Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([N:9]=[C:10]=S)[N:3]=1.C(N(CC)CC)C.Cl.Cl.[NH2:21][CH2:22][C:23]1([OH:31])[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1.C(N=C=NC(C)C)(C)C>CN(C)C=O>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10]2[O:31][C@:23]3([CH2:22][N:21]=2)[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]3)=[N:3][C:2]=1[Cl:1]
Reactant: S=C=Nc1ccc(Cl)c(Cl)n1
Reactant: NCC1(O)CN2CCC1CC2
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Clc1ccc(NC2=NC[C@@]3(CN4CCC3CC4)O2)nc1Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
To 2,3-dichloro-6-isothiocyanatopyridine (0.47 g, 2.29 mmol) in N,N-dimethylformamide (20 mL) was added triethylamine (0.8 mL, 5.7 mmol) and 3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.54 g, 2.34 mmol) at room temperature. The reaction was stirred at 70° C. for 2 hours, cooled to room temperature and concentrated in vacuo. The crude urea was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH). The product was then treated with N,N-dimethylformamide (20 mL) and N,N′-diisopropylcarbodiimide (1.07 mL, 6.88 mmol). The reaction was heated to 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude product was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH) to yield (R)—N-(5,6-dichloropyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.36 g, 1.08 mmol, 47% yield) as a white powder. 1H NMR (500 MHz, DMSO-D6) δ ppm 8.31 (d, J=1.22 Hz, 1H), 7.84 (s, 1H), 6.80 (s, 1H), 3.85 (d, J=10.07 Hz, 1H), 3.57 (d, J=10.38 Hz, 2H), 2.98 (s, 3H), 2.69-2.78 (m, 3H), 2.65 (t, J=7.78 Hz, 3H), 2.00 (s, 2H), 1.86 (s, 2H), 1.58 (dd, J=7.48, 2.90 Hz, 2H), 1.56 (s, 1H), 1.41-1.49 (m, 2H). MS (LC/MS) R.T.=0.81; [M+H]+=327.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[OH:16][CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1>>[F:13][C:12]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[N:19]1[CH2:20][CH2:21][CH:17]([OH:16])[CH2:18]1
Reactant: OC1CCNC1
Reactant: FC(F)(F)c1ccc(Br)c(C(F)(F)F)c1
Product: OC1CCN(c2ccc(C(F)(F)F)cc2C(F)(F)F)C1
Yield: 45 %

Procedure:
The title compound (6.84 g, yield 45%) was obtained from 1-bromo-2,4-bis(trifluoromethyl)benzene and 3-hydroxypyrrolidine by a method similar to that in Reference Example 1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.[OH:13][C@@H:14]([CH3:28])[CH2:15][CH2:16]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCCCCC>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:16][CH2:15][C@@H:14]([OH:13])[CH3:28])[CH:6]=1
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCC[C@H](C)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(OCC[C@H](C)O)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 44.2 %

Procedure:
To a stirring solution of (3-hydroxy-phenyl)-acetic acid methyl ester (0.93 g, 0.0056 mole) and toluene-4-sulfonic acid-(S)-3-hydroxy-butyl ester (1.5 g, 0.0061 mole) (from above) in anhydrous DMF (10 mL) was added Cs2CO3 (2.0 g, 0.006 mole). The reaction was heated to 100° C. and stirred for 4 hours. The mixture was cooled to RT and filtered. The filtrate was poured into H2O (50 mL) and extracted three times with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography over silica gel (silica gel 60, EM Science) using 30% EtOAc:hexane as eluent to afford 0.59 g (44% yield) of the title compound as an oil: MS (ESI) 239.0 (M+H+).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:13]([CH:21]([CH3:23])[CH3:22])[C:14]1[CH:19]=[N:18][CH:17]=[C:16]([Cl:20])[N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.CN([CH:28]=[O:29])C>>[CH2:6]([N:13]([CH:21]([CH3:23])[CH3:22])[C:14]1[N:15]=[C:16]([Cl:20])[C:17]([CH:28]=[O:29])=[N:18][CH:19]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: CC(C)N(Cc1ccccc1)c1cncc(Cl)n1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)N(Cc1ccccc1)c1cnc(C=O)c(Cl)n1
Reaction time: 0.25 h
Yield: 70 %

Procedure:
Phosphoryl chloride (5.6 ml) was added dropwise to DMF (12 mL) at 0° C. The mixture was stirred for 15 min, and a solution of N-benzyl-6-chloro-N-(1-methylethyl)pyrazin-2-amine (3.40 g) in DMF (3 mL) was added dropwise thereto. The mixture was stirred at 100° C. for 13 hr, water (50 mL) was added at 0° C., and the mixture was stirred at room temperature for 1 hr. The mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 5→20% ethyl acetate/hexane) to give the title compound (2.42 g, 70%) as a pale-yellow oil.
Reaction SMILES: C1COCC1.[OH-].[Na+].C([O:15][C:16]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:17])C1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[CH2:29]([O:28][C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[CH:27][C:18]=1[C:16]([OH:17])=[O:15])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(OCc1ccccc1)c1ccc2ccccc2c1OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2ccccc2c1OCc1ccccc1

Procedure:
Method slightly modified, THF (30 mL) instead of MeOH and 5M NaOH (32 mL) were added to the rbf containing compound 1-Benzyloxy-naphthalene-2-carboxylic acid benzyl ester (1.40 g, 3.80 mmol). A condenser was added and the mixture was refluxed for 9 hours. The mixture was diluted with H2O (100 mL) and citric acid (17.70 g, 92.12 mmol) was added to pH-4. Extracted with CH2Cl2 (3×100 mL), washed with H2O (2×150 mL) and saturated NaCl (1×150 mL). NMR showed final product with small percent of starting material. Purification was achieved by recrystallization in hexanes (2×20 mL). Solvent removed under pressure and concentrated in vacuo. Yield: 0.652 g of white crystals (62%). 1H NMR (400 MHz, CDCl3) δ 5.24 (s, 2H), δ 7.43-7.54 (m, 3H), δ 7.61-7.68 (m, 2H), δ 7.75 (d, J=8.7 Hz, 1H), δ 7.93 (dd, J=7.3 Hz, 1 Hz, 1H), δ 8.10 (d, J=8.7 Hz, 1H), δ 8.25 (d, J=7.8 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].N1C=CC=CC=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(Cl)Cl>[C:6]([O:5][C:1]([NH:2][NH:3][C:16](=[O:18])[CH3:17])=[O:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NN
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NNC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl carbazate (1.0 g, 7.6 mmol) and pyridine (3.1 ml) in methylene chloride (5 ml) was slowly added acetic acid anhydride (1.5 ml) and the mixture was stirred overnight. The mixture was added to methylene chloride (50 ml) and washed with water (2×10 ml) and brine (10 ml) and dried (MgSO4), filtered and concentrated in vacuo to give 0.95 g of N'-acetylhydrazinecarboxylic acid tert-butyl ester as a yellow oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([NH2:8])=[O:7])[CH2:2]1.C(Cl)(=O)[C:10](Cl)=[O:11].[NH2:15][C:16]1[N:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:24]=2)=[CH:18][CH:17]=1.O>ClCCCl.C1COCC1>[C:30]([NH:29][C:25]1[CH:24]=[C:23]([O:22][C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:10]([NH:8][C:6]([CH:3]3[CH2:4][CH2:5][O:1][CH2:2]3)=[O:7])=[O:11])=[N:21][CH:20]=2)[CH:28]=[CH:27][N:26]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)Nc1cc(Oc2ccc(N)nc2)ccn1
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)C1CCOC1
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)C3CCOC3)nc2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.2 %

Procedure:
A solution of Example B2 (0.104 g, 0.901 mmol) in DCE (3 mL) was treated with oxalyl chloride (0.079 mL, 0.901 mmol), stirred at RT for 1 h, then heated at 75° C. for 1 h. The mixture was cooled to RT, treated with a solution of Example A2 (0.11 g, 0.450 mmol) and TEA (0.188 mL, 1.351 mmol) in THF (4 mL) and stirred at RT for 1 h. The mixture was treated with water, extracted with 10% MeOH/DCM (1×), then DCM (1×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-((5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)tetrahydrofuran-3-carboxamide (42 mg, 24%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.98 (s, 2H), 10.56 (s, 1H), 8.24 (d, J=2.9 Hz, 1H), 8.18 (d, J=5.7 Hz, 1H), 8.08 (d, J=9.0 Hz, 1H), 7.72 (dd, J=9.0, 2.9 Hz, 1H), 7.64 (d, J=2.4 Hz, 1H), 6.69 (dd, J=5.7, 2.4 Hz, 1H), 3.87 (t, J=8.3 Hz, 1H), 3.76-3.75 (m, 2H), 3.67-3.66 (m, 1H), 3.28-3.26 (m, 1H), 2.08-2.06 (m, 2H), 2.03 (s, 3H); MS (ESI) m/z: 386.2 (M+H+).
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH:8]1[CH2:12][CH2:11][O:10][CH2:9]1.Br[CH2:14][C:15]1[C:16]([Cl:28])=[C:17]([CH:21]=[CH:22][C:23]=1[S:24]([CH3:27])(=[O:26])=[O:25])[C:18]([OH:20])=[O:19].Cl>CN(C=O)C>[Cl:28][C:16]1[C:15]([CH2:14][O:7][CH:8]2[CH2:12][CH2:11][O:10][CH2:9]2)=[C:23]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1CBr
Reactant: OC1CCOC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1COC1CCOC1
Temperature: -15 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
At 0° C., 25 ml of DMF and 3.25 g (28 mmol) of potassium tert-butoxide were initially charged and mixed with 2.5 g (27.5 mmol) of 3-hydroxytetrahydrofuran. The solution was cooled to −15° C., and 4.7 g (140 mmol) of 3-bromomethyl-2-chloro-4-methylsulfonylbenzoic acid were added. The mixture was then stirred at 15-20° C. for one hour. The reaction was poured into 45 g of ice/water, acidified with 2N HCl and extracted with EA. The organic phases were dried with MgSO4, filtered and concentrated. This gave 5.41 g of a viscous oil of a purity of about 66% according to HPLC. Yield about 60%
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:18][CH3:19])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][C:7]2=[O:17].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.[CH3:66][N:67]1[CH2:73][CH2:72][CH2:71][NH:70][CH2:69][CH2:68]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH2:15]([O:14][C:12]([C:9]1[O:10][C:11]2[C:6]([C:7](=[O:17])[CH:8]=1)=[CH:5][C:4]([O:18][CH3:19])=[CH:3][C:2]=2[N:70]1[CH2:71][CH2:72][CH2:73][N:67]([CH3:66])[CH2:68][CH2:69]1)=[O:13])[CH3:16]
Reactant: CCOC(=O)c1cc(=O)c2cc(OC)cc(Br)c2o1
Reactant: CN1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(=O)c2cc(OC)cc(N3CCCN(C)CC3)c2o1
Temperature: 80 °C
Yield: 60 %

Procedure:
Into a 250 mL 3 neck round bottom flask equipped with a reflux condenser, nitrogen inlet and magnetic stirrer is placed 1.5 g (4.59 mmol, 1.0 equiv.) of 8-Bromo-6-methoxy-4-oxo-4H-chromene-2-carboxylic acid ethyl ester (Reference Example 2c), 84 mg (0.092 mmol, 0.02 equiv.) of tris dibenzylidineacetone dipalladium, 342 mg (0.55 mmol, 0.12 equiv.) of racemic 2,2′-bis(diphenylphosphino)-1,1′-binapthyl and 2 g of 4 A molecular sieves. To this in suspension is added 150 mL of dry toluene. To the stirred suspension is then added 628 mg, 684 μL, (5.50 mmol, 1.2 equiv.) of 1-methylhomopiperazine, followed by 2.05 g (6.3 mmol, 1.4 equiv.) of cesium carbonate. The mixture is then heated to 80° C. for 3 days. At the end of this time completion was monitored by LC/MS analysis of an aliquot. When the reaction was determined to be complete it was cooled to room temperature then filtered through a plug of diatomaceous earth with toluene washing to remove solid by products. Purification by flash chromatography, using a gradient of 5 to 20% methanol in methylene chloride as eluent, yielded 1.0 g, (60%) of the desired product.
Reaction SMILES: I[C:2]([C@@H:4]([C@H:6]([C@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[OH:5])=O.[C-:14]#[N:15].[Na+]>CN(C=O)C>[CH2-:2][C:4]([CH3:6])=[O:5].[CH2-:2][C:4]([CH3:6])=[O:5].[C:14]([CH2:2][C@H:4]([OH:5])[C@@H:6]([OH:7])[C@@H:8]([OH:9])[C@H:10]([OH:11])[CH:12]=[O:13])#[N:15]
Reactant: O=C(I)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O
Product: [CH2-]C(C)=O

Procedure:
Compound 27 was prepared following a procedure by Streicher and Wunsch (Carbohydr. Res. 338(22): 2375-85 (2003)). Referring to Scheme 7, iodo-galactose (120 mg, 0.32 mmol) and NaCN (51 mg, 1 M) were heated to 110° C. in DMF for 12 h. The mixture was cooled, partitioned with CH2Cl2-water and the layers separated. The aqueous layer was further washed with CH2Cl2 (2×) and the combined organics washed with brine, dried (Na2SO4), filtered and concentrated to a brown oil. FCC purification (9:1 to 4:1 hexanes-EtOAc gradient) led to the pure product. Yield: 10 mg (12%). 1H-NMR (CDCl3) δ: 1.33 (s, 3H), 1.35 (s, 3H), 1.45 (s, 3H), 1.54 (s, 3H), 2.65 (dd, J =6.8 Hz, 16 Hz, 1H), 2.70 (dd, J=6.8 Hz, 16 Hz, 1H), 4.05 (dt, J=2.0 Hz, 7.2 Hz, 1H), 4.24 (dd, J=2.0 Hz, 8.0 Hz, 1H), 4.34 (dd, J=2.8 Hz, 4.8 Hz, 1H), 4.65 (dd, J=2.8 Hz, 8.0 Hz, 1H), 5.50 (d, J=5.2 Hz).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][SH:18])=[CH:15][CH:14]=1.[H-].[Na+]>CN(C)C=O>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][S:18][C:2]2[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: O=C(O)c1cnccc1Cl
Reactant: COc1ccc(CS)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CSc2ccncc2C(=O)O)cc1
Temperature: 0 °C

Procedure:
A stirred and ice-cooled mixture of 788 mg (0.005 mole) 4-chloronicotinic acid [prepared by the process set forth in W. C. J. Ross, J. Chem. Soc. (C), 1816 (1966)]and 771 mg (0.005 mole) of 4-methoxybenzylmercaptan in 6 mL of dry N,N-dimethylformamide was treated with 480 mg (0.012 mole) of 60% sodium hydride dispersion. The reaction was stirred at room temperature for 4 hours during which a thick solid formed, which was taken up in 75 mL of ice water. After extraction with 25 mL of hexane, the aqueous layer was acidified with 2.5N hydrochloric acid to precipitate 4-(4-methoxybenzylthio)--nicotinic acid; yield 1.2 g (89% of theory), m.p. 230° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:54]1[CH:59]=[CH:58][C:57]([CH2:60][CH2:61]O)=[CH:56][CH:55]=1>C(Cl)Cl>[ClH:13].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:61][CH2:60][C:57]4[CH:58]=[CH:59][N:54]=[CH:55][CH:56]=4)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: OCCc1ccncc1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCc1ccncc1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
Diethyl azodicarboxylate (315 μl, 2 mmol) was added dropwise to a solution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (319.5 mg, 1 mmol), (prepared as described for the starting material in Example 24), triphenylphosphine (524 mg, 2 mmol) and 2-(4-pyridyl)ethanol (160 mg, 1.25 mmol), (Zhur. Obshchei. Khim. 1958, 28, 103-110), in methylene chloride (7 ml). The mixture was stirred for 1 hour at ambient temperature and the solvent was removed by evaporation. The residue was triturated with ether, the solid collected by filtration and purified by column chromatography eluting with methylene chloride/acetonitrile/methanol (85/10/5). The purified solid product was dissolved in a mixture of methylene chloride (50 ml) and methanol (50 ml) and 5M hydrochloric acid in isopropanol (0.5 ml) was added. After diluting with isopropanol (20 ml), the mixture was concentrated by evaporation. The precipitated solid was collected by filtration and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(4-pyridyl)ethoxy)quinazoline hydrochloride (125 mg, 25%).
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:7]=[N:6][CH:5]=1.[Li+].[OH-]>CO.C1COCC1.CCOC(C)=O>[Cl:20][C:16]1[CH:15]=[C:14]2[C:19]([C:11]([S:10][C:8]3[CH:7]=[N:6][CH:5]=[C:4]([CH:9]=3)[C:3]([OH:22])=[O:2])=[C:12]([CH3:21])[NH:13]2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1cncc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1[nH]c2cc(Cl)ccc2c1Sc1cncc(C(=O)O)c1
Temperature: 50 °C

Procedure:
5-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-nicotinic acid methyl ester (0.050 g, 0.15 mmol) was dissolved in MeOH:THF (1:1, 4 mL) and LiOH (1 M aq., 1 mL) was added. The reaction was heated to 50° C. for 3.5 hours then cooled. The reaction was acidified with HCL (1 M aq., 1 mL), diluted with EtOAc, dried over MgSO4, then filtered and concentrated to supply the title compound. Mass spectrometric data: [M+H]+=319.
Reaction SMILES: [Cl:1][CH:2]([SiH:4]([CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:5])[CH3:3].C1(=O)[NH:19]C(=O)C2=CC=CC=C12.[K]>>[ClH:1].[CH2:8]([CH2:7][CH2:6][SiH:4]([CH3:5])[CH:2]([NH2:19])[CH3:3])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(Cl)[SiH](C)CCCc1ccccc1
Agent: [K]
Product: CC(N)[SiH](C)CCCc1ccccc1
Product: Cl

Procedure:
The title compound was prepared from (α-chloroethyl)benzylethylmethylsilane and potassium phthalimide by a procedure similar to the one described in Example 1, Step A.
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]([CH2:10]Br)[C:6]([NH2:9])=[N:7][CH:8]=1.Cl.[CH3:13][O:14][C:15](=[O:21])[C@H:16]1[CH2:20][CH2:19][CH2:18][NH:17]1.C(N(CC)CC)C>CC#N.O>[CH3:13][O:14][C:15]([C@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[CH2:10][C:5]1[C:6]([NH2:9])=[N:7][CH:8]=[C:3]([Br:2])[CH:4]=1)=[O:21]
Reactant: Nc1ncc(Br)cc1CBr
Reactant: COC(=O)[C@H]1CCCN1
Agent: Br
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CCCN1Cc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.3 %

Procedure:
A suspension of 5-bromo-3-bromomethyl-pyridin-2-ylamine hydrobromide (8.00 g, 23.1 mmol) and D-proline methyl ester hydrochloride (4.53 g, 27.4 mmol) in CH3CN (100 mL) was treated with a solution of triethylamine (10.4 mL, 74.0 mmol) in CH3CN (100 mL). After stirring at room temperature for 5 h, the cloudy mixture was diluted with H2O (300 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 99:1 to 98:2) gave the title compound (6.55 g, 90%) as a colorless oil: MS (ESI) m/e 314 (M+H)+
Reaction SMILES: IC.[Br:3][C:4]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[C:8]([F:18])[C:7]([OH:19])=[C:6]([CH:20]=[O:21])[CH:5]=1.[C:22](=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:3][C:4]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[C:8]([F:18])[C:7]([O:19][CH3:22])=[C:6]([CH:20]=[O:21])[CH:5]=1
Reactant: O=Cc1cc(Br)c(-c2ccc(F)cc2F)c(F)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C=O)cc(Br)c(-c2ccc(F)cc2F)c1F
Yield: 93.2 %

Procedure:
Iodomethane (0.907 g) was added at room temperature to a mixture of 6-bromo-2,2′,4′-trifluoro-3-hydroxybiphenyl-4-carbaldehyde (1.41 g), potassium carbonate (1.18 g), and DMF (20 mL), and the resultant mixture was stirred at 60° C. for 3 hours in a nitrogen atmosphere. Water was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.37 g).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]([N+:15]([O-])=O)=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])[C:6]=1[F:27])[CH:2]=[CH2:3].[Cl-].[NH4+].O>CO.O1CCOCC1.[Fe]>[CH2:1]([NH:4][C:5]1[C:14]([NH2:15])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])[C:6]=1[F:27])[CH:2]=[CH2:3]
Reactant: C=CCNc1c([N+](=O)[O-])cc(C(=O)OC)c(Nc2ccc(I)cc2F)c1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: C=CCNc1c(N)cc(C(=O)OC)c(Nc2ccc(I)cc2F)c1F

Procedure:
A suspension of methyl 4-(allylamino)-3-fluoro-2-(2-fluoro-4-iodophenylamino)-5-nitrobenzoate and ammonium chloride (4.42 g, 79 mmoles) in a mixture of MeOH (20 ml) and dioxane (20 ml) is heated until it became a clear solution. Iron powder (4.42 g, 79 mmoles) is added and the resulting mixture is heated under reflux overnight. Water is added and the reaction mixture is filtered through celite. The solvent is removed under reduced pressure and the crude material is purified by flash chromatography to give the title compound.
Reaction SMILES: [Br-:1].[CH:2]1([C:8]([OH:34])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]([O:11][CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][N+:14]2([CH:19](C2C=CON=2)[C:20](=[O:22])[NH2:21])[CH3:18])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Br-].OC[C@H]1CCC[N+]1(CC(=O)N[C:47]1[CH:51]=[CH:50][O:49][N:48]=1)C.[Br-].O[C@@H]1CCC[N+](CC(=O)NC2C=CON=2)(C)C1>>[Br-:1].[CH:2]1([C:8]([OH:34])([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:9]([O:11][CH:12]2[CH2:13][CH2:17][CH2:16][CH2:15][N+:14]2([CH2:19][C:20](=[O:22])[NH:21][C:47]2[CH:51]=[CH:50][O:49][N:48]=2)[CH3:18])=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: C[N+]1(C(C(N)=O)c2ccon2)CCCC1COC(=O)C(O)(c1ccccc1)C1CCCCC1
Reactant: C[N+]1(CC(=O)Nc2ccon2)CCC[C@@H]1CO
Agent: C[N+]1(CC(=O)Nc2ccon2)CCC[C@@H](O)C1
Agent: [Br-]
Product: C[N+]1(CC(=O)Nc2ccon2)CCCCC1OC(=O)C(O)(c1ccccc1)C1CCCCC1

Procedure:
This compound is prepared by an analogous method to (1R/S,2R)-2-((R/S)-(2-Cyclohexyl-2-hydroxy-2-phenyl-acetoxymethyl)-1-(isoxazol-3-yl carbamoylmethyl)-1-methyl-pyrrolidinium bromide (Example 1) by replacing (1R/S,2R)-2-hydroxymethyl-1-(isoxazol-3-ylcarbamoyl-methyl)-1-methyl-pyrrolidinium bromide (Intermediate B) with (1R/S,2R)-3-Hydroxy-1-(isoxazol-3-ylcarbamoylmethyl)-1-methyl-piperidinium bromide (Intermediate C).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([CH3:24])([CH3:23])[C:19]([NH:21][CH3:22])=[O:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:39]2[CH:40]=[N:41][C:42]([NH2:45])=[N:43][CH:44]=2)O1>>[NH2:45][C:42]1[N:43]=[CH:44][C:39]([C:2]2[N:3]=[C:4]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18]([CH3:24])([CH3:23])[C:19]([NH:21][CH3:22])=[O:20])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:40][N:41]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CNC(=O)C(C)(C)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CNC(=O)C(C)(C)N1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-[4-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazin-1-yl]-N-methyl-isobutyramide (Example 88) was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine in General Procedure A. Purification on silica yielded 173. NMR 400 MHz (CDCl3): 2.56 (6H, b, CH3), 2.80 (3H, d(J=4.93), CH3), 3.83 (2H, s, CH2), 3.88 (4H, m, CH2), 4.03 (4H, m, CH2), 5.19 (2H, s, NH), 7.26 (1H, s, ar), 9.28 (2H, s, ar). MH+ 512.37