Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]3[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[C:12]3=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[Li+].[OH-].Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]3[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:12]3=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccc(C)c(F)c3)c(-c3ccc(C)c(F)c3)nc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)c(F)c2)N(CCCCCCC(=O)O)CCC3)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl 7-(2,3-bis(3-fluoro-4-methylphenyl)-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (121 mg, 0.238 mmol) in THF (2 ml) and water (2 ml) was treated with LiOH (45.7 mg, 1.907 mmol) and the resulting mixture was stirred at RT for 18 h. The mixture was acidified to pH 4 with HCl and extracted with DCM. The organic extracts were combined, dried (sodium sulphate), filtered and concentrated in vacuo. The residue was azeotroped with ether to afford the title compound;
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.C([Li])CCC.CN(C)[CH:20]=[O:21].Cl>O1CCCC1.CCCCCC>[O:10]1[C:4]2[CH:3]=[C:2]([CH:20]=[O:21])[CH:12]=[CH:11][C:5]=2[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: Brc1ccc2c(c1)OCCCC2
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)OCCCC2
Temperature: 25 °C
Yield: 105.8 %

Procedure:
To a solution of 2.01 g (8.8 mmol) of 8-bromo-2,3,4,5-tetrahydro-1-benzoxepine in 54 mL of anhydrous tetrahydrofuran and 13.5 mL of hexane under nitrogen cooled in a dry ice/acetone bath was added dropwise 4.1 mL (10.2 mmol, 1.15 equiv) of 2.5M n-butyllithium in tetrahydrofuran, keeping the internal temperature <−65° C. The mixture was stirred with cooling for 45 minutes. A solution of 1.03 mL (13.3 mmol, 1.5 equiv) dimethylformamide in 9 mL of anhydrous tetrahydrofuran was added dropwise over 5 minutes. The mixture was stirred overnight while warming to ambient temperature. The reaction mixture was poured into 81 mL of 2N HCl, and the layers were separated. The aqueous layer was extracted with 3×85 mL of ether. The combined organic layer was washed with 75 mL each of water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 1.64 g of a yellow oil. Purification by flash chromatography (5-40% ethyl acetate in hexanes) gave the product as a colorless oil. MS (m+1)=177.2; 1H NMR (400 MHz, CDCl3) 9.92 (s, 1H), 7.49 (m, 2H), 7.29 (d, 1H, J 7.5 Hz), 4.03 (m, 2H), 2.89 (m, 2H), 2.00 (m, 2H), 1.76 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:35][C@H:36]([OH:43])[C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25]C)=[O:24])=[C:19]([O:27][CH:28]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH2:35][C@H:36]([OH:43])[C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[C:19]([O:27][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)[CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(-c2ccc(CCN(C[C@H](O)c3cccnc3)C(=O)OC(C)(C)C)cc2)cc1OC1CCCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(C(=O)O)c(OC3CCCCCC3)c2)cc1)C[C@H](O)c1cccnc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.5 %

Procedure:
To a solution of methyl 4′-[2-[(tert-butoxycarbonyl)-[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-3-(cycloheptyloxy)-4-biphenylcarboxylate (813 mg) in methanol (8.1 ml) and tetrahydrofuran (2.4 ml) was added 1N sodium hydroxide (4.14 ml) and the mixture was stirred at room temperature for 24 hours. The mixture was quenched by the addition of 1N hydrochloric acid (4.14 ml) and the solvent was removed by evaporation. The residue was chromatographed on silica gel (eluent: hexane/ethyl acetate) to give 4′-[2-[(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-3-(cycloheptyloxy)-4-biphenylcarboxylic acid (575 mg) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[F:51][C:52]1[CH:64]=[CH:63][C:62]([F:65])=[CH:61][C:53]=1[O:54][CH:55]1[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1>CN(C=O)C.O>[F:51][C:52]1[CH:64]=[CH:63][C:62]([F:65])=[CH:61][C:53]=1[O:54][CH:55]1[CH2:56][CH2:57][N:58]([C:16](=[O:18])[CH2:15][NH:14][C:12]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:11][N:10]=2)=[O:13])[CH2:59][CH2:60]1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: Fc1ccc(F)c(OC2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2cc(F)ccc2F)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 0.03 h
Yield: 49.2 %

Procedure:
To a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (0.075 g, 0.0003 mol) in DMF (2 mL) was added DIPEA (0.135 g, 0.0012 mol), HOBt (0.061 g, 0.00045 mol) and EDCI.HCl (0.086 g, 0.00045 mol) at ambient temperature. After 2 minutes, 4-(2,5-difluoro-phenoxy)-piperidine hydrochloride (0.076 g, 0.0003 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was collected and washed with brine solution, dried over sodium sulfate and concentrated. The resulting residue was purified by column chromatography using neutral aluminum oxide (5% methanol in chloroform) to afford 0.065 g (49%) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2,5-difluoro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 441.17 (M+1)+, 91.07%, 1H NMR (DMSO-d6): δ 13.8 (bs, 1H), 8.0 (bs, 1H), 7.8 (m, 2H), 7.4 (m, 5H), 7.2 (m, 1H), 6.8 (m, 1H), 4.6 (m, 1H), 4.2 (m, 2H), 3.9 (m, 1H), 3.8 (m, 1H), 2.0 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:21]([O-:24])(=[O:23])=O)[C:5]2[C:10]([C:11]=1[NH:12][C:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH+:25]1[CH:30]=[CH:29]C=[CH:27][CH:26]=1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH2:26]([N:25]([CH2:30][CH3:29])[S:21]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11]2[N:12]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:1][C:2]=2[CH:3]=1)(=[O:24])=[O:23])[CH3:27]
Reactant: c1cc[nH+]cc1
Reactant: O=C(Nc1c(O)cc(S(=O)(=O)[O-])c2ccccc12)c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCN(CC)S(=O)(=O)c1cc2oc(-c3ccccc3)nc2c2ccccc12
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
A mixture of 3.43 g pyridinium 3-hydroxy-4-(N-benzoylamino)-1-naphthalenesulfonate and 10 ml thionyl chloride was refluxed for 3.5 hours. Toluene (20 ml) was added and the excess thionyl chloride was distilled off with toluene under reduced pressure. The solid residue was dissolved in 50 ml methylene chloride and 10 ml diethylamine was added portionwise while stirring. After 30 min, the reaction mixture was poured into 100 ml ice-water and extracted with 100 ml dichloromethane. The organic phase was separated, washed with water, and dried over sodium sulfate. Evaporation of the solvent gave 2.52 g N,N-diethyl-2-phenylnaphth[1,2-d]oxazole-5-sulfonamide of high purity by NMR. Recrystallization from 95% ethanol gave an analytical sample, m.p. 157° C.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][C:17]=3Br)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[CH2:33]([Zn]CC)[CH3:34]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][C:17]=3[CH2:33][CH3:34])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(Br)c1
Reactant: CC[Zn]CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(CC)c1
Reaction time: 4 h
Yield: 37 %

Procedure:
Ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-bromophenyl)acetate (Example 46 step C; 30 mg, 0.058 mmol) was diluted with THF (1 mL) followed by the addition of 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (4.8 mg, 0.0058 mmol) and diethylzinc (0.13 ml, 0.15 mmol). After stirring for 4 hours, the reaction loaded directly onto a silica gel column, eluting with 5-50% ethyl acetate/hexane to yield ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-ethylphenyl)acetate (10 mg, 37% yield).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:27])[NH:20][C:21]3[C:26]\2=[CH:25][CH:24]=[CH:23][CH:22]=3)/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:8][CH:9]=1)([OH:3])=O.Cl.CN.[CH3:31][N:32](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(N(CC)CC)C>[CH3:31][NH:32][C:1]([C:4]1[CH:5]=[C:6]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:27])[NH:20][C:21]3[C:26]\2=[CH:25][CH:24]=[CH:23][CH:22]=3)/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: O=C1Nc2ccccc2/C1=C(/Nc1cccc(C(=O)O)c1)c1ccccc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 18 from (Z)-3-[1-(3-carboxyphenylamino)-1-phenyl-methylidene]-2-indolinone, methylamine-hydrochloride, TBTU, HOBt and triethylamine in DMF.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][C:21]([N+:27]([O-:29])=[O:28])=[CH:22][CH:23]=4)[NH:18][C:17]3=S)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[OH-:33].[K+].O.OO>C(O)C.C(O)(=O)C>[F:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][C:21]([N+:27]([O-:29])=[O:28])=[CH:22][CH:23]=4)[NH:18][C:17]3=[O:33])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=S)[nH]c3cc([N+](=O)[O-])ccc3c2=O)CC1
Agent: OO
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)[nH]c3cc([N+](=O)[O-])ccc3c2=O)CC1
Reaction time: 2.5 h

Procedure:
To a stirred mixture of 7 parts of 3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,3-dihydro-7-nitro-2-thioxo-4(1H)-quinazolinone, 120 parts of a solution of potassium hydroxide in ethanol 5% and 10 parts of water were added dropwise 100 parts of a hydrogen peroxide solution 3% during a 10 minutes period. Upon completion, stirring was continued for 2.50 hours at room temperature. Then there were added 100 parts of water and the whole was neutralized with acetic acid. The precipitated product was filtered off and crystallized from a mixture of N,N-dimethylacetamide and water, yielding 4.8 parts of 3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-7-nitro-2,4(1H,3H)-quinazolinedione; mp. 238.1°-240.1° C. (23).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:18]3[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:22]=3)[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]=2[CH:3]=1.[F:30][C:31]([F:40])([F:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH2:38]>>[C:26]([O:25][C:23]([N:21]1[CH:22]=[C:18]([C:9]2[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[C:4]3[CH:3]=[C:2]([NH:38][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[C:31]([F:30])([F:39])[F:40])[N:7]=[CH:6][C:5]=3[CH:8]=2)[CH:19]=[N:20]1)=[O:24])([CH3:28])([CH3:29])[CH3:27]
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Br)cc3n2C(=O)OC(C)(C)C)cn1
Reactant: Nc1ccccc1C(F)(F)F
Product: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Nc4ccccc4C(F)(F)F)cc3n2C(=O)OC(C)(C)C)cn1
Yield: 88 %

Procedure:
The title compound was prepared in 88% yield from compound (10) and 2-trifluoromethyl phenylamine using the method described for Preparation 35. 1H-NMR (CDCl3, 500 MHz): δ 1.49 (s, 9H), 1.69 (s, 9H), 6.61 (d, J=0.95 Hz, 1H), 6.82 (br s, 1H, NH), 7.12 (t, J=7.57 Hz, 1H), 7.51 (t, J=8.20 Hz, 1H), 7.61 (m, 1H), 7.65 (d, J=7.57 Hz, 1H), 7.83 (d, J=0.63 Hz, 1H), 7.89 (d, J=8.20 Hz, 1H), 8.22 (d, J=0.95 Hz, 1H), 8.50 (d, 0.95 Hz, 1H). 19F-NMR (CDCl3): δ −61.43.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][SH:6].Br[C:10]1[C:11]([C:16]#[N:17])=[N:12][CH:13]=[CH:14][CH:15]=1>C1COCC1>[C:16]([C:11]1[C:10]([S:6][CH2:5][C:4]([F:8])([F:7])[F:3])=[CH:15][CH:14]=[CH:13][N:12]=1)#[N:17]
Reactant: FC(F)(F)CS
Reactant: N#Cc1ncccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ncccc1SCC(F)(F)F
Temperature: 50 °C

Procedure:
A suspension of sodium hydride (60% oil dispersion, 180 mg, 4.52 mmol) in dry THF (17 mL) under N2 was treated with trifluoroethanethiol (0.40 mL, 4.52 mmol) and the mixture was heated to 50° C. When gas evolution ceased (ca. 1 h), 3-bromo-2-cyanopyridine was added and the mixture was heated to reflux for 4 h. The solvent wag removed in vacuo and the residue was taken up in CH2Cl2 and filtered to remove precipitated sodium bromide. The filtrate was concentrated at reduced pressure to afford the title compound as an orange oil:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.[N:13]1([C:18]2[C:19]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1.C(N=C=NCCCN(C)C)C>>[CH2:15]1[CH2:14][N:13]([C:18]2[CH:23]=[CH:22][CH:21]=[N:20][C:19]=2[N:24]2[CH2:25][CH2:26][N:27]([C:10]([C:2]3[NH:1][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH:3]=3)=[O:12])[CH2:28][CH2:29]2)[CH2:17][CH2:16]1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: c1cnc(N2CCNCC2)c(N2CCCC2)c1
Agent: CCN=C=NCCCN(C)C
Product: O=C(c1cc2ccccc2[nH]1)N1CCN(c2ncccc2N2CCCC2)CC1

Procedure:
Following the general procedure of EXAMPLE 16A and making non-critical variations but starting with indole-2-carboxylic acid (0.12 g), 1-[3-(1-pyrrolidinyl)-2-pyridinyl]piperazine (PREPARATION 48, 0.17 g) and 1-(ethyl)-3-(dimethylaminopropyl)carbodiimide (0.17 g), the title compound is obtained, mp 181°-182°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH:19]12[NH:26][CH:23]([CH2:24][CH2:25]1)[CH2:22][O:21][CH2:20]2>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:26]3[CH:19]4[CH2:25][CH2:24][CH:23]3[CH2:22][O:21][CH2:20]4)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Reactant: C1CC2COCC1N2
Agent: Cl
Product: CC(C)(C)OC(=O)N1Cc2ccc(N3C4CCC3COC4)cc2C1

Procedure:
Prepared in analogy to Example A3(d) from 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride. Yellow oil. MS (m/e): 331.4 ([M+H]+, 100%).
Reaction SMILES: [C:1]1([C:25]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=O)[C:18]2[C:19]3[C:24]4[C:3](=[CH:4][CH:5]=[C:6]5[C:23]=4[C:22]4[C:9](=[CH:10][CH:11]=[C:12]6[C:21]=4[C:20]=3[C:15](=[CH:16][CH:17]=2)[CH:14]=[CH:13]6)[CH:8]=[CH:7]5)[CH:2]=1.[OH-].[Na+]>C(O)COCCO>[C:1]1([CH2:25][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C:18]2[C:19]3[C:24]4[C:3](=[CH:4][CH:5]=[C:6]5[C:23]=4[C:22]4[C:9](=[CH:10][CH:11]=[C:12]6[C:21]=4[C:20]=3[C:15](=[CH:16][CH:17]=2)[CH:14]=[CH:13]6)[CH:8]=[CH:7]5)[CH:2]=1
Reactant: O=C(O)CCC(=O)c1cc2ccc3ccc4ccc5ccc6ccc1c1c6c5c4c3c21
Agent: [Na+]
Agent: [OH-]
Solvent: OCCOCCO
Product: O=C(O)CCCc1cc2ccc3ccc4ccc5ccc6ccc1c1c6c5c4c3c21
Temperature: 180 °C
Yield: 86 %

Procedure:
The Huang-Minlon method was used essentially as described in Clar and Zanders (1958), with modifications to increase the overall yield of the acid: 3-coronenoyl propionic acid (100mg), 80% hydrated hydrazine (74.8 μl), NaOH (60mg), and diethylene glycol (249μl) were combined in a 5ml round-bottomed flask. The mixture was refluxed for 90 minutes at 180° C, then water and excess hydrazine hydrate were distilled off until the temperature rose to 200° C. The mixture was refluxed for an additional 3.5 hours at 195° C., cooled to room temperature and diluted with water and 2M HCl. The resulting solid was collected by vacuum filtration and washed with cold water and 2M HCl. The product was recrystallized from xylene, dried under vacuum for 48 hours. 50mg of crystalline product was further purified by flash chromatography on a silica gel G column (100cm×2.5cm; 40 micron particle size) with a nitrogen pressure of 5-10 p.s.i. using ethyl acetate/xylene (2:1; v/v) as the running solvent. The eluant was tested using TLC (silica gel G plates) and THF/xylene (1:1; v/v) as the running solvent. The pure 4-coronenyl butyric acid (FIG. 1, compound III) exhibited a single spot (Rf=0.65) under these conditions. Fractions containing pure product were pooled and dried by rotary evaporation. A yield of 86% was obtained (66.4 mg) with a melting point of 273° C. IR and NMR analysis showed spectra consistent with the expected product. Compound III in THF had an absorption band ε294 =23,644±97 80M-1 cm-1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N:19]2[S:23](=[O:25])(=[O:24])[N:22](CC3C=CC(OC)=CC=3OC)[C:21](=[O:37])[CH2:20]2)=[CH:11][C:12]2[CH2:16][CH:15]([CH3:17])[S:14][C:13]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:10]([N:19]2[S:23](=[O:24])(=[O:25])[NH:22][C:21](=[O:37])[CH2:20]2)=[CH:11][C:12]2[CH2:16][CH:15]([CH3:17])[S:14][C:13]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2C(=O)CN(c3cc4c(cc3OCc3ccccc3)SC(C)C4)S2(=O)=O)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1Cc2cc(N3CC(=O)NS3(=O)=O)c(OCc3ccccc3)cc2S1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5-(6-benzyloxy-2-methyl-2,3-dihydrobenzo[b]thiophen-5-yl)-2-(2,4-dimethoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (71 mg, 0.13 mmol) in DCM (8 mL) is added TFA (10 mL) and the mixture is stirred at RT for 4 h. TFA and DCM are removed under vacuum to give the title compound and it is used directly in the next step: (M+H)+=301.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:14]2[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[S:17][C:13]=2[C:12](=[O:24])[N:11]=[CH:10]1.[CH2:25](B(O)O)[CH3:26].P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:25]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:14]2[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[S:17][C:13]=2[C:12](=[O:24])[N:11]=[CH:10]1)[CH3:26]
Reactant: CCB(O)O
Reactant: O=c1ncn(Cc2ccccc2Br)c2nc(N3CCOCC3)sc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: CCc1ccccc1Cn1cnc(=O)c2sc(N3CCOCC3)nc21
Yield: 57.1 %

Procedure:
A mixture of 4-[(2-bromophenyl)methyl]-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (120 mg, 0.295 mmol), ethylboronic acid (32.7 mg, 0.442 mmol) and potassium phosphate (125 mg, 0.589 mmol) in Toluene (2 mL) was charged into a microwave tube under N2, followed by the addition of S-Phos (12.10 mg, 0.029 mmol), and Pd(OAc)2 (3.31 mg, 0.015 mmol). The mixture was irradiated with microwave at 150° C. for 15 min. The solvent was removed and the residue was partitioned between DCM and brine. The organic layer was concentrated and the residue was purified by reverse phase HPLC (5% org˜50% org) to give the product (60 mg, 58%). LCMS (ES) m/z 357.1 (M+H)+, 1H NMR (400 MHz, CDCl3-d1)) δppm 8.50 (br, s, 1H), 7.38 (m, 1H), 7.33 (m, 1H), 7.25 (m, 1H), 7.09 (m, 1H), 5.48 (s, 2H), 3.86 (m, 4H), 3.69 (m, 4H), 2.71 (q, 2H), 1.25 (t, 3H).
Reaction SMILES: C(OC(=O)[C@H](CC1C=CC=C(OC2C=CC(O)=CC=2)C=1)NC(=O)C(F)(F)F)C.C([O:31][C:32](=[O:64])[C@H:33]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([O:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][C:56]3[CH:61]=[CH:60][C:59]([O:62]C)=[CH:58][CH:57]=3)=[CH:51][CH:50]=2)[CH:43]=1)[NH:34]C(=O)C(F)(F)F)C>>[OH:62][C:59]1[CH:58]=[CH:57][C:56]([O:55][C:52]2[CH:53]=[CH:54][C:49]([O:48][C:44]3[CH:43]=[C:42]([CH:47]=[CH:46][CH:45]=3)[CH2:41][C@@H:33]([C:32]([OH:64])=[O:31])[NH2:34])=[CH:50][CH:51]=2)=[CH:61][CH:60]=1
Reactant: CCOC(=O)[C@H](Cc1cccc(Oc2ccc(Oc3ccc(OC)cc3)cc2)c1)NC(=O)C(F)(F)F
Agent: CCOC(=O)[C@H](Cc1cccc(Oc2ccc(O)cc2)c1)NC(=O)C(F)(F)F
Product: N[C@@H](Cc1cccc(Oc2ccc(Oc3ccc(O)cc3)cc2)c1)C(=O)O

Procedure:
In a similar manner to Example 49-1), 3-[4-(4-hydroxyphenoxy)-phenoxy]-L-phenylalanine was synthesized by deprotecting by a conventional method from N-trifluoroacetyl-3-(4-hydroxyphenoxy)-L-phenylalanine ethyl ester via N-trifluoroacetyl-3-[4-(4-methoxyphenoxy)phenoxy]-L-phenylalanine ethyl ester. N-Trifluoroacetyl-3-[4-(4-methoxyphenoxy)phenoxy]-L-phenylalanine ethyl ester: m.p.: 67-71° C.; IR (Nujol): 3324, 1745, 1707, 1559, 1507, 1501 cm−1; APCI-MS m/z: 504 [M+H]+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]2=[O:17])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[N:18]1([CH2:24][CH2:25][OH:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[H-].[Na+].O>C1COCC1.CCOC(C)=O>[N+:8]([C:7]1[CH:6]=[CH:5][C:4]([N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]2=[O:17])=[CH:3][C:2]=1[O:26][CH2:25][CH2:24][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)([O-:10])=[O:9]
Reactant: OCCN1CCCCC1
Reactant: O=c1ccccn1-c1ccc([N+](=O)[O-])c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=c1ccccn1-c1ccc([N+](=O)[O-])c(OCCN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a suspension of 1-(3-fluoro-4-nitrophenyl)pyridin-2(1H)-one (0.70 g, 2.99 mmol) in anhydrous THF (6 mL) at room temperature, a pre-mixed solution of 1-piperidineethanol (0.40 mL, 3.02 mmol) and NaH (60%, 157 mg, 3.92 mmol) in anhydrous THF (8 mL) was added. After addition, the suspension became clear. The mixture was stirred at room temperature overnight. HPLC showed that the reaction was incomplete. Another pre-mixed solution of 1-piperidineethanol (0.40 mL, 3.02 mmol) and NaH (60%, 157 mg, 3.92 mmol) in anhydrous THF (5 mL) was added. After 1 h of stirring, the reaction was completed. H2O and EtOAc were added. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give 1-(4-nitro-3-(2-(piperidin-1-yl)ethoxy)phenyl)pyridin-2(1H)-one (0.74 g).