O)cc1F
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)N(C)C)c2)c1CCC(=O)OCC
Product: Cc1ccc(-c2cc(OCCCCCCc3cccc(OCCCC(=O)O)c3CCC(=O)O)cc(C(=O)N(C)C)c2)cc1F
Yield: 30 %

Procedure:
The title compound was prepared according to the general procedure described in Steps 3 and 4 of Method F starting from 4-[3-[6-(3-bromo-5-dimethylcarbamoyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester and 3-fluoro-4-methylphenylboronic acid. LC/MS indicated a purity of 100% as measured by UV 214 nM. Yield: 30% (after two steps)
Reaction SMILES: CC1C=C(N2CCN(CC3C=CC(C(F)(F)F)=CC=3)C2=O)SC=1C(OCC)=O.[CH:29]1([CH2:32][N:33]2[CH2:38][CH2:37][CH2:36][N:35]([C:39]3[S:40][C:41]([C:45]([O:47]CC)=[O:46])=[C:42]([CH3:44])[N:43]=3)[C:34]2=[O:50])[CH2:31][CH2:30]1>>[CH:29]1([CH2:32][N:33]2[CH2:38][CH2:37][CH2:36][N:35]([C:39]3[S:40][C:41]([C:45]([OH:47])=[O:46])=[C:42]([CH3:44])[N:43]=3)[C:34]2=[O:50])[CH2:31][CH2:30]1
Reactant: CCOC(=O)c1sc(N2CCCN(CC3CC3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)cc1C
Product: Cc1nc(N2CCCN(CC3CC3)C2=O)sc1C(=O)O
Yield: 78 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace ethyl 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiophene-2-carboxylate with ethyl 2-(3-(cyclopropylmethyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained as a colorless solid in 78% yield: MS (ES+) m/z 296.2 (M+1).