Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1([CH2:17][C:18]([OH:20])=[O:19])[O:10][C:6]2=[CH:7][CH:8]=[CH:9][C:5]2=[CH:4][CH:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1CCCCC1.[N+:27]([O-:32])([N+]([O-])=O)=[O:28]>C(Cl)(Cl)Cl>[N+:27]([C:2]1([CH2:17][C:18]([OH:20])=[O:19])[O:10][C:6]2=[CH:7][CH:8]=[CH:9][C:5]2=[CH:4][CH:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-:32])=[O:28]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: O=C(O)CC1(Br)OC2=CC=CC2=CC1c1ccccc1
Solvent: C1CCCCC1
Solvent: ClC(Cl)Cl
Product: O=C(O)CC1([N+](=O)[O-])OC2=CC=CC2=CC1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-bromo-3-phenyl-4-benzofuranacetic acid (12.1 g., 0.0365 mole) and cyclohexane (3.3 g., 0.04 mole) in 100 ml. of chloroform is treated with 5 g. of dinitrogen tetroxide in 20 ml. of chloroform dropwise. The mixture is stirred for 16 hours at about 25° C. then at 50°-55° C. for about 20 minutes. The mixture is washed with water, and the organic layer is treated with an aqueous base. The aqueous layer is acidified, then extracted with dichloromethane. The organic layer is washed thrice with water, dried and evaporated. Two recrystallizations from benzene give light yellow solid 2-nitro-3-phenyl-4-benzofuranacetic acid, m.p. 187.5°-189.5° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[C:21](OCC)(=[O:23])[CH3:22].O>O1CCCC1>[O:23]=[C:21]([CH3:22])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C(C)=O)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
A stirred solution of 10 grams (0.061 mole) of ethyl phenylacetate in 125 mL of tetrahydrofuran is cooled to -78° C., and 33.5 mL (0.067 mole) of lithium diisopropylamide (2M solution in heptane-tetrahydrofuranethyl-benzene) is slowly added dropwise at a rate to maintain the reaction mixture temperature below -60° C. Upon completion of addition, the reaction mixture is stirred at -78° C. for about one hour. After this time, 6.5 mL (0.067 mole) of ethyl acetate is added dropwise. Upon completion of addition, the reaction mixture is stirred for about one hour at -78° C. The reaction mixture is then allowed to warm to ambient temperature. After this time the reaction mixture is poured into 200 mL of water, and the mixture is extracted with one 100 mL portion of diethyl ether. The aqueous layer is made acidic with aqueous 10% hydrochloric acid, and then it is extracted with three 150 mL portions of diethyl ether. The combined extracts are dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 6.6 grams of ethyl 3-oxo-2-phenylbutanoate. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].[I:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>CC(C)=O.O>[I:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][O:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:19][CH:18]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: BrCc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: N#Cc1ccc(OCc2ccc(I)cc2)cc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 24.9 %

Procedure:
To a stirred solution of 4-cyano phenol (1 g, 8.4 mmol) in acetone (15 ml) was added K2CO3 (3.48 g, 25.0 mmol), followed by 4-iodobenzyl bromide (2.7 g, 9.2 mmol) at 20-35° C. and the reaction mixture was stirred at 70° C. for 6 h. The progress of the reaction was monitored by TLC. After 6 h of stirring, the mixture was cooled to 20-35° C., diluted with water (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine (50 ml), followed by drying over anhydrous Na2SO4 and filtering. The filtrate was rotary evaporated to get residue which was purified by column chromatography using a mixture of 5% ethyl acetate/hexane as an eluent to get the desired compound as a white solid (700 mg, 35%). 1H NMR (400 MHz, DMSO-d6) δ 7.80-7.75 (m, 4H), 7.26 (d, J=8.3 Hz, 2H), 7.19-7.15 (m, 2H), 5.18 (s, 2H).
Reaction SMILES: [S:1]([N:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:20]=O)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].Cl.[NH2:23][OH:24].N1C=CC=CC=1>CCO>[S:1]([N:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:20]=[N:23][OH:24])[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C=O)cccc32)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C=NO)cccc32)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of 42 (900 mg, 3 mmol) in EtOH (10 mL) was added hydroxylamine hydrochloride (1.0 g, 15 mmol) and pyridine (1.0 mL). After the reaction mixture was stirred at 70° C. overnight, the solvent was removed in vacuo to afford 800 mg (85%) of 1-tosyl-1H-indole-4-carbaldehyde oxime (44) as white solid: MS (ESI) m/z=315 [M+1]+.
Reaction SMILES: [O-]CC.[Na+].C([O:7][CH:8]=[C:9]([C:15](OCC)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])C.O.[NH2:21][NH2:22].Cl>C(O)C.O>[CH2:13]([O:12][C:10]([C:9]1[C:8](=[O:7])[NH:21][NH:22][CH:15]=1)=[O:11])[CH3:14]
Reactant: NN
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c[nH][nH]c1=O
Temperature: 80 °C
Yield: 84.5 %

Procedure:
To a solution of sodium ethoxide (20.8 g, 0.31 mol) and diethyl ethoxymethylenemalonate (20 mL, 0.10 mol) in ethanol (400 mL), was added hydrazine monohydrate (10.0 mL, 0.20 mol) with cooling in an ice-cold water bath. The mixture was then heated at 80° C. for 3 h. The resulting mixture was diluted with water (200 mL) and neutralized with 10M HCl solution until pH 6. The mixture was extracted several times with chloroform. The aqueous layer was acidified to pH 2 and extracted again with chloroform. The combined organic layers were dried (Na2SO4) and concentrated to a solid which was washed with methanol and ether and dried to give the product (13.2 g, 80%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ7.89 (s, 1H), 4.15 (q, 211, J=7.12 Hz), 1.23 (t, 3H, J=7.11 Hz).
Reaction SMILES: [OH-].[Li+].C([O:6][CH:7]([CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([O:28][CH2:29][O:30][CH3:31])([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=1[CH2:32][CH2:33][CH3:34])[CH3:8])(=O)C>CO>[F:21][C:20]([F:22])([F:23])[C:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][CH2:10][CH2:9][CH:7]([OH:6])[CH3:8])=[C:14]([CH2:32][CH2:33][CH3:34])[CH:15]=1)([O:28][CH2:29][O:30][CH3:31])[C:24]([F:25])([F:27])[F:26]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1OCCCC(C)OC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1OCCCC(C)O
Temperature: 60 °C
Yield: 93.2 %

Procedure:
A 2 mol/L Lithium hydroxide solution (2 mL) was added to a mixed solution of 5-[4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethyl)oxypropan-2-yl]-2-propylphenyloxy]pent-2-yl acetate (80.4 mg, 169 μmol) in methanol (1.5 mL) at room temperature, followed by heating at an external temperature of 60° C. in an oil bath overnight. After completion of the reaction, methanol was evaporated under reduced pressure. The pH was adjusted to 7 by adding 4 mol/L hydrochloric acid (2 mL) to the residue. After extraction with chloroform-water, the organic layer was washed with a saturated sodium chloride solution and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. 68.1 mg of the title compound (yield: 93%) was obtained as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@H:5]([C:14]([OH:16])=[O:15])[CH2:4][CH2:3]1.OS(O)(=O)=O.[OH-].[Na+].[C:24](=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.CO>[CH3:24][O:15][C:14]([C@@H:5]1[CH2:4][CH2:3][C:2](=[O:1])[N:6]1[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:16]
Reactant: O=C(O)[C@@H]1CCC(=O)N1Cc1ccccc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)[C@@H]1CCC(=O)N1Cc1ccccc1

Procedure:
The crude (S)-5-oxo-1-(phenylmethyl)-2-pyrrolidinecarboxylic acid (160 g, 0.73 mol) was dissolved in 300 mL of toluene and 550 mL of methanol. To the solution was added 9 mL of conc H2SO4 and the solution was heated to reflux overnight. The solution was cooled in an ice bath and neutralized to pH 5 with 25% NaOH, followed by adding 50 mL of saturated sodium bicarbonate to bring the solution to pH 7. The methanol was removed on a rotary evaporator and the residue was diluted with 500 mL of water and extracted with methylene chloride. The combined extracts were washed with brine and dried over MgSO4. Evaporation of the solvent afforded 132 g of (S)-5-oxo-1-(phenylmethyl)-2-pyrrolidinecarboxylic acid methyl ester as an oil which was >95% pure by NMR. 1H NMR (CDCl3) δ 2.0-2.6 (m,4H,CH2 's), 3.68 (s,3 H,CH3), 3.95 (dd, 1 H,J=4,9 Hz, H-4), 4.02 and 5.03 (AB, 2 H,Jgem =16 Hz, CH2Ph), 7.2-7.4 (m, 5 H, arom).
Reaction SMILES: [CH2:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:6][C:7]([F:14])([F:13])[C:8]([F:12])=[C:9]([F:11])[F:10]>>[F:10][C:9]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([F:11])[CH:8]([F:12])[C:7]([F:14])([F:13])[F:6]
Reactant: C1CCCC1
Reactant: FC(F)=C(F)C(F)(F)F
Product: FC(C(F)(F)F)C(F)(F)C1CCCC1
Yield: 71 %

Procedure:
Cyclopentane (65 mmole) and hexafluoropropene (22 mmole) heated at 290° for 2 days gave a 71% yield (based on hexafluoropropene consumed) of analytically and spectroscopically pure 1,1,2,3,3,3-hexafluoropropylcyclopentane: ##STR15## identical with material prepared by an alternative route.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])C=O.ClC1C=CC=C([C:30]([O:32]O)=[O:31])C=1>C(Cl)Cl>[CH:30]([O:32][C:10]1[CH:13]=[CH:14][C:15]([O:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])=[C:8]([O:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:9]=1)=[O:31]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COCCOCOc1ccc(C=O)cc1OCOCCOC
Solvent: ClCCl
Product: COCCOCOc1ccc(OC=O)cc1OCOCCOC
Yield: 86.4 %

Procedure:
5.4 g (17 mmol) of 3,4-di(2-methoxyethoxymethoxy)-benzaldehyde was dissolved in 216 ml of methylene chloride, and 4.4 g (20 mmol) of 80% m-chloroperbenzoic acid was added thereto. The mixture was refluxed at a boiling point for 20 hours. The reaction solution was washed with a sodium bicarbonate aqueous solution and with a saturated sodium chloride aqueous solution and then dried. The solvent was distilled off under reduced pressure to obtain 4.85 g (yield: 86%) of O-formyl-3,4-di(2-methoxyethoxymethoxy)phenol. The product was used for the subsequent reaction without purification.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18]OS(C)(=O)=O)[O:15][C:14]3=[O:24])=[CH:9][C:8]=2[F:25])[CH2:3][CH2:2]1.[CH3:26][N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[S:32]>>[O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][N:29]4[CH:30]=[CH:31][N:27]([CH3:26])[C:28]4=[S:32])[O:15][C:14]3=[O:24])=[CH:9][C:8]=2[F:25])[CH2:3][CH2:2]1
Reactant: CN1CCNC1=S
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(C3=CCOCC3)c(F)c2)C(=O)O1
Product: Cn1ccn(C[C@H]2CN(c3ccc(C4=CCOCC4)c(F)c3)C(=O)O2)c1=S
Yield: 9.2 %

Procedure:
Essentially the procedure of Example 37 was used, but starting with (5R)-3-(4-(3,6-dihydro-2H-pyran-4-yl)-3-fluorophenyl)-5-methanesulfonyloxymethyloxazolidin-2-one (300 mg, 0.81 mM), and 1-methylimidazolidin-2-thione (100 mg, 0.88 mM) and heating the reaction at 60° for 1.5 hours. Chromatography on two columns gave the desired product (29 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:9]=2[CH:10]=1)=[O:5])C.[OH-].[Na+]>C1COCC1.C(O)C>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:8]2[O:7][C:6]([C:4]([OH:5])=[O:3])=[CH:10][C:9]=2[CH:11]=1
Reactant: CCOC(=O)c1cc2cc(OC)ccc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2oc(C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
The above prepared 5-methoxy-benzofuran-2-carboxylic acid ethyl ester (0.500 g, 2.27 mmol) was dissolved in 4.6 mL of THF/ethanol=1/1 and treated with 2.27 mL of aq. NaOH (3M, 3 eq.). The mixture was stirred for 2 h at ambient temperature and was then poured onto crashed ice/AcOEt/HCl dil.; the organic layer was washed with water, dried over sodium sulfate, and evaporated to dryness to leave 0.428 g of the title acid as off-white solid.
Reaction SMILES: [CH2:1]([Si:6]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH2:10][CH:9]([C:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:25]([C@H:28]1[CH2:33][CH2:32][C@H:31]([Mg]C2C=CC=CC=2)[CH2:30][CH2:29]1)[CH2:26][CH3:27].[Cl-].Cl>O1CCCC1>[CH2:1]([Si:6]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH2:10][CH:9]([C:12]2([C:17]3[CH2:16][CH2:15][CH:14]=[CH:13][CH:12]=3)[CH:17]=[CH:16][C:15]([C@H:31]3[CH2:30][CH2:29][C@H:28]([CH2:25][CH2:26][CH3:27])[CH2:33][CH2:32]3)=[CH:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCC[C@H]1CC[C@H]([Mg]c2ccccc2)CC1
Reactant: CCCCC[Si]1(c2ccccc2)CCC(C2=CCC(=O)CC2)CC1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCCCC[Si]1(c2ccccc2)CCC(C2(C3=CC=CCC3)C=CC([C@H]3CC[C@H](CCC)CC3)=CC2)CC1
Reaction time: 5 h

Procedure:
34.1 g of 4-(4-n-pentyl-4-phenyl-4-silacyclohexyl)-3-cyclohexenone was dropped in 250 ml of a tetrahydrofuran solution of 0.5 moles of trans-(4-n-propylcyclohexyl)phenylmagnesium chloride, followed by agitation at room temperature for 5 hours. The resultant mixture was charged into diluted hydrochloric acid and extracted with ether. The resultant ether solution was washed with brine, dried and concentrated, followed by addition, to the resultant residue, of 300 ml of benzene and 800 mg of p-toluenesulfonic acid monohydrate and removal of generated water under reflux. When the generation of water stopped, the benzene solution was washed with brine, dried and concentrated, followed by purification through column chromatography to obtain 36.8 g of 1-(4-n-pentyl-4-phenyl-4-silacylohexyl)-4-(trans-4-n-propylcyclohexyl)phenyl-1,3-cyclohexadiene at a yield of 70%. The results of 1H-NMR analysis of the compound are shown below. 1H-NMR (CDCl3) δ:0.50-2.75(41H, m), 5.62-5.90(1H, m), 6.18-6.36(1H, m), 7.05-7.70(9H, m) ppm
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([O:12]C)[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:25])[N:7]2[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([O:23][CH3:24])=[O:22])[CH:15]=1.ClC1C=CC=C(Cl)C=1N1C2C(=C([C:45]3[CH:50]=[CH:49][C:48]([F:51])=[CH:47][C:46]=3[F:52])C=C(O)C=2)CCC1=O>>[F:51][C:48]1[CH:47]=[C:46]([F:52])[CH:45]=[CH:50][C:49]=1[C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:25])[N:7]2[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([O:23][CH3:24])=[O:22])[CH:15]=1
Reactant: O=C1CCc2c(-c3ccc(F)cc3F)cc(O)cc2N1c1c(Cl)cccc1Cl
Reactant: COC(=O)c1ccc(C)c(N2C(=O)CCc3c(Br)cc(OC)cc32)c1
Product: COC(=O)c1ccc(C)c(N2C(=O)CCc3c(-c4ccc(F)cc4F)cc(O)cc32)c1

Procedure:
5-(2,4-Difluorophenyl)-3,4-dihydro-7-hydroxy-1-(3-methoxycarbonyl-6-methylphenyl)-2(1H)-quinolinone was prepared from 5-bromo-3,4-dihydro-7-methoxy-1-(3-methoxycarbonyl-6-methylphenyl)-2(1H)-quinolinone (INTERMEDIATE 15) by a procedure analogous to that described in INTERMEDIATE 3. Mass spectrum (ESI) 424.1 (M+1). 1H NMR (500 MHz, DMSO-d6): δ 9.44 (s, 1H); 7.96 (d, J=8.0 Hz, 1H); 7.75 (s, 1H); 7.59 (d, J=8.0 Hz, 1H); 7.41 (m, 2H); 7.18 (t, J=6.0 Hz, 2H); 6.33 (s, 1H); 5.63 (s, 1H); 3.84 (s, 3H); 2.61 (m, 4H); 2.09 (s, 3H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([NH:27]C(=O)OC(C)(C)C)[CH2:23]2)=[N:4][CH:5]=[C:6]([C:8](=[O:21])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:7]=1.[N:35]1[CH:40]=[C:39](B(O)O)[CH:38]=[N:37][CH:36]=1>>[NH2:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:39]3[CH:40]=[N:35][CH:36]=[N:37][CH:38]=3)=[CH:7][C:6]([C:8]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:20])[F:19])=[CH:14][CH:15]=3)=[O:21])=[CH:5][N:4]=2)[CH2:23]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Reactant: OB(O)c1cncnc1
Product: N[C@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncnc2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 93 using (S)-tert-butyl (1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate (Stage 96.1) and pyrimidin-5-ylboronic acid. LC-MS (Condition 6) tR=0.89 min, m/z=445.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:5]=[CH:4][C:3]=1[NH:20][CH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1.[CH3:30][C:31]1([CH3:39])[C@@H:36]2[C@H:32]1[C:33](=[O:38])[O:34][C:35]2=O.CC(O)=O>C(#N)C>[C:26]([C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:20]2[C:3]3[CH:4]=[CH:5][C:6]([O:8][CH2:9][C:10]4[CH:19]=[CH:18][C:17]5[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=5)[N:11]=4)=[CH:7][C:2]=3[N:1]=[C:35]2[CH:36]2[CH:32]([C:33]([OH:38])=[O:34])[C:31]2([CH3:39])[CH3:30])=[CH:29][CH:28]=1)#[N:27]
Reactant: CC1(C)[C@@H]2C(=O)OC(=O)[C@@H]21
Reactant: N#Cc1ccc(CNc2ccc(OCc3ccc4ccccc4n3)cc2N)cc1
Solvent: CC(=O)O
Solvent: CC#N
Product: CC1(C)C(C(=O)O)C1c1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(C#N)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 49.1 %

Procedure:
To a solution of 4-(((2-amino-4-(quinolin-2-ylmethoxy)phenyl)amino)methyl)benzonitrile (124 mg, 0.33 mmol) in acetonitrile (3 mL) was added cis-6,6-dimethyl-3-oxabicyclo[3.1.0]hexane-2,4-dione (49 mg, 0.33 mmol) and the solution heated to 80° C. for 4 h. AcOH (1 mL) was then added and the heating continued at 80° C. for an additional 16 h. The resulting mixture was cooled to RT and the mixture was concentrated to dryness. The residue purified using FCC to provide 81.4 mg of the title compound. MS (ESI): mass calcd. for C31H26N4O3, 502.20; m/z found, 503.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J=8.6 Hz, 1H), 8.11 (d, J=8.3 Hz, 1H), 7.84 (d, J=8.1 Hz, 1H), 7.78-7.73 (m, 1H), 7.70-7.65 (m, 3H), 7.59-7.54 (m, 1H), 7.33 (d, J=2.3 Hz, 1H), 7.19-7.09 (m, 4H), 5.49-5.39 (m, 4H), 2.32 (d, J=8.3 Hz, 1H), 1.99 (d, J=8.3 Hz, 1H), 1.20 (s, 3H), 1.01 (s, 3H).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].S(=O)(=O)(O)O.O.[C:18](=O)(O)[O-].[Na+]>CO>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:18])=[O:7])=[CH:4][C:3]=1[OH:11]
Reactant: O=C(O)c1ccc(I)c(O)c1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(I)c(O)c1

Procedure:
A solution of 4-iodo-3-hydroxybenzoic acid (2.71 g, 10 mmol) and sulphuric acid (0.7 ml) in methanol (17 ml) is refluxed for 6 h. 20 ml of water are added and the mixture is basified with sodium bicarbonate until neutral. The mixture is extracted with ethyl ether (60 ml). The organic phase is washed with twice 30 ml of water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. The product is purified by flash chromatography on a column of silica (50% ethyl acetate, 50% heptane).
Reaction SMILES: C([NH:4]CC1SC=C(CN2CCN([C@@H]([C@@H](C)CC)C(OC(C)(C)C)=O)C2=O)N=1)(C)C.C([O-])(O)=O.[Na+].Cl[C:36]([O:38][CH2:39][CH:40]1[C:52]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[C:46]2[C:41]1=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:37]>C(#N)C.O>[C:36]([NH2:4])([O:38][CH2:39][CH:40]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:46]2[C:41]1=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:37]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N1CCN(Cc2csc(CNC(C)C)n2)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 141.4 %

Procedure:
A solution of the product of Example 283A (59 mg) in acetonitrile (0.9 mL) and water (0.3 mL) was treated with NaHCO3 (34 mg, 2.4 equivalents) followed by 9-fluorenylmethyl chloroformate (53 mg, 1.2 equivalents) at 25° C. for 1.5 h. The solvents were evaporated and the residue was purified using ethyl acetate:chloroform (1:4) to give 47 mg (40%) of FMOC-amine which was dissolved in dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL) and stirred at 25° C. for 1 h. The solvents were evaporated, and the acid was used directly for the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.[CH2:12]1[C@H:21]2[C@H:16]([CH2:17][CH2:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=32)[NH:15][CH2:14][CH2:13]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH2:1][C:2]1[CH:3]=[C:4]([C:5]([N:15]2[C@@H:16]3[C@@H:21]([C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[CH2:18][CH2:17]3)[CH2:12][CH2:13][CH2:14]2)=[O:7])[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: Nc1cc(C(=O)O)ccc1F
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Nc1cc(C(=O)N2CCC[C@@H]3c4ccccc4CC[C@@H]32)ccc1F
Yield: 47 %

Procedure:
The title compound is prepared from 3-amino-4-fluoro-benzoic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 47% of theory; LC (method 4): tR=1.94 min; Mass spectrum (ESI+): m/z=325 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@H:25]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:26]([O:28]C)=[O:27])[N:3]=1>CO.[OH-].[Na+]>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@H:25]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:26]([OH:28])=[O:27])[N:3]=1
Reactant: COC(=O)[C@@H](CC(C)C)Nc1nc(Cl)c2c(c1F)CN(Cc1ccc(OC)cc1OC)C2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CN2Cc3c(F)c(N[C@H](CC(C)C)C(=O)O)nc(Cl)c3C2=O)c(OC)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of (R)-methyl 2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)-4-methylpentanoate (2.9 g, 6.04 mmol) in MeOH (10 mL) and 1N NaOH (40.0 mL) was stirred at 50° C. for 2 h. UPLC showed 30% starting material remained. Additional saturated NaOH solution (5 mL) was added and the reaction mixture was stirred for 3 h at 50° C. The solvent was removed and the resulting residue was dispersed in H2O (100 mL) and acidified to pH 3 using HCl. After stirring at RT for 2 h, the solid was filtered to give the title compound. [M+H] calc'd for C22H25ClFN3O5, 466. found, 466.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[Br-]>C(OCC)(=O)C>[CH3:20][O:19][C:17](=[O:18])[C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:3][CH:4]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)CBr
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1ccc(C(=O)OC)cc1

Procedure:
A solution of aniline, triethyl amine, and ethyl bromoacetate was heated to 60° C. for 2.5 days. The reaction mixture was cooled, and TLC (25% EtOAc/hex) showed mostly starting material and a higher Rf spot. Additional base, bromide, and continued heat for 2 days brought little change by TLC. The reaction mixture was cooled, diluted with ethyl acetate, extracted with 10% HCl, dried over sodium sulfate, filtered, adsorbed onto silica, and purified by flash column using 10-30% ethyl acetate/hexanes to obtain 101 as a white solid.