Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[Cl:34])[C:28](Cl)=[O:29].Cl>N1C=CC=CC=1>[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[Cl:34])[C:28]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=3)=[O:7])=[CH:22][CH:23]=1)=[O:29]
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3-c3ccccc32)cc1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3-c3ccccc32)cc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 107.3 %

Procedure:
A mixture of 150 mg (0.5 mmol) of 5-(4-aminobenzoyl)-5,6-dihydrophenanthridine and 115 mg (0.55 mmol) of 3,4-dichlorobenzoyl chloride in 1 ml of pyridine is stirred at room temperature for 6 hours. To the mixture is added 6 ml of 2N HCl and the mixture stirred and filtered to give a solid. The solid is washed with water, 2N sodium carbonate and water to give 254 mg of crystals, m.p. 94°-95° C. The solid is chromatographed on thick layer silica gel plates with hexane ethyl-acetate (1:1) as solvent to give 107 mg of solid. Mass Spec (FAB) 473 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25][CH2:26][CH3:27])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:7]2.[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1>C1COCC1>[CH2:26]([O:25][C:20]1[CH:19]=[C:18]([C@H:12]([N:8]2[C:9](=[O:11])[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[NH:1][C:31]([CH:28]3[CH2:30][CH2:29]3)=[O:32])[CH2:7]2)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:23]=[CH:22][C:21]=1[OH:24])[CH3:27]
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3cccc(N)c3C2=O)ccc1O
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1O
Temperature: 60 °C
Yield: 18.7 %

Procedure:
To a mixture of (S)-7-amino-2-(1-(3-ethoxy-4-hydroxyphenyl)-2-(methylsulfonyl)ethyl)isoindolin-1-one (5.86 g, 15.0 mol) in THF (60 mL) was added cyclopropanecarbonyl chloride (1.5 mL, 16.1 mmol). The mixture was heated to 60° C. for 1 hour then cooled to room temperature. The solvent was removed and the crude residue purified using column chromatography (MeOH/CH2Cl2; 0-5% over 60 minutes) to give 4.7 g of crude, 68% yield. Further purification was then carried out by prep-HPLC to give (S)—N-(2-(1-(3-ethoxy-4-hydroxyphenyl)-2-(methylsulfonyl)ethyl)-3-oxoisoindolin-4-yl)cyclopropanecarboxamide as a white solid (1.38 g, 20% yield). HPLC: HPLC: Hypersil DBS C8 column, 250×4.6 mm, 5 μm; 99/1 to 85/15 over 15 min Gradient CH3CN/10 mM aq. KH2PO4, 1.0 mL/min, 35° C., run time 20 minutes: tR 12.45 minutes. 1H-NMR (DMSO-d6): 10.51 (1H, s), 9.07 (1H, s), 8.22-8.25 (1H, d), 7.47-7.53 (1H, t), 7.18-7.20 (1H, d), 7.01 (1H, d), 6.78-6.86 (2H, m), 5.82-5.87 (1H, m), 4.61-4.67 (1H, d), 3.91-4.33 (5H, m), 3.02 (3H, s), 1.76-1.82 (1H, m), 1.31-1.36 (3H, t), 0.82-0.96 (4H, m); LC-MS ES+ (M+1) 459.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:8](OCCCO)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:20](OC1C=CC(O)=CC=1)[C:21]1C=CC=CC=1>[O-]CCCC.[O-]CCCC.[O-]CCCC.[O-]CCCC.[Ti+4]>[C:1]([O:6][CH2:7][CH2:20][CH2:21][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: OCCCOCc1ccccc1
Reactant: C=C(C)C(=O)OC
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: [Ti+4]
Agent: CCCC[O-]
Product: C=C(C)C(=O)OCCCCc1ccccc1
Temperature: 25 °C
Yield: 213.7 %

Procedure:
A three neck round bottom flask containing a teflon coated magnetic stirring bar was successively charged with 95 mL (0.884 mol) of methyl methacrylate (2), 4.22 g (0.012 mol) of titanium tetrabutoxide (Ti(OC4H9)4), 50 mL (0.316 mol) of 3-benzyloxy-1-propanol (1), and 14.6 g (0.073 mol) of 4-benzyloxyphenol (4-BOP). An addition funnel, thermometer, and a short path still head with thermometer and receiver flask were placed in the flask necks. The flask was placed in an oil bath and the temperature was increased until distillation began. Methyl methacrylate (2) was placed in the addition funnel and was added dropwise at the same rate as the distillate. The reaction mixture was heated for 4 hours and then cooled to room temperature. The crude product was vacuum distilled to isolate 36.5 g (0.156 mol, 49%) of 3-benzyloxypropyl methacrylate (3) as a clear, colorless liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH2:8].Cl[C:10]1[N:22]=[CH:21][CH:20]=[CH:19][C:11]=1[C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[O:13].[H-].[Na+].O>O1CCOCC1>[CH2:17]([N:14]([CH2:15][CH3:16])[C:12](=[O:13])[C:11]1[CH:19]=[CH:20][CH:21]=[N:22][C:10]=1[NH:8][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[CH3:1])[CH3:18]
Reactant: Cc1ccncc1N
Reactant: CCN(CC)C(=O)c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(CC)C(=O)c1cccnc1Nc1cnccc1C
Yield: 84.9 %

Procedure:
Into a 1-neck round-bottom flask was added 4-methylpyridin-3-amine (1.02 g, 0.00940 mol) and 2-chloro-N,N-diethylnicotinamide (2.00 g, 0.00940 mol) in 1,4-dioxane (20 mL), and then sodium hydride (0.94 g, 0.024 mol) was added. The reaction was heated at reflux for 1 hour. The mixture was allowed to cool and water was added. The mixture was then extracted with ethyl acetate 3× and the combined organic extracts were washed with water, brine, dried over MgSO4, and concentrate in vacuo. Upon cooling, the product crystallized. The crystalline solid was filtered off, washed with ether and dried to give 2.27 g of the desired product. 1H NMR (300 MHz, CDCl3): δ 9.15 (s, 1H), 8.21-8.24 (m, 2H), 7.90 (br s, 1H), 7.47 (dd, 1H J1=7.5, J2=1.8 Hz), 7.11 (d, 1H, J=4.8 Hz), 6.75 (dd, 1H, J1=7.5, J2=5.1 Hz), 3.46-3.51 (m, 4H), 2.29 (s, 3H), 1.25 (t, 6H). MS [M+1]=285.
Reaction SMILES: [CH:1]([C@@H:14]1[CH2:20][C@@H:19]2[C@@H:17]([O:18]2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:24]=1[CH2:25][NH2:26]>>[CH:1]([C@@H:14]1[CH2:20][C@@H:19]([OH:18])[C@H:17]([NH:26][CH2:25][C:24]2[CH:27]=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:23]=2[O:22][CH3:21])[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: c1ccc(C(c2ccccc2)[C@@H]2C[C@H]3O[C@H]3CO2)cc1
Product: COc1ccc(CN[C@@H]2CO[C@H](C(c3ccccc3)c3ccccc3)C[C@H]2O)c(OC)c1
Yield: 70 %

Procedure:
(1S, 4S, 6R)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]heptane 28a (0.020 g, 0.075 mmol) was reacted with 2,4-dimethoxybenzylamine (0.25 g, 1.50 mmol) (Procedure E) to yield (2S, 4R, 5R)-2-benzhydryl-5-(2,4-dimethoxybenzylamino)-tetrahydropyran-4-ol, (−)-29e, 0.025 g (Yield; 70%, [α]D=(−)3.70, c=1, CHCl3).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C:14]2[C:9](=[N:10][C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=2)[NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].O=[CH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl.CO>[C:1]([O:4][C@@H:5]1[C:14]2[C:9](=[N:10][C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=2)[N:8]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCCCC=O
Reactant: CC(=O)O[C@H]1CCNc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CO
Product: CCOC(=O)CCCCCCN1CC[C@H](OC(C)=O)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-2,3-diphenyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazin-8-yl acetate (Intermediate HBS) (46 mg, 0.133 mmol) in DCE (7 ml) was added ethyl 7-oxoheptanoate (68.8 mg, 0.4 mmol) followed by sodium triacetoxyborohydride (226 mg, 1.065 mmol). The reaction mixture was left to stir at room temperature overnight under an atmosphere of nitrogen. A further portion of ethyl 7-oxoheptanoate (71.8 mg, 0.417 mmol) was added. The reaction mixture was left to stir for a further 5 hours under an atmosphere of nitrogen. Water (20 ml) was added and the resulting mixture was extracted with EtOAc (3×20 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated to give a crude oil. The resulting crude product was purified by chromatography on silica eluting with 0-40% EtOAc/iso-hexane to afford an oil. The compound was passed through a pre-conditioned Isolute SCX-2 SPE column loading with MeOH and eluting with 1M ammonia in MeOH (20 ml) to afford the title compound;
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH:3]1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].N1C=CC=CC=1.[C:27](Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>ClCCCl>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:4][CH:3]1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2NC1=O
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC1CN(C(=O)C(C)(C)C)c2ccccc2NC1=O
Yield: 71.2 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (700 mg) obtained from Reference Example 1 was suspended in 1,2-dichloroethane (20 ml). Pyridine (237 mg) and pivaloyl chloride (362 mg) were added thereto, and the mixture was refluxed for two hours. After the reaction mixture was allowed to cool, crystals that precipitated were collected by filtration, to thereby obtain 650 mg of the title compound (yield: 71%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[CH:20]1[CH2:26][C:25](=O)[O:24][C:22](=[O:23])[CH2:21]1.[Cl:28]CCl>Cl.O1CCOCC1>[ClH:28].[I:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:25]([CH2:26][CH:20]([C:11]3[CH:12]=[CH:13][C:14]4[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:10]=3)[CH2:21][C:22]([OH:24])=[O:23])[NH:9][C:4]=2[CH:3]=1
Reactant: ClCCl
Reactant: Nc1ccc(I)cc1N
Reactant: O=C1CC(c2ccc3ccccc3c2)CC(=O)O1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CC(Cc1nc2ccc(I)cc2[nH]1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Iodo-1,2-phenylenediamine (0.47 g) and 3-(2-naphthyl)glutaric anhydride (0.48 g) were dissolved in dichloromethane (6 ml) with heating. The dark solution was stirred at rt for 1 h. The precipitate formed was collected by suction filtration, washed with dichloromethane, and dried in vacuo to give a mixture of regioisomeric amides (0.82 g) as light red solid. This solid was dissolved in 4M HCl in 1,4-dioxane (3 ml) and the dark solution was heated to reflux for 1 h. The precipitate formed is isolated by suction filtration of the still hot mixture and washed with 1,4-dioxane, hot acetic acid, and finally diethyl ether to provide 4-(5-iodo-2-benzimidazolyl)-3-(2-naphthyl)butanoic acid HCl (0.71 g) as light red solid.
Reaction SMILES: Cl[C:2]([F:14])([CH2:5][C:6]([Cl:13])([CH3:12])[CH:7]([O:10][CH3:11])[O:8][CH3:9])[C:3]#[N:4].Cl.CN(C)C=O>[Hg].C(#N)C.[Cd]>[Cl:13][C:6]([CH3:12])([CH:7]([O:8][CH3:9])[O:10][CH3:11])[CH2:5][CH:2]([F:14])[C:3]#[N:4]
Reactant: COC(OC)C(C)(Cl)CC(F)(Cl)C#N
Agent: Cl
Agent: [Cd]
Agent: [Hg]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COC(OC)C(C)(Cl)CC(F)C#N
Yield: 357.7 %

Procedure:
A reaction mixture containing 5 g (0.045 mole) of cadmium metal dissolved in 100 g of mercury and 100 ml of acetonitrile was brought to reflux and 10.8 g (0.04 mole) of 2,4-dichloro-2-fluoro-5,5-dimethoxy-4-methylpentanenitrile and 0.05 mole of dimethylformamidehydrochloride in 50 ml of acetonitrile were added dropwise. After the addition was complete refluxing was maintained for an additional 5 hours. The salts and Hg were removed by filtration and the solvent was removed in vacuo. The residue was distilled through a Kuglerohr apparatus to afford 30 g of crude 4-chloro-2-fluoro-5,5-dimethoxy-4-methylpentanenitrile which was distilled through a spinning band column. Fractions boiling between 52°-55° C., 0.3 mm Hg, were collected and were shown to be essentially pure diasteromeric 4 -chloro-2-fluoro-5,5-dimethoxy-4-methylpentanenitriles, 'Hnmr (Acetone d6TMS) δ 1.5-1.75 (m, 3H, --CH3); δ 2.60 (dm, 2H, -- CH2 --), JHF 20.76 z; δ 3.58 ##STR7## δ 5.8 (dt, 1H, --CHF--); JH2F 46.6 Hz. IR NaCl neat 2260 cm-1 ; 1070 cm-1.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][NH:8][N:7]=1)[CH3:4].Cl[CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([O:26][CH2:27][C:28]2[N:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:31][C:32]=2[CH3:33])[CH:25]=1.O>CN(C)C=O>[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[C:24]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:31][C:32]=3[CH3:33])[CH:25]=2)[N:7]=1)[CH3:4]
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1cncc(CCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2cncc(OCc3nc(-c4ccccc4)oc3C)c2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl)propionate (318 mg) and 3-chloromethyl-5-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (472 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[5-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-yl]propionate (616 mg, yield: 84%) as a colorless oily substance from the fraction eluted with ethyl acetate.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([B:16]2[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]2)=[CH:12]3)C=CC=[CH:3][CH:2]=1.C1(B(O)O)CC1>>[CH:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([B:16]2[O:20][C:19]([CH3:21])([CH3:22])[C:18]([CH3:23])([CH3:24])[O:17]2)=[CH:12]3)[CH2:2][CH2:3]1
Reactant: CC1(C)OB(c2cc3cccc(-c4ccccc4)c3[nH]2)OC1(C)C
Agent: OB(O)C1CC1
Product: CC1(C)OB(c2cc3cccc(C4CC4)c3[nH]2)OC1(C)C

Procedure:
Prepared according to the procedures described above for 7-phenyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using cyclopropylboronic acid in place of phenylboronic acid. 1H NMR (CDCl3, 400 MHz): δ 0.75-0.82 (m, 2H), 0.95-1.04 (m, 2H), 2.08 (m, 1H), 6.59 (dd, J=3.0, 2.0 Hz, 1H), 6.96 (d, J=7.1 Hz, 1H), 7.06 (t, J=7.6 Hz, 1H), 7.25 (m, 1H), 7.52 (d, J=7.8 Hz, 1H) and 8.39 (br s, 1H) ppm. LC-MS (ES, Pos.): 158 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[CH3:12][N:13]([CH:15](OC)OC)[CH3:14]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])/[CH:10]=[CH:12]/[N:13]([CH3:15])[CH3:14]
Reactant: CC(=O)c1ccc(F)cc1F
Reactant: COC(OC)N(C)C
Product: CN(C)/C=C/C(=O)c1ccc(F)cc1F
Yield: 82 %

Procedure:
The title compound was prepared in 82% yield from 1-(2,4-difluorophenyl)ethanone and DMF-DMA according to the procedure for the preparation of Example 12, part A. 1H NMR (400 MHz, CDCl3): δ 2.90 (3H, s), 3.11 (3H, s), 5.59-5.62 (1H, m), 6.77-6.83 (1H, m), 6.88-6.93 (m, 1H), 7.75-7.83 (2H, m).
Reaction SMILES: [OH:1][C:2]([C:5]([OH:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[BH:9]([OH:17])[O:10][CH:11](I)[CH2:12][CH:13]([F:15])[F:14].C[Si]([N-:22][Si](C)(C)C)(C)C.[Li+].[ClH:28].O1CCOCC1>C1COCC1>[OH:1][C:2]([C:5]([OH:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[BH:9]([OH:17])[O:10][CH:11]([NH2:22])[CH2:12][CH:13]([F:15])[F:14].[ClH:28]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: OBOC(I)CC(F)F
Agent: CC(C)(O)C(C)(C)O
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: NC(CC(F)F)OBO
Temperature: -78 °C
Reaction time: 12 h

Procedure:
1-Iodo-3,3-difluoropropanyl boronate pinacol (2.7 g, 8.1 mmol) was dissolved in THF (10 mL) and was added dropwise to a solution of lithium bis(trimethylsilyl)amide (9.68 mL, 9.68 mmol, 1.0 M in THF) dissolved in anhydrous THF (10 mL) and cooled to −78° C. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. It was concentrated in vacuo and hexane was added. The reaction mixture was cooled to −78° C., followed by the dropwise addition of 4 N anhydrous hydrogen chloride in dioxane (6.05 mL, 24.2 mmol). The mixture was allowed to warm to room temperature and stirred for 5 hours. The reaction mixture was evaporated and chloroform was added. Insoluble material was removed by filtration. The filtrate was evaporated almost to dryness and hexanes were added. Upon standing the product crystallized. It was isolated and washed with cold hexane to yield 1.1 g (52%), mp 138-141° C. 1H NMR (CDCl3) δ 7.68 (bs, 3H), 6.22-6.01 (tt, 1H), 3.42 (m, 1H), 2.76-2.51 (m, 2H), 1.32 (s, 12H). 19F NMR δ −115.2 to −115.5 (dt, CHF2). HRMS calculated for C9H18B1O2F2N+H: 222.1. Found: 222.1.
Reaction SMILES: Cl.Cl.NC1C=C(C2C(C3C=CC(O)=C(N)C=3)=NC3C(=CC=C(C(O)=O)C=3)N=2)C=CC=1O.[NH2:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[NH2:42])[C:36]([OH:38])=[O:37].[CH3:43][O:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]([C:53]([C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=2)=O)=O)=[CH:47][CH:46]=1>>[CH3:62][O:61][C:58]1[CH:57]=[CH:56][C:55]([C:53]2[C:51]([C:48]3[CH:47]=[CH:46][C:45]([O:44][CH3:43])=[CH:50][CH:49]=3)=[N:32][C:33]3[C:41](=[CH:40][CH:39]=[C:35]([C:36]([OH:38])=[O:37])[CH:34]=3)[N:42]=2)=[CH:60][CH:59]=1
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Agent: Cl
Agent: Nc1cc(-c2nc3ccc(C(=O)O)cc3nc2-c2ccc(O)c(N)c2)ccc1O
Product: COc1ccc(-c2nc3ccc(C(=O)O)cc3nc2-c2ccc(OC)cc2)cc1

Procedure:
Briefly, the AB2 monomer, 2,3-bis(3-amino-4-hydroxyphenyl)quinoxaline-6-carboxylic acid dihydrochloride, is synthesized by condensing 3,4-diaminobenzoic acid and 4,4′-dimethoxybenzil to afford 2,3-bis(4-methoxyphenyl) quinoxaline-6-carboxylic acid, followed by demethylation in hydrobromic acid in acetic acid to form 2,3-bis(4-hydroxyphenyl) quinoxaline-6-carboxylic acid. The latter is then nitrated using nitric acid (70% conc.) in acetic acid at room temperature, yielding 2,3-bis(3-nitro-4-hydroxyphenyl) quinoxaline-6-carboxylic acid. The desired monomer is prepared by catalytic reduction in the presence of palladium catalyst in 10% hydrochloric acid.
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:5]([NH:7][C@H:8]([C:19]([O:21]C)=[O:20])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)=[O:6])[CH2:3][OH:4].O>CC(O)(C)C>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])[C@H:2]([C:5]([NH:7][C@H:8]([C:19]([OH:21])=[O:20])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)=[O:6])[CH2:3][OH:4]
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(N[C@@H](CO)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1

Procedure:
In a second step, enzymatic hydrolysis of Z-Ser-Trp-OMe was accomplished using Alcalase 2.5 L DX (Int. J. Peptide Protein Res. 1990, 52) and subsequent catalytic hydrogenolysis provided the desired peptide as an off-white solid. To that end the purified Z-Ser-Trp-OMe was dissolved in tBuOH and water and Alcalase 2.5 L DX (Novozymes, Bagsvaerd, Denmark) was added. The mixture was stirred until (almost) all starting material was consumed. The mixture was then concentrated in vacuo and the residue taken up in water of pH 7. The aqueous mixture was extracted with ethyl acetate to remove any remaining starting material and subsequently the aqueous phase was acidified. The desired product, i.e. Z-Ser-Trp-OH, was isolated by extraction with ethyl acetate; the extract was dried over sodium sulphate and concentrated in vacuo.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:10][C@@H:9]([NH2:11])[CH2:8][CH2:7][C:5]=2[N:6]=1.[S:12]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)([O:15][CH2:16][CH2:17][CH3:18])(=[O:14])=[O:13]>CN(C)C=O.CC(OC)(C)C>[CH2:16]([NH:11][C@@H:9]1[CH2:8][CH2:7][C:5]2[N:6]=[C:2]([NH2:1])[S:3][C:4]=2[CH2:10]1)[CH2:17][CH3:18].[CH3:23][C:22]1[CH:24]=[CH:25][C:19]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:20][CH:21]=1
Reactant: CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: Nc1nc2c(s1)C[C@@H](N)CC2
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CCCN[C@@H]1CCc2nc(N)sc2C1
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
A 72 liter unjacketed reactor was charged with 1.84 kg (10.87 mol) of (6R)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole ((6R) diamine), followed by 14.7 L of dimethyl formamide (DMF). Under continuous stirring, the mixture was heated to a temperature of between 65° C. and 68° C. A solution of 2926 grams propyl tosylate and 1761 grams diisopropylethyleamine in 3.5 L DMF was added slowly over a period of 2 hours. The reaction was continued at 67° C. for an additional 4 hours, after which the solution was gradually cooled to room temperature (18° C. to 22° C.) and stirred for an additional 15 hours. The solution was diluted with 14.7 L of MTBE over a time period of 30 minutes, and stirred for an additional 1 hour. The precipitated material was collected by filtration and washed with 7.3 L MTBE, followed by 3 washes of 3.7 L each of ethanol, and a wash with 9.2 L heptane. The washed precipitated cake was dried under high vacuum at 30° C. to 35° C. The final weight of the dried product was 2090-grams, representing a 50% yield.
Reaction SMILES: [Br:1][C:2]1([Br:9])[CH2:4][C:3]1([Br:8])[CH2:5][CH2:6][OH:7].N1C=CC=CC=1.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>C(Cl)Cl>[Br:1][C:2]1([Br:9])[CH2:4][C:3]1([Br:8])[CH2:5][CH2:6][O:7][S:22]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: OCCC1(Br)CC1(Br)Br
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: O=S(=O)(OCCC1(Br)CC1(Br)Br)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.1 %

Procedure:
While cooling a solution of 3.00 g (0.00929 mol) of 1,1,2-tribromo-2-(2-hydroxyethyl)cyclopropane in methylene chloride with 0.901 ml (0.0111 mol) pyridine to 0° C., 1.18 ml (0.00929 mol) of benzene sulfonyl chloride was added dropwise via pipet. Allowed to warm to room temperature. After 3 days, water was added. The resulting mixture was transferred to a separatory funnel and the phases were separated. The organic layer was dried over MgSO4 and filtered. The solvent was removed from the filtrate in vacuo to yield 3.10 g of 80% pure 1,1,2-tribromo-2-(2-benzenesulfonyloxyethyl)cyclopropane as an oil.