Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:20])=[C:4]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[C:10](C)[N:9]=2)[CH:5]=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:45][C@H:46]1[CH2:48][C@H:47]1[C:49](O)=[O:50].C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[F:45][C@H:46]1[CH2:48][C@H:47]1[C:49]([NH:18][C:13]1[N:14]=[CH:15][C:16]2[C:11]([CH:12]=1)=[CH:10][N:9]=[C:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([F:1])[C:3]=1[CH3:20])[CH:17]=2)=[O:50]
Reactant: Cc1c(F)cncc1-c1cc2cnc(N)cc2c(C)n1
Reactant: O=C(O)[C@@H]1C[C@@H]1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(F)cncc1-c1cc2cnc(NC(=O)[C@@H]3C[C@@H]3F)cc2cn1
Temperature: 70 °C
Yield: 44.1 %

Procedure:
A mixture of 7-(5-fluoro-4-methylpyridin-3-yl)-5-methyl-2,6-naphthyridin-3-amine (80 mg, 0.30 mmol), HATU (246 mg, 0.63 mmol), (1S,2S)-2-fluorocyclopropanecarboxylic acid (62 mg, 0.60 mmol), and N,N-diisopropylethylamine (0.21 mL, 1.19 mmol) in DMF (2 mL) was heated at 70° C. for 8 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (25 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue that was purified by reverse phase HPLC purification (5-85% acetonitrile in water w/0.1% NH4OH, 14 minutes). Desired fractions were combined and evaporated in vacuo to afford the title compound as an off-white solid (45 mg, 43%). 1H NMR (400 MHz, DMSO) δ 11.24 (s, 1H), 9.31 (s, 1H), 8.74 (s, 1H), 8.57 (s, 1H), 8.56 (s, 1H), 8.07 (s, 1H), 4.98 (m, 1H), 2.90 (s, 3H), 2.36 (s, 3H), 2.30 (m, 1H), 1.78-1.66 (m, 1H), 1.28-1.17 (m, 1H). LCMS (Method G): RT=7.78 min, M+H+=355.0.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([S:29]([C:32]4[CH:41]=[CH:40][CH:39]=[CH:38][C:33]=4[C:34]([O:36][CH3:37])=[O:35])(=[O:31])=[O:30])[CH:25]=3)[N:20]=2)=[CH:15][CH:14]=1.[OH-].[Ca+2].[OH-]>ClCCl>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([S:29]([C:32]4[CH:41]=[CH:40][CH:39]=[CH:38][C:33]=4[C:34]([O:36][CH3:37])=[O:35])(=[O:31])=[O:30])[CH:25]=3)[N+:20]=2[O-:6])=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccccc1S(=O)(=O)c1ccc2nc(-c3ccc(F)cc3)ccc2c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)c1ccc2c(ccc(-c3ccc(F)cc3)[n+]2[O-])c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 42.9 %

Procedure:
3-Chloroperoxybenzoic acid (77%; 82 mg, 0.37 mmol) was added to a solution of methyl 2-{[2-(4-fluorophenyl)quinolin-6-yl]sulfonyl}benzoate [Example 30] (103 mg, 0.24 mmol) in dichloromethane (10 mL). The resulting mixture was stirred at room temperature under nitrogen for 2 days. Calcium hydroxide (308 mg, 4.16 mmol) was added and the resulting slurry stirred for 2 hours. The mixture was filtered and the filter cake washed thoroughly with dichloromethane. The filtrate was evaporated and the residue purified by flash chromatography, eluting with 10-25% diethyl ether/dichloromethane, followed by trituration with diethyl ether to give the title compound as a pale yellow solid (45 mg, 42%). 1H NMR (500 MHz, CDCl3) δ 8.94 (1H, d, J 9.2 Hz), 8.60 (1H, s), 8.28 (1H, m), 8.19 (1H, dd, J 1.6, 9.2 Hz), 8.02 (2H, dd, J 5.4, 8.7 Hz), 7.87 (1H, d, J 8.7 Hz), 7.71-7.61 (4H, m), 7.22 (2H, t, J 8.6 Hz), 3.95 (3H, s); m/z (ES+) 438 [MH+].
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[C:16]12([CH2:26][CH2:27]O)[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2.C(N(C(C)C)CC)(C)C.[CH3:38][O:39][C:40](=[O:63])[C@H:41]([CH2:50][C:51]1[N:55]=[CH:54][N:53](C(OC(C)(C)C)=O)[CH:52]=1)[NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>ClCCl>[CH3:38][O:39][C:40](=[O:63])[C@H:41]([CH2:50][C:51]1[N:55]([CH2:27][CH2:26][C:16]23[CH2:25][CH:20]4[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]4)[CH2:17]2)[CH2:23]3)[CH:54]=[N:53][CH:52]=1)[NH:42][C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44]
Reactant: COC(=O)[C@H](Cc1cn(C(=O)OC(C)(C)C)cn1)NC(=O)OC(C)(C)C
Reactant: OCCC12CC3CC(CC(C3)C1)C2
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1cncn1CCC12CC3CC(CC(C3)C1)C2)NC(=O)OC(C)(C)C
Temperature: -55 °C
Reaction time: 24 h

Procedure:
A solution of 11.8 mL trifluoromethanesulfonic anhydride in 70 mL dichloromethane is chilled to -70° C. and treated dropwise with a solution composed of 12.6 g 1-adamantyl-2-hydroxyethane, 12.2 mL diisopropylethylamine and 70 mL dichloromethane. The solution is allowed to warm to -55° C. over 45 min then a solution of 25 g N,1-bis-BOC-histidine methyl ester (J. Chem. Soc., Perkin Trans. I 1982; 1553-61.) in 70 mL dichloromethane is added dropwise. The reaction is then stirred at 25° C. for 24 hr and poured into pH=7, 0.25M potassium phosphate buffer (500 mL), stirring vigorously. The organic layer is separated, washed with the same buffer, dried and concentrated. 3-(2-(1-Adamantyl)ethyl)-N-BOC-histidine methyl ester is isolated by chromatography on silica gel (chloroform-methanol, 99:1) as a gum. NMR (CDCl3) 3.85 (m,2H,NCH2).
Reaction SMILES: [Br-].[F:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([F:30])[C:28]=1[F:29])[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[O-].[Na+].[CH:34]([CH:36]1[CH2:41][CH2:40][C:39](=[O:42])[CH2:38][CH2:37]1)=O.O>C1COCC1>[F:30][C:27]1[CH:26]=[C:5]([CH:6]=[CH:34][CH:36]2[CH2:41][CH2:40][C:39](=[O:42])[CH2:38][CH2:37]2)[CH:4]=[C:3]([F:2])[C:28]=1[F:29]
Reactant: O=CC1CCC(=O)CC1
Reactant: Fc1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc(F)c1F
Agent: C[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCC(C=Cc2cc(F)c(F)c(F)c2)CC1
Yield: 70.5 %

Procedure:
A suspension of 3,4,5-trifluorobenzyltriphenylphosphonium bromide (234 g) in THF (500 ml) was stirred in a nitrogen gas stream, followed by adding sodium methoxide (32.4 g) little by little at room temperature, stirring the reaction solution at room temperature for one hour, dropwise adding a solution of 4-formylcyclohexanone (50 g) in THF (250 ml), stirring the mixture at room temperature for 2 hours, adding it to water (1 l) extracting with ethyl acetate (1 1), washing the organic layer with water, drying over anhydrous MgSO4, concentrating the solvent under reduced pressure, to obtain 4-(2'-(3",4",5"-trifluorophenyl)ethenyl)cyclohexanone (71 g).
Reaction SMILES: [OH-].[Na+].[N+](C1C=CC(C([O:12][CH2:13][C@:14]([OH:23])([CH3:22])[CH2:15][N:16]2[CH:20]=[C:19]([I:21])[CH:18]=[N:17]2)=O)=CC=1)([O-])=O>C(#N)C>[I:21][C:19]1[CH:18]=[N:17][N:16]([CH2:15][C@:14]([CH3:22])([OH:23])[CH2:13][OH:12])[CH:20]=1
Reactant: C[C@@](O)(COC(=O)c1ccc([N+](=O)[O-])cc1)Cn1cc(I)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: C[C@@](O)(CO)Cn1cc(I)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydroxide (3 M in water, 3.25 mL, 9.74 mmol) was added to a solution of (S)-2-hydroxy-3-(4-iodo-1H-pyrazol-1-yl)-2-methylpropyl 4-nitrobenzoate (2.80 g, 6.49 mmol) in acetonitrile (40 mL). The mixture was stirred at room temperature for 1 h, then concentrated under reduced pressure, diluted with EtOAc, and washed with hydrochloric acid (1N), water and brine. The organic layers were separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-10% MeOH/DCM) to afford (S)-3-(4-iodo-1H-pyrazol-1-yl)-2-methylpropane-1,2-diol. MS ESI calc'd. for C17H12N2O2 [M+H]+ 283. found 283. 1H NMR (500 MHz, DMSO-d6) δ 7.76 (s, 1H), 7.48 (s, 1H), 4.79 (t, J=5.5 Hz, 1H), 4.53 (s, 1H), 4.09-4.00 (m, 2H), 3.17-3.11 (m, 2H), 0.89 (s, 3H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH:7]1[C:15]2[C:10](=[C:11]([CH2:16][CH2:17][C:18]#[N:19])[CH:12]=[CH:13][CH:14]=2)[CH:9]=[N:8]1>C1COCC1>[NH:7]1[C:15]2[C:10](=[C:11]([CH2:16][CH2:17][CH2:18][NH2:19])[CH:12]=[CH:13][CH:14]=2)[CH:9]=[N:8]1
Reactant: N#CCCc1cccc2[nH]ncc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCCc1cccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
To a stirred solution of the 1.0M LAH in THF (8.3 mL, 8.30 mmol) at 0° C. was added drop wise a solution of 3-(1H-Indazol-4-yl)-propionitrile (0.94 g, 5.491 mmol) in anhydrous THF (20 mL) over 3 min. The resultant reaction mixture was gradually warmed and stirred at room temp for 2 h. The reaction was quenched by cooling in an ice bath followed by adding aq. 1N NaOH (1 mL). The suspension was filtered through celite, washed well with THF, concentrated and extracted with 3/1: EtOAc/THF. The organic layer were washed with brine (20 mL). The organic layer washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered, concentrated give 3-(1H-Indazol-4-yl)-propylamine (684.1 mg, 71.1%) as a pale yellow oil. MS m/e 173.3 (M+H+). This was taken to next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Si:8]([C:23]2[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=2)([C:16]2[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:30]=[CH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C([O-])([O-])=O.[K+].[K+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].CC([O-])=O.CC([O-])=O.[Pd+2].CC(N(C)C)=O>[C:6]1([CH:30]=[CH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=1[Si:8]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:30]=[CH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:30]=[CH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:30]=[CH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: C=Cc1ccccc1
Reactant: Brc1ccc([Si](c2ccc(Br)cc2)(c2ccc(Br)cc2)c2ccc(Br)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC(=O)N(C)C
Product: C(=Cc1ccccc1[Si](c1ccccc1C=Cc1ccccc1)(c1ccccc1C=Cc1ccccc1)c1ccccc1C=Cc1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 52 %

Procedure:
A round bottom flask (50 mL) equipped with a teflon coated stir bar was charged with tetrakis(4-bromophenyl)silane (326 mg, 0.5 mmol), styrene (2.0 g, 12 mmol), Pd(OAc)2 (14 mg, 12 mol %), K2CO3 (690 mg, 5 mmol), n-Bu4NBr (645 mg, 2 mmol), and DMA (10 mL). The flask was fitted with a rubber septum and purged with nitrogen prior to heating (80° C.) with stirring for 48 hours. The reaction mixture was allowed to cool to room temperature, diluted with CH2Cl2, and washed five times with brine. The organic phase was dried with MgSO4, filtered through silica gel and the solvent was evaporated under reduced pressure. The residue was dissolved in CHCl3 and precipitated with hexanes. The colorless needle-like crystals were collected (52% yield). 1H NMR (CDCl3): δ 7.61 (d, J=8.0 Hz, 8H), 7.55 (m, 16H), 7.38 (t, J=7.3 Hz, J=8.0 Hz, 8H), 7.29 (t, J=7.3 Hz, 4H), 7.17 (AA′BB′ pattern, J=16.4 Hz, 8H). 13C NMR (CDCl3) δ 138.5, 137.1, 136.7, 133.4, 129.5, 128.6, 128.4, 127.7,126.5, 125.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)[N:19]=3)[C:10]3[C:11]([N:17]=2)=[N:12][C:13](Cl)=[CH:14][CH:15]=3)=[CH:4][CH:3]=1.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CC([O-])(C)C.[Na+].CC(O)=O>C1(C)C(C)=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)[N:19]=3)[C:10]3[C:11]([N:17]=2)=[N:12][C:13]([NH:37][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:14][CH:15]=3)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nc3nc(Cl)ccc3n2-c2ccnc(NC3CCCC3)n2)cc1
Reactant: NCc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Product: Fc1ccc(-c2nc3nc(NCc4ccccc4)ccc3n2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 160 °C
Yield: 41.7 %

Procedure:
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(chloro)imidazo[4,5-b]pyridine (100 mg; 0.25 mmol), R-(+)-BINAP (10 mg; 0.016 mmol), Pd2(dba)3 (22 mg; 0.024 mmol) are suspended in xylene (16 ml), benzylamine (0.53 ml; 4.9 mmol) is added, followed by NaOtBu (47 mg; 0.49 mmol) and heated to 160° C. for 10 min. under argon. The reaction mixture is poured on water (100 ml) containing HOAc (2 ml) and extracted with TBME three times. The combined organic phases are washed with 2N Na2CO3, dried over Na2SO4 and evaporated to dryness. Purification via SiO2 chromatography (TMBE/hexane 6:4 to 10:0) and recrystallisation from TBME yields the title compound as colorless crystals (50 mg: 50%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([CH3:24])[C:12]2[CH:13]=[C:14]([O:21][CH3:22])[CH:15]=[C:16]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=2[O:10][C:9]1=[O:23].C(OCC)(=O)C.Cl>C(OCC)C.O>[CH3:20][C:17]([C:16]1[CH:15]=[C:14]([O:21][CH3:22])[CH:13]=[C:12]([C:8]([CH3:24])([CH3:7])[CH2:9][OH:23])[C:11]=1[OH:10])([CH3:18])[CH3:19]
Reactant: COc1cc(C(C)(C)C)c2c(c1)C(C)(C)C(=O)O2
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCOCC
Product: COc1cc(C(C)(C)C)c(O)c(C(C)(C)CO)c1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
In 500 ml of diethyl ether was suspended 18 g of lithium aluminum hydride followed by addition of a solution of 3,3-dimethyl-7-(1,1-dimethylethyl)-5-methoxy-2(3H)-benzofuranone (104 g) in diethyl ether (400 ml) over a period of 1 hour with stirring at ambient temperature. The mixture was further stirred at ambient temperature for 1 hour. The reaction mixture was held under cooling in an ice bath and 60 ml of ethyl acetate, 100 ml of water and 900 ml of 10% hydrochloric acid were successively added. After phase separation, the aqueous layer was extracted with ethyl acetate and the organic layers were pooled, washed with saturated aqueous, sodium chloride solution, dried over magnesium sulfate and concentrated. The resultant crude product was crystallized from hexane to give 100 g of 2-(1,1-dimethylethyl)-6-(1,1-dimethyl-2-hydroxyethyl)-4-methoxyphenol as colorless crystals.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[O:3].C(#N)C.FC(F)(F)C(O)=[O:18].FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O>O>[OH:18][CH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[O:3]
Reactant: COc1ccc(C(C)=O)cc1
Reactant: O=C(O)C(F)(F)F
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: COc1ccc(C(=O)CO)cc1
Yield: 54.2 %

Procedure:
4-Methoxyacetophenone (10 g; 66.59 mmol) was added to a solution of acetonitrile (350 ml), water (70 ml) and trifluoroacetic acid (TFA) (10.26 ml; 133.20 mmol). Then (bis(trifluoroacetoxy)iodo)benzene was added, and the reaction mixture was heated under reflux for 3 h. The acetonitrile was then stripped off in a rotary evaporator, and the reaction mixture was partitioned in NaHCO3 solution/CH2Cl2. After extraction with CH2Cl2 (2×), the combined organic phases were dried over MgSO4, and the solvent was removed in a rotary evaporator. Purification by column chromatography (CH2Cl2/MeOH 50:1) resulted in 2-hydroxy-1-(4-methoxyphenyl)ethanone (6.0 g; 36.1 mmol). MS: 167.15 (M+H); Rt: 0.83 min (method: gradient 0 min 96% H2O (0.05% TFA) 2.0 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 μL (YMC J'sphere ODS H80 20X2 1.4μ); 30° C.)
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH:18]([O:20][C:21](=[O:23])[CH3:22])[C:17](=[O:24])[NH:16][C:15]1=[O:25])[C:8]2=[O:13])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH:18]([O:20][C:21](=[O:23])[CH3:22])[C:17](=[O:24])[NH:16][C:15]1=[O:25])[C:8]2=[O:13]
Reactant: CC(=O)OC1CC(N2Cc3c(cccc3[N+](=O)[O-])C2=O)C(=O)NC1=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)OC1CC(N2Cc3c(N)cccc3C2=O)C(=O)NC1=O

Procedure:
A solution of 3-(4-nitro-1-oxoisoindolin-2-yl)-2,6-dioxo-5-acetoxypiperidine (0.9 g, 3.1 mmol) and Pd/C (10%, 0.1 g) in methanol (100 mL) is shaken under hydrogen (50-60 psi) for 3 hours. The suspension is filtered through a pad of Celite and washed with methanol to give 3-(4-amino-1-oxoisoindolin-2-yl)-2,6-dioxo-5-acetoxypiperidine which is further purified by column chromatography.
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+].C(O)(=O)C>O>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH2:28])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCC(=O)O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 300 mg (0.56 mmol) of 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide hydrochloride, 15 ml of ethanol, 4 ml of water and 120 mg (3.0 mmol) of sodium hydroxide was stirred for two hours at room temperature. Then the mixture was diluted with about 20 ml of water and made weakly alkaline with glacial acetic acid. The product which crystallized out was suction filtered, washed with water, and dried at 60° C. in vacuo.
Reaction SMILES: C([Cl:4])(=O)C.Cl.C(OC([N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:25][CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[O:21][C:20]2=[O:30])[CH2:15][CH2:14]1)=O)(C)(C)C>CO>[ClH:4].[CH:26]1[C:23]2[CH2:24][CH2:25][N:19]([CH:16]3[CH2:17][CH2:18][NH:13][CH2:14][CH2:15]3)[C:20](=[O:30])[O:21][C:22]=2[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCc3ccccc3OC2=O)CC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CO
Product: O=C1Oc2ccccc2CCN1C1CCNCC1
Reaction time: 0.17 h
Yield: 97.2 %

Procedure:
Acetyl chloride (0.2 mL, 2.8 mmol) was added to 2 mL of methanol and stirred for 10 min. This solution of HCl in MeOH was added to 58 mg of 1-t-butyloxycarbonyl-4-(8,9-dihydro-7H-5-oxa-7-aza-benzocyclohepten-6-one-7-yl)-piperidine (Step A) and stirred for 2 hr. The reaction was concentrated in vacuo, the residue was diluted with EtOAc and the solution was concentrated again in vacuo leaving 46 mg of the title compound which was sufficiently pure for use in the next step. 1H NMR (500 MHz, CDCl3): δ2.06 (m, 2H), 2.35 (m, 2H), 3.02 (m, 4H), 3.5-3.8 (m, 4H), 4.35 (br s, 1H), 7.1-7.3 (m, 4H), 9.6 (br, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([C:19]5[CH:24]=[CH:23][C:22]([CH2:25][N:26]6[CH2:31][CH2:30][NH:29][CH:28]([CH3:32])[CH2:27]6)=[CH:21][CH:20]=5)[CH:17]=4)[N:12](S(C4C=CC(C)=CC=4)(=O)=O)[CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:43]1COCC1.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:32][CH:28]1[N:29]([CH3:43])[CH2:30][CH2:31][N:26]([CH2:25][C:22]2[CH:23]=[CH:24][C:19]([C:16]3[CH:17]=[C:18]4[C:10]([C:6]5[CH:5]=[C:4]6[C:9](=[CH:8][CH:7]=5)[NH:1][CH:2]=[CH:3]6)=[CH:11][NH:12][C:13]4=[N:14][CH:15]=3)=[CH:20][CH:21]=2)[CH2:27]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(-c4ccc(CN5CCNC(C)C5)cc4)cnc32)cc1
Reactant: C1CCOC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CC1CN(Cc2ccc(-c3cnc4[nH]cc(-c5ccc6[nH]ccc6c5)c4c3)cc2)CCN1C
Reaction time: 1 h

Procedure:
3-(1H-indol-5-yl)-5-(4-((3-methylpiperazin-1-yl)methyl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (40 mg) was suspended in 3 mL of methanol and THF (1 mL) and treated with paraformaldehyde (−50 mg) and stirred for one hour. To this was added 50 mg of sodium triacetoxyborohydride. The reaction stirred 1 hr at room temperature. The mixture was concentrated in vacuo, taken up in EtOAc and washed with water and brine and dried over MgSO4. The residue was suspended in methanol and treated with 5 N NaOH and heated at 50 C for one hour. The mixture was diluted with dichloromethane and washed with water and brine, dried over MgSO4 and purified by MPLC silica gel chromatography (0-20% MeOH in DCM) to yield an analytical sample 10 mg (436 M+H).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[CH3:27][C:28]1[N:29]=[CH:30][S:31][C:32]=1[C:33]([C:35]1[N:36]=[CH:37][N:38]2[CH:42]=[C:41]([Sn](CCCC)(CCCC)CCCC)[S:40][C:39]=12)=[O:34]>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])=[C:8]([C:41]3[S:40][C:39]4=[C:35]([C:33]([C:32]5[S:31][CH:30]=[N:29][C:28]=5[CH3:27])=[O:34])[N:36]=[CH:37][N:38]4[CH:42]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3scnc3C)c2s1
Product: Cc1ncsc1C(=O)c1ncn2cc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Yield: 50.6 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(4-methylthiazol-5-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (92 mg) was prepared in the same manner as in step a) of Example 1, except that 112 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 165 mg of 7-(4-methylthiazol-5-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2>CO.[Pt]=O>[NH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[OH:1])[CH2:7][CH2:8][CH2:9]1
Reactant: Oc1cccc2cccnc12
Agent: O=[Pt]
Solvent: CO
Product: Oc1cccc2c1NCCC2

Procedure:
A solution of 2.5 g (17.2 mmol) of 8-hydroxyquinoline in 50 ml of methanol was treated with 680 mg of platinum oxide and was hydrogenated in a Parr apparatus at 40 PSI until hydrogen absorption ceased. The suspension was filtered through Celite, the filtrate was evaporated and the residue was recrystallized from dichloromethane: hexane to provide 1.82 g of analytically pure, green tinged needles: melting point 117.5°-119° C.
Reaction SMILES: Br[C:2]1[C:14](=[O:15])[N:13]([CH2:16][CH3:17])[C:5]2[N:6]=[C:7]([S:11][CH3:12])[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1.[NH:18]1[C:22](B(O)O)=[CH:21][CH:20]=[N:19]1.C(Cl)Cl.C(N(CC)CC)C>COCCOC.O>[CH2:16]([N:13]1[C:5]2[N:6]=[C:7]([S:11][CH3:12])[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=[C:2]([C:20]2[NH:19][N:18]=[CH:22][CH:21]=2)[C:14]1=[O:15])[CH3:17]
Reactant: CCn1c(=O)c(Br)cc2c(C)nc(SC)nc21
Reactant: OB(O)c1ccn[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CCn1c(=O)c(-c2ccn[nH]2)cc2c(C)nc(SC)nc21
Temperature: 25 °C
Yield: 77.4 %

Procedure:
To a solution of 6-bromo-8-ethyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (0.765 g, 2.43 mmol) in DME-H2O (10:1 11 mL) was added 1H-pyrazol-5-ylboronic acid (Frontier, 0.408 g, 3.65 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2Cl2 (Pd(dpppf), 0.198 g, 0.243 mmol) and triethylamine (0.736 g, 7.29 mmol) at room temperature. Then the reaction mixture was heated to reflux and reacted for 4 h. After cooling down to room temperature, the reaction mixture was partitioned with water and ethyl acetate. After separation, the organic layer was dried with Na2SO4, and the product 8-ethyl-4-methyl-2-(methylthio)-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (0.567 g, 77% yield) was obtained by silica gel column chromatography. 1H NMR (400 MHz, CDCl3): δ 13.3 (bs, 1H), 8.54 (s, 1H), 7.82-7.07 (m, 2H), 4.45 (q, J=7.2 Hz, 2H), 2.71 (s, 3H), 2.60 (s, 3H), 1.26 (t, J=7.2 Hz, 3H).