Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5].[CH2:9](O)[CH2:10][CH2:11][CH3:12]>Cl>[ClH:1].[CH2:9]([O:7][C:6](=[O:8])[C@H:3]([CH2:4][SH:5])[NH2:2])[CH2:10][CH2:11][CH3:12]
Reactant: N[C@@H](CS)C(=O)O
Reactant: CCCCO
Agent: Cl
Product: CCCCOC(=O)[C@@H](N)CS
Yield: 30 %

Procedure:
L-Cysteine hydrochloride (100 g) was dissolved in 250 ml of butanol saturated with dry HCl. The solution was heated under reflux for 4 hours. Excess of solvent was evaporated under evaporator. Ethyl acetate (150 ml) was added to the residue to give crystals. The crystals were recrystallized from ethyl acetate, mp 91° C., yield 30%, IR (KBr) 1745 cm-1 ; NMR (CDCl3) δ9.2-8.4 (b, 3, NH3⊕), 4.7 (t, 1, --CH), 4.3 (t, 2-, --CH2)--,, 3.3 (b, 2, CH2S), 1.0 (t, 3, --CH3 --), 1.0-3.0 (m, 4, --CH2CH2).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[N:8]1([C:13]([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1>O1CCOCC1>[O:5]=[C:4]([N:19]1[CH2:18][CH2:17][N:16]([CH2:15][C:13](=[O:14])[N:8]2[CH2:9][CH2:10][CH2:11][CH2:12]2)[CH2:21][CH2:20]1)[CH2:3][CH2:2][C:1]([OH:6])=[O:7]
Reactant: O=C(CN1CCNCC1)N1CCCC1
Reactant: O=C1CCC(=O)O1
Solvent: C1COCCO1
Product: O=C(O)CCC(=O)N1CCN(CC(=O)N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 4.75 h

Procedure:
0.72 g of succinic anhydride and then 1.5 cm3 of 95% 1-(pyrrolidinocarbonylmethyl)-piperazine are added to 20 cm3 of dioxane in a round-bottomed flask kept under a nitrogen atmosphere. After stirring for 4.75 hours at room temperature, the solvent is evaporated under reduced pressure (2.7 kPa) at 20° C., to give 2.4 g of 4-oxo-4-[4-(2-oxo-2-pyrrolidin-1-ylethyl)piperazin-1-yl]butyric acid in the form of a pale yellow paste which is used as it is.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][N:6]=[C:5]2[C:12]([OH:14])=[O:13].[OH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CCO>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([C:12]([OH:14])=[O:13])=[N:6][NH:7]2)=[CH:3][C:2]=1[C:20]1[CH:21]=[CH:22][C:17]([CH2:16][OH:15])=[CH:18][CH:19]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: O=C(O)c1n[nH]c2cc(Cl)c(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(O)c1n[nH]c2cc(Cl)c(-c3ccc(CO)cc3)cc12
Temperature: 110 °C
Yield: 15.1 %

Procedure:
A mixture of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (200.0 mg, 0.73 mmol), 4-(hydroxymethyl)phenylboronic acid (90.0 mg, 0.59 mmol), 2 N aqueous potassium carbonate (1.1 mL, 2.2 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(I I) (60.0 mg, 0.073 mmol) in toluene (1.5 mL) and EtOH (2.3 mL) was degassed with N2 for 3 minutes and heated to 110° C. for 5 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was acidified to pH 5 and concentrated in vacuo. The crude material was purified by reverse phase HPLC (Column: Phenomenex Synergi C18 150×30 mm, 4 μm; 28% MeCN in water (0.225% TFA) to 28% MeCN in water (0.225% TFA) for 12 min; Flow Rate: 30 mL/min) to afford the title compound (27 mg, 11% yield) as a white solid. MS (ES+) 302.9 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 8.11 (s, 1H), 7.76 (s, 1H), 7.45 (m, 4H), 4.69 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:23])=[C:6]([CH:22]=1)[CH2:7][C:8]1[CH:21]=[CH:20][C:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[CH:10][CH:9]=1.[Li][C:25](C)(C)C.C[Si](C)(C)[O:31][C@@H:32]1[C@@H:37]([O:38][Si](C)(C)C)[C@H:36]([O:43][Si](C)(C)C)[C@@H:35]([CH2:48][O:49][Si](C)(C)C)[O:34][C:33]1=[O:54].CS(O)(=O)=O>C1COCC1.CO.C(OC(=O)C)C>[Si:13]([O:12][C:11]1[CH:20]=[CH:21][C:8]([CH2:7][C:6]2[CH:22]=[C:2]([C@@:33]3([O:54][CH3:25])[C@H:32]([OH:31])[C@@H:37]([OH:38])[C@H:36]([OH:43])[C@@H:35]([CH2:48][OH:49])[O:34]3)[CH:3]=[CH:4][C:5]=2[Cl:23])=[CH:9][CH:10]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: [Li]C(C)(C)C
Reactant: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(O[Si](C)(C)C(C)(C)C)cc3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Yield: 55.4 %

Procedure:
To a solution of (4-(5-bromo-2-chlorobenzyl)phenoxy)(tert-butyl)dimethylsilane (67.0 g, 0.163 mol, prepared by following the procedure given in US20070049537) in dry THF (1.0 L), tBuLi (228 mL, 0.342 mol, 1.6 M solution in pentane) was added at −78° C. The reaction mixture was stirred at the same temperature for 30 mM. A solution of (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (77.8 g, 0.167 mol, prepared following the procedure given in US20070049537) in dry THF (272 mL) was introduced into it at the same temperature and stirred for another 4 h. A solution of methanesulfonic acid (18.35 mL, 0.283 mol) in methanol (586 mL) was added and the temperature was raised to r.t. gradually and stirred for 16 h. The reaction was quenched by the addition of saturated aqueous solution of NaHCO3 (500 mL) and volatiles were evaporated in vacuo. The residue obtained was dissolved in ethylacetate (1 L), washed with water (500 mL) and brine (500 mL) successively. The organic layer was dried over anhydrous Na2SO4 and volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 1:9 MeOH:DCM) to provide title compound (47.37 g, 55.4%) as off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([CH:22]([NH2:24])[CH3:23])[C:16]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[C:15]2[C:31]1[O:32][C:33]([CH3:36])=[N:34][N:35]=1.C(N(CC)C(C)C)(C)C>C(O)CCC>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:24][CH:22]([C:17]2[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[C:15]([C:31]3[O:32][C:33]([CH3:36])=[N:34][N:35]=3)[C:14]3[C:19](=[CH:20][CH:21]=[C:12]([F:11])[CH:13]=3)[N:18]=2)[CH3:23])[N:5]=[CH:4][N:3]=1
Reactant: Cc1nnc(-c2c(-c3ccccn3)c(C(C)N)nc3ccc(F)cc23)o1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1nnc(-c2c(-c3ccccn3)c(C(C)Nc3ncnc(N)c3C#N)nc3ccc(F)cc23)o1
Temperature: 120 °C
Reaction time: 20 h

Procedure:
A mixture of 4-amino-6-chloropyrimidine-5-carbonitrile (0.030 g, 0.192 mmol), 1-(6-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)-3-(pyridin-2-yl)quinolin-2-yl)-ethanamine (0.067 g, 0.192 mmol), and N,N-diisopropylethylamine (0.167 mL, 0.959 mmol) in 1-butanol (1.918 mL) was stirred at 120° C. After 20 h, the mixture was removed from heat and to the cooled mixture was added water (50 mL) and DCM (50 mL). The organic layer was concentrated in vacuo to give the crude material as a light yellow solid. The light yellow solid was absorbed onto a plug of silica gel and purified by silica gel column chromatography eluting with a gradient of 0% to 50% DCM:MeOH:NH4OH (89:9:1) in DCM, to provide 4-amino-6-((1-(6-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)-3-(2-pyridinyl)-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.56-8.62 (1H, m), 8.22-8.29 (1H, m), 7.85-7.93 (3H, m), 7.82 (1H, td, J=7.7, 1.8 Hz), 7.58 (1H, d, J=7.2 Hz), 7.42-7.47 (1H, m), 7.38 (1H, ddd, J=7.6, 4.9, 1.2 Hz), 7.24 (2H, br. s.), 5.54 (1H, quin, J=6.7 Hz), 2.34 (3H, s), 1.39 (3H, d, J=6.7 Hz); LC-MS (ESI) m/z 468.1 [M+H]+.
Reaction SMILES: Cl.[O:2]=[C:3]1[N:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[CH2:6][C:5]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:4]1.[Cl:23][C:24]1[CH:29]=[C:28]([CH:30]=O)[CH:27]=[C:26]([Cl:32])[C:25]=1[C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1.C(O)(=O)C.C([BH3-])#N>ClCCCl.CO>[Cl:23][C:24]1[C:25]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[C:26]([Cl:32])[CH:27]=[C:28]([CH2:30][N:20]2[CH2:21][CH2:22][C:5]3([O:4][C:3](=[O:2])[N:7]([C:8]4[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=4)[CH2:6]3)[CH2:18][CH2:19]2)[CH:29]=1
Reactant: COC(=O)c1ccc(N2CC3(CCNCC3)OC2=O)cc1
Reactant: O=Cc1cc(Cl)c(-c2ccc(F)cc2)c(Cl)c1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)c1ccc(N2CC3(CCN(Cc4cc(Cl)c(-c5ccc(F)cc5)c(Cl)c4)CC3)OC2=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 4-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)benzoate (27 mg, 0.084 mmol) (from Example 1-1, Step 2) and 2,6-dichloro-4′-fluorobiphenyl-4-carboxaldehyde (15 mg, 0.056 mmol) (from Step 3) in DCE (2 mL) and methanol (2 mL) in a 20 mL scintillation vial was added acetic acid (10 uL, 0.168 mmol) and MP-cyanoborohydride resin (56 mg, 0.140 mmol, 2.49 mmol/g). The mixture was shaken at room temperature for 18 hours and was then filtered to remove the resin. The volatiles were removed in vacuo and the residue was used directly in Step 5
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([OH:14])[C:6]([CH3:15])=[C:5]([C:16]([F:19])([F:18])[F:17])[N:4]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:29][CH3:30]>CC(C)=O>[F:21][C:2]([F:20])([F:1])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([O:14][CH2:29][CH3:30])[C:6]([CH3:15])=[C:5]([C:16]([F:19])([F:18])[F:17])[N:4]=1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C)c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C)c1OCC
Yield: 77.7 %

Procedure:
A mixture of 7.8 g (0.0246 mol) of product of Example 35, 3.5 g of K2CO3, 20 g of iodoethane, and 100 ml of acetone was held at reflux for 2 days and concentrated. The reaction mixture was treated with 150 ml of water and extracted with 200 ml of ether. The ether extract was dried and concentrated. The residual solid (7.5 g) was recrystallized from hexane at low temperature to give 6.6 g (77.7%) of product; mp 72.5°-74° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH3:14])=[O:12].ClC1C=CN=CN=1.CO[CH2:24][N:25]([CH2:30][Si](C)(C)C)[C:26]([CH3:29])([CH3:28])[CH3:27].FC(F)(F)C(O)=O>ClCCl>[C:26]([N:25]1[CH2:30][C@@H:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[C@H:10]([C:11]([O:13][CH3:14])=[O:12])[CH2:24]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: COCN(C[Si](C)(C)C)C(C)(C)C
Reactant: COC(=O)/C=C/c1ccc(F)cc1F
Agent: Clc1ccncn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CN(C(C)(C)C)C[C@H]1c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a stirred solution of methyl (2E)-3-(2,4-difluorophenyl)acrylate from preparation 3 (10 g, 50.5 mmol) and N-(methoxymethyl)-2-methyl-N-[(trimethylsilyl)methyl]propan-2-amine (preparation 4) (10.3 g, 50.5 mmol) in dichloromethane (200 mL) at room temperature under dry nitrogen was added trifluoroacetic acid (0.39 mL, 5.1 mmol). The resulting mixture was stirred at room temperature under dry nitrogen for 17 hours. To the reaction mixture was then added a further portion of N-(methoxymethyl)-2-methyl-N-[(trimethylsilyl)methyl]propan-2-amine (from preparation 4) (3.9 g, 19.2 mmol) and trifluoroacetic acid (0.39 mL, 5.1 mmol). The resulting mixture was stirred at room temperature under dry nitrogen for 18 hours, then quenched by the addition of saturated sodium bicarbonate solution (200 mL) and extracted with ethyl acetate (3×75 mL). The combined organic layers were dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was purified by an automated flash column chromatography system (CombiFlash® Separation System Sg 100c by Isco) using a pre-packed column (Redisep™ Disposable Columns for Flash Chromatography by Isco, 40 g column) eluting with 5% ethyl acetate in pentane increasing polarity with a linear gradient up to 100% ethyl acetate over the course of 1 hour. The residue was then subjected to chiral HPLC (eluting with 95:5 hexane:isopropyl alcohol at 80 mL/min at ambient temperature on a Chirapak AD500*80 mm column) to afford the desired enantiomer of the title compound, which we designate here Enantiomer 1, and which was obtained as the faster running enantiomer (retention time 8 minutes) as a clear oil (6.1 g, 80%) with enantiomeric excess of >99% as determined by chiral HPLC with reference to a racemic standard. The undesired enantiomer was obtained as the slower eluting component (Enantiomer 2, retention time 8.7 min) 1H NMR (400 MHz, CDCl3) δH 1.10 (9H, s), 2.80 (1H, m), 3.00 (1H, m), 3.15 (3H, m), 3.60 (3H, s), 3.80 (1H, m), 6.80 (2H, m), 7.40 (1H, m); LRMS (APCI) 298 (100%) [MH+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([C@@H:16]([NH:21][C:22](=[O:45])[O:23][CH2:24][CH2:25][O:26][P:27]([O:37]CC2C=CC=CC=2)([O:29]CC2C=CC=CC=2)=[O:28])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:10]=1.C1CC=CCC=1>[Pd].CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([C@@H:16]([NH:21][C:22](=[O:45])[O:23][CH2:24][CH2:25][O:26][P:27]([OH:37])([OH:29])=[O:28])[C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[C@H:11]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:10]=1
Reactant: CC(C)(C)[C@H](NC(=O)OCCOP(=O)(OCc1ccccc1)OCc1ccccc1)C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CO
Product: CC(C)(C)[C@H](NC(=O)OCCOP(=O)(O)O)C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1

Procedure:
2-{[bis(benzyloxy)phosphoryl]oxy}ethyl (1S)-1-{[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]carbonyl}-2,2-dimethylpropylcarbamate (9-2, 11 mg, 0.015 mmol, 1 equiv), 1,4-cyclohexadiene (1 mL, excess) and 10% Pd/C (5 mg) were added to methanol (4 mL) and the mixture was stirred under a nitrogen atmosphere. After 30 minutes another 5 mg of 10% Pd/C was added and stirring was continued for an additional hour. The reaction was filtered and the filtrate concentrated. The residue was purified by reverse phase LC (H2O/CH3CN gradient w/0.1% TFA present) to give 2-(phosphonooxy)ethyl (1S)-1-{[(2S)-4-2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]carbonyl}-2,2-dimethylpropylcarbamate (9-3) as a colorless foam. 1H NMR (500 MHz, CDCl3) major rotamer: δ 7.34-7.20 (m, 5H), 7.12-6.92 (m, 3H), 6.38 (s, 1H), 5.93 (bs, 1H), 5.21 (d, 1H, J=14 Hz), 4.91 (d, 1H, J=14 Hz), 4.41 (d, 1H, J=10 Hz), 4.38-3.97 (m, 7H), 0.91 (s, 9H). LRMS m/z (M+H) 539.5 found, 538.2 required.
Reaction SMILES: [CH2:1]1[N:8]([CH2:9][CH2:10][N:11]2[CH2:18][C:16](=[O:17])[O:15][C:13](=[O:14])[CH2:12]2)[CH2:7][C:5](=[O:6])[O:4][C:2]1=[O:3].[S:19]([NH2:29])(=[O:28])([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)=[O:20].[I:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1>CN(C=O)C>[C:5]([CH2:7][N:8]([CH2:1][C:2]([NH:35][C:34]1[CH:36]=[CH:37][C:31]([I:30])=[CH:32][CH:33]=1)=[O:3])[CH2:9][CH2:10][N:11]([CH2:12][C:13](=[O:14])[NH:27][C:24]1[CH:23]=[CH:22][C:21]([S:19](=[O:28])(=[O:20])[NH2:29])=[CH:26][CH:25]=1)[CH2:18][C:16]([OH:15])=[O:17])([OH:4])=[O:6]
Reactant: O=C1CN(CCN2CC(=O)OC(=O)C2)CC(=O)O1
Reactant: Nc1ccc(I)cc1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(NC(=O)CN(CCN(CC(=O)O)CC(=O)Nc2ccc(I)cc2)CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.5 %

Procedure:
A solution of EDTA dianhydride (256 mg, 1.0 mmol) and sulfanilamide (172 mg, 1.0 mmol) in DMF (10.0 mL) was stirred at room temperature for 4 h. 4-Iodoaniline (219 mg, 1.0 mmol) was added to the reaction mixture and the resulting reaction mixture was stirred at room temperature for at least 12 hours (overnight). The solvent was evaporated under reduced pressure and purified over AmberChrom™ resin eluting with CH3CN/water to give the title compound (35.4 mg, 5.5%) as a white solid. 1H NMR (400 MHz, DMSO) δ 10.41 (brs, 1H), 10.19 (s, 1H), 7.79 (d, J=8.0 Hz, 2H), 7.73 (d, J=8.0 Hz, 2H), 7.61 (d, J=8.8 Hz, 2H), 7.47 (d, J=8.8 Hz, 2H), 7.24 (s, 2H), 3.50-3.46 (m, 8H), 2.80 (s, 4H); MS (ESI), 648 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:27]([C:29]1[S:30][CH:31]=[CH:32][C:33]=1[Br:34])=[O:28].CCOCC.CCCCCCC>O1CCCC1>[CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[C:27]([C:29]1[S:30][CH:31]=[CH:32][C:33]=1[Br:34])=[O:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)c1sccc1Br
Reactant: c1ccc(COCn2cnc3ccccc32)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: O=C(c1sccc1Br)c1nc2ccccc2n1COCc1ccccc1
Temperature: -78 °C
Reaction time: 0.42 h

Procedure:
To a stirred solution of 1-benzyloxymethyl-1H-benzimidazole (648 mg, 2.72 mmol, Example 1B) in tetrahydrofuran (15 mL) at −78° C. under nitrogen is added n-butyllithium (1.30 mL of a 2.5 M solution in hexanes, 3.25 mmol) over 5 minutes and the resulting yellow solution is stirred at −78° C. After 25 minutes, a solution of 3-bromo-thiophene-2-carboxylic acid methoxy-methyl-amide (680 mg, 2.72 mmol, Example 1A) in tetrahydrofuran (10 mL) is added over 15 minutes and the reaction stirred at −78° C. After 1 hour the reaction is warmed to ambient temperature and stirred for an additional 2 hours. The reaction is quenched with saturated ammonium chloride and the mixture extracted with ethyl acetate. The organic layer is washed with water and brine successively, dried over magnesium sulfate, and concentrated under reduced pressure to a yellow oil. The crude material is chromatographed on silica, eluting with 40% ethyl acetate/heptane, to give the product. Trituration with ether/heptane affords (1-benzyloxymethyl-1H-benzimidazol-2-yl)-(3-bromothiophen-2-yl)methanone as an off-white powder; TLC Rƒ0.52 (silica, 1:1 ethyl acetate/heptane); LC/MS: (M+H 427.0, RT=3.84 minutes); 1H NMR[(CD3)2SO), 300 MHz]: δ 8.18 (d, 1H, 5.2 Hz), 7.90-7.82 (m, 2H), 7.55-7.50 (m, 1H), 7.45-7.38 (m, 2H), 7.25-7.17 (m, 5H), 6.13 (s, 2H), 4.58 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[C:28]([O:32][C:33]([NH:35][C@@H:36]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][S:48]([CH3:51])(=[O:50])=[O:49])=[CH:43][CH:42]=1)[C:37](O)=[O:38])=[O:34])([CH3:31])([CH3:30])[CH3:29].C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:28]([O:32][C:33]([NH:35][C@@H:36]([CH2:40][C:41]1[CH:42]=[CH:43][C:44]([O:47][S:48]([CH3:51])(=[O:50])=[O:49])=[CH:45][CH:46]=1)[C:37]([O:10][C@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[CH2:8][C:7]1[C:6]([Cl:26])=[CH:5][N+:4]([O-:27])=[CH:3][C:2]=1[Cl:1])=[O:38])=[O:34])([CH3:30])([CH3:31])[CH3:29]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OS(C)(=O)=O)cc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OS(C)(=O)=O)cc1)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (100 mg, 0.24 mmol) and (S)-2-(tert-butoxycarbonyl-amino)-3-(4-(methylsulfonyloxy)phenyl)propanoic acid (172 mg, 0.48 mmol) were dissolved in DMF (3 ml). DMAP (35 mg, 0.29 mmol) and EDC (92 mg, 0.48 mmol) were added, and the mixture was stirred at RT for 3 hours, then was quenched with HCl 1N and extracted with EtOAc. The organic layer was washed with HCl 1N and NaHCO3 sat. sol., then was dried over Na2SO4 and evaporated under vacuum to give 155 mg (85%) of the title compound which was employed in the next step without any further purification. MS/ESI+ 761.14 [MH]+.
Reaction SMILES: S(CCC[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:33]#[N:34])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25]CCCS([O-])(=O)=O)=[CH:21][CH:20]=2)[C:17]#[N:18])=[CH:11][CH:10]=1)([O-])(=O)=O.[Na+].[Na+].COC1C=CC(/C(=C(/C2C=CC(OC)=CC=2)\C#N)/C#N)=CC=1>>[OH:8][C:9]1[CH:10]=[CH:11][C:12](/[C:15](=[C:16](/[C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)\[C:17]#[N:18])/[C:33]#[N:34])=[CH:13][CH:14]=1
Reactant: N#CC(=C(C#N)c1ccc(OCCCS(=O)(=O)[O-])cc1)c1ccc(OCCCS(=O)(=O)[O-])cc1
Agent: COc1ccc(/C(C#N)=C(\C#N)c2ccc(OC)cc2)cc1
Agent: [Na+]
Product: N#C/C(=C(/C#N)c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To prepare sodium 1,2-bis[4-(3-sulfonatopropoxyl)phenyl]-1,2-dicyanoethene (3), (1) (0.2903 g, 1 mmol) was dissolved in 10 mL distilled DCM under N2 atmosphere in a 50 mL two-valves round bottom flask. Boron trifluoride methyl sulfide complex (5.26 mL, 50 mmol) was added into the solution slowly. The resulting mixture was stirred at ambient temperature overnight. The solution was concentrated under a stream of N2 and partitioned between 1 M HCl and ethyl acetate. The combined organic later were washed with H2O and brine, dried over Na2SO4 and concentrated to give 2,3-bis(4-hydroxyphenyl)fumaronitrile (2) without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[Cl:8]>S(Cl)(Cl)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[Cl:8])[C:11](=[O:13])[CH2:10][CH2:9]2
Reactant: O=C(O)CCc1ccc(Cl)c(Cl)c1
Solvent: O=S(Cl)Cl
Product: O=C1CCc2cc(Cl)c(Cl)cc21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 435.8 %

Procedure:
A mixture of 20 g of 3-(3,4-dichlorophenyl)-propionic acid [J. Med. Chem., Vol. 16(2) (1973), p. 101-106 ] and 100 ml of thionyl chloride was refluxed for 30 minutes and the thionyl chloride was then evaporated. The residue was taken up in 20 ml of methylene chloride and the solution was poured into a suspension of 20 g of aluminum chloride in 150 ml of methylene chloride. The mixture was stirred for one hour at room temperature and 30 minutes at 50° C. The mixture was poured over ice and was stirred for 30 minutes and then was extracted with methylene chloride. The organic phase was washed with water, dried and evaporated to dryness and the residue was taken up in ether and vacuum filtered. The product was dried to obtain 80 g of the desired product melting at 155° C.
Reaction SMILES: COC[O:4][CH2:5][C@@H:6]1[CH2:10][N:9]([C:11]2[CH:12]=[CH:13][C:14]3[O:19][CH2:18][C:17](=[O:20])[NH:16][C:15]=3[CH:21]=2)[C:8](=[O:22])[CH2:7]1.O1CCCC1.Cl.ClCCl>CO>[OH:4][CH2:5][C@@H:6]1[CH2:10][N:9]([C:11]2[CH:12]=[CH:13][C:14]3[O:19][CH2:18][C:17](=[O:20])[NH:16][C:15]=3[CH:21]=2)[C:8](=[O:22])[CH2:7]1
Reactant: COCOC[C@H]1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1COc2ccc(N3C[C@@H](CO)CC3=O)cc2N1
Temperature: 60 °C
Reaction time: 18 h
Yield: 89.4 %

Procedure:
To a solution of 6-{(4S)-4-[(methoxymethoxy)methyl]-2-oxopyrrolidin-1-yl}-2H-1,4-benzoxazin-3(4H)-one (1.49 g, 4.86 mmol) in methanol (10 ml)/tetrahydrofuran (10 ml) was added 4N Hydrochloric acid (2 ml) at room temperature and the mixture was heated to 60° C. and stirred for 18 hours. The reaction solution was poured into a mixture of dichloromethane and a saturated sodium hydrogen carbonate aqueous solution and the resultant was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. A mixed solvent of dichloromethane/methanol (10:1) was added to the obtained solid to prepare a slurry and the solid was collected by filtration to yield 1.14 g (90%) of the title compound in the form of a light yellow solid.