Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][S:14][CH2:13][CH2:12]1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+].[Na+].[Cl-].CN(C)C1C=CC=CC=1.[CH2:41]([O:48][C:49](Cl)=[O:50])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C1COCC1.O.CCOC(C)=O.CCCCCC>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:49]([O:48][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:50])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][S:14][CH2:13][CH2:12]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(N2CCSCC2)c(F)c1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)c1ccccc1
Product: O=C(Nc1ccc(N2CCSCC2)c(F)c1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 92.7 %

Procedure:
The 4-(2-fluoro-4-nitrophenyl)thiomorpholine (3.67 g, 8.255 mmol) was dissolved in THF (75 mL) and then treated with a solution of sodium hydrosulfite (26.4 g, 151.56) in water (150 mL). The reaction was slightly exothermic. After an hour, the reaction was found to be complete by TLC (30% EtOAc/hexane, UV short wave). After cooling to 0° C. in an ice bath, the reaction was quenched with NaHCO3 (25.5 g, 303.12 mmol). Next, the reaction was diluted with pH 7 buffer (500 mL). After this solution was saturated with solid NaCl, the product was extracted into CH2Cl2 (4×500 mL). The combined extracts were dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure to yield a yellow solid that was stored in the freezer overnight (16 hours). The crude amine (1.826 g, 8.601 mmol) was dissolved in dry THF (85 mL) and then cooled to -20° C. (MeOH/ice bath). The solution was treated with N,N-dimethylaniline (1.36 mL, 10.75 mmol) and then allowed to stir at -20° C. for 15 minutes. Next, benzylchloroformate [1.42 mL (corrected for 95% purity), 9.46 mmol] was added dropwise. A precipitate fomed almost immediately. The reaction was allowed to stir for an additional 15 minutes before the bath was removed. Upon warming to room temperature under N2 (1 hour), the reaction was found to be complete by TLC (30% EtOAc/hexane, UV short wave). The reaction was diluted with EtOAc (200 mL) and then washed with both water (2×200 mL) and brine (200 mL). The aqueous portions were combined and then back-extracted with more EtOAc (2×200 mL). The organic portions were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield a yellowish solid. This crude material was chromatographed on silica gel (150 g, packed with 5% EtOAc/hexane), eluting with 2 L of 5% EtOAc/hexane, 1 L of 10% EtOAc/hexane (CH2Cl2 was added to maintain solubility) to give 2.65 g (50%) of the title compound as an off-white crystalline solid with a melting point of 142° C. and a HRMS (M+) calculated for C18H19N2O2FS 346.1151, found 346.1157.
Reaction SMILES: [F:1][C:2]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:3]=1[O:4][C:5]1[C:13]2[N:12]=[CH:11][N:10]([CH3:14])[C:9]=2[C:8]([CH:15]=C)=[CH:7][C:6]=1[C:17]1[C:18]2[CH:27]=[N:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:19]=2[C:20](=[O:24])[N:21]([CH3:23])[CH:22]=1.I([O-])(=O)(=O)=[O:42].[Na+]>O.O1CCCC1.C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:3]=1[O:4][C:5]1[C:13]2[N:12]=[CH:11][N:10]([CH3:14])[C:9]=2[C:8]([CH:15]=[O:42])=[CH:7][C:6]=1[C:17]1[C:18]2[CH:27]=[N:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:33])[CH3:34])[C:19]=2[C:20](=[O:24])[N:21]([CH3:23])[CH:22]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc(-c2cn(C)c(=O)c3c2cnn3COCC[Si](C)(C)C)c(Oc2ccc(F)cc2F)c2ncn(C)c12
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2cc(C=O)c3c(ncn3C)c2Oc2ccc(F)cc2F)c2cnn(COCC[Si](C)(C)C)c2c1=O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
A mixture of 4-[4-(2,4-difluorophenoxy)-1-methyl-7-vinyl-1H-benzimidazol-5-yl]-6-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one (0.076 g, 0.13 mmol) and sodium metaperiodate (0.0865 g, 0.404 mmol) in water (0.23 mL) and tetrahydrofuran (3.10 mL) was treated with 0.16M solution of osmium tetraoxide in water (0.172 mL, 0.0270 mmol). The resultant reaction mixture was stirred at 60° C. for 30 min. The reaction mixture was diluted with water and ethyl acetate. Layers were separated and the organic layer was washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo to give a crude residue. Purification by flash column chromatography (100% hexanes to 100% EtOAc [EtOAc contained 5% MeOH]) gave the desired product (50.6 mg, 66%). LCMS calculated for C28H30F2N5O4Si (M+H)+: m/z=566.2. found: 566.1.
Reaction SMILES: [CH2:1]([C:3]1[S:42][C:6]2[N:7]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]4[NH:40][C:39](=[O:41])[O:38][N:37]=4)=[CH:26][CH:25]=3)[C:8](=[O:22])[N:9]([CH2:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=O)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Cl.[NH2:44][O:45][CH2:46][CH3:47].N1C=CC=CC=1.Cl>O.C(Cl)(Cl)Cl.C(O)C>[CH2:46]([O:45][N:44]=[C:13]([C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)[CH2:12][N:9]1[C:10](=[O:11])[C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[S:42][C:6]=2[N:7]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:40][C:39](=[O:41])[O:38][N:37]=3)=[CH:26][CH:25]=2)[C:8]1=[O:22])[CH3:47]
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(F)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Reactant: CCON
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCON=C(Cn1c(=O)c2cc(CC)sc2n(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c1=O)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 6-ethyl-3-[2-(4-fluorophenyl)-2-oxoethyl]-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.2 g), (aminooxy)ethane hydrochloride (0.04 g), pyridine (10 mL) and ethanol (10 mL) was stirred at 100° C. for 16 hr. To the reaction mixture were added chloroform and water, and the mixture was adjusted to pH 4 with 1N hydrochloric acid. The chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a stereoisomer mixture (0.1 g, 48%).
Reaction SMILES: B.C1COCC1.[CH2:7]([N:14]1[CH2:19][CH2:18][O:17][CH:16]([CH:20]([CH:22]2[CH2:24][CH2:23]2)[OH:21])[C:15]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O.CO>[CH2:7]([N:14]1[CH2:19][CH2:18][O:17][CH:16]([CH:20]([CH:22]2[CH2:24][CH2:23]2)[OH:21])[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1C(C(O)C2CC2)OCCN1Cc1ccccc1
Agent: B
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: OC(C1CC1)C1CN(Cc2ccccc2)CCO1
Temperature: 60 °C
Yield: 60.9 %

Procedure:
Borane-THF complex (1M solution in THF, 30 mL, 30 mmol, 4.1 eq) is added slowly to a solution of 75 (1.9 g, 7.3 mmol) in THF (100 mL). The reaction is heated to 60° C. After 24 hours MeOH and hydrochloric acid (2M, excess) are added and the resulting mixture heated for one hour at the same temperature. After careful addition of saturated NaHCO3 solution and EtOAc the aqueous layer is extracted with EtOAc. The combined organic layers are washed with brine, dried over magnesium sulphate and the solvent is removed in vacuo. Purification by ion exchange chromatography gives 76 (1.1 g, 61%). MW 247.34; C15H21NO2; LCMS (6 min method) m/z 248 [M+H]+, RT 2.48 min
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10]Cl)=[N:7][C:6]=2[CH:12]=1.C([O-])([O-])=O.[K+].[K+].[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[N:7][C:6]=2[CH:12]=1
Reactant: C1CCNC1
Reactant: ClCc1nc2cc(Br)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc2oc(CN3CCCC3)nc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2 g (8.11 mmol) 5-bromo-2-chloromethyl-benzoxazole in 30 mL DMF is combined with 2.24 g (16.22 mmol) K2CO3 and 0.9 mL (10.78 mmol) pyrrolidine and stirred for 24 hours at RT. The reaction mixture is diluted with water and extracted with EtOAc. The organic phase is dried over Na2SO4, the desiccant is filtered off and the filtrate is evaporated down.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH:19]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:22]([O:29][C:30]([N:32]([CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[CH:33]([CH2:35][CH3:36])[CH3:34])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH2:19][N:40]2[CH2:39][CH2:38][CH:37]([N:32]([C:30]([O:29][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:31])[CH:33]([CH2:35][CH3:36])[CH3:34])[CH2:42][CH2:41]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CC1CN(Cc2ccccc2)CC1c1ccccc1
Reactant: CCC(C)N(C(=O)OCc1ccccc1)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)N(C(=O)OCc1ccccc1)C1CCN(CC2CN(Cc3ccccc3)CC2c2ccccc2)CC1
Yield: 80.7 %

Procedure:
The title compound was prepared from 20 mg of 1-Benzyl-3-(SR)-formyl-4-(SR)-phenylpyrrolidine, 24 mg of 4-(N-(benzyloxycarbonyl)-N-secbutylamino)piperidine-hydrochloride, 0.013 mL of DIEA and 24 mg of sodium triacetoxyborohydride using a procedure analogous to that described in Example 9, Step B to provide 32 mg of the title compound. HPLC (YMC "Octyl" 4.6×250 mm column, 60:40 v/v H2O/CH3CN+0.5% TFA, 1.5 mL/min, 200 nm): Retention Time: 12.99 min. 1H NMR (300 MHz, CDCl3): δ0.70-0.82 (m, 3H), 1.16 (t, J =6.4 Hz, 3H), 1.37-1.95 (m, 10H), 2.34-2.66 (m, 6H), 2.83-2.99 (m, 4H), 3.69 (ABq, J =13 Hz, 2H), 5.11 (s, 2H), 7.14-7.39 (m, 15H). Mass Spectrum (ESI): 540.6 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]2([CH2:12][CH3:13])[O:11][CH2:10][CH2:9][O:8]2)[S:5][CH:6]=1.C([Li])CCC.CN(C)[CH:21]=[O:22]>>[CH2:12]([C:7]1([C:4]2[S:5][CH:6]=[C:2]([CH:21]=[O:22])[CH:3]=2)[O:11][CH2:10][CH2:9][O:8]1)[CH3:13]
Reactant: CN(C)C=O
Reactant: CCC1(c2cc(Br)cs2)OCCO1
Agent: [Li]CCCC
Product: CCC1(c2cc(C=O)cs2)OCCO1

Procedure:
In a manner similar to that of Example 9(g), by reaction of 12 g (45.6 mmol) of 2-(4-bromo-2-thienyl)-2-ethyl-[1,3]dioxolane with 20 mL (50 mmol) of 2.5 M butyllithium and 3.9 mL (50 mmol) of dimethylformamide, the desired product is obtained in the form of a yellow oil (m=4.6 g, Y=48%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[NH2:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1.C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[N:5]1[CH:6]=[CH:7][C:2]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:18][CH:19]=2)=[CH:3][CH:4]=1
Reactant: Clc1ccncc1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1ccc(Nc2ccncc2)cc1

Procedure:
4.57 g (31 mmol) of 4-chloropyridine and 5.03 g (31 mmol) of ethyl 4-aminobenzoate were dissolved in 100 ml of xylene. 12.7 ml (92 mmol) of triethylamine was added to the obtained solution and the resultant mixture was heated under reflux for 50 hours. The solvent was evaporated, and the residue was diluted with water. After the extraction with dichloromethane followed by washing with saturated Aqueous NaCl solution and drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17]C)[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([NH:30][O:31]C3CCCCO3)=[O:29])=[CH:22][CH:21]=2)=[C:4]([CH3:38])[CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:21]=[CH:22][C:23](/[CH:26]=[CH:27]/[C:28]([NH:30][OH:31])=[O:29])=[CH:24][CH:25]=2)=[C:4]([CH3:38])[CH:3]=1
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(=O)NOC4CCCCO4)cc3)c(-c3ccc(F)cc3C)sc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(F)ccc1-c1sc2cc(O)ccc2c1Oc1ccc(/C=C/C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.4 %

Procedure:
To a 30 mL screw cap vial, (E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)acrylamide (53 mg, 0.099 mmol) was dissolved in DCM (1 mL). The vial was charged with BBr3 (1.0 M in hexanes, 0.298 mL, 0.298 mmol) and the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was quenched with 4 mL MeOH and stirred for 10 min. The mixture was concentrated onto silica gel and the crude material was purified by reverse phase HPLC (acidic condition, 0.1% TFA in 30-100% CH3CN/H2O) to afford (E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)-N-hydroxyacrylamide (16 mg, 0.037 mmol, 37% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm=2.25 (s, 3H,) 6.19 (d, J=16.17 Hz, 1H), 6.66-6.84 (m, 4H), 6.88 (dd, J=9.85, 2.78 Hz, 1H), 7.06-7.26 (m, 3H), 7.26-7.45 (m, 3H). LC/MS (m/z, MH+): 436.1.
Reaction SMILES: C(OP([CH2:9][C:10]1[N:11]=[CH:12][N:13]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=1)(=O)OCC)C.CC([O-])(C)C.[K+].[CH3:40][C:41]([CH3:51])([CH3:50])[C:42]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=O.C1CCCCC1>C1COCC1>[CH3:40][C:41]([CH3:51])([CH3:50])[C:42]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[CH:9][C:10]1[N:11]=[CH:12][N:13]([C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:14]=1
Reactant: CCOP(=O)(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)OCC
Reactant: CC(C)(C)C(=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC(C)(C)C(=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of (1-trityl-1H-imidazol-4-ylmethyl)-phosphonic acid diethyl ester (341 mg; CAS 473659-21-1) at r.t. in THF (7.5 ml) under an argon atmosphere was added potassium tert-butylate (83 mg). The mixture was then stirred at r.t. for 15 minutes, and 2,2-dimethylpropiophenone (0.1 ml) was added in one portion. The mixture (clear brown orange solution) was heated to 80° C. and stirring at that temperature was continued for 24 hours. The reaction mixture was directly adsorbed on silica gel. The product was isolated by chromatography (gradient: cyclohexane→cyclohexane/EtOAc 65:35) to give 4-(3,3-dimethyl-2-phenyl-but-1-enyl)-1-trityl-1H-imidazole (135 mg; not completely pure) as light yellow solid. MS (ISP): 243.2 ([Trt]+)
Reaction SMILES: [CH:1]1([NH:4][S:5]([NH:8][C@@H:9]([CH2:20][C:21]2[O:22][C:23]([CH2:26][C:27]3[S:28][C:29]4[CH:35]=[C:34]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[CH:33]=[CH:32][C:30]=4[N:31]=3)=[N:24][N:25]=2)[C:10]([O:12]CC2C=CC=CC=2)=O)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C[O-].[Na+].CO.Cl>C1COCC1>[CH:1]1([N:4]2[C:10](=[O:12])[C@H:9]([CH2:20][C:21]3[O:22][C:23]([CH2:26][C:27]4[S:28][C:29]5[CH:35]=[C:34]([C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)[CH:33]=[CH:32][C:30]=5[N:31]=4)=[N:24][N:25]=3)[NH:8][S:5]2(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(OCc1ccccc1)[C@H](Cc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1)NS(=O)(=O)NC1CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1[C@H](Cc2nnc(Cc3nc4ccc(-c5ccccc5)cc4s3)o2)NS(=O)(=O)N1C1CC1
Reaction time: 0.5 h
Yield: 35.6 %

Procedure:
To a solution of Compound 181b (41 mg, 0.070 mmol) in THF (3 mL) at 0° C. was slowly added a solution of 25% NaOMe in MeOH (0.035 mL, 0.15 mmol) dissolved in THF (0.5 mL) and the mixture was stirred for 30 min. The reaction was quenched with the addition of cold 1.0 M HCl (0.70 mL, 0.70 mmol) at 0° C., then the mixture was extracted with DCM. The extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc/hexanes to give Compound 181c (12 mg, 36% yield) as a yellow foam. 1H NMR (400 MHz, CDCl3) δ 8.08-8.03 (m, 2H), 7.73 (dd, J=8.6, 1.8 Hz, 1H), 7.66-7.59 (m, 2H), 7.51-7.43 (m, 2H), 7.42-7.35 (m, 1H), 4.73 (s, 2H), 4.69 (dd, J=9.0, 3.5 Hz, 1H), 3.54 (dd, J=16.8, 3.6 Hz, 1H), 3.41-3.30 (m, 1H), 2.70 (dt, J=7.1, 3.4 Hz, 1H), 1.21-1.05 (m, 2H), 1.04-0.86 (m, 2H). LCMS=1.9 min using analytical method (M), 482.0 (M+H)+.
Reaction SMILES: F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(C(C)C)CC)(C)C.[N:34]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([C:44]([OH:46])=O)[CH:42]=2)[CH:37]=[CH:36][CH:35]=1.[CH3:47][O:48][C:49](=[O:58])[C:50]1[CH:55]=[CH:54][C:53]([NH2:56])=[CH:52][C:51]=1[Cl:57]>O1CCCC1>[CH3:47][O:48][C:49](=[O:58])[C:50]1[CH:55]=[CH:54][C:53]([NH:56][C:44]([C:41]2[CH:42]=[C:43]3[C:38]([CH:37]=[CH:36][CH:35]=[N:34]3)=[CH:39][CH:40]=2)=[O:46])=[CH:52][C:51]=1[Cl:57]
Reactant: O=C(O)c1ccc2cccnc2c1
Reactant: COC(=O)c1ccc(N)cc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)c2ccc3cccnc3c2)cc1Cl
Temperature: 25 °C
Yield: 35 %

Procedure:
Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (6.03 g, 12.9 mmol, 1.1 equiv.) and diisopropyl ethyl amine (3.19 g, 12.9 mmol, 1.1 equiv.) were added to a solution of quinoline-7-carboxylic acid (2.03 g, 11.75 mmol) in tetrahydrofuran (100 ml) and the resultant mixture stirred for 10 minutes. 4-Amino-2-chlorobenzoic acid methyl ester (2.40 g, 12.9 mmol, 1.1 equiv.) in tetrahydrofuran (20 ml) was added and the mixture refluxed for 16 hours. Additional Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (1.10 g, 2.36 mmol, 0.2 equiv.) and diisopropyl ethyl amine (0.61 g, 4.7 mmol, 0.4 equiv.) were added and the mixture refluxed for a further 16 hours. The mixture was evaporated then dissolved in isopropanol (100 ml). Water (5 ml) and 60% aqueous perchloric acid (0.5 ml) were added and the mixture was refluxed for 24 hours. The mixture was filtered while hot then left to cool to room temperature whereupon a crystalline solid was formed. The solid was filtered and washed with cold isopropanol (20 ml) and dichloromethane (20 ml) to give 2-chloro-4-[(quinoline-7-carbonyl)-amino]-benzoic acid methyl ester, 1.42 g (35% yield), as a tan solid. LC @215 nm; Rt 1.11: 100%, m/z (ES+): 341 (M+H+.); δH (400 MHz; d6-DMSO) 10.96 (1H, br.s), 9.05 (1H, m), 8.73 (1H, s), 8.49 (1H, d), 8.18-8.10 (3H, m), 7.94 (2H, s), 7.68 (1H, dd), 3.86 (3H, s).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@:16]1([O:21][CH2:20]1)[C@@H:17]([OH:19])[CH3:18]>CN(C)C=O>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@:16]([OH:21])([C@@H:17]([OH:19])[CH3:18])[CH2:20][N:3]1[CH:7]=[N:6][CH:5]=[N:4]1
Reactant: c1nc[nH]n1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 80 °C
Yield: 37 %

Procedure:
To an ice cooled suspension of dry NaH (0.216 g, 0.009 mole) in N,N-dimethylformamide (10 ml), 1H-1,2,4-Triazole (0.691, 0.010 mole) was added in small portions under an atmosphere of nitrogen. The mixture was slowly brought to room temperature and a solution of compound 7a, (2S,3R)-3-(2,4-Difluorophenyl)-3,4-epoxy-2-butanol (1.0 g, 0.005 mole) in N,N-dimethylformamide (2 ml) was added. The resulting mixture was heated at 80° C. for 2 hours. The solvent was removed under reduced pressure and 50 g of crushed ice was added to the residue. The so formed mixture was extracted with ethyl acetate (100 ml, 2×50 ml). The combined organic layers were washed with water (20 ml) brine (50 ml) and dried over MgSO4. The solvent was removed in vacuo and the residue was chromatographed on silica gel. Elution with methanol in chloroform (0% -3%) gave the title compound 9a as an amorphous solid (0.5 g, 37%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C@@H:5]1[CH2:9][C@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH3:2].CC(C)C>>[CH2:1]([O:3][C:4](=[O:21])[C@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C[C@H](O)CN1C(=O)OCc1ccccc1
Agent: CC(C)C
Product: CCOC(=O)[C@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1

Procedure:
N-CBZ-cis-4-hydroxy-D-proline (5.00 g, 18.8 mmol) was esterified by refluxing in ethanol (300 mL) containing a catalytic amount of p-toluenesulfonic acid monohydrate (0.3 g, 1.6 mmol). Wet ethanol was collected in a Dean-Stark trap. After 16 h, the trap was emptied whenever full until the reaction volume had decreased to about 50 mL. The tosic acid was neutralized with an excess of NaHCO3 (0.5 g, 6 mmol). After removal of volatiles in vacuo, the residue was diluted with ethyl acetate (100 mL) and the mixture stirred for 0.5 h to remove the oily product from the sodium salts. Solids were removed by filtration through Celite and the filter cake was washed with ethyl acetate (50 mL). Concentration of the combined filtrate and washings in vacuo provided 5.6 g (100%) of the crude cis hydroxy ester as a colorless oil: 1H NMR and IR spectra were identical in all respects to those of the enantiomer N-(benzyloxycarbonyl)-cis-4-hydroxy-L-proline ethyl ester; 13C NMR (75.5 MHz, CDCl3) δ 174.54, 174.35, 154.87, 154.21, 136.24, 136.11, 128.39, 128.31, 127.99, 127.96, 127.83, 127.74, 70.99, 70.01, 67.18, 61.88, 61.72, 58.17, 57.77, 55.90, 55.60, 38.54, 37.64, 13.93, 13.80; LRMS (CI, 70 eV, isobutane) m/e 294 (MH+, 81), 250 (100), 220 (23), 91 (66); HRMS (EI, 50 eV) m/e 293.1267 (293.1263 calcd for C15H19NO5).
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:30]([O:32]CC5C=CC=CC=5)=[O:31])=[C:21]5[C:25]=4[O:24][CH:23]([CH2:26][N:27]([CH3:29])[CH3:28])[CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:40])[C:8](=[O:41])[C@H:7]2[CH2:42][CH3:43])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:30]([OH:32])=[O:31])=[C:21]5[C:25]=4[O:24][CH:23]([CH2:26][N:27]([CH3:29])[CH3:28])[CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:40])[C:8](=[O:41])[C@H:7]2[CH2:42][CH3:43])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)OCc4ccccc4)c4c3OC(CN(C)C)C4)nc2N1C1CCCC1
Agent: [Pd]
Solvent: CO
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OC(CN(C)C)C4)nc2N1C1CCCC1
Reaction time: 12 h
Yield: 30.3 %

Procedure:
Benzyl 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2-(dimethylaminomethyl)-2,3-dihydrobenzofuran-4-carboxylate 29h (120 mg, 0.20 mmol) was dissolved in 20 mL of methanol followed by the addition of palladium/carbon (12 mg, 10%). The reaction solution was stirred for 12 hours and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2-(dimethylaminomethyl)-2,3-dihydrobenzofuran-4-carboxylic acid 29j (30 mg, yield: 25.8%) as a white solid.