Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:25]4[CH:37]=[CH:36][C:28](/[CH:29]=[CH:30]/[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:27][C:26]=4[CH3:38])[CH:14]=[CH:15][C:16]=3[O:17]CC3C=CC=CC=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.B(Br)(Br)Br.CCOC(C)=O.CCCCCC>C(Cl)Cl>[C:1]12([C:11]3[CH:12]=[C:13]([C:25]4[CH:37]=[CH:36][C:28](/[CH:29]=[CH:30]/[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:27][C:26]=4[CH3:38])[CH:14]=[CH:15][C:16]=3[OH:17])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CCOC(=O)/C=C/c1ccc(-c2ccc(OCc3ccccc3)c(C34CC5CC(CC(C5)C3)C4)c2)c(C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)/C=C/c1ccc(-c2ccc(O)c(C34CC5CC(CC(C5)C3)C4)c2)c(C)c1
Reaction time: 2 h

Procedure:
A mixture of 1.44 g (2.84 mmol) of ethyl (E)-4-[3-(1-adamantyl)-4-benzyloxyphenyl]-3-methylcinnamate was stirred in 10 ml of CH2Cl2 at −78° C. under Ar while 8.0 ml of 1.0 M BBr3 in CH2Cl2 was added slowly over a period of 0.5 hour. The reaction mixture was stirred for 2 hours more, at which time the reaction was complete. The mixture was extracted with EtOAc, washed with brine and water, dried (MgSO4), filtered, and concentrated. Flash column chromatography (20% EtOAc/hexane) yielded a pale-yellow solid (0.86 g, 73%: m.p. 193–195° C.; Rf0.47 (20% EtOAc/hexane); 1H NMR (300 MHz, CDCl3) δ 1.78, 2.14 (2 s, 12, AdCH2), 2.09 (s, 3, AdCH), 1.35 (t, J=7.2 Hz, 3 CH3), 2.31 (s, 3, ArCH3), 4.27 (q, J=7.6 Hz, 2, CH2), 4.94 (s, 1, OH), 6.46 (d, J=16.4 Hz, 1, HC═CCO), 6.71 (d, J=8.4 Hz, 1, ArH), 7.03 (dd, J=8.4, 1.6 Hz, 1, ArH), 7.16 (d, J=2.8 Hz, 1, ArH), 7.25 (s, 1, ArH), 7.39 (dd, J=9.2, 2.4 Hz, 1, ArH), 7.41 (s, 1, ArH), 7.71 ppm (d, J=16.0 Hz, 1, C═CHCO).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][C:3]=1[CH3:18].CC(O)C.[OH-].[Na+].Cl>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][C:3]=1[CH3:18]
Reactant: Cc1cc2c(cc1Br)C(=O)C1(CCC(=O)CC1)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc2c(cc1Br)C(=O)C1(CCC(O)CC1)C2
Temperature: 25 °C
Yield: 98 %

Procedure:
6′-Bromo-5′-methylspiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione (Intermediate 2, 1.38 g, 4.49 mmol) and propan-2-ol (16.6 mL, 215 mmol) were heated to 75° C. Ground NaOH (0.176 g, 4.40 mmol) was added. The resulting mixture was heated at reflux for 1.5 h and was then allowed to cool to r.t. The mixture was concentrated to half the volume and then water (15 mL) and toluene (15 mL) were added together with 6 M aq. HCl (0.749 mL, 4.49 mmol). The layers were separated and the aqueous layer was re-extracted with toluene (15 mL). The combined organic layers were dried over Na2SO4, concentrated and dried in vacuo to afford 1.36 g (98% yield) of the title compound as a mixture of isomers (˜70:30 mixture of isomers with the hydroxyl group in equatorial and axial position) and this mixture was used in the next step without further purification: MS (ES+) m/z 308, 311 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[C:13](=[O:43])[NH:14][C@@:15]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][C:39]([F:42])([F:41])[F:40])=[CH:31][CH:30]=3)([C:25]([F:28])([F:27])[F:26])[CH2:16][C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[O:11])=[CH:5][CH:4]=1>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([CH:12]2[CH:17]([C:18]3[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=3)[CH2:16][C:15]([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][CH2:38][C:39]([F:42])([F:41])[F:40])=[CH:33][CH:34]=3)([C:25]([F:26])([F:27])[F:28])[NH:14][C:13]2=[O:43])=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(NC(=O)C2=C(c3ccc(C)cc3)C[C@](c3ccc(OCCCC(F)(F)F)cc3)(C(F)(F)F)NC2=O)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(NC(=O)C2C(=O)NC(c3ccc(OCCCC(F)(F)F)cc3)(C(F)(F)F)CC2c2ccc(C)cc2)cc1
Reaction time: 8 h

Procedure:
To a solution of Example 6-2 (90 mg, 0.15 mol) in MeOH (2 mL) was added 10% palladium on carbon (5 mg). The mixture was stirred under hydrogen (50 psi) overnight. Additional palladium on carbon (5 mg) was added and the reaction was stirred under hydrogen (50 psi) for an additional 1 h. The catalyst was removed by filtration through a pad of Celite® and the solution was concentrated in vacuo. The products were partly separated by preparative HPLC (CH3CN/H2O/TFA). Fractions containing the two products were combined and separated by chiral HPLC method D to provide Example 16-1 and Example 16-2. Data for Example 16-1: LCMS Anal. Calc'd for C31H30F6N2O4 608.57, found [M+H] 609.2. 1H NMR (400 MHz, CD3OD) δ 1.97-2.14 (m, 2H), 2.25 (s, 3H), 2.32-2.46 (m, 2H), 2.54-2.69 (m, 2H), 3.17 (td, J=11.82, 3.85 Hz, 1H), 3.60 (d, J=11.54 Hz, 1H), 3.71 (s, 3H), 4.10 (t, J=6.05 Hz, 2H), 6.76 (d, J=8.79 Hz, 2H), 6.99-7.12 (m, 6H), 7.13-7.23 (m, 2H), 7.55 (d, J=8.79 Hz, 2H). Analytical chiral HPLC method D RT=6.75 min, 99% ee. Data for Example 16-2: LCMS Anal. Calc'd for C31H30F6N2O4 608.57, found [M+H] 609.2. 1H NMR (400 MHz, CD3OD) δ 7.52 (d, J=8.8 Hz, 2H), 7.25-7.20 (m, 2H), 7.19-7.15 (m, 2H), 7.14-7.10 (m, 2H), 7.02-6.97 (m, 2H), 6.81-6.75 (m, 2H), 4.07 (t, J=6.0 Hz, 2H), 3.94-3.84 (m, 1H), 3.73 (s, 3H), 3.60 (d, J=12.1 Hz, 1H), 2.90 (dd, J=14.8, 3.3 Hz, 1H), 2.45-2.32 (m, 2H), 2.31 (dd, 1H, overlaps with peak at δ 2.27), 2.27 (s, 3H), 2.08-1.98 (m, 2H). Preparative chiral HPLC method D: RT=10.9 min, 99% ee.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH2:35][OH:36])([CH2:33][OH:34])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:13]([C:29]([F:32])([F:31])[F:30])[CH:12]=1)(C)(C)C.[ClH:38].O1CCOCC1>C(Cl)Cl>[ClH:38].[NH2:7][C:8]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:13]([C:29]([F:30])([F:31])[F:32])[CH:12]=1)([CH2:33][OH:34])[CH2:35][OH:36]
Reactant: CC(C)(C)OC(=O)NC(CO)(CO)CCc1ccc(OCCCCCc2ccccc2)c(C(F)(F)F)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(CO)(CO)CCc1ccc(OCCCCCc2ccccc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Compound 5-1 (560 mg) was dissolved in methylene chloride (5 ml), hydrogen chloride-containing dioxane (4 mol/l 5 ml) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (410 mg) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:14])[C:9]([OH:11])=O.[CH:23]([N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)([CH3:25])[CH3:24]>>[CH:23]([N:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:9](=[O:11])[CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[O:14])[CH2:28][CH2:27]1)([CH3:25])[CH3:24]
Reactant: O=C(Nc1ccc(Cl)cc1)NC(C(=O)O)c1ccccc1Cl
Reactant: CC(C)N1CCC(N)CC1
Product: CC(C)N1CCC(NC(=O)C(NC(=O)Nc2ccc(Cl)cc2)c2ccccc2Cl)CC1

Procedure:
The titled compound was prepared analogously as describe in Example 82, using 2-(2-chlorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid and 1-isopropyl-4-aminopiperidine. MS 463.1, 464.1, 465.1 and 466.1 (M+H, 2Cl pattern).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].O.[CH2:6]([O:8][C:9](=[O:54])[C:10]([CH3:53])([CH3:52])[CH2:11][C:12]1[N:13]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:45]=[N:46][C:47]([O:50][CH3:51])=[CH:48][CH:49]=3)=[CH:40][CH:39]=2)[C:14]2[C:19]([C:20]=1SC(C)(C)C)=[CH:18][C:17]([O:26][CH2:27][C:28]1[S:29][C:30]3[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=3[N:32]=1)=[CH:16][CH:15]=2)[CH3:7]>C(Cl)Cl>[CH2:6]([O:8][C:9](=[O:54])[C:10]([CH3:53])([CH3:52])[CH2:11][C:12]1[N:13]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:45]=[N:46][C:47]([O:50][CH3:51])=[CH:48][CH:49]=3)=[CH:40][CH:39]=2)[C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([O:26][CH2:27][C:28]1[S:29][C:30]3[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=3[N:32]=1)=[CH:16][CH:15]=2)[CH3:7]
Reactant: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3nc4ccccc4s3)ccc2n1Cc1ccc(-c2ccc(OC)nc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(C)(C)Cc1cc2cc(OCc3nc4ccccc4s3)ccc2n1Cc1ccc(-c2ccc(OC)nc2)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Aluminum chloride (0.18 g, 1.37 mmol) was suspended in CH2Cl2 (1 mL), and water (19 uL, 1.0 mmol) was added slowly at room temperature. The mixture was stirred for 5 minutes, and then cooled to 0° C. 3-{5-(Benzothiazol-2-ylmethoxy)-3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic acid ethyl ester (0.12 g, 0.17 mmol) was added in CH2Cl2 (1 mL), and the reaction was stirred at room temperature for 2 hours. Once no starting material was observed by tlc, water was added and the mixture was extracted with CH2Cl2. The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated. The residue was purified to give the desired product (H-1).
Reaction SMILES: [N+](C1C=CC=CC=1)([O-])=[O:2].Br[C:11]1[CH:12]=[C:13]2[C:26]3[CH:16]([CH2:17][C@@H:18]4[C@@H:23]([C:24]=3[CH:25]=1)[CH2:22][C@H:21]([NH:27][C:28](=[O:34])[N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:20][N:19]4[CH3:35])[CH2:15][N:14]2[Si](C(C)(C)C)(C)C>>[CH2:32]([N:29]([CH2:30][CH3:31])[C:28]([NH:27][C@H:21]1[CH2:22][C@H:23]2[C@@H:18]([CH2:17][CH:16]3[C:26]4[C:13](=[CH:12][CH:11]=[C:25]([OH:2])[C:24]2=4)[NH:14][CH2:15]3)[N:19]([CH3:35])[CH2:20]1)=[O:34])[CH3:33]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(Br)cc4c3C(C[C@H]2N(C)C1)CN4[Si](C)(C)C(C)(C)C
Reactant: O=[N+]([O-])c1ccccc1
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c(O)ccc4c3C(CN4)C[C@H]2N(C)C1

Procedure:
With nitrobenzene and 3-(13-bromo-1-tert-butyldimethylsilyl-2,3-dihydro-6-methyl-8α-ergolinyl)-1,1-diethylurea:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:31])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:24]([CH:26]3[CH2:30][CH2:29][NH:28][CH2:27]3)=[O:25])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[CH3:32][O:33][CH2:34][C:35](Cl)=[O:36]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:31])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:24]([CH:26]3[CH2:30][CH2:29][N:28]([C:35](=[O:36])[CH2:34][O:33][CH3:32])[CH2:27]3)=[O:25])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCNC2)C[C@H]1c1ccc(Cl)cc1
Reactant: COCC(=O)Cl
Product: COCC(=O)N1CCC(C(=O)N2C[C@@H](N(C)C(=O)Oc3ccc(F)cc3)[C@H](c3ccc(Cl)cc3)C2)C1

Procedure:
In analogy to the procedure described for the synthesis of example 73, the title [(3S,4R)-4-(4-chloro-phenyl)-1-(1-(2-methoxy-acetyl)-pyrrolidine-3-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-1-(pyrrolidine-3-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester instead of rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using methoxyacetyl chloride instead of propionyl chloride and was obtained as a light yellow oil. MS m/e: 518.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[C:14]([CH:19]3OCC[O:20]3)[CH:13]=2)=[CH:7][C:6]=1[O:24][CH3:25])[CH3:2].Cl>C1COCC1.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[C:14]([CH:19]=[O:20])[CH:13]=2)=[CH:7][C:6]=1[O:24][CH3:25])[CH3:2]
Reactant: CCOC(=O)c1ccc(Oc2ccc(Br)c(C3OCCO3)c2)cc1OC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(Oc2ccc(Br)c(C=O)c2)cc1OC
Temperature: 25 °C
Yield: 59.8 %

Procedure:
To a solution of compound 6 (5.6 g, 13.23 mmol) in THF (50 mL) at 0° C. was added 2N HCl (50 mL). The resulting mixture was stirred at rt O/N. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (50 mL). The organic layer was dried over Na2SO4, and concentrated under reduced pressure to give crude product, which was purified by column chromatography (silica gel, 10% EtOAc in hexane) to afford the title compound 7 (3.0 g, 60%) as a pale yellow solid. 1H NMR 400 MHz (CDCl3) δ: 10.35 (s, 1H), 7.82 (d, J=8.6 Hz, 1H), 7.60 (d, J=8.6 Hz, 1H), 7.58 (d, J=2.7 Hz, 1H), 7.19 (dd, J=8.6, 3.1 Hz, 1H), 6.60 (d, J=2.0 Hz, 1H), 6.51 (dd, J=8.6, 2.3 Hz, 1H), 4.39 (q, J=7.0 Hz, 2H), 3.81 (s, 3H), 1.40 (t, J=7.0 Hz, 3H); MS (ES) m/z: 379 (M+1)+, 381 (M+3)+.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[N:7]=1.C(N(CC)CC)C.[CH2:17]([Si:19]([C:24]#[CH:25])([CH2:22][CH3:23])[CH2:20][CH3:21])[CH3:18]>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Cl:8][C:6]1[N:7]=[C:2]([C:18]#[C:17][Si:19]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:20][CH3:21])[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: Nc1ncc(Cl)nc1Br
Reactant: C#C[Si](CC)(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[Si](C#Cc1nc(Cl)cnc1N)(CC)CC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 250 ml round bottom flask was charged with 3-bromo-5-chloro-pyrazin-2-ylamine (2) (1 g, 4.8 mmol), THF (10 ml), copper iodide (9 mg, 0.05 mM) and PdCl2(PPh3)2 (34 mg, 0.05 mmol) under nitrogen. To the reaction mixture, triethylamine (2 ml, 14.4 mmol) and triethylsilylacetylene (1 ml, 5.76 mmol) were added. The reaction mixture was stirred at room temperature for 3 h, then concentrated in vacuo and the residue was purified by flash chromatography, using as eluent pentane/EtOAc 10% to 30%, to give the title compound as an off white solid (1.2 g, 100%). 1H NMR (CDCl3): 0.7-0.8 (6H, qd), 1.0-1.1 (9H, t), 5.0-5.1 (2H, brs), 7.95 (1H, s). MS (ES+): 268.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]#[N:8].Br[CH2:10][CH2:11]Cl.[H-].[Na+]>CS(C)=O.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([C:7]#[N:8])[CH2:11][CH2:10]1
Reactant: N#CCc1ccco1
Reactant: ClCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CC1(c2ccco2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of furan-2-acetonitrile (28.4 g) and 1-bromo-2-chloroethane (33.1 ml) in dimethyl sulphoxide (50 ml) was added slowly to a stirred suspenson of sodium hydride (60% dispersion in mineral oil ; 31.85 g) in dry dimethyl sulphoxide (300 ml) keeping the internal temperature just below 35° C. by occasional cooling. After stirring for 18 hours at ambient temperature the mixture was diluted with water (500 ml) and extracted with ether (1×200 then 2×100 ml). The combined extracts were dried over potassium carbonate and evaporated to an oil which was distilled at reduced pressure to give 1-(2-furyl)cyclopropanecarbonitrile (28.0 g) as a colourless oil, bp 54° C./0.55 mbar.
Reaction SMILES: CS(O[C@H:6]1[CH2:10][C@@H:9]([CH2:11][OH:12])[C@@H:8]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:7]1)(=O)=O.CN(C)C=O.[N-:26]=[N+:27]=[N-:28].[Na+]>>[N:26]([C@@H:6]1[CH2:10][C@@H:9]([CH2:11][OH:12])[C@@H:8]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:7]1)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@@H](OS(C)(=O)=O)C[C@H]1CO
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](N=[N+]=[N-])C[C@H]1CO
Temperature: 55 °C

Procedure:
To a solution of (1S,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-(hydroxymethyl)-cyclopentyl methanesulfonate (0.470 g, 0.00145 mol) in N,N-Dimethylformamide (6 mL, 0.08 mol) was added sodium azide (0.4 g, 0.006 mol) 23° C., and the mixture was heated at 55° C. for 3 hours. The reaction was cooled to 23° C., quenched by addition of water and extracted with Et20 (3×), dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (10 to 25% ethyl acetate/hexane) to obtain 211 mg (53.7%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH2:30][O:31][CH3:32])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[O:33]1[CH2:38][CH2:37][N:36]([CH2:39][C:40]2[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=2)[CH2:35][CH2:34]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:43]2[CH:42]=[CH:41][C:40]([CH2:39][N:36]3[CH2:37][CH2:38][O:33][CH2:34][CH2:35]3)=[CH:45][CH:44]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH2:30][O:31][CH3:32])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: COCCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: OB(O)c1ccc(CN2CCOCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COCCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 39.5 %

Procedure:
A solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-((2-methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (110 mg, 0.21 mmol), (4-(morpholinomethyl)phenyl)boronic acid (99 mg, 0.33 mmol), sodium carbonate (83 mg, 0.78 mmol) in 4 ml of dioxane was degassed with argon for 20 min, Pd(PPh3) (25 mg, 0.02 mmol) was added to the mixture and heated to 100° C. for overnight. The reaction was cooled to room temperature and diluted with water, compound was extracted in 10% MeOH in DCM, dried over Na2SO4, concentrated and crude product purified by silica gel (100-200) chromatography to obtain the title compound (50 mg 38%).
Reaction SMILES: [CH:1]1[C:6](N=C=S)=[CH:5][C:4]2[C:10]([O:12][C:13]3([C:23]4[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=4[O:21][C:15]4[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]3=4)[C:3]=2[CH:2]=1)=[O:11]>C([O-])(O)=O.[Na+]>[CH:1]1[CH:6]=[CH:5][C:4]([C:10]([OH:12])=[O:11])=[C:3]([C:13]2[C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[O:21][C:22]3[C:23]=2[CH:24]=[CH:25][C:26]([CH:27]=3)=[O:28])[CH:2]=1
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12

Procedure:
A quantity of fluorescein isothiocyanate sufficient to modify one amine group in about every 2000 is added to a solution of chitlac (200 mg, Mw˜1.5×106 of ex. 1) in NaHCO3 0.5 M (65 mL). The solution is maintained under agitation in darkness for 24 hours, dialyzed against NaHCO3 0.05 M (3 changes) and against deionized water until conductivity is 4 μS at 4° C. Finally, the solution is filtered through 0.45 μm Millipore filters and lyophilized.
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[F:22].[I:23]I>O1CCCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([I:23])[C:15]=1[F:22]
Reactant: II
Reactant: COc1ccc(Br)c(F)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc(Br)c(F)c1I
Temperature: -78 °C

Procedure:
Into a 25-mL round-bottom flask (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed (i-Pr)2NH (1.26 g, 12.48 mmol, 1.25 equiv), tetrahydrofuran (7 mL). This was followed by the addition of n-BuLi (2.5M in hexane) (4.8 mL) dropwise with stirring at −78° C. The mixture was stirred for 1 h at −78° C. Then this solution was added to the solution a solution of 1-bromo-2-fluoro-4-methoxybenzene (2.04 g, 9.95 mmol, 1.00 equiv) in tetrahydrofuran (5 mL) at −78 degree C. and stirred for 30 min, then I2 (3.048 g, 12.00 mmol, 1.2 equiv) was added. The resulting solution was stirred for 30 min at −78° C. in a liquid nitrogen bath. The reaction progress was monitored by GCMS. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 2×20 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with petroleum ether. This resulted in 2.0 g (61%) of 1-bromo-2-fluoro-3-iodo-4-methoxybenzene as a light yellow solid. Mass spectrum (GC, m/z): Calcd. for C7H5BrFIO, 330.9 (M). found 330.9.
Reaction SMILES: C(N1CCN(CC(NC2C=C(C=CC=2)C(NCCC(O)=O)=O)=O)CC1)(=N)N.[C:28]([N:38]1[CH2:43][CH2:42][N:41]([CH:44]([C:69](=[NH:71])[NH2:70])[C:45](NC2C=C(C=CC=2)C(NCCC(OCC2C=CC=CC=2)=O)=O)=[O:46])[CH2:40][CH2:39]1)([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29].N1(CC([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=O)CCNCC1.C(NC(=N)SC)(OCC1C=CC=CC=1)=O>>[C:28]([N:38]1[CH2:39][CH2:40][N:41]([CH:44]([C:69](=[NH:71])[NH2:70])[C:45]([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=[O:46])[CH2:42][CH2:43]1)([O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:29]
Reactant: N=C(N)C(C(=O)Nc1cccc(C(=O)NCCC(=O)OCc2ccccc2)c1)N1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)CN1CCNCC1
Agent: CSC(=N)NC(=O)OCc1ccccc1
Agent: N=C(N)N1CCN(CC(=O)Nc2cccc(C(=O)NCCC(=O)O)c2)CC1
Product: CC(C)(C)OC(=O)C(C(=N)N)N1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
3-(3-(4-amidinopiperazin-1-ylacetamido)benzamido)propionic acid, m.p. 270° (decomposition), from benzyl 3-(3-(4-CBZ-amidinopiperazin-1-ylacetamido)benzamido)propionate (FAB 601; obtainable by reacting tert-butyl piperazin-1-ylacetate with N-CBZ-S-methylisothiourea to give tert-butyl 4-CBZ-amidinopiperazin-1-ylacetate, cleaving the tert-butyl group with 4 N HCl in dioxane and condensing the resulting 4-CBZ-amidinopiperazin-1-ylacetic acid with benzyl 3-(3-aminobenzamido)propionate);
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][N:8]([C:22](=[O:26])[C@H:23]([CH3:25])[NH2:24])[CH:9]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].C([O-])(=O)C.O=[C:38]([CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:39]([O:41][CH2:42][CH3:43])=[O:40]>C(O)C.[Ni]>[C:1]([O:5][C:6](=[O:27])[CH2:7][N:8]([C:22](=[O:26])[C@H:23]([CH3:25])[NH:24][CH:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[CH:9]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Reactant: COc1cc2c(cc1OC)C(N(CC(=O)OC(C)(C)C)C(=O)[C@H](C)N)CC2
Agent: [Ni]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)N(CC(=O)OC(C)(C)C)C1CCc2cc(OC)c(OC)cc21
Yield: 33.3 %

Procedure:
L-Alanyl-N-(5,6-dimethoxyindan-1-yl)glycine tert-butyl ester (4.0 g) is dissolved in 80 ml of ethanol, and 0.77 g of sodium acetate, 4.0 g of acetate acid, 4.0 g of ethyl 2-oxo-4-phenyl-butyrate, 12 g of molecular sieve 3A and 6.0 g of Raney nickel are added. Thereafter, the reaction and treatment are carried out as in Example 2 to give 2.0 g of N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-N-(5,6-dimethoxyindan-1-yl)glycine tert-butyl ester as slightly yellow oil.
Reaction SMILES: O.[N+:2]([C:5]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:6]=1[NH2:7])([O-:4])=[O:3].[Br:15]Br.N>C(O)(=O)C>[Br:15][C:8]1[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=[C:5]([N+:2]([O-:4])=[O:3])[C:6]=1[NH2:7]
Reactant: BrBr
Reactant: Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: N
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(Br)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred mixture of H2O (3.75 L) and acetic acid (375 mL) at RT was added 2,4-dinitroaniline (500 g, 2.73 mol) followed by drop wise addition of bromine (210 mL, 4.09 mol) over 30 min. The reaction mixture was stirred at RT for 15 min and then heated to 100° C. for 2 h. The reaction was cooled to RT and poured onto ice-cold H2O (5-6 L) and basified (pH 8-10) with aqueous ammonia. The solid was filtered, washed with cold H2O and dried under vacuum. This solid was washed with n-pentane to obtain i (600 g, 84%).