Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1)(=[O:3])[NH2:2]>FC(F)(F)C(O)=O>[NH:10]1[CH2:11][CH2:12][CH:7]([CH2:6][CH2:5][CH2:4][C:1]([NH2:2])=[O:3])[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCC(N)=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)CCCC1CCNCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 230.8 %

Procedure:
tert-Butyl 4-(3-carbamoylpropyl)piperidine-1-carboxylate (0.38 g, 1.4 mmol, Production example 44-1) was dissolved in trifluoroacetic acid (2 ml) and the reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure and then azeotropically distilled with toluene. The residue was partitioned between tetrahydrofuran and a saturated aqueous solution of sodium hydrogencarbonate; and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure; and the residue was purified by silica gel chromatography (Fuji Silysia NH, ethyl acetate-methanol system) to yield the title compound (0.55 g, quantitative) as pale yellow oil.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:14]=1[CH3:23])C1C=CC=CC=1.C(O)(C(F)(F)F)=O.C1(SC)C=CC=CC=1>>[OH:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[O:12][C:13]1[C:14]([CH3:23])=[CH:15][C:16]([N+:20]([O-:22])=[O:21])=[CH:17][C:18]=1[CH3:19]
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1OCc1ccccc1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1O
Yield: 95.4 %

Procedure:
A solution of 4-(3-benzyloxy-4-methoxyphenoxy)-3,5-dimethylnitrobenzene (1.65 g), TFA (3.5 mL) and thioanisole (2.2 mL) were stirred for 4 h. The reaction was partitioned between ethyl acetate and water, the organic layer dried over sodium sulfate and concentrated in vacuo. Flash chromatography afforded 4-(3-hydroxy-4-methoxyphenoxy)-3,5-dimethylnitrobenzene (1.2 g) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[O:40]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[CH2:53]O)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:53][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2[O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:6][N:7]=1
Reactant: Oc1ccc(Br)nc1
Reactant: OCc1ccccc1Oc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Brc1ccc(OCc2ccccc2Oc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-bromopyridin-3-ol (1.76 g) in tetrahydrofuran (20 ml), 3.20 g of triphenylphosphine, 5.52 ml of diethyl azodicarboxylate (45% toluene solution) and 2.43 g of (2-phenoxyphenyl)methanol were added, and the reaction solution was stirred overnight at room temperature. The reaction solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate/hexane (0:100-15:85)) to afford the title compound as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH:13]([OH:18])[CH2:14][CH:15]([CH3:17])[CH3:16])[C:9]1=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][N:22]=1.C(P(CCCC)CCCC)CCC.C1CCN(C(/N=N/C(N2CCCCC2)=O)=O)CC1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH:13]([O:18][C:24]2[CH:23]=[N:22][C:21]([Cl:20])=[CH:26][CH:25]=2)[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc(Cl)nc1
Reactant: CC(C)CC(O)C1CCN(C(=O)OC(C)(C)C)C1=O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(/N=N/C(=O)N1CCCCC1)N1CCCCC1
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Product: CC(C)CC(Oc1ccc(Cl)nc1)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Yield: 20.9 %

Procedure:
Bubble nitrogen through a solution of 3-(1-hydroxy-3-methyl-butyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (D1) (600 mg, 2.33 mmol) and 2-chloro-5-hydroxy-pyridine (0.451 g, 3.50 mmol) in toluene (10 mL) at room temperature for 10 minutes. Add tri-n-butylphosphine (0.872 mL, 3.50 mmol) followed by azodicarboxylic acid dipiperidide (0.882 g, 3.50 mmol). Heat the reaction mixture to 70° C., and stir over night. Add additional 3-(1-hydroxy-3-methyl-butyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (D1) (600 mg, 2.33 mmol), tri-n-butylphosphine (0.872 mL, 3.50 mmol) and azodicarboxylic acid dipiperidide (0.882 g, 3.50 mmol). Continue to stir at 70° C. for 3 hours. Cool the mixture to room temperature and pour into saturated aqueous NaHCO3. Extract with ethyl acetate (2×), combine the organic extracts, dry (Na2SO4), filter and concentrate. Purify the crude residue by silica gel chromatography eluting with 0-20% ethyl acetate in hexanes to afford 180 mg of 3-[1-(6-chloro-3-pyridyloxy)-3-methyl-butyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (D2) for chiral separation.
Reaction SMILES: I[C:2]1[S:3][C:4]2[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.[Cu][C:14]#[N:15].CN(C)C=O.C(N)CN>O.C1(C)C=CC=CC=1>[CH3:12][O:11][C:10]1[C:4]2[S:3][C:2]([C:14]#[N:15])=[CH:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: N#C[Cu]
Reactant: COc1cccc2cc(I)sc12
Solvent: CN(C)C=O
Solvent: NCCN
Solvent: Cc1ccccc1
Product: COc1cccc2cc(C#N)sc12
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 8.7 %

Procedure:
A solution of 2-iodo-7-methoxy-1-benzothiophene (10.0 g, 0.35 mol), copper (1) cyanide (6.17 g, 0.68 mol) and anhydrous N,N-dimethylformamide (40 mL) are warmed to 130° C. After 2.5 h at 130° C. no starting material is detectable as measured by HPLC at 220 nm. The reaction is cooled to 40° C. and a solution 25% v/v ethylenediamine in water (30 mL) and toluene (20 mL) are added. The mixture is stirred to room temperature. Additional toluene (30 mL) is added and the heterogeneous mixture is filtered. The layers of the mother liquors are separated and the aqueous layer is extracted with toluene (3×50 mL). The combined organic extracts were washed with water (2×50 mL), dried (MgSO4) and the solvent evaporated in vacuo to give the title compound (5.78 g, 88%), which was used without further purification; δH (300 MHz, CDCl3) 7.79 (1H, s, 3-ArH), 7.46–7.38 (1H, m, 4-ArH), 7.37–7.31 (1H, m, 5-ArH), 6.88–6.82 (1H, m, 6-ArH) and 3.94 (3H, s, OCH3).
Reaction SMILES: [C:1]1([C:7]2[S:11][CH:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:15]1([C:22](=[O:24])[CH3:23])[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[C:1]1([C:7]2[S:11][CH:10]=[C:9]([C:12]([N:18]3[CH2:19][CH2:20][CH2:21][N:15]([C:22](=[O:24])[CH3:23])[CH2:16][CH2:17]3)=[O:14])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)N1CCCNCC1
Reactant: O=C(O)c1csc(-c2ccccc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N1CCCN(C(=O)c2csc(-c3ccccc3)c2)CC1
Reaction time: 0.5 h
Yield: 17.1 %

Procedure:
5-Phenyl-thiophene-3-carboxylic acid (0.1 g, 0.5 mmol) was dissolved in DMF (3 mL). 1-[1,4]Diazepan-1-yl-ethanone (0.5 mmol), DIPEA (1.5 mmol) and HATU (0.5 mmol) were added and the reaction mixture stirred for 0.5 hours. Ethyl acetate (20 mL) was added and the organic solution was washed with 1 N hydrochloric acid, dried with magnesium sulfate, filtered and the solvent removed by evaporation. The residue was purified by HPLC, eluting with 70%-90% acetonitrile in water (0.1% formic acid) over 30 minutes. The fractions containing the desired product were concentrated under vacuum and freeze-dried to give the title compound (28 mg). LCMS m/z 329.20 [M+H]+ R.T.=8.20 min (Analytical Method 1). 1H NMR (400 MHz, CHCl3-d): δ 7.6 (m, 2H), 7.55-7.3 (m, 5H), 3.9-3.5 (m, 8H), 2.1 (s, 3H), 2.0-1.3.2 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[CH:3]=1.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(=O)([O-])[O-].[Cs+].[Cs+].[F:64][C@@H:65]1[CH2:69][NH:68][C@@H:67]([C:70]2[CH:75]=[CH:74][CH:73]=[C:72]([F:76])[CH:71]=2)[CH2:66]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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:64][C@@H:65]1[CH2:69][N:68]([C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]3[CH:3]=2)[C@@H:67]([C:70]2[CH:75]=[CH:74][CH:73]=[C:72]([F:76])[CH:71]=2)[CH2:66]1
Reactant: Fc1cccc([C@H]2C[C@H](F)CN2)c1
Reactant: CCOC(=O)c1cnn2ccc(Br)cc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn2ccc(N3C[C@@H](F)C[C@@H]3c3cccc(F)c3)cc12
Temperature: 120 °C

Procedure:
A N2 purged flask was charged with ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (27 mg, 0.1 mmol), tris(dibenzylideneacetone)dipalladium(0) (2 mg, 2 μmol), xantphos (5 mg, 8 μmol), cesium carbonate (46 mg, 0.14 mmol), 1,4-dioxane (0.5 mL) and (2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidine (I-6) (18 mg, 0.1 mmol). The contents were heated to 120° C. for 12 hours. Upon cooling to room temperature the reaction was partitioned with EtOAc and water. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered and reduced to dryness. The crude product was purified by column chromatography on silica gel with EtOAc/hexanes gradient as eluant to yield ethyl 5-((2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (X-1). 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1 H), 8.16 (d, J=7.6 Hz, 1 H), 7.31 (td, J=5.6, 7.6 Hz, 1 H), 7.05 (d, J=7.6 Hz, 1 H), 6.98 (d, J=2.8 Hz, 1 H), 6.96-6.91 (m, 2 H), 6.24 (dd, J=2.8, 8.0 Hz, 1 H), 5.39 (d, J=52.8 Hz, 1 H), 5.04 (dd, J=7.2, 9.2 Hz, 1H), 4.34-4.26 (m, 2 H), 4.17-3.90 (m, 2 H), 2.93-2.81 (m, 1 H), 2.11 (dddd, J=3.6, 9.2, 13.2, 40.8 Hz, 1 H). MS m/z 372.1 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:36]([O:43][CH2:44][CH2:45][CH2:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53]Br)=[CH:49][CH:48]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCCC1>[CH2:36]([O:43][CH2:44][CH2:45][CH2:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][C@H:11]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:10][C@@H:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:49][CH:48]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: BrCc1ccc(CCCOCc2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(CCCOCc2ccccc2)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.08 g (3.38 mmol) di-tert-butyl N-(tert-butoxycarbonyl)-L-glutamate in tetrahydrofuran (18 mL) at −78° C., lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (1.0 M in tetrahydrofuran, 6.20 mL) was added dropwise. The solution was stirred for 2 h, then 1-[3-(benzyloxy)propyl]-4-(bromomethyl)benzene (1.01 g, 2.82 mmol) dissolved in 5 mL tetrahydrofuran were added slowly. The reaction was stirred for additional 2 h and then quenched by the addition of 10 mL of 2 N aqueous hydrogen chloride. The mixture was warmed to room temperature poured into 10 mL 1 N aqueous hydrogen chloride and extracted with dichloromethane (3×30 mL). The organic phases were dried over magnesium sulfate and concentrated in vacuo. The crude product was purified on silica gel using a hexane/ethyl acetate gradient, and the appropriate fractions were combined and concentrated.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@:9]2([CH2:17][F:18])[C@@H:15]3[C@@H:13]([CH2:14]3)[O:12][C:11]([NH2:16])=[N:10]2)[C:5]([F:8])=[N:6][CH:7]=1.FC(F)(F)C([NH2:23])=O.C(=O)([O-])[O-].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>C(Cl)Cl.[Cu]I.O1CCOCC1>[NH2:23][C:2]1[CH:3]=[C:4]([C@:9]2([CH2:17][F:18])[C@@H:15]3[C@@H:13]([CH2:14]3)[O:12][C:11]([NH2:16])=[N:10]2)[C:5]([F:8])=[N:6][CH:7]=1
Reactant: NC1=N[C@](CF)(c2cc(Br)cnc2F)[C@H]2C[C@H]2O1
Reactant: NC(=O)C(F)(F)F
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC1=N[C@](CF)(c2cc(N)cnc2F)[C@H]2C[C@H]2O1
Temperature: 120 °C
Yield: 75.2 %

Procedure:
A sealable vial was charged with (1R,5S,6R)-5-(5-bromo-2-fluoropyridin-3-yl)-5-(fluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine (8f-B, 0.1016 g, 0.319 mmol), trifluoroacetamide (0.072 g, 0.639 mmol), copper(I) iodide (0.018 g, 0.096 mmol) and potassium carbonate (0.177 g, 1.278 mmol), followed by dioxane (1.8 mL) and trans-N,N′-dimethylcyclohexane-1,2-diamine (0.015 mL, 0.096 mmol). The reaction mixture was purged with nitrogen for 5 min and then heated at 120° C. for 20 h. The cooled reaction mixture was diluted with CH2Cl2 and washed with aqueous saturated NaHCO3 solution. The layers were separated and the aqueous layer was extracted with 15% MeOH/CH2Cl2. The combined organic extracts were dried over MgSO4 and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography (1% to 10% MeOH/CH2Cl2) afforded the title compound (0.061 g, 0.240 mmol, 75% yield) as a tan amorphous solid. MS (ESI, positive ion) m/z: 255.1 (M+H)
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl(O)(=O)(=O)=O>C(OC(C)=O)(C)(C)C>[C:1]1([CH2:7][C:8]([O:10][C:1]([CH3:7])([CH3:6])[CH3:2])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccccc1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 137.1 %

Procedure:
A solution of 2-phenylacetic acid (12 g, 88 mmol) in tBuOAc (250 mL) in a 1 L round-bottomed flask was treated with perchloric acid, 70% redistilled (0.212 mL, 3.53 mmol), and stirred at room temperature for 20 hours. The solution was transferred very slowly to stirred mixture of saturated aqueous NaHCO3 and Et2O, which resulted in bubbling. The resulting layers were separated and the organic layer washed with saturated aqueous NaHCO3, dried over MgSO4, filtered, and concentrated to give tert-butyl 2-phenylacetate (11.6 g, 68% yield). 1H NMR (500 MHz, chloroform-d) δ 7.34-7.29 (m, 2H), 7.28-7.22 (m, 3H), 3.52 (s, 2H), 1.44 (s, 9H).
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([C:19]([NH:25][C:26]3[CH:30]=[C:29]([CH2:31][C:32](O)=[O:33])[NH:28][N:27]=3)=[N:20][CH:21]=[N:22]2)=[CH:17][CH:16]=1.P(Cl)(Cl)(Cl)=O.CCOCC>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([C:19]([NH:25][C:26]3[CH:30]=[C:29]([CH2:31][C:32]([NH:4][C:3]4[CH:5]=[CH:6][CH:7]=[C:8]([F:9])[C:2]=4[F:1])=[O:33])[NH:28][N:27]=3)=[N:20][CH:21]=[N:22]2)=[CH:17][CH:16]=1
Reactant: Nc1cccc(F)c1F
Reactant: O=C(O)Cc1cc(Nc2ncnc3cc(OCCCCl)ccc23)n[nH]1
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(Cc1cc(Nc2ncnc3cc(OCCCCl)ccc23)n[nH]1)Nc1cccc(F)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
2,3-difluoroaniline (1.15 g, 8.95 mmol) was added to a suspension of (3-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)acetic acid (2.70 g, 7.46 mmol) in pyridine (30 ml) and the reaction cooled to 0° C. Phosphorous oxychloride (1.14 g, 7.46 mmol) was added dropwise and the reaction stirred at 0° C. for 1 hour. The reaction was warmed to ambient temperature and more phosphorous oxychloride (0.5 ml) added. The reaction was stirred for 4.5 hours. The reaction mixture was diluted with ethyl acetate:ether (100 ml: 37 ml) and stirred for 18 hours. The precipitate was filtered, suspended in water and neutralised with ammonium hydroxide (7%, 15 ml). The resultant yellow suspension was filtered, washed with water and dried (phosphorous pentoxide) to yield 2-(3-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)-N-(2,3-difluorophenyl)acetamide as an orange powder (3.15 g, 89% yield):
Reaction SMILES: Cl.O1CCOCC1.[Cl:8][C:9]1[C:10]([C:26]#[N:27])=[N:11][CH:12]=[C:13]([C:15]2[N:19](C3CCCCO3)[N:18]=[CH:17][CH:16]=2)[CH:14]=1>C(O)C>[Cl:8][C:9]1[C:10]([C:26]#[N:27])=[N:11][CH:12]=[C:13]([C:15]2[NH:19][N:18]=[CH:17][CH:16]=2)[CH:14]=1
Reactant: N#Cc1ncc(-c2ccnn2C2CCCCO2)cc1Cl
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: N#Cc1ncc(-c2ccn[nH]2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.1 %

Procedure:
4 M hydrogen chloride in dioxane (1.1 ml, 4.40 mmol) was added to a solution of 3-chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)picolinonitrile (1.1 g, 3.81 mmol) in absolute ethanol (15 ml) and stirred at RT for 3 h. Solvents were evaporated and water was added to the residue. The mixture was neutralised with saturated NaHCO3 and extracted with EtOAc. The organic phase was dried over anhydrous Na2SO4, filtered and evaporated to give 0.796 g of the product. 1H-NMR (400 MHz; d6-DMSO): δ 7.10 (d, 1H), 7.92 (d, 1H), 8.58 (d, 1H), 9.17 (d, 1H), 13.4 (bs, 1H).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2-]C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Pd+2]>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:2]1[O:6][C:5]([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(-c2ccc(Br)o2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: [Pd+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [CH2-]c1ccccc1
Solvent: Cc1ccccc1
Product: N#Cc1cccc(-c2ccc(-c3ccccn3)o2)c1
Temperature: 110 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
Similarly, Pd(PPh3)4 (22 mg, 0.019 mmol) was added to a solution of 3-(5-bromofuran-2-yl)-benzonitrile (35 mg, 0.14 mmol) and 2-tributylstannylpyridine (71 mg, 0.19 mmol) in toluene (2 mL) under argon. In a similar manner, benzylbis(triphenylphosphine)palladium(II) chloride (10.5 mg, 0.014 mmol) was added to a solution of 3-(5-bromofuran-2-yl)-benzonitrile (35 mg, 0.14 mmol) and 2-tributylstannylpyridine (75 mg, 0.20 mmol) in toluene (2 mL) under argon. Both solutions were stirred at 110° C. for 18 h. After cooling to room temperature, the mixtures were combined since TLC of both reactions proved to be identical. The solvent was removed in vacuo from the combined product. Chromatography (5g silica gel SPE tube, dichloromethane) followed by triturating with 10% ethyl acetate in hexanes afforded 26.2 mg (38%) of 3-(5-(2-pyridyl)-2-furyl)-benzonitrile. 1H-NMR (CDCl3), δ (ppm): 8.63 (d, 1H), 8.05 (s, 1H), 7.96 (d, 1H), 7.77 (m, 3H), 7.54 (m, 2H), 7.20 (m, 1H), 6.89 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:21]([C:23]3[O:24][C:25]4[C:30]([C:31](=[O:40])[C:32]=3[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH3:22])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[C:13]([O:19]C)[CH:12]=3)[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:21]([C:23]3[O:24][C:25]4[C:30]([C:31](=[O:40])[C:32]=3[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH3:22])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([OH:19])[CH:12]=3)[C:3]=12
Reactant: COc1ccc(-c2nn(C(C)c3oc4ccccc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2ccc(O)c(O)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 23.4 %

Procedure:
To a solution of example 97 (0.180 g, 0.0.335 mmoles) in dichloromethane (10 ml), BBr3 (1M in dichloromethane, 1.8 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N HCl solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated to afford the title compound as off-white pale solid (0.040 g, 24% yield). MP: 193-195° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 9.27(s,1H), 9.22(s,1H), 8.05(dd, J=7.3,1.4Hz, 1H), 8.03(s,1H), 7.86(m, 1H), 7.68(d, J=8.4Hz, 1H), 7.53(t, J=7.7Hz, 1H), 7.35(s,1H), 7.27(br s, 1H), 7.05-6.86(m,5H), 6.02(q, J=7.0 Hz, 1H),1.87(d, J=7.0Hz, 3H). Mass: 509.84(M).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:11]>>[C:1]1([S:7][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: COc1ccc(C(=O)CBr)cc1
Product: COc1ccc(C(=O)CSc2ccccc2)cc1

Procedure:
Thiophenol and 2-bromo-4'-methoxyacetophenone were converted to the title compound by the procedure of Preparation 1. mp 83° C.-85° C. EA calculated for C15H14O2S: C, 69.74; H, 5.46. Found: C, 69.52; H, 5.48.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:10]2[CH2:21][CH2:20][N:19]3[C:12](=[CH:13][C:14]4[CH2:15][C:16]([CH3:23])([CH3:22])[CH2:17][C:18]=43)[C:11]2=[O:24])[C:7]=1[CH:8]=[O:9].[CH3:25][N:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([NH:41][C:42]2[CH:47]=[CH:46][N:45]=[C:44]([CH3:48])[N:43]=2)[C:27]1=[O:49].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[CH3:22][C:16]1([CH3:23])[CH2:15][C:14]2[CH:13]=[C:12]3[N:19]([CH2:20][CH2:21][N:10]([C:6]4[CH:5]=[N:4][CH:3]=[C:2]([C:30]5[CH:29]=[C:28]([NH:41][C:42]6[CH:47]=[CH:46][N:45]=[C:44]([CH3:48])[N:43]=6)[C:27](=[O:49])[N:26]([CH3:25])[CH:31]=5)[C:7]=4[CH:8]=[O:9])[C:11]3=[O:24])[C:18]=2[CH2:17]1
Reactant: CC1(C)Cc2cc3n(c2C1)CCN(c1cncc(Br)c1C=O)C3=O
Reactant: Cc1nccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: Cc1nccc(Nc2cc(-c3cncc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3C=O)cn(C)c2=O)n1
Temperature: 100 °C
Yield: 53.1 %

Procedure:
A sealed tube was charged with 3-bromo-5-{4,4-dimethyl-9-oxo-1,10-diazatricyclo-[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-pyridine-4-carbaldehyde 107f (210 mg, 0.54 mmol), 1-methyl-3-(pyrimidin-4-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one 213b (177 mg, 0.54 mmol), PdCl2(dppf) (42 mg, 0.050 mmol), K3PO4 (210 mg, 1.0 mmol), and sodium acetate (85 mg, 1.0 mmol), acetonitrile (8 mL), and water (0.5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 4 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 20:1 dichloromethane/methanol to afford 215a (150 mg, 53%). MS-ESI: [M+H]+ 524.2.
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([C@@H:26]([NH2:28])[CH3:27])[CH:23]=[CH:24][CH:25]=1>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([C@@H:26]([NH:28][CH2:16][CH2:15][C:2]2([OH:1])[CH2:14][CH2:13][C:5]3([O:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][O:10]3)[CH2:4][CH2:3]2)[CH3:27])[CH:23]=[CH:24][CH:25]=1
Reactant: COc1cccc([C@H](C)N)c1
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Product: COc1cccc([C@H](C)NCCC2(O)CCC3(CC2)OCC(C)(C)CO3)c1
Yield: 82 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-1-(3-methoxy-phenyl)-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 82% of theory; LC (method 6): tR=1.12 min; Mass spectrum (ESI+): m/z=378 [M+H]+.