Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:4]1[N:9]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:8]=[CH:7][NH:6][C:5]1=[O:20])[C:2]#[CH:3].[N:21]([C@@H:24]1[CH2:33][CH2:32][CH2:31][C:30]2[CH:29]=[C:28]([CH:34]=[O:35])[CH:27]=[CH:26][C:25]1=2)=[N+:22]=[N-:23].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CC(O)(C)C>[O:20]=[C:5]1[NH:6][CH:7]=[CH:8][N:9]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C@@H:4]1[CH2:1][C:2]1[N:23]=[N:22][N:21]([C@@H:24]2[CH2:33][CH2:32][CH2:31][C:30]3[CH:29]=[C:28]([CH:34]=[O:35])[CH:27]=[CH:26][C:25]2=3)[CH:3]=1
Reactant: C#CC[C@@H]1C(=O)NC=CN1S(=O)(=O)c1ccc(C)cc1
Reactant: [N-]=[N+]=N[C@@H]1CCCc2cc(C=O)ccc21
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CC(C)(C)O
Product: Cc1ccc(S(=O)(=O)N2C=CNC(=O)[C@H]2Cc2cn([C@@H]3CCCc4cc(C=O)ccc43)nn2)cc1

Procedure:
(R)-3-(Prop-2-ynyl)-4-(4-methylbenzenesulfonyl)-3,4-dihydropyrazin-2(1H)-one (2.5 mmol, 1.0 eq) and (R)-5-azido-5,6,7,8-tetrahydronaphthalene-2-carbaldehyde (2.5 mmol, 1 eq) were placed in t-BuOH to stir. An aqueous solution of sodium ascorbate (600 μL, 0.1 eq) was added, followed by the addition of an aqueous solution of CuSO4.5H2O (600 μL, 0.1 eq). The reaction mixture was allowed to stir overnight. The solvents were removed and the residue was purified by SiO2 (1 to 5% MeOH in DCM) to afford the title compound. MS (m/z): 492.4 (m+H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:10]([C:17](OC)=[O:18])=[CH:11][S:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[CH2:1]([S:8][C:9]1[C:10]([CH2:17][OH:18])=[CH:11][S:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1csc([N+](=O)[O-])c1SCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: O=[N+]([O-])c1scc(CO)c1SCc1ccccc1
Reaction time: 0.25 h

Procedure:
Methyl 4-(benzylthio)-5-nitrothiophene-3-carboxylate (5g, 16.2 mmol) in dichloromethane (150 mL) at −40° C. was reacted with diisobutylaluminum hydride (1 M in dichloromethane, 36 mL, 2.2 equivalents) added dropwise. The reaction was stirred for 15 minutes after complete addition, quenched with 10% aqueous sodium potassium tartrate solution and stirred at 25° C. for 1 hour. The organic layer was separated, filtered through celite ® (dratomaceous earth) and the filtrate was concentrated under reduced pressure. The resulting oil was purified by flash chromatography on silica gel with a Biotage-40s column eluting with 2:98 methanol/dichloromethane to give [4-(benzylthio)-5-nitrothien-3-yl]methanol as an oil, (4.32 g, 95%). 1H NMR (300 MHz, CDCl3) δ ppm 4.21 (s, 2H), 4.39 (s, 2H), 7.11 (m, 3H), 7.23 (m, 2H) 7.40 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]4[O:48][CH2:47][CH2:46][C:45]=4[CH:49]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1CC(C(C)(C)C)(C)O[SiH3])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:59](Cl)(=[O:61])C>CO>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]4[O:48][CH2:47][CH2:46][C:45]=4[CH:49]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH2:59][OH:61])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc4c(c3)CCO4)c2)O[C@H](CC(C)(O[SiH3])C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: CC(=O)Cl
Solvent: CO
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc4c(c3)CCO4)c2)O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 1 h
Yield: 586.4 %

Procedure:
[[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl]-6-methoxy-tetrahydropyran-2-yl]tert-butyl-dimethyl-methoxy]silane 5g (11.86 g, 14.4 mmol) was dissolved in 100 mL methanol, followed by addition of acetyl chloride (152 μL, 2.17 mmol). The reaction mixture was stirred for 1 hour and concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system D to obtain the title compound [(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 5h (9.0 g, yellow liquid), yield: 88.1%.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:71]/[O:72][C:73]([C:86]2[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=2)([C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)[C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)/[C:27]([NH:29][C@@H:30]2[C:69](=[O:70])[N:32]3[C:33]([C:57]([O:59][CH2:60][C:61]4[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][CH:62]=4)=[O:58])=[C:34]([CH:37]=P(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:92]1([CH:95]=O)[CH2:94][CH2:93]1>ClCCl>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:71]/[O:72][C:73]([C:80]2[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=2)([C:74]2[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=2)[C:86]2[CH:87]=[CH:88][CH:89]=[CH:90][CH:91]=2)/[C:27]([NH:29][C@@H:30]2[C:69](=[O:70])[N:32]3[C:33]([C:57]([O:59][CH2:60][C:61]4[CH:62]=[CH:63][C:64]([O:67][CH3:68])=[CH:65][CH:66]=4)=[O:58])=[C:34](/[CH:37]=[CH:95]\[CH:92]4[CH2:93][CH2:94]4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=CC1CC1
Reactant: COc1ccc(COC(=O)C2=C(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@@H]3[C@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2=C(/C=C\C3CC3)CS[C@@H]3[C@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Methoxyphenylmethyl 7β-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(triphenylphosphoranyliden)methyl-3-cephem-4-carboxylate (8.2 g) and cyclopropanecarboxaldehyde (5 ml) were dissolved in dichloromethane (40 ml), followed by stirring at room temperature for 16 hours. After the solvent was distilled off under reduced pressure, the residue was purified by chromatography on a silica gel column whereby the title compound (1.1 g) was obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.[Br:17][C:18]1[CH:19]=[C:20]([F:37])[C:21]([NH:28][C:29]2[C:34]([Cl:35])=[CH:33][N:32]=[C:31](Cl)[N:30]=2)=[C:22]([CH:27]=1)[C:23]([NH:25][CH3:26])=[O:24]>>[Br:17][C:18]1[CH:19]=[C:20]([F:37])[C:21]([NH:28][C:29]2[C:34]([Cl:35])=[CH:33][N:32]=[C:31]([NH:16][C:13]3[CH:14]=[CH:15][C:8]4[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=4[CH:12]=3)[N:30]=2)=[C:22]([CH:27]=1)[C:23]([NH:25][CH3:26])=[O:24]
Reactant: CNC(=O)c1cc(Br)cc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: CNC(=O)c1cc(Br)cc(F)c1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl

Procedure:
5-Bromo-2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-3-fluoro-N-methyl-benzamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 5-bromo-2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 308c. Product isolated as an off-white foam (22 mg, 12%). LCMS (m/e) 577 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.61 (s, 1H), 8.07 (s, 1H), 7.48 (s, 1H), 7.44 (d, 1H, J=9.3 Hz), 7.19 (s, 1H), 7.06-6.97 (m, 2H), 6.91 (d, 1H, J=8.1 Hz), 6.28-6.18 (m, 1H), 3.57 (t, 2H, J=5.6 Hz), 3.38 (s, 3H), 2.90 (d, 3H, J=4.9 Hz), 2.92-2.84 (m, 2H), 2.83-2.65 (m, 8H); 19F-NMR (CDCl3, 400 MHz) δ −109.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][C:41](=[O:49])[NH:42][C:43]([C:46]([OH:48])=O)([CH3:45])[CH3:44])=[CH:33][C:32]=2[CH3:50])=[C:28]([CH:51]([CH3:53])[CH3:52])[NH:27][N:26]=1)(=O)C.[OH:54][CH2:55][CH2:56][N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1.NC(C)(C)C(N)=O>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][C:41](=[O:49])[NH:42][C:43]([C:46]([N:60]4[CH2:61][CH2:62][N:57]([CH2:56][CH2:55][OH:54])[CH2:58][CH2:59]4)=[O:48])([CH3:44])[CH3:45])=[CH:33][C:32]=3[CH3:50])=[C:28]([CH:51]([CH3:52])[CH3:53])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: OCCN1CCNCC1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCC(=O)NC(C)(C)C(=O)O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CC(C)(N)C(N)=O
Product: Cc1cc(OCCCC(=O)NC(C)(C)C(=O)N2CCN(CCO)CC2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 78 using 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)-ethylcarbamoyl]propoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole and 1-(2-hydroxyethyl)-piperazine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl)-5-isopropyl-1H-pyrazole and 2-amino-2-methylpropionamide, respectively.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:7]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[CH2:28][NH2:29].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[CH2:28][NH:29][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:7]=1
Reactant: NCc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(F)ccc2[N+](=O)[O-])CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2cc(NCc3cc(Cl)cc(Cl)c3)ccc2[N+](=O)[O-])CC1
Yield: 41 %

Procedure:
t-Butyl 4-(5-fluoro-2-nitrophenyl)piperazine-1-carboxylate (1.3 mmol), 3,5-dichlorobenzylamine (1.3 mmol), N,N-diisopropylethylamine (1.3 mmol) were stirred at 80° C. in dry acetonitrile (25 mL) for 72 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 25% ethyl acetate in hexanes to afford the title compound (41%). 1H NMR (400 MHz, CDCl3): δ 9.38 (br, 1 H), 7.67 (d, 1 H), 7.31 (s, 1 H), 7.21 (s, 2 H), 6.13 (dd, 1 H), 5.70 (d, 1 H), 4.42 (d, 2 H), 3.54 (m, 4 H), 3.38 (m, 4 H), 1.49 (s, 9 H). MS (ESI) m/z: Calculated: 481.37; Observed: 482.6 (M+H+).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].[OH-].[Na+].[Na+].[Cl-].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH4-].[Na+]>CO>[ClH:1].[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH:6][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Product: COC(=O)[C@H](CO)NCc1ccccc1
Temperature: 4 °C
Reaction time: 0.5 h

Procedure:
A solution of 20 g (0.129 mol) L-serine methyl ester hydrochloride (XXIV) in 100 mL MeOH was adjusted to pH 8 with 12.9 mL 10M NaOH thus precipitating NaCl. Benzaldehyde (15.0 g, 0.141 mol) was added and stirred well for 30 min. After cooling to 4° C., 2.43 g (0.064 mol) NaBH4 was added in parts over one hour. The reaction was then warmed to ambient temperature and stirred for another hour. Analysis by ion pair HPLC showed that aside from the desired product, identified by co-elution with material obtained by esterification of N-benzyl-L-serine, the only other product observed was benzyl alcohol. The reaction was filtered, concentrated, and dried. The thick residue was dissolved in 120 mL acetone, refiltered to remove more salt, adjusted to between pH 1 to 1.5 with HCL gas, 750 mL Et2O added, product collected by centrifugation, and dried, giving 28.1 g colorless hygroscopic solid. Chromatographic comparison to purified material showed this to contain 91.6 mmol (71%). MS (E.I., direct insertion) m/z(% relative abundance) 210(MH+)(5), 178(55), 150(64), 118(6), 106(29), 91(100); HRMS (+DCI, CH4) m/z calcd for C11H16NO3 (MH+) 210.113, found 210.112
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.I[C:36]1[C:45]([CH3:46])=[CH:44][C:39]([C:40]([NH:42][CH3:43])=[O:41])=[CH:38][C:37]=1[CH3:47].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1(C)C=CC=CC=1>[CH3:47][C:37]1[CH:38]=[C:39]([C:40](=[O:41])[NH:42][CH3:43])[CH:44]=[C:45]([CH3:46])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: CNC(=O)c1cc(C)c(I)c(C)c1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CNC(=O)c1cc(C)c(-c2ccc(F)c3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)OC)c(C)c1
Temperature: 120 °C
Reaction time: 5 h

Procedure:
In a microwave vial, methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (75 mg), 4-iodo-N,3,5-trimethylbenzamide (93 mg), K3PO4 (102 mg) and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (S-Phos) (7 mg) are suspended in toluene (1.8 mL) and water (0.2 mL) and purged for 10 minutes with argon. Palladium-(II)-acetate (4 mg) is added, the vial is sealed and the mixture is stirred at 120° C. for 5 hours. After cooling to ambient temperature the mixture is partitioned between ethyl acetate and water. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 100:0→80:20) to give the title compound. Yield: 16 mg; LC (method 25): tR=1.32 min; Mass spectrum (ESI+): m/z=504 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:18]2[O:17][CH:16]([CH2:19][NH2:20])[CH2:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>>[CH2:34]([O:33][C:31](=[O:32])[NH:20][CH2:19][CH:16]1[CH2:15][C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:1]([CH3:3])[CH3:2])[C:18]=2[O:17]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)c1ccccc1-c1cccc2c1OC(CN)C2
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1ccccc1-c1cccc2c1OC(CNC(=O)OCc1ccccc1)C2

Procedure:
Treatment of (±)-[7-(2-isopropylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylamine (1.69 g, 5.56 mmol) with diisopropylethylamine (1.08 g, 8.34 mmol) and benzyl chloroformate (1.04 g, 6.12 mmol) generally according to the procedure described for Intermediate 12 gave 1.92 (89%) of (±)-benzyl[7-(2-isopropylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a yellow oil. Rf=0.66 (silica, ethyl acetate:hexanes 1:4); Anal. calcd. for C26H27NO3: C, 77.78; H, 6.78; N, 3.49. Found: C, 77.5; H, 6.7; N, 3.33. Chiral HPLC separation of (±)-[7-(2-isopropylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OD, hexane:isopropanol 9:1) provided two fractions. Fraction 1 (Rt=8.131 min, Chiralcel OD, hexane:isopropanol 9:1); Fraction 2 (Rt=11.048 min, Chiralcel OD, hexane:isopropanol 9:1).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([NH:10][NH2:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:36][C:37]1[C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=[CH:39][N:38]=1.C(=O)([O-])O.[Na+]>CN(C=O)C.O>[NH2:36][C:37]1[C:42]([C:43]([NH:11][NH:10][C:8]([C:7]2[CH:12]=[CH:13][C:4]([CH:2]([CH3:1])[CH3:3])=[CH:5][CH:6]=2)=[O:9])=[O:44])=[CH:41][CH:40]=[CH:39][N:38]=1
Reactant: Nc1ncccc1C(=O)O
Reactant: CC(C)c1ccc(C(=O)NN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1ccc(C(=O)NNC(=O)c2cccnc2N)cc1
Yield: 66.7 %

Procedure:
A mixture of 4-(1-methylethyl)benzohydrazide (2194 mg), HOBt.H2O (2073 mg), EDCI HCl (2595 mg) and 2-aminopyridine-3-carboxylic acid (1700 mg) in dehydrated DMF (50 mL) was stirred at 60° C. overnight. The reaction mixture was added to a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate and diisopropyl ether to give the title compound (2.4489 g) as a white solid. The mother liquor was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (276.1 mg) as a white solid.
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH2:12]([S:19][CH2:20][CH2:21][NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC>>[CH2:12]([S:19][CH2:20][CH2:21][NH:22][C:1](=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1cccnc1
Reactant: NCCSCc1ccccc1
Agent: CC
Product: O=C(NCCSCc1ccccc1)c1cccnc1

Procedure:
30 grams of ethyl nicotinate and 80 grams of 2-benzylthio ethylamine are heated for 12 hours at 170°-180° C. The ethane liberated during the reaction is removed by means of a Dean Stark apparatus. After cooling, the reaction mixture is dissolved in 400 cc of carbon tetrachloride; by addition of petroleum ether, the N-(2-benzylthioethyl)nicotinamide crystallizes: 47 g. By crystallization in a mixture of carbon tetrachloride and cyclohexane, there are recovered colorless crystals of the above product melting at 79° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH:6]=[C:7]([O:9]C)[CH:8]=1.B(Br)(Br)Br>>[CH3:13][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][C:5]1[CH:6]=[C:7]([OH:9])[CH:8]=[C:3]([OH:2])[CH:4]=1
Reactant: COc1cc(C=C(C)c2ccccc2)cc(OC)c1
Agent: BrB(Br)Br
Product: CC(=Cc1cc(O)cc(O)c1)c1ccccc1
Yield: 63 %

Procedure:
This compound was made from 1-(3,5-dimethoxyphenyl)-2-phenylpropene (13). and BBr3. in 63% yield by the same procedure as described in example 1(c). 1HNMR (CD3C(O)CD3, ppm): δ 2.21 (d, J=1.5 Hz, 3H), 6.23 (t, J=2.2 Hz, 1H), 6.36 (d, J=2.2Hz, 2H), 6.68 (m, 1H), 7.2-7.6 (m, 5H).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>>[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([NH:1][N:2]2[N:11]=[C:10]([S:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:19])=[O:32])=[CH:26][CH:25]=1)(=[O:22])=[O:23]
Reactant: Nn1nc(Sc2ccccc2)c2ccccc2c1=O
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Product: CS(=O)(=O)c1ccc(CC(=O)Nn2nc(Sc3ccccc3)c3ccccc3c2=O)cc1

Procedure:
The product from Example 57B and 2-(4-(methylsulfonyl)phenyl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ 11.78 (s, 1H), 8.34 (dd, J=7.9, 1.1, 1H), 8.08 (d, J=7.7, 1H), 8.03-7.97 (m, 1H), 7.97-7.92 (m, 1H), 7.92-7.87 (m, 2H), 7.60 (d, J=8.3, 2H), 7.45-7.40 (m, 2H), 7.40-7.30 (m, 3H), 3.81 (s, 2H), 3.22 (s, 3H); MS (APCI+) M/Z 466 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]C)=[CH:9][C:8]=1[F:15])[CH3:2].B(Br)(Br)Br.CO>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[F:15])[CH3:2]
Reactant: CCOC(=O)CCc1ccc(OC)cc1F
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(O)cc1F
Temperature: -78 °C
Reaction time: 3 h
Yield: 80.2 %

Procedure:
3-(2-Fluoro-4-methoxy-phenyl)-propionic acid ethyl ester (2.5 g, 11.05 mmol) obtained in Step B was dissolved in anhydrous DCM (10 mL). 1M BBr3 solution (33 mL, 33.15 mmol) was added thereto at −78° C., and the mixture was stirred at room temperature for 3 hours. After the termination of the reaction, MeOH was added to the reactant. The mixture was concentrated under reduced pressure and purified by column chromatography (eluent, EtOAc/Hex=1/2) to obtain the title compound (1.88 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13](/[CH:16]=[C:17](/[N+:20]([O-:22])=[O:21])\[CH2:18][CH3:19])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].C(=O)(O)[O-].[Na+:27]>O>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13](/[CH:16]=[C:17](/[N+:20]([O-:22])=[O:21])\[CH2:18][CH3:19])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O-:10])=[O:9].[Na+:27]
Reactant: CC/C(=C\c1ccc(OCCCC(=O)O)c(Cl)c1Cl)[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC/C(=C\c1ccc(OCCCC(=O)[O-])c(Cl)c1Cl)[N+](=O)[O-]

Procedure:
1.0297 g of (E)-4-[2,3-Dichloro-4-(2-nitro-1-butenyl)phenoxy]butyric acid is dissolved 33 ml of 0.1N sodium bicarbonate and sufficient isotonic buffer to make a final volume of 100 ml. The water from all sources was pyrogen free. The solution is sterilized by filtration. This solution is 3 mM in active antisickling agent.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.O=[CH:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]>>[CH3:28][C:27]([O:26][C:25]([NH:24][CH2:23][CH2:22][NH:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[CH:7]=1)=[O:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCNC(=O)OC(C)(C)C

Procedure:
This compound was prepared from ethyl 3-amino-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate and t-butyl N-(2-oxoethyl)carbamate employing methods similar to those described in Example 202 and was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J=1.4 Hz, 1 H), 7.80 (br, 1 H), 7.13 (dd, J=7.9, 5.8 Hz, 2 H), 6.98-6.93 (m, 3 H), 4.85 (br, 1 H), 4.38 (q, J=7.1 Hz, 2 H), 3.90 (s, 2 H), 3.30 (m, 4 H), 1.43-1.38 (m, 12 H); MS m/z 418 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH2:26][CH:27]=[CH2:28])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[N:12]=2)[NH:7][CH:6]=1)=[O:4].C(O)C>[Pd].CO>[CH3:1][C:2]([CH3:29])([CH2:26][CH2:27][CH3:28])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[N:12]=2)[NH:7][CH:6]=1)=[O:4]
Reactant: C=CCC(C)(C)C(=O)c1c[nH]c2ncc(-c3cc(OC)c(OC)c(OC)c3)nc12
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CCCC(C)(C)C(=O)c1c[nH]c2ncc(-c3cc(OC)c(OC)c(OC)c3)nc12
Reaction time: 72 h
Yield: 52.5 %

Procedure:
A mixture of 2,2-dimethyl-1-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-pent-4-en-1-one (0.036 g, 0.091 mmol), 3 mL of ethanol (a small amount of methanol was also added to help solubility) and 10% Pd/C (10 mg) was stirred under a hydrogen atmosphere (balloon) for 3 d, then filtered through Celite and concentrated to afford 0.019 g (53%) of 2,2-dimethyl-1-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-pentan-1-one as a yellow solid.