Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([C:7]1[C:11]2[CH:12]=[N:13][C:14]([NH:16][C:17]([NH:19][C@@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])=[O:18])=[CH:15][C:10]=2[NH:9][N:8]=1)C(=O)C)[CH3:2].[B-](F)(F)(F)[F:29].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CC(N(C)C)=O.CO>[CH2:1]([NH:3][C:7]1[C:11]2[CH:12]=[N:13][C:14]([NH:16][C:17]([NH:19][C@@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])=[O:18])=[C:15]([F:29])[C:10]=2[NH:9][N:8]=1)[CH3:2]
Reactant: F[B-](F)(F)F
Reactant: CCN(C(C)=O)c1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CO
Solvent: CC(=O)N(C)C
Product: CCNc1n[nH]c2c(F)c(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)—N-Ethyl-N-(6-(3-(1-phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-3-yl)acetamide (154 mg, 0.420 mmol) was dissolved in DMA (1 mL) and methanol (1 mL), charged with powdered Selectfluor® (164 mg, 0.462 mmol), and stirred at room temperature overnight. The reaction was then to heated to 55° C. for 8 h. The resulting crude residue was purified by mass-triggered reverse phase HPLC. Fractions containing pure compound were filtered through a PS-HCO3 cartridge and the filtrate was concentrated in vacuo to give (R)-1-(3-(ethylamino)-7-fluoro-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. for C19H21FN6O2 [M+1]+ 385. found 385.
Reaction SMILES: [F:1][C:2]1[C:3]([F:15])=[C:4]([F:14])[C:5]([F:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]=12.[CH3:16][C@@H:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl>[C:18]1([C@H:17]([N:24]2[C:11](=[O:12])[C:6]3[C:7](=[C:2]([F:1])[C:3]([F:15])=[C:4]([F:14])[C:5]=3[F:13])[C:8]2=[O:10])[CH3:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Reactant: C[C@@H](N)c1ccccc1
Solvent: ClC(Cl)Cl
Product: C[C@H](c1ccccc1)N1C(=O)c2c(F)c(F)c(F)c(F)c2C1=O
Temperature: 180 °C
Yield: 65.1 %

Procedure:
220 mg of tetrafluorophthalic anhydride and 121 mg of (R)-α-methylbenzylamine were charged in an egg-plant type flask of 50 ml, followed by stirring under heating at a temperature of 180° C. for 2 hours. After cooled, the reaction product was dissolved in chloroform, purified by silica gel column chromatography (eluent; methylene k chloride:methanol=30:1 v/v), recrystallized from a mixed solvent of n-hexane-ethyl acetate, to obtain 210 mg of the desired product as colorless needles. Yield: 65%. m.p. 95.5-96° C.; [α]20 D=41.5° (C=0.348 AcOEt); MS(EI+) 323 (M)+
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19][C:20](=[O:22])[CH3:21])[C@H:7](Br)[O:6]1)=[O:4].[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[OH:33])[CH:28]=[O:29]>>[CH3:1][O:2][C:3]([C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19][C:20](=[O:22])[CH3:21])[C@H:7]([O:33][C:32]2[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][C:25]=2[F:24])[O:6]1)=[O:4]
Reactant: COC(=O)[C@H]1O[C@@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=Cc1ccc(O)c(F)c1
Product: COC(=O)[C@H]1O[C@@H](Oc2ccc(C=O)cc2F)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 81.3 %

Procedure:
14.2 g (35.8 mmol) of (2S,3S,4S,5R,6S)-3,4,5-triacetoxy-6-bromo-tetrahydro-pyran-2-carboxylic acid methyl ester is reacted analogously to Example LE1a with 5.05 g of 3-fluoro-4-hydroxybenzaldehyde, and after working-up and purification, 13.3 g (29.1 mmol, 81%) of the title compound is isolated.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3(NCCO)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH:10]3[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(NCCO)(c1ccccc1)C(=O)N2
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc(C)c1-c1ccc2c(c1)C(c1ccccc1)C(=O)N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-(3,5-dimethylisoxazol-4-yl)-3-(2-hydroxyethylamino)-3-phenylindolin-2-one (32 g, 0.1 mmol) in dichloromethane (500 mL) was added trifluoroacetic acid (20 g) and triethylsilane (20 g). The brown solution was stirred at ambient temperature for 3 h and concentrated in vacuo to dryness. The residue was diluted with dichloromethane (500 mL), washed with saturated ammonium chloride solution (200 mL), brine (3×400 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was crystallized from ether to give the title compound. 1H NMR (400 MHz, DMSO-d6): δH 10.63 (s, 1H), 7.18-7.36 (m, 6H), 6.99-7.04 (m, 2H), 4.82 (s, 1H), 2.32 (s, 3H), 2.15 (s, 3H). MS (ESI) m/e [M+1]+ 305.
Reaction SMILES: C([O-])(=O)C.[Na+].Br[CH:7](Br)[C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].[F:15][C:16]1[C:29]([NH:30][NH2:31])=[CH:28][C:19]2[N:20]([CH2:25][C:26]#[CH:27])[C:21](=[O:24])[CH2:22][O:23][C:18]=2[CH:17]=1>O>[F:15][C:16]1[C:29]([NH:30][N:31]=[CH:7][C:8](=[O:9])[C:10]([F:13])([F:12])[F:11])=[CH:28][C:19]2[N:20]([CH2:25][C:26]#[CH:27])[C:21](=[O:24])[CH2:22][O:23][C:18]=2[CH:17]=1
Reactant: O=C(C(Br)Br)C(F)(F)F
Reactant: C#CCN1C(=O)COc2cc(F)c(NN)cc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: C#CCN1C(=O)COc2cc(F)c(NN=CC(=O)C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixed solution of 8.0 g (97.2 mmol) of sodium acetate and 50 ml of water was added under ice cooling 6.6 g (24.3 mmol) of 1,1-dibromo-3,3,3-trifluoroacetone, and the reaction was allowed to proceed at 80° C. for 30 minutes. Then, the reaction mixture was cooled to 0° C., to which 4.4 g (18.7 mmol) of 7-fluoro-6-hydrazino-4-propargyl-2H-1,4-benzoxazin-3-one was added, and the reaction mixture was stirred at room temperature for 2 hours. The precipitated crystals were collected by filtration, washed twice with 10 ml of water, and dried, which afforded 6.3 g (18.37 mmol) of 7-fluoro-6-trifluoroacetylmethylidenhydrazino-4-propargyl-2H-1,4-benzoxazin-3-one [another name: 3,3,3-trifluoro-2-oxopropanal 1-(7-fluoro-3-oxo-4-propargyl-2H-1,4-benzoxazin-6-ylhydrazone)], m.p. 190.6° C. (decomp.).
Reaction SMILES: [CH3:1][N:2]([CH3:4])O.[H-].[Na+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]3[C:18]([CH2:21]Cl)=[N:19][N:20]=[C:16]3[CH2:15][N:14]=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[C:12]=2[CH:29]=1>CN(C)C=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]3[C:18]([CH2:21][N:2]([CH3:4])[CH3:1])=[N:19][N:20]=[C:16]3[CH2:15][N:14]=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[C:12]=2[CH:29]=1
Reactant: ClCc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2
Reactant: CN(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)Cc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2

Procedure:
In the manner given in Example 16, a solution of N,N-dimethylhydroxylamine in dimethylformamide is treated with sodium hydride suspended in mineral oil, and the mixture is treated with 8-bromo-1-(chloromethyl)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 8-bromo-1-[(dimethylamino)methyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, N1 -oxide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:16]3[CH:12]([CH2:13][N:14](C(OC=C)=O)[CH2:15]3)[C:11](=[O:22])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[ClH:30]>O1CCOCC1>[ClH:30].[F:29][C:25]1[CH:24]=[C:23]([C:8]2([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH:16]3[CH:12]([CH2:13][NH:14][CH2:15]3)[C:11](=[O:22])[CH2:10][CH2:9]2)[CH:28]=[CH:27][CH:26]=1
Reactant: C=COC(=O)N1CC2C(=O)CCC(c3cccc(F)c3)(c3cccc(F)c3)C2C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1CCC(c2cccc(F)c2)(c2cccc(F)c2)C2CNCC12
Temperature: 60 °C
Reaction time: 16 h

Procedure:
(3aRS,7aRS)-7,7-Bis(3-fluorophenyl)-2-vinyloxycarbonylperhydro-4-isoindolone (64.5 g) is treated with a 6N solution (330 cc) of hydrochloric acid in dioxane for 30 minutes at 25° C. The solution is concentrated to dryness under reduced pressure (2.7 kPa) and the residue taken up with ethanol (500 cc). The solution is heated to 60° C. for 6 hours and stirred for 16 hours at 25° C., then concentrated to one half under reduced pressure (2.7 kPa), and the crystals formed are drained and washed with isopropyl ether, then dried. 7,7-Bis(3-fluorophenyl)perhydro-4-isoindolone hydrochloride (48.7 g) is obtained. M.p. 264° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][OH:29])=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)=[C:4]([F:30])[CH:3]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][S:39]([CH3:38])(=[O:41])=[O:40])=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)=[C:4]([F:30])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCOCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOCCOc1cc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.9 %

Procedure:
Compound 29a (0.035 gram, 0.076 mmol) was dissolved in dichloromethane (4.3 ml) and triethylamine (0.032 gram, 3.82 mmol) was added to the resulting solution. Methanesulfonyl chloride (MsCl, 0.025 gram, 0.022 mmol) was then added and the resulting mixture was stirred at room temperature for 3 hours. The mixture was thereafter extracted twice with CH2Cl2, washed with brine and dried over sodium sulfate. The crude residue was purified by silica gel column chromatography, using a mixture of 2% methanol in dichloromethane as eluent, to give Compound 32a (0.012 gram, 29% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:23][CH2:24][CH:25]=[CH2:26].O>O1CCCC1>[CH2:10]([O:9][C:7](=[O:8])[C:6]([CH2:4][CH2:3][CH:2]=[CH2:6])([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:23][CH2:24][CH:25]=[CH2:26])[CH3:11]
Reactant: CCOC(=O)Cc1cccs1
Reactant: C=CCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCC(CCC=C)(C(=O)OCC)c1cccs1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Ethyl 2-(thiophen-2-yl)acetate (2.35 g) was dissolved in tetrahydrofuran (30 mL) and cooled to −78° C. Lithium bis(trimethylsilyl)amide (2.31 g) in THF (1M solution, 13.8 mL) was added and the solution was stirred for 30 minutes. 4-Bromo-but-1-ene (1.4 mL) was added and the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was re-cooled to −78° C. and lithium bis(trimethylsilyl)amide (2.31 g) in THF (1M solution, 13.8 mL) was added and the solution was stirred for 30 minutes. 4-Bromo-but-1-ene (1.4 mL) was added and the reaction mixture was allowed to warm to room temperature and stand overnight. HPLC-MS analysis indicated that the reaction was incomplete so the reaction was again cooled to −78° C. and further aliquots of lithium bis(trimethylsilyl)amide (1M solution, 10 mL) and 4-bromo-but-1-ene (1.0 mL) were added following the procedure outlined above. After stirring for a further 2 hours, water (30 mL) was added and the reaction was extracted with diethyl ether (2×60 mL). The combined organic extracts were dried (MgSO4) and evaporated. The resulting oil was purified by column chromatography on silica eluting with ethyl acetate/isohexane (1/99) afford the sub-titled compound (3.18 g).
Reaction SMILES: FC1C=CC2C(C3CCN([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:19]([CH:22](C)[CH3:23])[C:18]4=[O:25])CC3)=NOC=2C=1.[F:28][C:29]1[CH:43]=[CH:42][C:32]2[C:33]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[N:34][O:35][C:31]=2[CH:30]=1.BrCC.Cl>>[F:28][C:29]1[CH:43]=[CH:42][C:32]2[C:33]([N:36]3[CH2:41][CH2:40][N:39]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:19]([CH2:22][CH3:23])[C:18]4=[O:25])[CH2:38][CH2:37]3)=[N:34][O:35][C:31]=2[CH:30]=1
Reactant: Fc1ccc2c(N3CCNCC3)noc2c1
Reactant: CC(C)N1CCN(CCN2CCC(c3noc4cc(F)ccc34)CC2)C1=O
Agent: Cl
Solvent: CCBr
Product: CCN1CCN(CCN2CCN(c3noc4cc(F)ccc34)CC2)C1=O

Procedure:
This product is prepared in the same manner as the compound of Example 1 but using 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperazine instead of 4-(6-fluoro-1,2-benzisoxazol-3-yl)-piperidine in Step 1, and using bromoethane instead of 2-bromopropane in Step 2. The hydrochloride of the title compound so obtained melts at 201°-204° C.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][O:8][C:9]2=[O:12])=[CH:5][CH:4]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][O:8][C:9]2=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)OC2
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=C1OCc2ccc(O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
A solution of 6-methoxy-3H-isobenzofuran-1-one (50 g, 0.3 moles), prepared as described in example 34, in CH2Cl2 (250 ml) under N2 at −5° C., was dropwise added with BBr3 (360 ml 0.36 moles). At the end of the addition the solution was stirred at room temperature overnight, then cooled and added with further BBr3 (60 ml, 60 mmoles). The stirring was kept on for 4 hours at room temperature. The mixture was cooled and added with CH3OH (250 ml), then dried under vacuum to give a solid which was triturated in ethyl ether and washed with ethyl ether and ethyl acetate. After drying under vacuum at 40° C. a solid was obtained which was joined to the solid yielded by drying the mother liquors, discolouring and triturating in ethyl ether. There were obtained 33.51 g of the title compound (yield: 73%).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[CH3:23][N:24]([CH3:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][N:33]=1)[C:28](O)=[O:29]>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:28]([C:27]4[CH:31]=[CH:32][N:33]=[C:25]([N:24]([CH3:34])[CH3:23])[CH:26]=4)=[O:29])[CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: CN(C)c1cc(C(=O)O)ccn1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCNC3)c21
Agent: Cl
Product: CN(C)c1cc(C(=O)N2CCC[C@H](COc3cccc4c3C(N)=NS(=O)(=O)N4)C2)ccn1

Procedure:
Prepared as in Example 2 from (S)-4-amino-5-(piperidin-3-ylmethoxy)-1H-benzo[c][1,2,6]thiadiazine 2,2-dioxide hydrochloride (Example 2a) and 2-(dimethylamino)isonicotinic acid (8%). 1H NMR (400 MHz, DMSO-d6, 60° C.) δ 1.45 (br m, 2H), 1.68 (br m, 1H), 1.90 (br m, 1H), 2.16 (br m, 2H), 3.00 (s, 6H), 3.30-4.09 (br m, 4H), 6.44 (d, J=5.6 Hz, 1H), 6.47 (s, 1H), 6.61 (d, J=8.4 Hz, 1H), 6.69 (d, J=6.8 Hz, 1H), 7.39 (t, J=8.0 Hz, 1H), 7.67 (br s, 2H), 10.67 (br s, 1H). MS 459 (MH+)
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14](=[O:15])[C:13]2[CH:17]=[CH:18][C:10]([Cl:9])=[C:11]([N+:19]([O-:21])=[O:20])[CH:12]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Br)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 4-bromoaniline (2.58 g 14.99 mmol) in dry CH2Cl2 (100 mL) was treated with 4-chloro-3-nitrobenzoyl chloride (3.60 g, 17.99 mmol) and N,N-diisopropyl-ethylamine (3.14 mL, 17.99 mmol), and the resulting mixture stirred at room temperature for 17 hours. The solvent was concentrated under vacuum giving the title compound and the residue taken up in ethyl acetate (100 mL) and washed with water and brine. The organic extract was dried over Na2SO4, filtered and concentrated under vacuum giving the title compound as a tan solid (5.132 g, 14.45 mmol, 96%).
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[ClH:4].[CH3:5][O:6][C:7]1[CH:27]=[CH:26][CH:25]=[CH:24][C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>C(OCC)C>[ClH:4].[CH3:5][O:6][C:7]1[CH:27]=[CH:26][CH:25]=[CH:24][C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:20](=[NH:21])[O:3][CH2:1][CH3:2])=[CH:22][CH:23]=1
Reactant: CCO
Reactant: COc1ccccc1OCCCCCOc1ccc(C#N)cc1
Agent: Cl
Solvent: CCOCC
Product: CCOC(=N)c1ccc(OCCCCCOc2ccccc2OC)cc1
Temperature: 5 °C
Reaction time: 84 h

Procedure:
Ethanol (2 B anhydrous, 16.5 L) is cooled with an ice-salt bath to 0° C. Anhydrous hydrogen chloride is introduced until the solution is saturated (~8 hours). At this time the internal temperature is 5° C. To this is added 4-[5-(2-methoxyphenoxy)pentoxy]benzonitrile (1.64 kg, 5.26 mol) as a solid within a period of 10 minutes. At this point additional hydrogen chloride is introduced to maintain saturation at 5° C. for another 8 hours. Almost complete solution is achieved and the color is yellow. The reaction mixture is stirred for a total of 84 hours and the temperature range maintained is 5°-10° C. The resulting slurry is diluted with diethyl ether (52 L) to complete precipitation. The slurry is stirred for 1 hours and filtered. The filter cake is washed with diethyl ether (3×4 L) and air-dried for 1/2 hour to yield ethyl 4-[5-(2-methoxyphenoxy)pentoxy]benzenecarboximidate hydrochloride which is used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]([C:18]2([C:21]3[C:26]([F:27])=[CH:25][C:24]([Cl:28])=[CH:23][N:22]=3)[CH2:20][CH2:19]2)=[O:17])[C@H:13]([C:29]([OH:31])=O)[CH2:12]1)(=[O:10])=[O:9].[CH:32]1([NH:35][C:36](=[O:44])[C:37](=[O:43])[C@@H:38]([NH2:42])[CH:39]([CH3:41])[CH3:40])[CH2:34][CH2:33]1>>[Cl:28][C:24]1[CH:25]=[C:26]([F:27])[C:21]([C:18]2([C:16]([N:14]3[CH2:15][C@H:11]([S:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])(=[O:9])=[O:10])[CH2:12][C@H:13]3[C:29]([NH:42][C@@H:38]([CH:39]([CH3:41])[CH3:40])[C:37](=[O:43])[C:36]([NH:35][CH:32]3[CH2:34][CH2:33]3)=[O:44])=[O:31])=[O:17])[CH2:19][CH2:20]2)=[N:22][CH:23]=1
Reactant: CC(C)[C@H](N)C(=O)C(=O)NC1CC1
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ncc(Cl)cc2F)CC1
Product: CC(C)[C@H](NC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ncc(Cl)cc2F)CC1)C(=O)C(=O)NC1CC1

Procedure:
The title compound was prepared in analogy to Example 1, using (2S,4R)-4-(2-Chloro-benzenesulfonyl)-1-[1-(5-chloro-3-fluoro-pyridin-2-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid and (S)-3-Amino-4-methyl-2-oxo-pentanoic acid cyclopropylamide in step 1. MS (m/e)=653.14 [M+H+].
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]#[C:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]#[C:22][CH2:23][N:24]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]2=[O:34])=[N:19][CH:20]=1.C(O)(=O)C.[H][H]>CN(C=O)C.[Pd]>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][N:24]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]2=[O:34])=[N:19][CH:20]=1
Reactant: O=C1c2ccccc2C(=O)N1CC#Cc1ccc(C#CCN2C(=O)c3ccccc3C2=O)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1CCCc1ccc(CCCN2C(=O)c3ccccc3C2=O)nc1
Yield: 63.8 %

Procedure:
A mixture of 2-(3-{5-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl-prop-1-ynyl]pyridin-2-yl}prop-2-ynyl)-1H-isoindole-1,3(2H)-dione (5-1) (200 mg), 10% Pd/C (50 wt %; 60 mg), and acetic acid (1 mL) in DMF (1 mL) was stirred at ambient temperature under 1 atmospheric pressure of hydrogen for 2 days. The catalyst was removed by filtration through Solka-floc and washed with ethanol. The filtrate and wash were combined and concentrated under reduced pressure to give 11-1 (130 mg) as colorless crystals.
Reaction SMILES: Cl.[O:2]1CCO[CH:3]1[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1>C1COCC1.O>[F:14][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[OH:13])[CH:3]=[O:2]
Reactant: Oc1ccc(C2OCCO2)cc1F
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(O)c(F)c1
Yield: 95.2 %

Procedure:
A solution of 1N HCl (1 mL) and 4-[1,3]dioxolan-2-yl-2-fluoro-phenol (250 mg, 1.35 mmol) in THF (2 mL) was stirred, at room temperature for 1 hour. The mixture was diluted with water and extracted with methylene chloride (4×10 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum. The residue was chromatographed (silica gel, hexanes/ethyl acetate 1:1) to produce 3-Fluoro-4-hydroxy-benzaldehyde as a white solid (180 mg, 95%). 1H-NMR (CDCl3, 200.15 MHz): 9.84 (d, 1H, J=2.4), 7.68–7.59 (m, 2H), 7.15 (t, 1H, J=8.5), 6.5 (sa, 1H).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])[CH2:7][CH2:6]2)[O:4]CC1.Cl.O>O1CCOCC1>[O:4]=[C:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]#[N:14])[CH2:9][CH2:10]1
Reactant: N#Cc1ccccc1C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccccc1C1CCC(=O)CC1
Temperature: 80 °C

Procedure:
To a stirring solution of 2-(1,4-Dioxaspiro[4.5]dec -8-yl)benzonitrile (8.7 g, 35.7 mmol) in dioxane (200 mL) was added 1N HCl (200 mL) and the reaction heated to 80° C. for 2 hours. The reaction was cooled to room temperature and poured into water (1 L) the mixture was extracted with ethyl acetate (3×250 mL). The combined organics were washed with brine (200 mL) and then dried over anhydrous magnesium sulfate, filtered and concentrated at reduced pressure to give the product.
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:8]([I:18])[C:7]([F:19])=[C:6]([Cl:20])[CH:5]=1)(=[O:3])[CH3:2].[CH2:21](O)[CH2:22][OH:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:20][C:6]1[CH:5]=[C:4]([C:1]2([CH3:2])[O:23][CH2:22][CH2:21][O:3]2)[C:9]([O:10][CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:8]([I:18])[C:7]=1[F:19]
Reactant: OCCO
Reactant: CCOC(=O)C(C)Oc1c(C(C)=O)cc(Cl)c(F)c1I
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)Oc1c(C2(C)OCCO2)cc(Cl)c(F)c1I
Yield: 56.8 %

Procedure:
A solution of ethyl 2-(6-acetyl-4-chloro-3-fluoro-2-iodophenoxy)propanoate (3.58 g, 8.63 mmol) and 1,2-ethanediol (1.20 mL, 21.6 mmol) in toluene (16.3 mL) was treated with p-toluenesulfonic acid monohydrate (246 mg, 1.30 mmol) and heated at reflux in a flask fitted with a Dean-Stark trap filled with sieves. The reaction mixture was cooled and poured into saturated sodium bicarbonate (150 mL) and extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give a crude residue. Purification by flash column chromatography (100% hexanes to 10% EtOAc/hexanes) gave the desired product (2.25 g, 57%) as a mixture of enantiomers. LCMS calculated for C15H18ClFIO5 (M+H)+: m/z=459.0; found: 459.0.