Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([C:20](O)=[O:21])=[CH:18][CH:19]=1)=[O:14]>>[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([C:20](=[O:21])[NH:10][CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH3:9])=[CH:18][CH:19]=1)=[O:14]
Reactant: CC(N)c1cccc(Br)c1
Reactant: COC(=O)c1ccc(C(=O)O)s1
Product: COC(=O)c1ccc(C(=O)NC(C)c2cccc(Br)c2)s1

Procedure:
The title compound was prepared in an analogous manner to that described in example 1, step 1 from 1-(3-bromo-phenyl)-ethylamine and thiophene-2,5-dicarboxylic acid monomethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:21])[C:6]([Cl:20])=[CH:7][C:8]=1[C:9]([NH:11][CH:12]1[CH:17]([O:18][CH3:19])[CH2:16][NH:15][CH2:14][CH2:13]1)=[O:10].C(=O)([O-])[O-].[K+].[K+].[CH3:28][O:29][C:30](=[O:33])[CH2:31]Br>CN(C=O)C>[CH3:28][O:29][C:30](=[O:33])[CH2:31][N:15]1[CH2:14][CH2:13][CH:12]([NH:11][C:9](=[O:10])[C:8]2[CH:7]=[C:6]([Cl:20])[C:5]([NH2:21])=[CH:4][C:3]=2[O:2][CH3:1])[CH:17]([O:18][CH3:19])[CH2:16]1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NC1CCNCC1OC
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CN1CCC(NC(=O)c2cc(Cl)c(N)cc2OC)C(OC)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.2 %

Procedure:
A mixture containing 313 mg norcisapride and 276 mg potassium carbonate in 10 ml DMF was treated with 153 mg of bromo-acetic acid methyl ester. The reaction was stirred at ambient temperature for 8 hr. Extractive workup with waterdichloromethane followed by flash chromatography afforded 455 mg of product.
Reaction SMILES: C(OC(=O)/[C:7](/[C:26]#[N:27])=[CH:8]\[NH:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[C:13]([N+:19]([O-:21])=[O:20])=[CH:12][C:11]=1[C:22]([O:24]C)=O)(C)(C)C.C(#N)C.C1CCN2C(=NCCC2)CC1>OS(C(F)(F)F)(=O)=O.CCOC(C)=O.CCCCCC>[CH2:17]([O:16][C:14]1[CH:15]=[C:10]2[C:11]([C:22]([OH:24])=[C:7]([C:26]#[N:27])[CH:8]=[N:9]2)=[CH:12][C:13]=1[N+:19]([O-:21])=[O:20])[CH3:18]
Reactant: CCOc1cc(N/C=C(/C#N)C(=O)OC(C)(C)C)c(C(=O)OC)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCCCCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOc1cc2ncc(C#N)c(O)c2cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.4 %

Procedure:
A 100-mL round-bottomed flask equipped with an overhead stirrer, a condenser and a thermocouple is charged with (Z)-2-Cyano-3-(5′-ethoxy-2′-methoxycarbonyl-4′-nitrophenyl)amino-2-propenoic acid t-butyl ester (2.5 g, 6.3 mmol) and acetonitrile (50 mL). The triflic acid (0.12 mL, 0.21 mmol) is added to the heterogeneous reaction medium. Upon disappearance of the starting material as evidenced by TLC (20% EtOAc/hexane), the DBU (4.0 mL, 4.25 mmol) is added to the reaction mixture. The reaction is then heated to reflux and monitored for completion (>95% by HPLC—Phenomenex 3 micron Phenyl-hexyl column (150×4.6 mm)). The reaction is then quenched with 10% HCl (100 mL) and diluted with water (400 mL). After stirring for 15 minutes at room temperature the suspension is filtered and the collected solid allowed to “air” dry. The collected solid is suspended in ethyl acetate (25 mL) at room temperature and filtered again and allowed to “air” dry. This procedure provides 1.15 g (70%) of the title compound as a beige solid that is >95% product by NMR integration. 1H NMR (300 MHz, DMSO-d6): 12.9 (s, 1H), 8.79 (s, 1H), 8.51 (s, 1H), 7.24 (s, 1H), 4.27 (q, J=7 Hz, 2H), 1.41 (t, J=7 Hz, 3H).
Reaction SMILES: [NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([C:11]([OH:13])=O)[CH2:3][C:4]1[C:5]([F:10])=[CH:6][CH:7]=[CH:8][CH:9]=1.[NH:21]([CH3:46])[C@H:22]([C:26]([N:28]([CH3:45])[C@H:29]([C:42]([NH2:44])=[O:43])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:32]=1)=[O:27])[CH:23]([CH3:25])[CH3:24].O>C1COCC1>[NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([C:11]([N:21]([CH3:46])[C@H:22]([C:26]([N:28]([CH3:45])[C@H:29]([C:42]([NH2:44])=[O:43])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([C:38]([CH3:41])([CH3:39])[CH3:40])[CH:32]=1)=[O:27])[CH:23]([CH3:25])[CH3:24])=[O:13])[CH2:3][C:4]1[C:5]([F:10])=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CN[C@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1F)C(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1ccccc1F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To a solution of Boc-Phe(2-F)-OH (0.20 g, 0.706 mmol), N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (0.21 g, 0.578 mmol) and CMPI (0.20 g, 0.783 mmol) in THF (6 ml), TEA (0.30 ml, 2.15 mmol) was added under cooling with ice and stirred at room temperature overnight. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: chloroform:methanol:aqueous ammonia=60:1:0.05) to give Boc-Phe(2-F)-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (0.33 g, 91%).
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[C:11]1([CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[O:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:20](=[O:21])[CH2:19][CH2:18][CH2:17][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:6][C:5]=2[CH:4]=[CH:3]1
Reactant: O=C(O)CCCc1ccccc1
Reactant: c1cc2c(o1)CCNC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCc1ccccc1)N1CCc2occc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride, 0.18 g (1.1 mmol) of 4-phenylbutyric acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel chromatography (hexane/ethyl acetate=3/1) to yield the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:14][CH2:15][NH:16]C(=O)OC(C)(C)C)[C:7]([CH3:24])=[C:6]2[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CCOC(C)=O>[NH2:16][CH2:15][CH2:14][N:8]1[C:7]([CH3:24])=[C:6]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13]
Reactant: COc1ccc2c(=O)n(CCNC(=O)OC(C)(C)C)c(C)c(-c3ccccc3)c2c1
Solvent: CCOC(C)=O
Product: COc1ccc2c(=O)n(CCN)c(C)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-butyl 2-(6-methoxy-3-methyl-1-oxo-4-phenylisoquinolin-2(1H)-yl)ethylcarbamate (800 mg) was dissolved in 200 mL EtOAc and cooled to 0 C. HCl gas was bubbled through the solution for 5 min, and the reaction was warmed to room temp. After stirring for 4 h, the reaction was filtered to isolate the hydrochloride salt of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[NH:34][C:35]1[S:36][C:37]([CH3:40])=[N:38][N:39]=1>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:21])[CH3:20])=[O:23])=[C:28]([NH:34][C:35]2[S:36][C:37]([CH3:40])=[N:38][N:39]=2)[CH:29]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: Cc1nnc(Nc2cc(F)ccc2CN)s1
Product: Cc1nnc(Nc2cc(F)ccc2CNC(=O)c2nc3n(c(=O)c2OCc2ccccc2)CCOC3(C)C)s1

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and N-(2-(aminomethyl)-5-fluorophenyl)-5-methyl-1,3,4-thiadiazol-2-amine, derived from reduction of intermediate 124, 4-fluoro-2-(5-methyl-1,3,4-thiadiazol-2-ylamino)benzonitrile. LCMS (+ESI, M+H+) m/z 551.
Reaction SMILES: N(OCC)=O.[N:6]([O-:8])=O.[Na+].S(=O)(=O)(O)O.[CH3:15][C:16](=O)[CH2:17][CH2:18][C:19](=[O:21])[CH3:20]>C(O)C.O.Cl.CCOCC>[CH3:15][C:16]1[O:8][N:6]=[C:18]([C:19](=[O:21])[CH3:20])[CH:17]=1
Reactant: CC(=O)CCC(C)=O
Reactant: O=N[O-]
Agent: CCON=O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CC(=O)c1cc(C)on1
Temperature: 50 °C
Reaction time: 6 h
Yield: 69.6 %

Procedure:
Ethyl nitrite gas was generated in situ by addition of a solution of sodium nitrite (100 g, 1.44 mol) in 50 mL of ethanol and 400 mL of water dropwise into a solution of 50 mL of concentrated sulfuric acid in 50 mL of ethanol and 400 mL of water in a stand-alone reaction vessel. The ethyl nitrite gas generated was bubbled into another reaction flask containing a mixture of hexane-2,5-dione (80 g, 700.88 mmol) in concentrated hydrochloric acid (10 mL). The resulting solution was stirred for 6 hr at 50° C. After cooling to room temperature, the reaction mixture was diluted with ether (600 mL) then washed with of saturated sodium carbonate solution (2×500 mL) and brine (500 mL). The organic layer was dried with anhydrous sodium sulphate then concentrated in vacuo. The crude product was purified by distillation under reduced pressure (12 mm Hg) and the fraction with the boiling point of 70° C. was collected to give 61 g (69%) of the title compound as a colorless liquid: 1H NMR (300 MHz, CDCl3) delta 6.36 (s, 1H), 2.63 (s, 3H), 2.49 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[CH:7]=[N+]=[N-])([CH3:4])([CH3:3])[CH3:2].[Sn](Cl)Cl.[CH3:14][O:15][C:16](=[O:27])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[C:20]([Cl:26])[CH:19]=1>C(Cl)Cl.[Cl-].[Na+].O>[C:1]([O:5][C:6](=[O:10])[CH2:7][C:24]([C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C:16]([O:15][CH3:14])=[O:27])=[CH:19][C:20]=1[Cl:26])=[O:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C=[N+]=[N-]
Reactant: COC(=O)Cc1ccc(C=O)c(Cl)c1
Agent: Cl[Sn]Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)Cc1ccc(C(=O)CC(=O)OC(C)(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A flame-dried flask is charged with tert-butyl-diazoacetate (0.62 mL, 4.48 mmol) and anhydrous tin(II) chloride (168 mg, 0.88 mmol) in dry DCM (10 mL). (3-Chloro-4-formyl-phenyl)-acetic acid methyl ester 14 (500 mg, 2.35 mmol) is dissolved in DCM (5 mL) and added dropwise to the reaction mixture. After stirring for 6 h at room temperature the reaction mixture is poured into brine (50 mL) and extracted with ether (3×50 mL). The combined organic layers are dried (MgSO4), filtered, concentrated and purified on reverse phase HPLC (H2O/MeCN gradient) to afford 3-(2-Chloro-4-methoxycarbonylmethyl-phenyl)-3-oxo-propionic acid tert-butyl ester 56 as a white solid: MS calculated for C16H19Cl2NaO5 (M+Na+) 349.1, found 349.1.
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:14]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]2[CH:20]=[CH:21][C:22]([C:24]#[N:25])=[CH:23][C:12]=2[N:11]=1)C1C=CC=CC=1>CO.Cl.[Pd]>[NH2:25][CH2:24][C:22]1[CH:21]=[CH:20][C:13]2[N:14]([CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])[C:10]([CH2:9][OH:8])=[N:11][C:12]=2[CH:23]=1
Reactant: CC(C)CCn1c(COCc2ccccc2)nc2cc(C#N)ccc21
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)CCn1c(CO)nc2cc(CN)ccc21
Reaction time: 48 h
Yield: 137.2 %

Procedure:
To a solution 2-benzyloxymethyl-1-(3-methyl-butyl)-1H-benzoimidazole-5-carbonitrile (1.12 g, 3.36 mmol) in methanol (50 mL) and concentrated HCl (2.5 mL) was added 10% Pd/C (120 mg). This mixture was rocked under a hydrogen atmosphere in a Parr shaker(45 psi) for 48 hrs. The catalyst was removed by filtration and the solution concentrated in vacuo to give [5-aminomethyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-yl]-methanol (1.14 g, 100%) as a tan solid. A small portion was purified by prep HPLC (30-100% B) to give C-[2-Benzyloxymethyl-1-(3-methyl-butyl)-1H-benzoimidazol-5-yl]-methylamine; HCl salt:
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:29]=[CH:28][CH:27]=[CH:26][C:19]=1[CH2:20][CH:21]([C:23]([OH:25])=[O:24])[NH2:22]>>[C:23]([CH:21]([NH:22][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:20][C:19]1[CH:26]=[CH:27][CH:28]=[CH:29][C:18]=1[O:17][CH3:16])([OH:25])=[O:24]
Reactant: COc1ccccc1CC(N)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: COc1ccccc1CC(Nc1nc2ccc(Cl)cc2cc1C(=O)O)C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-methoxy-DL-phenylalanine to provide the title compound in good yield.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1B(O)O.CCN(C(C)C)C(C)C>C(O)C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][CH:3]=1
Reactant: Cc1nc(Br)ccc1F
Reactant: OB(O)c1c(F)cccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1nc(-c2c(F)cccc2F)ccc1F
Temperature: 120 °C
Yield: 88 %

Procedure:
To a solution of 6-bromo-3-fluoro-2-methylpyridine (1.0 equiv.) in ethanol and toluene (1:1, 0.2 M) was added 2,6-difluorophenylboronic acid, DIEA (5 equiv.) and Pd(PPh3)4 (0.2 equiv.). The reaction was heated in the microwave at 120° C. for 30 min. The solution was filtered and rinsed with ethyl acetate. The volatiles were removed in vacuo and the crude was purified via silica gel column chromatography eluting with ethyl acetate and hexanes (2.5-20% ethyl acetate). Upon concentration of the pure fractions, 6-(2,6-difluorophenyl)-3-fluoro-2-methylpyridine was isolated in 88% yield. LC/MS=224.1 (M+H), Rt=0.87 min.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[CH2:6]1)=[O:4].[OH-].[Na+].O1CCCC1>O>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][O:17][C:14]2[CH:13]=[CH:12][C:11]([N:7]3[C:8](=[O:10])[CH2:9][CH:5]([C:3]([OH:4])=[O:2])[CH2:6]3)=[CH:16][CH:15]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)C1CC(=O)N(c2ccc(OCc3ccc(F)cc3)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CC(=O)N(c2ccc(OCc3ccc(F)cc3)cc2)C1
Temperature: 50 °C
Yield: 84.8 %

Procedure:
A suspension of 7.12 g (20.7 mmol) of (RS)-1-[4-(4-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methyl ester in 10.3 ml of a solution of sodium hydroxide (1N) is prepared and tetrahydrofurane is added until a clear solution is obtained. The mixture is heated to 50° C. for 1 hour. For the working-up, the tetrahydrofurane is evaporated under reduced pressure. The white suspension obtained is diluted with water, then filtered. The white product is treated with toluene and evaporated under reduced pressure to remove most of the water. The azetropic distillation is repeated three times. There are obtained 5.78 g (85% of theory) of (RS)-1-[4-(4-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([NH:19][CH2:20][C:21]([O:23]CC)=[O:22])=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].O.Cl>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CNC(=O)N1CCN(c2ccccc2C(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)NCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
A mixture of ethyl N-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}glycinate obtained in Example 4 (430 mg), lithium hydroxide monohydrate (420 mg), water (50 mL), and tetrahydrofuran (50 mL) was stirred at room temperature for 3 h. 6 M hydrochloric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to provide the title compound (350 mg, 89%) as a colorless solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]([CH3:13])=[CH:11][C:7]2[NH:8][CH:9]=[N:10][C:6]=2[CH:5]=1.Cl[CH2:15][C:16]1[CH:26]=[CH:25][C:19]2[N:20]=[C:21]([S:23][CH3:24])[S:22][C:18]=2[CH:17]=1>CN(C=O)C>[CH3:3][C:4]1[C:12]([CH3:13])=[CH:11][C:7]2[N:8]([CH2:15][C:16]3[CH:26]=[CH:25][C:19]4[N:20]=[C:21]([S:23][CH3:24])[S:22][C:18]=4[CH:17]=3)[CH:9]=[N:10][C:6]=2[CH:5]=1
Reactant: Cc1cc2nc[nH]c2cc1C
Reactant: CSc1nc2ccc(CCl)cc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc2ccc(Cn3cnc4cc(C)c(C)cc43)cc2s1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94.7 %

Procedure:
To a stirred mixture of anhydrous DMF (15 mL) and sodium hydride (60% dispersion in mineral oil, 105 mg, 2.63 mmol) at 0° C. under nitrogen, was added portionwise 5,6-dimethyl-1H-benzo[d]imidazole (215 mg, 1.4 mmol). The reaction mixture was stirred for 5 min. A solution of 6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (320 mg, 1.4 mmol) from Step 4 of Example 36 in anhydrous DMF (2 mL) was added dropwise. The reaction mixture was allowed to warm to rt and stir for 1 h. The reaction solution was poured into ice-water and extracted with EtOAc (50 mL×3). The combined organic layers were further washed with water (20 mL), then brine (20 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 6-((5,6-dimethyl-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (450 mg, 96%) as a yellow solid which was not purified further. 1H NMR (300 MHz, CDCl3) δ 7.86 (s, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.59 (s, 1H), 7.46 (s, 1H), 7.24-7.26 (m, 1H), 7.03 (s, 1H), 5.40 (s, 2H), 2.77 (s, 3H), 2.37 (s, 3H), 2.32 (s, 3H); LCMS (ESI) m/z 340 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20]([OH:22])=O)=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[CH3:25][O:26][CH2:27][CH2:28][NH2:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:25][O:26][CH2:27][CH2:28][NH:29][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:22]
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: COCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2C
Yield: 48.9 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide (51 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzo-imidazole-5-carboxylic acid (90 mg), 2-methoxyethylamine (21 mg), HBTU (114 mg), and DIEA (66 uL). LC/MS: m/z 416.8. 1H NMR (DMSO-d6, 400 MHz): δ 12.36 (bs, 1H), 8.46 (s, 1H), 8.06 (s, 1H), 7.91 (s, 1H), 7.75 (s, 1H), 7.64 (s, 1H), 7.46 (d, 1H), 7.38 (dd, 1H), 3.62 (bs, 3H), 3.50-3.39 (m, 4H), 3.27 (s, 3H).
Reaction SMILES: [O:1]=[C:2]([CH3:16])[CH2:3][C:4]([NH:6][CH2:7][CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5].[N+:17]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O)([O-:19])=[O:18].N1CCCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.O>[C:2]([C:3](=[CH:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=1)[C:4]([NH:6][CH2:7][CH:8]=[CH:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:5])(=[O:1])[CH3:16]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CC(=O)NCC=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Solvent: O
Product: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)NCC=Cc1ccccc1

Procedure:
1.03 g (4.74 mmol) of 3-oxo-N-(3-phenyl-2-propene-1-yl)butyramide, 723 mg (4.78 mmol) of 3-nitrobenzaldehyde and 0.2 ml (2.02 mmol) of piperidine were heated under reflux in the presence of a catalytic amount of p-toluenesulfonic acid in 30 ml of benzene overnight while water was removed. Ethyl acetate was added to the reaction mixture. After washing with 2 N hydrochloric acid and then with a saturated aqueous sodium hydrogencarbonate solution, the organic layer was dried over anhydrous sodium sulfate. After the concentration under reduced pressure, the residue was purified by the silica gel chromatography (hexane/ethyl acetate=2/1) to obtain the title compound.
Reaction SMILES: [N:1]#[N:2].[C:3]([NH:8][C:9]1[NH:10][C:11](=[O:44])[C:12]2[N:13]=[CH:14][N:15]([C@@H:18]3[O:30][C@H:29]([CH2:31][O:32][C:33]4(C(=O)C(C)C)[CH2:38][CH2:37][CH2:36][CH2:35][O:34]4)[C@@H:21]([O:22][CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][O:24]4)[C@@H:19]3[OH:20])[C:16]=2[N:17]=1)(=[O:7])[CH:4]([CH3:6])[CH3:5].[OH-].[Na+].C(O)(=O)C.C([O-])(O)=O.[Na+]>N1C=CC=CC=1.CO.O.CCO.CO>[N:1]#[N:2].[C:3]([NH:8][C:9]1[NH:10][C:11](=[O:44])[C:12]2[N:13]=[CH:14][N:15]([C@@H:18]3[O:30][C@H:29]([CH2:31][O:32][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][O:34]4)[C@@H:21]([O:22][CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][O:24]4)[C@@H:19]3[OH:20])[C:16]=2[N:17]=1)(=[O:7])[CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@@H]2O[C@H](COC3(C(=O)C(C)C)CCCCO3)[C@@H](OC3CCCCO3)[C@@H]2O)c(=O)[nH]1
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)C(=O)Nc1nc2c(ncn2[C@@H]2O[C@H](COC3CCCCO3)[C@@H](OC3CCCCO3)[C@@H]2O)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
N2 -Isobutyryl-9-(2'-isobutyryl-3', 5'-di-O-[tetrahydropyran-2-yl]-β-D-arabinofuranosyl) guanine (5.58 g) was dissolved in pyridine-MeOH-H2O (65:30:15, 52 mL) at room temperature. The solution was cooled to 0° C. and 52 mL of 2 N NaOH in EtOH-MeOH (95:5) was added slowly, followed by stirring for 2 hours at 0° C. Glacial acetic acid was added to pH 6, and saturated NaHCO3 was added to pH 7. The reaction mixture was evaporated under reduced pressure and the residue coevaporated with toluene. The residue was then dissolved in EtOAc (150 mL) and washed 3× with saturated NaHCO3. The organic phase was evaporated and the residue purified by silica gel column chromatography using EtOAc-MeOH (95:5) as the eluent, yielding 3.85 g (78.3%) of product.