Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]=1[C:24]([OH:26])=[O:25])CCCCCCCCC.S(Cl)(Cl)=O.O[C:32]1[CH:49]=[CH:48][C:35]([C:36]([O:38][CH2:39][C:40]([C:46]#[N:47])([CH3:45])[CH2:41][CH2:42][CH2:43][CH3:44])=[O:37])=[CH:34][CH:33]=1.[H-].[Na+].Cl>C1C=CC=CC=1.CCOCC.O>[CH2:24]([O:25][C:17]1[CH:12]=[C:13]([C:24]([O:26][C:32]2[CH:49]=[CH:48][C:35]([C:36]([O:38][CH2:39][C:40]([C:46]#[N:47])([CH3:45])[CH2:41][CH2:42][CH2:43][CH3:44])=[O:37])=[CH:34][CH:33]=2)=[O:25])[C:14]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:15][CH:16]=1)[CH2:13][CH2:12][CH2:17][CH2:16][CH2:15][CH2:14][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCOc1cccc(-c2ccccc2)c1C(=O)O
Reactant: CCCCC(C)(C#N)COC(=O)c1ccc(O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCOc1ccc(-c2ccccc2)c(C(=O)Oc2ccc(C(=O)OCC(C)(C#N)CCCC)cc2)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 129.3 %

Procedure:
211 mg (1.18 mM) of decyloxybiphenylcarboxylic acid and 2.5 ml of thionyl chloride were heat-refluxed for 2 hours, followed by distilling-off of excessive thionyl chloride. To the resultant acid chloride was added a solution of 339 mg (1.18 mM) of 2-cyano-2-methylhexyl p-hydroxybenzoate and 263 mg (2.36 mM) of thiethylenediamine in 5 ml of dry benzene, followed by 2 hours of stirring under heating at 50° C. Then, a solution of 56.5 mg (2.36 mM) of sodium hydride in 2 ml of dry benzene was added, followed by 2 hours of heat-refluxing. After the reaction, the mixture was cooled to room temperature, followed by addition of 5 ml of 1N-hydrochloric acid and 12 ml of distilled water and extraction with ether. The ether solution was dried on sodium sulfate, followed by distilling-off of the solvent and purification by thin layer chromatography (developer solvent: benzene/methylene chloride=1:3) to obtain 230 mg of 2-cyano-2 -methylhexyl p-(p-decyloxybiphenyl carbonyloxy)benzoate. Yield: 32.1%. [α]D -4.6 degrees (c1, methylene chloride). Phase transition temperatures (°C.): ##STR34##
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([O:10][C:11]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22]2[N:23]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([CH:31]=O)=[CH:26][CH:25]=3)=[C:16]2[C:12]=1[CH2:13][NH:14][C:15]2=[O:40])(=[O:9])=[O:8].[NH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([O:10][C:11]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22]2[N:23]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])[C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([CH2:31][N:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)=[CH:26][CH:25]=3)=[C:16]2[C:12]=1[CH2:13][NH:14][C:15]2=[O:40])(=[O:8])=[O:9]
Reactant: C1CCNCC1
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(=O)(=O)c1ccccn1)CNC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1cc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(=O)(=O)c1ccccn1)CNC2=O
Yield: 35.3 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-(2-pyridinesulfonyloxy)-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (0.318 g, 0.564 mmol) was dissolved in acetonitrile (10.0 mL), and the solution was treated with piperidine (1.10 mL, 11.3 mmol), acetic acid (0.646 mL, 11.3 mmol) and sodium triacetoxyborohydride (0.359 g, 1.69 mmol), followed by purification by flash column chromatography (chloroform/methanol=85/15) to obtain 4-(2-pyridinesulfonyloxy)-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.126 g, 35%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]=1.[C:12](Cl)(=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>N1C=CC=CC=1>[C:12]([NH:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]=1)(=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: NC1=NC(=O)C2=CC=NC2=N1
Reactant: CCCCCCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCCC(=O)NC1=NC(=O)C2=CC=NC2=N1
Temperature: 85 °C
Yield: 80.1 %

Procedure:
2-Aminopyrrolo(2,3-d)pyrimidin-4-one (6.0 g) is suspendeed in pyridine (80 ml) and, with stirring on an ice bath, n-octanoyl chloride (22.8 g) is added. The reaction mixture is warmed at 85° C. for 30 minutes and the solvent is distilled off under reduced pressure. Dilute hydrochloric acid is added to the residue and the mixture is extracted with chloroform. The extracts are combined and concentrated to dryness. The residue is dissolved in 8% (W/V) alcoholic ammonia (50 ml) and the solution is allowed to stand at room temperature to give the above-identified compound (8.9 g) as crystals.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[Br:12][C:13]1[C:14]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[C:15]2[CH:21]=[N:20][NH:19][C:16]2=[N:17][CH:18]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:50]([O:54][C:55]([N:57]([CH:70]([CH3:72])[CH3:71])[CH2:58][C@H:59]([C:63]1[CH:68]=[CH:67][C:66]([Cl:69])=[CH:65][CH:64]=1)[C:60](O)=[O:61])=[O:56])([CH3:53])([CH3:52])[CH3:51]>C(Cl)Cl>[Br:12][C:13]1[C:14]([N:22]2[CH2:23][CH2:24][N:25]([C:60](=[O:61])[C@@H:59]([C:63]3[CH:64]=[CH:65][C:66]([Cl:69])=[CH:67][CH:68]=3)[CH2:58][N:57]([CH:70]([CH3:72])[CH3:71])[C:55](=[O:56])[O:54][C:50]([CH3:53])([CH3:51])[CH3:52])[CH2:26][CH2:27]2)=[C:15]2[CH:21]=[N:20][NH:19][C:16]2=[N:17][CH:18]=1
Reactant: Brc1cnc2[nH]ncc2c1N1CCNCC1
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(Br)cnc3[nH]ncc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
DIEA (0.0687 mL, 0.394 mmol) was added to 5-bromo-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (0.050 g, 0.0986 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.0380 g, 0.118 mmol) and (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (0.0337 g, 0.0986 mmol, see Example B) in DCM (1 mL) and stirred at room temperature for 16 hours. The reaction was concentrated to dryness. The resulting residue was dissolved in THF/MeOH (2 mL, 1:1), and a LiOH solution (1 mL, 2M) was added. The solution was stirred for 30 minutes, and then ether (20 mL) was added. The organic layer was separated, washed with brine (10 mL), and dried over sodium sulfate. After removal of the solvent, the resulting residue was purified by column chromatography (hexane:ethyl acetate, 1:1) to give (S)-tert-butyl 3-(4-(5-bromo-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-3-oxopropyl(isopropyl)carbamate as a solid. The solid was dissolved in DCM (1 mL), and TFA (0.4 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction was again concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The resulting solid was collected by filtration to give (S)-1-(4-(5-bromo-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-3-(isopropylamino)propan-1-one dihydrochloride (0.030 g, 53%). MS APCI (+) m/z 507.2 detected.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.C(=O)(O)[O-].[Na+].[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[C:23]([N:5]1[CH2:6][CH:2]([OH:1])[CH2:3][C@H:4]1[C:7]([OH:9])=[O:8])([O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:24]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)[C@@H]1CC(O)CN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@@H]1CC(O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
To 20 g (152.5 mmol) of 4-hydroxy-L-proline in 35 ml of water was added 36.7 g (436.8 mmol) of sodium bicarbonate and the mixture was cooled to 10° C. before 32.5 g (190.5 mmol) of benzylchloroformate wa added dropwise. The cooling bath was then removed and the mixture was allowed to stir for 24 hours at room temperature. The pH of the reaction was then adjusted to 1 with concentrated HCl solution and the mixture was extracted with 3×100 ml portions of methylene chloride. The organic layers were dried over Na2SO4 and evaporated in vacuum to provide 36.4 g of the product as an oil (90% yield). NMR(CDCl3): 7.30 (m,5H, aromatic), 5.12 (m,2H), 4.50 (m,2H), 4.36 (m,2H), 3.6 (m,2H), 2.38 (m,2H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5](O)[CH:6]=[C:7]([O:9]C)[CH:8]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[C:20]([O:22]C)[C:19]([O:24]C)=[C:18]([O:26]C)[CH:17]=1)=[O:15]>>[OH:2][C:3]1[C:4]2[CH:13]=[C:14]([C:16]3[CH:17]=[C:18]([OH:26])[C:19]([OH:24])=[C:20]([OH:22])[CH:21]=3)[O:15][C:5]=2[CH:6]=[C:7]([OH:9])[CH:8]=1
Reactant: COc1cc(O)cc(OC)c1
Reactant: COc1cc(C(=O)CBr)cc(OC)c1OC
Product: Oc1cc(O)c2cc(-c3cc(O)c(O)c(O)c3)oc2c1
Yield: 62 %

Procedure:
This compound was prepared using Method A from 3,5-dimethoxyphenol and 2-bromo-1-(3,4,5-trimethoxyphenyl)ethanone: Yield 62% following procedures A.2 and A.5; m.p. 260° C. (dec.); IR 3442, 3326, 1600, 1539, 1470, 1313, 1197, 1072, 1037 cm−1; 1H NMR (500 MHz, δ ppm, DMSO-d6) 9.67 (s, 1H), 9.22 (s, 1H), 8.97 (s, 2H), 8.29 (s, 1H), 6.81 (s, 1H), 6.69 (s, 2H), 6.37 (s, 1H), 6.14 (s, 1H); 13C NMR (75 MHz, δ ppm, CD3OD) 158.3, 157.3, 155.0, 151.9, 147.4, 134.8, 123.8, 113.1, 104.8, 98.7, 97.7, 90.8.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(=O)([O-])[O-].[K+].[K+].[Br:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[NH:20][C:19](=[O:26])/[C:18]/2=[CH:27]\[NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([OH:37])[CH:31]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[Br:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[NH:20][C:19](=[O:26])/[C:18]/2=[CH:27]\[NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[C:32]([OH:37])[CH:31]=1
Reactant: CCCCCCBr
Reactant: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCc1ccc(O)c(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1O
Temperature: 25 °C
Yield: 28.4 %

Procedure:
To a solution of 1-bromohexane (40.0 μl, 0.28 mmol) and tetrabutylammonium iodide (104 mg, 0.283 mmol) in anhydrous N,N-dimethylformamide (2 ML) is added of potassium carbonate (207 mg, 1.5 mmol). The mixture stirred at room temperature and (4Z)-6-bromo-4-{[(3,4-dihydroxybenzyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (100 mg, 0.26 mmol) is added. After the mixture is stirred at 65° C. for 30 min, the resulting mixture is concentrated and the residue is then partitioned between water (20 ml) and ethyl acetate (20 ml). The organic layer is then dried and purified by high performance liquid chromatography to give 35 mg of a white solid. MS (ESI) m/z 472.5 (M+1).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:12]3([CH2:18][NH2:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:20][C:21]([F:37])([F:36])[C:22]1[O:26][N:25]=[C:24]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[N:23]=1>>[C:1]1([C:7]2[CH:8]=[C:9]([C:12]3([CH2:18][NH:19][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][CH:35]=[C:27]([C:24]5[N:23]=[C:22]([C:21]([F:37])([F:36])[F:20])[O:26][N:25]=5)[CH:28]=4)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCC1(c2cc(-c3ccccc3)cs2)CCOCC1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCC1(c2cc(-c3ccccc3)cs2)CCOCC1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 20 %

Procedure:
This compound was synthesized from (4-(4-phenylthiophen-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (80 mg, yield 20%). 1H NMR (400 MHz, CDCl3) δ 8.43 (m, 1H), 8.25 (d, J=7.8 Hz, 1H), 7.96 (d, J=7.8 Hz, 1H), 7.62-7.58 (m, 3H), 7.45 (d, J=1.2 Hz, 1H), 7.40 (t, J=7.7 Hz, 2H), 7.31 (m, 1H), 7.23 (d, J=1.5 Hz, 1H), 6.15 (t, J=6.5 Hz, 1H), 3.96-3.91 (dt, J=11.9 Hz, 4.2 Hz, 2H), 3.74 (d, J=6.4 Hz, 2H), 3.71-3.66 (m, 2H), 2.18-2.14 (m, 2H), 2.08-2.03 (m, 2H). MS (ESI) m/z: Calculated for C26H22F3N3O3S: 513.13. found: 514.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[C:8]([CH:12]([CH3:14])[CH3:13])[O:9]2)=[CH:4][CH:3]=1.[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:11]([Br:23])=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)=[C:8]([CH:12]([CH3:13])[CH3:14])[O:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)c1oc2cc(N)ccc2c(=O)c1-c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: CC(C)c1oc2c(Br)c(N)ccc2c(=O)c1-c1ccc(Cl)cc1
Reaction time: 0.33 h

Procedure:
A stirred solution of 7-amino-3-(4-chlorophenyl)-2-isopropyl-chromen-4-one (0.36 g, 1.15 mmol) in chloroform (10 ml) is treated at room temperature with N-bromosuccinimide (0.21 g, 1.2 mmol, 1.05 eq.). After stirring for 20 min, the mixture is partitioned between water (150 ml) and ethyl acetate (50 ml). The organic phase is washed with brine (100 ml), dried (magnesium sulfate) and filtered, and the solvent is removed by evaporation in vacuo to afford the title compound as an orange solid. The product is used in the next step without further purification.
Reaction SMILES: [CH:1]([CH:4]1[N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7][N:6]2[C:17]3[CH:23]=[C:22]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[CH:20][C:18]=3[N:19]=[C:5]12)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([CH:4]1[NH:9][CH2:8][CH2:7][N:6]2[C:17]3[CH:23]=[C:22]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=[CH:20][C:18]=3[N:19]=[C:5]12)([CH3:3])[CH3:2]
Reactant: CC(C)C1c2nc3ccc(S(C)(=O)=O)cc3n2CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C1NCCn2c1nc1ccc(S(C)(=O)=O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 127.8 %

Procedure:
To a solution of tert-butyl 1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2(1H)-carboxylate (30 mg, 0.08 mmol, from preparation 1) in CH2Cl2 (1 mL) was added TFA (0.2 mL) under N2. The mixture was stirred at rt for 1 h. The mixture was concentrated to afford 1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine (30 mg, TFA salt) as a yellow solid, which was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:23])[C:7]=1[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19]C)[C:12]=1[O:21]C)=[O:10].I>CC(O)=O>[Cl:23][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([OH:19])[C:12]=1[OH:21])=[O:10]
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c(OC)c1OC
Agent: I
Solvent: CC(=O)O
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c(O)c1O
Temperature: 80 °C

Procedure:
2-(3,5-Dichloro-pyridin-4-yl)-1-(2,3,4-trimethoxy-phenyl)-ethanone from preparation 2 (1.25 g, 3.5 mmol) was dissolved in AcOH (100%, 9.25 mL) under argon. HI (55-58%, 4.55 mL) was added and the reaction mixture was heated at 80° C. for 18 hours. The reaction mixture was cooled to it and evaporated in vacuo. NaHCO3 (sat., 150 mL) was added slowly followed by NaCl (sat., 50 mL). The organic products were extracted with EtOAc (4×100 mL). The combined organic phases were washed twice with NaCl (sat, 100 mL), Na2S2O3 (10%, 100 mL), dried over Na2SO4 and evaporated in vacuo. 2-(3,5-Dichloro-pyridin-4-yl)-1-(2,3-dihydroxy-4-methoxy-phenyl)-ethanone was obtained as a brown solid. 1H NMR (CDCl3) δ=11.88 (1H, s), 8.54 (2H, s), 7.51 (1H, d), 6.60 (1H, d), 5.62 (1H, bs), 4.67 (2H, s), 4.00 (3H, s). Yield 0.935 g (81%)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[I-].C[N+]1C=CN([C:19](=[O:28])[N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)C=1.C(N(CC)CC)C>C(#N)C>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:10]=[CH:11][C:2]=1[O:1][C:19](=[O:28])[N:20]([CH3:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Oc1cnc2ccccc2n1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(C(=O)Oc1cnc2ccccc2n1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.6 %

Procedure:
A mixture of 2-hydroxyquinoxaline (0.44 g, 3.00 mmol) ), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 9, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours followed by heating at 40° C. for 24 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (30:70)) yielding the title compound (0.65 g, 77% yield) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:30][C@H:31]([OH:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=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)=[O:24])=[C:19]([S:26][CH:27]([CH3:29])[CH3:28])[CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][S:40]([NH2:43])(=[O:42])=[O:41].Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[OH:38][C@H:31]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:30][N:8]([CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([NH:43][S:40]([CH3:39])(=[O:42])=[O:41])=[O:24])=[C:19]([S:26][CH:27]([CH3:29])[CH3:28])[CH:18]=2)=[CH:15][CH:16]=1)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)Sc1cc(-c2ccc(CCN(C[C@H](O)c3ccccc3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)O
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)Sc1cc(-c2ccc(CCN(C[C@H](O)c3ccccc3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)NS(C)(=O)=O
Reaction time: 72 h
Yield: 6.7 %

Procedure:
To a solution of 4′-[2-[(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-3-(isopropylthio)-4-biphenycarboxylic acid (131 mg) in N,N-dimethylformamide (2.6 ml) were added methanesulfonamide (24.9 mg), 4-(dimethylamino)pyridine (43.7 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (91.4 mg) at room temperature and the mixture was stirred at the same temperature for 72 hours. The mixture was poured into aqueous hydrochloric acid solution (0.3N) and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/3) to give tert-butyl [(2R)-2-hydroxy-2-phenylethyl](2-[3′-(isopropylthio)-4′-[[(methylsulfonyl)amino]carbonyl]-4-biphenylyl]ethyl]-carbamate (10 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16]([N:18]=[C:19]=[S:20])[CH:17]=1)=[CH:5]2.[C:23]([O:27][C:28](=[O:37])[C@H:29]([CH2:31][O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[NH2:30])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28](=[O:37])[C@@H:29]([NH:30][C:19]([NH:18][C:16]1[CH:17]=[C:12]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([F:1])=[C:10]([F:11])[CH:9]=3)[CH:13]=[CH:14][C:15]=1[O:21][CH3:22])=[S:20])[CH2:31][O:32][C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC[C@H](N)C(=O)OC(C)(C)C
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N=C=S
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NC(=S)N[C@@H](COC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
The product from Example 35, Step A, 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenyl isothiocyanate (0.316 g, 1.0 mmol) was reacted with serine tert-butylether tert-butylester (0.226 g, 1.0 mmol) according to the procedure for Example 23, Step B to give the product after filtration through silica gel using hexanes/ethyl acetate, 1/1, v/v as eluant (0.377 g in 2 portions), mp 111-114° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[CH:11]=[C:6]([C:7]([O:9]C)=[O:8])[CH:5]=1.[OH-].[Na+]>CO.O.C(OCC)C>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:13]=[C:12]([O:14][CH:15]([CH3:16])[CH3:17])[CH:11]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1
Reactant: COC(=O)c1cc(OC(C)C)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: COC(=O)c1cc(OC(C)C)cc(C(=O)O)c1
Yield: 85.7 %

Procedure:
Stir 5-isopropoxy-isophthalic acid dimethyl ester (3.7 g, 14.7 mmol) and NaOH (0.56 g, 14 mmol) in methanol (100 mL) and water (2 mL) overnight at room temperature. Concentrate methanol and redissolve the residue in diethyl ether (100 mL) and water (100 mL). Separate the layers and wash with diethyl ether. Concentrate the diethyl ether layer and recover 5-isopropoxy-isophthalic acid dimethyl ester (0.45 g). Acidify the aqueous layer with 5 N HCl to about pH=2, extract with ethyl acetate (3×50 mL). Wash the combined organic layers with saturated aqueous sodium chloride, dry (sodium sulfate) and concentrate to give the title compound (3.0 g, 86%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18](=[O:19])[CH:17]3[CH:20]([C:25]([OH:27])=[O:26])[CH:21]4O[C:16]3([CH:23]=[CH:22]4)[CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl>[O:19]=[C:18]1[C:17]2[C:20]([C:25]([OH:27])=[O:26])=[CH:21][CH:22]=[CH:23][C:16]=2[CH2:15][N:14]1[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC34C=CC(O3)C(C(=O)O)C4C2=O)CC1
Agent: Cl
Product: O=C(O)c1cccc2c1C(=O)N(C1CCNCC1)C2
Yield: 92.8 %

Procedure:
3-(1-Tert-butoxycarbonyl-piperidin-4-yl)-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8-ene-6-carboxylic acid (6.35 g, 16.8 mmol) was dissolved in 37% hydrochloric acid (80 mL) and the resulted solution was refluxed for 3 hours. The solvent was removed under reduced pressure and the residue was diluted with methanol and decanted in order to obtained the desired product as a white solid (4.06 g, 82%).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[CH2:12]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29]I)[C:24](=[O:31])[CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[CH2:12]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:1]2[C:9]3[CH:8]=[CH:7][N:6]=[CH:5][C:4]=3[CH:3]=[CH:2]2)[C:24](=[O:31])[CH2:23]1)=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1CCI
Reactant: c1cc2[nH]ccc2cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CN(C(=O)OCc2ccccc2)CCN1CCn1ccc2cnccc21
Temperature: 25 °C

Procedure:
4-(Benzyloxycarbonyl)-1-(2-hydroxyethyl)-piperazin-2-one, prepared as described in EXAMPLE 94, part A. (0.26 g, 0.94 mmol) in methylene chloride (6 mL) is treated with triphenyl phosphine (0.60 g, 2.3 mmol), imidazole (0.16 g, 2.3 mmol), and iodine (0.47 g, 1.9 mmol) for 0.5 h at 0° C. The reactin mixture is partitioned between water and methylene chloride; the organic layer is concentrated and the residue is chromatographed (15% EtOAc/methylene chloride) to give 4-(benzyloxycarbonyl)-1-(2-iodoethyl)-piperazin-2-one (0.24 g, 0.62 mmol). Pyrrolo[3,2-c]pyridine (0.073 g, g, 0.62 mmol) is dissolved in DMF (3 mL) and treated with 60% sodium hydride (0.03 g, 0.74 mmol) and all of the 4-(benzyloxycarbonyl)-1-(2-iodoethyl)-piperazin-2-one from the previous step; the reaction mixture is stirred at r.t. for 16 g. The reaction mixture is concentrated to dryness and the residue is partitioned between water and methylene chloride. The organic layer is concentrated and subjected to chromatography (2-5% MeOH/methylene chloride) to yield the title compound (0.028 g, 0.074 mmol) Ion Spray MS m/z: 379, [M+1]+.