Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14](/[CH:17]=[CH:18]/[C:19](O)=[O:20])=[N:15][CH:16]=3)=[C:8]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[S:7][C:6]=2[CH:29]=1.[CH3:30][N:31](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CN.CN1CCOCC1>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14](/[CH:17]=[CH:18]/[C:19]([NH:31][CH3:30])=[O:20])=[N:15][CH:16]=3)=[C:8]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[S:7][C:6]=2[CH:29]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)/C=C/c1ccc(Oc2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cn1
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CNC(=O)/C=C/c1ccc(Oc2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 35.7 %

Procedure:
To a solution of (E)-3-(5-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)acrylic acid (0.057 g, 0.14 mmol) in DMF (1.406 mL) was added HATU (0.064 g, 0.17 mmol), methylamine hydrochloride (10.45 mg, 0.16 mmol) and NMM (0.077 mL, 0.70 mmol). The resulting mixture was stirred at room temperature for 48 h after which time the reaction was quenched with sat. aq. NH4Cl and extracted with EtOAc (3×). The combined organic layers were passed through a phase separator and concentrated in vacuo to afford the crude product which was purified by reverse phase HPLC (acidic condition, 3% TFA in 10-100% CH3CN/H2O) to afford (E)-3-(5-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)-N-methylacrylamide (30 mg, 0.05 mmol, 37% yield). 1H NMR (400 MHz, (CD3)2SO) δ ppm=2.67-2.72 (m, 3H), 6.77-6.90 (m, 4H), 7.14-7.23 (m, 2H), 7.30 (d, J=2.02 Hz, 1H), 7.36 (d, J=15.16 Hz, 1H), 7.44-7.51 (m, 3H), 8.42 (d, J=3.03 Hz, 1H). LC/MS (m/z, MH+): 419.3.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][OH:7].O.C(=O)([O-])O.[Na+].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C(OCC)(=O)C>[OH:7][CH2:6][C@H:2]1[CH2:3][CH2:4][CH2:5][N:1]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]
Reactant: OC[C@H]1CCCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC[C@@H]1CO

Procedure:
2 g (0.0198 mol) of (2R)-pyrrolidin-2-ylmethanol was dissolved in 20 mL of ethyl acetate, 20 mL of water was added thereto, and the mixture was stirred. 3.3 g (0.30 mol) of sodium hydrogencarbonate was added to the mixture, followed by stirring of the mixture for 5 minutes. 4.24 mL (0.03 mol) of benzyl chloroformate was added dropwise to the mixture, followed by stirring for 5 hours. After the ethyl acetate layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to quantitatively obtain the title compound.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][N:7]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]1=[O:23].Br[CH2:25][C:26]#[N:27].C(N(CC)CC)C>CN(C)C=O.O>[C:26]([CH2:25][N:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][N:7]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]1=[O:23])#[N:27]
Reactant: O=C1Nc2ccccc2C(c2ccccc2)N1CC1CCCN1
Reactant: N#CCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: N#CCN1CCCC1CN1C(=O)Nc2ccccc2C1c1ccccc1
Yield: 98.5 %

Procedure:
A solution of 203 mg (0.66 mmol) of 3-(pyrrolidin-2-yl)methyl-4-phenyl-3,4-dihydro-2(1H)-quinazolinone, 95 mg (0.79 mmol) of bromoacetonitrile and 283 mg (2.8 mmol) of triethylamine in 5 mL of dimethyl-formamide was stirred for 6 hours at 70° C. After being cooled, the reaction mixture was diluted with water, and the mixture was extracted with chloroform. The organic layer separated was washed with water, dried on potassium carbonate and concentrated in vacuo. The residue was purified by means of column chromatography (silica gel, 1:9 methanol:chloroform) to give 226 mg (0.65 mmol) of the title compound as an about 1:2 mixture of the diastereomers.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[F:15][C:16]([F:31])([F:30])[C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:20](Cl)=[O:21].[NH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33]1>>[F:15][C:16]([F:31])([F:30])[C:17]1[CH:18]=[C:19]([C:20]([N:6]2[CH:7]([C:34]3[C:35]4[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=4)[NH:32][CH:33]=3)[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[O:21])[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: c1ccc2c(c1)cnc1ccccc12
Reactant: c1ccc2[nH]ccc2c1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1c2ccccc2-c2ccccc2C1c1c[nH]c2ccccc12

Procedure:
(3,5-Bis-trifluoromethyl-phenyl)-[6-(1H-indol-3-yl)-6H-phenanthridin-5-yl]-methanone was prepared from phenanthridine, 3,5-bis(trifluoromethyl)benzoyl chloride, and indole according to GP 2. Yield, 8%. 1H-NMR (CD3OD): δ=6.22 (d, J=0.8 Hz, 1H), 6.29 (s, br., 1H), 6.79 (t, J=7.5 Hz, 1H), 7.05-7.14 (m, 2H), 7.16-7.27 (m, 2H), 7.37 (s, br., 1H), 7.42-7.52 (m, 2H), 7.58 (“t”, J≈7.3 Hz, 1H), 7.77 (s, br., 2H), 7.96 (s, br., 1H), 7.99 (dd, J=7.8 Hz, J=1.2 Hz, 2H), 8.12 (d, J=7.9 Hz, 1H); (+)-ESI-MS: m/z=537 [M+H]+, 420 [M-indole+H]+; (−)-ESI-MS: m/z=535 (M−H)−.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([NH:14][CH2:15][CH:16]=[CH2:17])[CH:12]=[CH2:13].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:14]([CH2:15][CH:16]=[CH2:17])[CH2:11][CH:12]=[CH2:13])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C=CCNCC=C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCN(CC=C)c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 59.5 %

Procedure:
A mixture of 4-fluoronitrobenzene (5.00 g, 35.44 mmol), diallylamine (3.48 g, 4.4 ml, 35.44 mmol) and K2CO3 (5.39 g, 38.98 mmol) in dry DMSO (40 ml) was heated at 100° C. under an atmosphere of argon for 3 h. The reaction mixture was then left to cool to room temperature (23° C.) and added to water (300 ml) and extracted with EtOAc (4×75 ml). The combined organics were washed with brine (100 ml) and dried (Na2SO4). The solvent was removed under reduced pressure to give a red oil that was purified by chromatography (2:1 Hexane/DCM) to give the title compound (4.60 g, 59%) as an orange oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:17]2[S:21][C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:18]=2)[CH:6]=[CH:7][C:8]=1OS(C(F)(F)F)(=O)=O)#[N:2].C(=O)([O-])[O-].[K+].[K+].O.[NH2:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=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.C1(C)C=CC=CC=1>[NH2:33][C:34]1[CH:39]=[C:38]([C:8]2[CH:7]=[CH:6][C:5]([C:17]3[S:21][C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:18]=3)=[CH:4][C:3]=2[C:1]#[N:2])[CH:37]=[CH:36][CH:35]=1
Reactant: COC(=O)c1ccc(-c2ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c2)s1
Reactant: Nc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc(-c3cccc(N)c3)c(C#N)c2)s1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A toluene (0.5 ml) suspension of 20 mg of methyl 5-(3-cyano-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)thiophene-2-carboxylate and 10 mg of potassium carbonate was added to 15 mg of 3-aminobenzeneboronic acid monohydrate, and in an argon atmosphere, 8 mg of tetrakis(triphenylphosphine)palladium was added thereto. The mixture was stirred overnight at 100° C., then cooled to room temperature, and filtered through Celite. The solvent was evaporated under reduced pressure to obtain methyl 5-(3′-amino-2-cyanobiphenyl-4-yl)thiophene-2-carboxylate.
Reaction SMILES: C(N)C=C.[CH2:5]([N:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:21])C1=S)[CH:6]=[CH2:7]>ClCCl>[CH2:5]([NH:8][CH2:13][CH2:12][CH2:11][NH:10][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21])[CH:6]=[CH2:7]
Reactant: C=CCN1CCCN(c2c(C)cccc2Cl)C1=S
Solvent: C=CCN
Solvent: ClCCl
Product: C=CCNCCCNc1c(C)cccc1Cl
Yield: 68.4 %

Procedure:
A mixture of allylamine (20 mL) and the hydrobromide salt of Step B (8.6 g) was heated at 100° C. under nitrogen for 30 minutes. The reaction mixture was cooled and partitioned between dichoromethane and 1N sodium hydroxide. The aqueous layer was extracted with dichloromethane, and the combined organic layers were dried over sodium sulfate and concentrated in vacuo to give a yellow oil. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with 1:1 ethyl acetate-hexane followed by 80:20 dichloromethane-methanol containing 0.2% ammonium hydroxide gave the title compound (5.0 g, 83.8%) as a yellow oil which was used as such in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.[NH2:10][NH2:11].O.ClC(Cl)(O[C:17](=[O:23])OC(Cl)(Cl)Cl)Cl>C1COCC1>[NH2:1][C:2]1[C:7]2[N:6]([C:17](=[O:23])[NH:10][N:11]=2)[CH:5]=[N:4][C:3]=1[Cl:9]
Reactant: NN
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1c(Cl)ncnc1Cl
Solvent: C1CCOC1
Solvent: O
Product: Nc1c(Cl)ncn2c(=O)[nH]nc12
Temperature: 25 °C
Reaction time: 50 h
Yield: 76 %

Procedure:
To a solution of 5-amino-4,6-dichloropyrimidine (1.64 g, 10 mmol) in THF (10 mL) at room temperature under argon was added H2NNH2 (0.96 g mg, 30 mmol). The resulting reaction mixture was stirred at room temperature under argon for 50 h. HPLC analysis indicated disappearance of the starting material. Water (100 mL) was added to the reaction mixture. The solid precipitate was collected by filtration and was washed with water (10 mL×3). The resulting solid was dissolved in a mixture of 20 mL of 1 M aqueous HCl and 10 mL of 1,4-dioxane. Triphosgene (7.6 g, 25.7 mmol) was then added. After the reaction mixture had stirred at room temperature under argon for 3 h, analysis by HPLC/MS indicated that the reaction was complete. Water (50 mL) was added to the reaction mixture. The solid precipitate was collected by filtration and was washed with water (5 mL×3). After the resulting solid was dried under vacuum, the title compound (1.41 g) was obtained as a tan solid. HPLC/MS: retention time=0.93 min, [M+H]30 =186. See also C. Temple, Jr., et al., J. Org. Chem., volume 33, pp. 530-533, 1968.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14][S:15][CH3:16])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[F:17][C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1.C(N=C=NC(C)C)(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:7][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14][S:15][CH3:16])([CH3:1])[CH2:3][C:4]([O:6][C:21]1[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=1)=[O:5]
Reactant: Oc1ccc(F)cc1
Reactant: CSSc1ccccc1C(C)(C)CC(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CSSc1ccccc1C(C)(C)CC(=O)Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a mixture of 3-methyl-3-(2-methyldisulfanylphenyl)butanoic acid, 4-fluorophenol (1.1 eq) and 4-(N,N-dimethylamino)pyridine (0.5 eq) in CH2Cl2 was added diisopropylcarbodiimide (1.5-2.0 eq) at 0° C. The mixture was stirred overnight at ambient temperature. The precipitate was filtered off and the filtrate concentrated by rotary evaporation. The crude product was purified on a silica gel column to afford 4-fluorophenyl 3-methyl-3-(2-methyldisulfanylphenyl)butanoate as a colorless oil in 62% yield: 1H NMR (CDCl3, 300 MHz) δ (ppm): 1.76 (s, 6H), 2.52 (s, 3H), 3.44 (s, 2H), 6.70 (dd, J=9.0, 4.2 Hz, 2H), 7.00 (t, J=9.0 Hz, 2H), 7.2-7.3 (m, 2H), 7.36 (dd, J=7.8, 1.5 Hz, 1H), 7.96 (dd, J=7.8, 1.2 Hz, 1H). 19F NMR (CD3CN, 282 MHz) δ (ppm): −119.2.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20].CCN(CC)CC>C(Cl)Cl>[C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C@H:8]1[CH2:9][CH2:10][C@H:11]([CH2:14][O:15][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:12][CH2:13]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@H]1CC[C@H](CO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[SiH2]OC(C)(C)[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of 27.6 g (107 mmol) of trans-[4-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohexyl]-methanol and 9.99 mL (128 mmol, 1.2 eq) of methanesulfonyl chloride in 350 mL of CH2Cl2 were added under stirring 29.6 mL (213 mmol, 2 eq) of Et3N within 20 min keeping the temperature at 0-10° C. The reaction mixture was stirred at RT for 1 h. It was then partitioned between CH2Cl2, 1M HCl and water. The CH2Cl2-phase was dried over MgSO4 and concentrated to yield 38.2 g of crude trans-methanesulfonic acid 4-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohexylmethyl ester as colorless viscous oil, MS: 354 (M+NH4+).
Reaction SMILES: [CH3:1][I:2].[Cl:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[CH3:14])=[CH:6][CH:5]=1>CC(C)=O>[I-:2].[Cl:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][CH:9]2[CH2:13][CH2:12][CH2:11][N+:10]2([CH3:1])[CH3:14])=[CH:6][CH:5]=1
Reactant: CN1CCCC1Cc1ccc(Cl)cc1
Reactant: CI
Solvent: CC(C)=O
Product: C[N+]1(C)CCCC1Cc1ccc(Cl)cc1
Product: [I-]

Procedure:
Add 3.72 g of methyl iodide dropwise, with stirring, to 5.5 g of 2-(4-chlorobenzyl)-1-methylpyrrolidine in 40 ml of acetone. Filter off the formed crystalline precipitate and recrystallize it twice from methanol/diethyl ether to obtain 6.9 g (75% of theory) of the title compound (m.p. 184° to 186°).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]([CH2:26][CH3:27])[N:19]=[C:20]3[CH:25]=[CH:24][CH:23]=[N:22][C:21]=23)=[CH:13][CH:12]=1.IC.[C:30](=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O>[CH2:26]([N:18]1[C:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][C:2]3[N:1]([CH3:30])[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)=[CH:12][CH:13]=2)=[C:21]2[N:22]=[CH:23][CH:24]=[CH:25][C:20]2=[N:19]1)[CH3:27]
Reactant: O=C([O-])[O-]
Reactant: CCn1nc2cccnc2c1-c1ccc(Oc2nc3ccccc3[nH]2)cc1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc2cccnc2c1-c1ccc(Oc2nc3ccccc3n2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
A mixture of 3-[4-(1H-benzimidazol-2-yloxy)phenyl]-2-ethyl-2H-pyrazolo[4,3-b]pyridine (25 mg) obtained in Example 3, iodomethane (5.72 μl), cesium carbonate (34.4 mg) and DMF (1 ml) was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and recrystallized from ethyl acetate/hexane to give the title compound (24.0 mg).
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19](O)[CH:20]2[CH2:22][CH:21]2[C:23]#[N:24])=[C:15]([O:26][CH3:27])[CH:14]=1.[CH3:28][S:29]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:41]=1[NH:40][CH:39]=[CH:38]2)(=[O:31])=[O:30].[Cl-].[NH4+]>ClCCCl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:38]2[C:37]3[C:41](=[C:33]([CH2:32][S:29]([CH3:28])(=[O:31])=[O:30])[CH:34]=[CH:35][CH:36]=3)[NH:40][CH:39]=2)[CH:20]2[CH2:22][CH:21]2[C:23]#[N:24])=[C:15]([O:26][CH3:27])[CH:14]=1
Reactant: COc1cc(Cl)ccc1C(O)C1CC1C#N
Reactant: CS(=O)(=O)Cc1cccc2cc[nH]c12
Agent: [Cl-]
Agent: [In+3]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: COc1cc(Cl)ccc1C(c1c[nH]c2c(CS(C)(=O)=O)cccc12)C1CC1C#N

Procedure:
104 mg (0.47 mmol) of indium(III) chloride and 0.05 ml (0.70 mmol) of trifluoroacetic acid were added to 93.0 mg (0.39 mmol) of the compound from Example 163A and 112 mg (0.47 mmol) of the compound from Example 86A with a purity of 88% under argon in 5 ml of 1,2-dichloroethane, and the mixture was heated under reflux for 2 h. Addition of the reaction mixture to saturated aqueous ammonium chloride solution was followed by extraction with dichloromethane, drying over magnesium sulfate, filtration and concentration. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 30.5 mg (18% of theory) of diastereomer 1 and 28.0 mg (17% of theory) of diastereomer 2 of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:11]([CH:12]3[CH2:15][NH:14][CH2:13]3)[N:10]=[C:9]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:8]=2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1.[NH:52]1[CH:56]=[CH:55][N:54]=[C:53]1[C:57](O)=[O:58]>CN(C=O)C.CCOCC>[F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:11]([CH:12]3[CH2:13][N:14]([C:57]([C:53]4[NH:52][CH:56]=[CH:55][N:54]=4)=[O:58])[CH2:15]3)[N:10]=[C:9]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:8]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Cc2cc(-c3ccncc3)nn2C2CNC2)cc1
Reactant: O=C(O)c1ncc[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCOCC
Product: O=C(c1ncc[nH]1)N1CC(n2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 4-(5-(4-fluorobenzyl)-1-(azetidin-3-yl)-1H-pyrazol-3-yl)pyridine (85 mg, 0.28 mmol) in DMF (3 mL) was added HOBt (45 mg, 0.33 mmol), EDCI (64 mg, 0.33 mmol), NMM (76 μL, 0.69 mmol) followed by imidazole-2-carboxylic acid (34 mg, 0.30 mmol) and the mixture stirred for 16 hours at room temperature. The volatiles were removed in vacuo and the residue purified directly by Biotage flash chromatography, eluting with 2-6% MeOH/DCM to yield a clear gum. Ether was added (5 mL) and the mix sonicated to give a white precipitate that was filtered off, washed with ether and dried in-vacuo to yield the title compound as a white solid, 78 mg, 70%. 1H NMR (400 MHz, DMSO-D6) δ ppm 13.04-13.12 (m, 1 H), 8.54 (d, 2 H), 7.74 (d, 2 H), 7.25-7.32 (m, 2 H), 7.18 (t, 2 H), 7.03-7.12 (m, 1 H), 6.66 (s, 1 H), 5.33-5.46 (m, 1 H), 4.77-4.92 (m, 2 H), 4.26-4.36 (m, 2 H), 4.12 (s, 2 H); m/z (APCI+) for C22H19N6FO 403.1 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][C@H:12]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH:13]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(OP([CH2:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])(OCC)=O)C.[H-].[Na+]>C1C=CC=CC=1.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][C@H:12]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])/[CH:13]=[CH:28]/[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOP(=O)(CC(=O)OCc1ccccc1)OCC
Reactant: CC(C)CC[C@H](C=O)CCCO[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC(C)CC[C@H](/C=C/C(=O)OCc1ccccc1)CCCO[Si](C)(C)C(C)(C)C

Procedure:
A solution of Example 8H (2.61 g, 9.16 mmol), benzyl diethylphosphonoacetate (2.83 g, 9.90 mmol), and sodium hydride (0.24 g, 10 mmol) in benzene (40 mL) at room temperature was stirred 2 hours, diluted with ethyl acetate, washed sequentially with saturated aqueous NH4Cl and pH 7 buffer, dried (MgSO4), filtered, and concentrated. Flash column chromatography (silica gel, 2:1 hexanes/CH2Cl2) provided the desired product. MS (ESI) m/e 419 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][NH:7][C:6]2=O.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2ncnc(Cl)c2cc1OC

Procedure:
The key starting material, 4-chloro-6,7-dimethoxyquinazoline, was prepared according to published procedures (Nomoto, et al., 1990, Chem. Pharm. Bull., 38:1591-1595; Thomas, C. L., 1970, IN:Catalytic Processes and Proven Catalysts, Academic Press, New York, N.Y.) as outlined below in Scheme 1. Specifically, 4,5-dimethoxy-2-nitrobenzoic acid (compound 1) was treated with thionyl chloride to form acid chloride, followed by reacting with ammonia to yield 4,5-dimethoxy-2-nitrobenzamide (compound 2). Compound 2 was reduced with sodium borohydride in the presence of catalytic amounts of copper sulphate to give 4,5-dimethoxy-2-aminobenzamide (compound 3), which was directly refluxed with formic acid to yield 6,7-dimethoxyquinazoline-4(3H)-one (compound 4). Compound 4 was refluxed with phosphorus oxytrichloride to give 4-chloro-6,7-dimethoxyquinazoline (compound 5) in good yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)[O:5][C:6]=1[Br:7].C([N-]C(C)C)(C)C.[Li+].[CH:23]([S:26]C(C)C)([CH3:25])[CH3:24].Cl>O1CCCC1>[Br:1][C:2]1[C:3]([S:26][CH:23]([CH3:25])[CH3:24])=[C:4]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)[O:5][C:6]=1[Br:7]
Reactant: CC(C)SC(C)C
Reactant: CC1(C)COC(c2cc(Br)c(Br)o2)=N1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)Sc1c(C2=NC(C)(C)CO2)oc(Br)c1Br
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of 9.63 g (29.81 mmol) of 2-(4,5-dibromo-2-furanyl)-4,4-dimethyloxazoline in dry tetrahydrofuran (30 mL) is added dropwise to a -78° C. solution of freshly generated lithium diisopropylamide (33.89 mmol, 1.14 equiv) in tetrahydrofuran (80 mL) under an argon atmosphere. The resulting solution is stirred at -78° C. for 10 min and a solution of 5.49 g (46.49 mmol, 1.56 equiv) of isopropyl sulfide in tetrahydrofuran (20 mL) is added dropwise to the reaction. The reaction is stirred for 3.75 hr at -78° to -10° C. and poured onto 5% aqueous HCl (350 mL). The resulting aqueous solution is extracted with diethyl ether (4X). The combined organic extracts are washed with aqueous saturated NaCl, dried (Na2SO4), and concentrated in vacuo. Flash chromatography (SiO2, 7×25 cm, 10% CH2Cl2 /10% ethyl acetate/hexane) affords 7.67 g (11.84 g theo.; 65%) of the desired product as a yellow solid. Recrystallization from hexane affords an analytical sample; mp 71°-72° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=3)[CH:7]=[CH:6][C:5]=2[N:4]2[CH2:27][CH2:28][C@H:29]([CH2:30][C:31]([OH:33])=[O:32])[C:3]=12.[Zn:34](OC(C)=O)OC(C)=O.O>C1COCC1>[Zn+2:34].[Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[C:15]([C:23]([F:24])([F:25])[F:26])[CH:14]=3)[CH:7]=[CH:6][C:5]=2[N:4]2[CH2:27][CH2:28][C@H:29]([CH2:30][C:31]([O-:33])=[O:32])[C:3]=12.[Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[C:15]([C:23]([F:24])([F:25])[F:26])[CH:14]=3)[CH:7]=[CH:6][C:5]=2[N:4]2[CH2:27][CH2:28][C@H:29]([CH2:30][C:31]([O-:33])=[O:32])[C:3]=12
Reactant: CC(=O)O[Zn]OC(C)=O
Reactant: CC(C)Oc1ccc(COc2ccc3c(c2)c(Cl)c2n3CC[C@@H]2CC(=O)O)cc1C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ccc(COc2ccc3c(c2)c(Cl)c2n3CC[C@@H]2CC(=O)[O-])cc1C(F)(F)F
Product: [Zn+2]
Temperature: 60 °C
Reaction time: 24 h

Procedure:
(R)-2-(9-Chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid [15 mg] was dissolved in THF [0.5 mL] and heated to 60° C. Aqueous Zn(OAc)2 [8.0 uL, 1.95 M] was added and the reaction mixture was cooled to 35° C. over 24 h. Water [8 uL] was added and the mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated to dryness and EtOAc was added to provide a white solid which was collected by filtration.