Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH:4]([C:6]1[CH:15]=[CH:14][C:9]([CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:8][CH:7]=1)[CH3:5])=[O:3].[N+](=[CH2:18])=[N-]>C(OCC)C>[CH2:10]([C:9]1[CH:8]=[CH:7][C:6]([C@@H:4]([CH3:5])[C:2]([O:1][CH3:18])=[O:3])=[CH:15][CH:14]=1)[CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)[C@H](C)c1ccc(CC(C)C)cc1

Procedure:
A solution of (R) (−)-ibuprofen (3.45 g) in ethyl ether, cooled to 5° C., is treated, dropwise, with a 0.6 M solution of diazomethane in ethyl ether, up to a persistent yellow colour. The solvent is removed—under vacuum; the residual oil is purified by flash chromatography to yield 3.3 g of methyl (R) (−) 2-(4′-isobutylphenyl)-propionate.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[CH:9]=[CH:10][C:11]([Cl:18])=[C:12]([S:14]([NH2:17])(=[O:16])=[O:15])[CH:13]=2)=[O:7])=[CH:4][CH:3]=1.[C:21]1([C:27]#[CH:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>O1CCCC1.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:18][C:11]1[CH:10]=[CH:9][C:8]([C:6](=[O:7])[C:5]2[CH:19]=[CH:20][C:2]([C:28]#[C:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:3][CH:4]=2)=[CH:13][C:12]=1[S:14]([NH2:17])(=[O:16])=[O:15]
Reactant: NS(=O)(=O)c1cc(C(=O)c2ccc(Br)cc2)ccc1Cl
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc(C(=O)c2ccc(C#Cc3ccccc3)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a degassed solution of 5-(4-bromo-benzoyl)-2-chloro-benzenesulfonamide (500 mg, 1.33 mmol), phenylacetylene (204 mg, 2.00 mmol), copper iodide (15 mg), triphenylphosphine (9 mg, 0.033 mmol) and triethylamine (0.278 mL, 2 mmol) in tetrahydrofuran (4 mL) is added dichlorobis(triphenylphosphine)-palladium (47 mg, 0.067 mmol). The reaction mixture is allowed to stir at room temperature for 18 hours then poured into water (25 mL) and extracted twice with ethyl acetate. The organic fractions are combined, washed twice with a saturated sodium chloride solution, dried with magnesium sulfate, filtered and concentrated in vacuo. The resulting residue is purified via silica gel chromatography (20-50% ethyl acetate in hexanes) to yield the title compound as a white solid. MS (m/z): 394 (M−1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:23][C:24](=[O:35])[C:25]1[CH:30]=[C:29](Cl)[CH:28]=[CH:27][C:26]=1[N+:32]([O-:34])=[O:33].[CH3:36][NH:37][CH2:38][CH2:39][CH2:40][NH:41][CH3:42]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:23][C:24](=[O:35])[C:25]1[CH:30]=[C:29]([N:37]([CH2:38][CH2:39][CH2:40][NH:41][CH3:42])[CH3:36])[CH:28]=[CH:27][C:26]=1[N+:32]([O-:34])=[O:33]
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CNCCCNC
Product: CNCCCN(C)c1ccc([N+](=O)[O-])c(C(=O)Nc2cc(NC(=O)c3ccnc(N4CCOCC4)c3)ccc2C)c1

Procedure:
In an analogous procedure to that described in the fifth paragraph of the portion of Note a) which is concerned with the preparation of starting materials, N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-5-chloro-2-nitrobenzamide was reacted with N-(3-methylaminopropyl)-N-methylamine to give N-[2-methyl-5-(2-morpholinopyrid4-ylcarbonylamino)phenyl]-5-[N-(3-methylaminopropyl)-N-methylamino]-2-nitrobenzamide: NMR Spectrum: (DMSOd6) 1.61–1.74 (m, 2H), 2.35 (s, 3H), 2.26 (m, 3H), 2.38–2.44 (m, 2H), 3.09 (s, 3H), 3.5–3.55 (m, 6H), 3.7–3.74 (m, 4H), 6.78 (s, 1H), 6.84 (d, 1H), 7.14 (d, 1H), 7.21 (d, 1H), 7.27 (s, 1H), 7.6 (d, 1H), 7.9 (s, 1H), 8.04 (d, 1H), 8.27 (d, 1H), 9.83 (s, 1H), 10.55 (s, 1H); Mass Spectrum: M+H+ 562.
Reaction SMILES: [C:1]1([C@H:7]2[C:11]([CH2:12][OH:13])=[CH:10][CH2:9][N:8]2[S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24]([Zn]CC)C.II.ClCI>[Cl-].[NH4+].C([Zn]CC)C.C(Cl)Cl>[C:1]1([CH:7]2[N:8]([S:14]([C:17]3[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=3)(=[O:16])=[O:15])[CH2:9][CH:10]3[C:11]2([CH2:12][OH:13])[CH2:24]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N2CC=C(CO)[C@@H]2c2ccccc2)cc1
Reactant: CC[Zn]CC
Agent: ClCI
Agent: II
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CC3CC3(CO)C2c2ccccc2)cc1
Yield: 97.7 %

Procedure:
To a flask containing racemic Intermediate 15, one enantiomer being [(S)-2-phenyl-1-(toluene-4-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]-methanol (19.0 g, 57.8 mmol), and methylene chloride (190 mL) at 0° C. and under nitrogen was added diethyl zinc (1.1M/toluene, 57.8 mL, 63.5 mmol) all at once via syringe. The reaction was stirred for twenty minutes and iodine (14.7 g, 57.7 mmol), another portion of diethyl zinc (1.1M/toluene, 57.7 mL, 63.5 mmol), and chloroiodomethane (8.8 mL, 121.3 mmol) were added in quick succession. The reaction was stirred at 0° C. for 3 hours at which point there was much white precipitate present. GC-MS analysis of an aliquot showed no product at this point. The nitrogen inlet was removed and replaced with a CaSO4 drying tube, a third portion of diethyl zinc (1.1M/toluene, 2.0 mL, 1.8 mmol) was added, and the reaction allowed to stir at room temperature overnight. GC-MS analysis of an aliquot showed complete conversion to product. The reaction was diluted with saturated ammonium chloride solution and the phases were separated. The organics were washed with brine, dried with sodium sulfate, filtered, and concentrated to give the title compound as a thick oil (19.4 g, 98%).
Reaction SMILES: [C:1]([O:6][CH2:7][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=4[Cl:36])[CH2:25][CH2:24]3)[CH:16]=2)[CH2:11][CH2:10][C:9]1=[O:37])(=[O:5])[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1COCC1>[C:1]([O:6][CH2:7][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=4[Cl:36])[CH2:25][CH2:24]3)[CH:16]=2)[CH:11]=[CH:10][C:9]1=[O:37])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)OCN1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCCC(=O)OCn1c(=O)ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Temperature: 25 °C
Yield: 62.6 %

Procedure:
To a stirred solution of Compound 2B (3.26 g, 5.94 mmol) in THF (100 mL) was added TFA (2.74 mL, 35.63 mmol) followed by DDQ (7.01 g, 30.88 mmol) in THF (40 mL). The reaction was stirred at room temperature over the weekend. The reaction was quenched with water (100 mL) and then poured into water (600 mL) and dichloromethane (100 mL). Solid NaHCO3 (100 g) was added and the mixture stirred for approximately 30 minutes. Dichloromethane (200 mL) was added and the mixture filtered. The collected filtrate was transferred to a separating funnel and the layers separated. The aqueous layer was extracted with dichloromethane (2×100 mL) and the combined organics washed with water (3×100 mL, brine (100 mL) and dried over MgSO4. After filtration, the volatiles were removed. The crude material was purified by silica chromatography eluting 0-4% Methanol/(1:1 ethyl acetate/dichloromethane). The oil was recrystallized from methanol to give Compound 2, (2.03 g, 3.72 mmol, 63% yield). 1H-NMR (300 MHz, CDCl3) δ 7.63 (1H, d), 7.45 (1H, d), 7.19-7.06 (2H, m), 6.99-6.90 (1H, m), 6.88-6.78 (2H, m), 6.52 (1H, d), 6.33 (2H, s), 4.06 (2H, t), 3.17-2.99 (4H, bs), 2.74-2.43 (6H, m), 2.35 (2H, t), 1.94-1.54 (6H, m), 0.93 (3H, t).
Reaction SMILES: [C:1]([C@@H:4]([NH:8][C:9]([C:11]1[N:12]=[C:13]([N:16]2[CH2:19][CH:18]([S:20][C:21]3[C@H:22]([CH3:52])[C@@H:23]4[C@@H:40]([C@H:41]([O:43][Si](C(C)(C)C)(C)C)[CH3:42])[C:39](=[O:51])[N:24]4[C:25]=3[C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])[CH2:17]2)[S:14][CH:15]=1)=[O:10])[CH:5]([CH3:7])[CH3:6])(=[O:3])[NH2:2].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O1CCCC1.O>[C:1]([C@@H:4]([NH:8][C:9]([C:11]1[N:12]=[C:13]([N:16]2[CH2:17][CH:18]([S:20][C:21]3[C@H:22]([CH3:52])[C@@H:23]4[C@@H:40]([C@H:41]([OH:43])[CH3:42])[C:39](=[O:51])[N:24]4[C:25]=3[C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])[CH2:19]2)[S:14][CH:15]=1)=[O:10])[CH:5]([CH3:6])[CH3:7])(=[O:3])[NH2:2]
Reactant: CC(C)[C@H](NC(=O)c1csc(N2CC(SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]4[C@H]3C)C2)n1)C(N)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)c1csc(N2CC(SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)C2)n1)C(N)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 48.5 %

Procedure:
To a solution of p-nitrobenzyl (1R,5S,6S)-2-{1-[4-((1S)-1-carbamoyl-2-methyl-propylcarbamoyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-t-butyldimethylsilyloxyethyl]-1-methylcarbapen-2-em-3-carboxylate (930 mg, 1.20 mmol) (obtained as described in Reference Example 47(3)) in tetrahydrofuran (47 ml) was added acetic acid (206 μl, 3.60 mmol) and 1 M tetrabutylammonium fluoride in tetrahydrofuran solution (3.60 ml, 3.60 mmol) in an ice bath and the mixture was stirred at room temperature for 2 days. After checking the completion of the reaction, ethyl acetate and water were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluant: ethyl acetate→ethyl acetate: methanol (95:5)) to afford p-nitrobenzyl (1R,5S,6S)-2-{1-[4-((1S)-1-carbamoyl-2-methyl-propylcarbamoyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (383 mg, yield 48%) as a pale yellow solid.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[O:15]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[O:18][CH2:17][CH:16]1[CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].CO>C(OCC)(=O)C>[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:29]3[CH2:30][CH2:31][N:26]([CH2:25][CH:16]4[O:15][C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=5[O:18][CH2:17]4)[CH2:27][CH2:28]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: c1ccc2c(c1)OCC(CN1CCNCC1)O2
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCN(CC2COc3ccccc3O2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]piperazine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 77% overall yield. FDMS m/e=423 (M+ of free base). α[D]589 =-10.21 (c=0.82, methanol).
Reaction SMILES: [OH:1][C:2]1([CH2:13][N+:14]([O-])=O)[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:14][CH2:13][C:2]1([OH:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CCOC(=O)N1CCC(O)(C[N+](=O)[O-])CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)N1CCC(O)(CN)CC1
Reaction time: 5 h

Procedure:
A mixture of ethyl 4-hydroxy-4-(nitromethyl)piperidine-1-carboxylate (5.2 g, 22.4 mmol) and 20% palladium hydroxide on carbon (0.50 g) in ethanol (190 mL) was hydrogenated at 35 psi (2.4×105 Pa) on a Parr apparatus for 5 h. The mixture was filtered through CELITE filter agent and the filtrate was concentrated. By 1H NMR analysis, the reaction was incomplete and the crude material was subjected to the reaction conditions again with fresh 20% palladium hydroxide on carbon (0.50 g) for another 24 h. The mixture was filtered through CELITE filter agent and the filtrate was concentrated to provide ethyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate, which was concentrated from chloroform to remove residual ethanol before using in the next reaction.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[NH:20][N:21]=[C:22]([CH3:24])[CH:23]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:2]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[NH:20][N:21]=[C:22]([CH3:24])[CH:23]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc(Nc2nc(-c3ccc(Br)cc3)nc3ccccc23)[nH]n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Nc2nc(-c3ccc(-c4ccccc4)cc3)nc3ccccc23)[nH]n1
Temperature: 80 °C
Yield: 51.4 %

Procedure:
Method H(i). To a mixture of [2-(4-bromo-phenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (196 mg, 0.51 mmol) and phenylboronic acid (75 mg, 0.62 mmol) in THF/water (1/1, 4 mL) is added Na2CO3 (219 mg, 2.06 mmol), triphenylphosphine (9 mg, 1/15 mol %) and palladium acetate (1 mg, 1/135 mol %). The mixture is heated at 80° C. overnight, the solvents are evaporated and the residue is purified by flash chromatography (gradient of CH2Cl2/MeOH) to give (2-biphenyl-4-yl-quinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine as a yellow solid (99 mg, 51%):1H NMR (DMSO) δ 2.37 (3H, s), 6.82 (1H, s), 7.39-7.57 (4H, m), 7.73-7.87 (6H, m), 8.57 (2H, d), 8.67 (1H, d), 10.42 (1H, s), 12.27 (1H, s); MS 378.2 (M+H)+
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([N:19]5[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]5)=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:7]=3[C:8]=2[CH:9]=1.CC1(C)C(C)(C)OB([C:42]2[CH:43]=[CH:44][C:45]([NH2:48])=[N:46][CH:47]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:25][N:22]1[CH2:23][CH2:24][N:19]([C:16]2[CH:17]=[CH:18][C:13]([C:12]3[C:6]4[CH2:5][C:4]5[S:3][C:2]([C:42]6[CH:43]=[CH:44][C:45]([NH2:48])=[N:46][CH:47]=6)=[CH:9][C:8]=5[C:7]=4[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:31])[CH3:33])[N:11]=3)=[CH:14][CH:15]=2)[CH2:20][CH2:21]1
Reactant: CN1CCN(c2ccc(-c3nn(COCC[Si](C)(C)C)c4c3Cc3sc(Br)cc3-4)cc2)CC1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN1CCN(c2ccc(-c3nn(COCC[Si](C)(C)C)c4c3Cc3sc(-c5ccc(N)nc5)cc3-4)cc2)CC1
Temperature: 100 °C
Yield: 75 %

Procedure:
A mixture of the corresponding 2-Bromo-6-[4-(4-methyl-piperazin-1-yl)-phenyl]-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (1.25 g, 2.3 mmol), 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (0.75 g, 3.4 mmol), Na2CO3 (2 M, 5.4 mL), and Pd(PPh3)2Cl2 (260 mg, 0.23 mmol) in toluene/ethanol (1:1, 15 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give the corresponding intermediate 5-[6-[4-(4-Methyl-piperazin-1-yl)-phenyl]-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-pyridin-2-ylamine as brown solid in 75% yield.
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].ON1C2C=CC=CC=2N=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH2:55][C:56](=[N:68]O)[C:57]1[N:58]=[CH:59][C:60]([C:63]([O:65][CH2:66][CH3:67])=[O:64])=[N:61][CH:62]=1>O1CCOCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]2[O:11][N:55]=[C:56]([C:57]3[N:58]=[CH:59][C:60]([C:63]([O:65][CH2:66][CH3:67])=[O:64])=[N:61][CH:62]=3)[N:68]=2)=[CH:12][CH:13]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)Cc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)c1cnc(C(N)=NO)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(-c2noc(-c3ccc(CC(C)C)cc3)n2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.1 %

Procedure:
A mixture of 4-isobutylbenzoic acid (0.28 g, 1.59 mmol), 1-hydroxybenzotriazole (0.042 g, 0.31 mmol), N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.51 g, 1.59 mmol), diisopropylethylamine (1.4 mL, 7.86 mmol) and dioxane (4 mL) was stirred at room temperature for 1 hour. Ethyl 5-[amino(hydroxyimino)methyl]pyrazine-2-carboxylate (0.33 g, 1.57 mmol) was added to the reaction mixture, stirred for 1.5 hours at room temperature and 6 hours at 100° C. The reaction mixture was cooled to room temperature, quenched with H2O (10 mL) and filtered. The precipitate was dissolved in EtOAc (10 mL), washed with 1N NaOH (3×10 mL) and brine (2×10 mL), dried (Na2SO4), filtered and concentrated in vacuo to yield the title compound (0.15 g, 27%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:5]=1[OH:16])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:5]=1[OH:16]
Reactant: O=[N+]([O-])c1ccc(-c2ccccc2)cc1O
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(-c2ccccc2)cc1O
Reaction time: 8 h

Procedure:
A solution of 2-nitro 5-phenyl phenol (1.2 g, 5.5 mmol) in methanol was treated with 10% Pd/C (1.2 g). The reaction mixture was flushed with hydrogen and allowed to stir overnight. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford desired (0.01 g, 98%) EI-MS m/z 186(M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([N:14]2[CH2:19][C@H:18]([CH3:20])[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:16][C@H:15]2[CH3:29])=[O:13])=[C:6]([CH:9]=1)[CH:7]=O.C([O-])(=O)C.[NH4+].C([BH3-])#[N:36].[Na+]>CO>[NH2:36][CH2:7][C:6]1[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[O:10][CH2:11][C:12]([N:14]1[CH2:19][C@H:18]([CH3:20])[N:17]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH2:16][C@H:15]1[CH3:29])=[O:13]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C=O
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CN
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To a solution of (2R,5S)-5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzaldehyde (1.86 g, 4.44 mmol) in MeOH (20 mL) was added ammonium acetate (3.42 g, 44 mmol) and sodium cyanoborohydride (0.195 g, 3.1 mmol). The resulting mixture was stirred overnight at ambient temperature. The reaction was quenched with concentrated hydrochloric acid and concentrated in vacuo. The residue was dissolved in water and basified with aqueous 3N NaOH (pH>10). The product was extracted with dichloromethane (2×) and ethyl acetate (2×). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (1.29 g, 69% yield)
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([S:8][CH2:9][CH2:10][C:11]([F:15])=[C:12]([F:14])[F:13])[O:6][CH:7]=1.[C-:16]#[N:17].[K+].C1OCCOCCOCCOCCOCCOC1.[I-].[Na+]>O.CN(C)C=O>[C:16]([CH2:2][C:3]1[N:4]=[C:5]([S:8][CH2:9][CH2:10][C:11]([F:15])=[C:12]([F:14])[F:13])[O:6][CH:7]=1)#[N:17]
Reactant: FC(F)=C(F)CCSc1nc(CCl)co1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1coc(SCCC(F)=C(F)F)n1
Temperature: 100 °C
Reaction time: 20 h
Yield: 26 %

Procedure:
1.2 g of 4-chloromethyl-2-(3,4,4-trifluoro-3-butenylthio)oxazole, 1 g of potassium cyanide, 0.1 g of 18-crown-6-ether and 0.1 g of sodium iodide were added to 20 ml of dimethylformamide (dehydrated) and stirred at 100° C. for 20 hours. After cooling, 200 ml of water was added to the reaction mixture and extracted with 100 ml of diethyl ether twice. The extracted diethyl ether layers were put together, washed with 200 ml of water, dried with magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (eluent: hexane:dichloromethane=2:1) to obtain 0.3 g of 4-cyanomethyl-2-(3,4,4-trifluoro-3-butenylthio)oxazole as colorless oil (yield 15.6%). n20D=1.4844.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6](=[O:12])[C:5]12[CH2:14][CH2:13]1.C(=[NH:28])(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>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].CCOC(C)=O.C1COCC1.O1CCOCC1>[NH2:28][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6](=[O:12])[C:5]12[CH2:14][CH2:13]1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CN1C(=O)C2(CC2)c2cc(Br)ccc21
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1C(=O)C2(CC2)c2cc(N)ccc21
Temperature: 25 °C
Yield: 93 %

Procedure:
Add 5′-bromo-1′-methylspiro[cyclopropane-1,3′-indolin]-2′-one (1.0 g, 4.0 mmol), benzophenone imine (1.4 g, 8.0 mmol), cesium carbonate (3.2 g, 10.0 mmol), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (BINAP, 500 mg, 0.80 mmol), tris(dibenzylideneacetone)dipalladium(0) [Pd2(dba)3, 500 mg, 0.55 mmol] to dioxane (20 mL), stir the reaction under nitrogen atmosphere at 110° C. overnight. Cool to room temperature; filter off the solid, concentrate the filtrate under reduced pressure to give a residue. Add hydrochloric acid (1N, 2 mL) and THF (15 mL) to the residue; stir the mixture for 30 mins at room temperature. TLC (PE:EtOAc=1:1) shows the reaction is almost complete. Concentrate the mixture under reduce pressure to give the crude product, purify by flash chromatography (silica gel, EtOAc:PE=1:1) to afford the title compound as a yellow solid (0.7 g, 93.3%). MS: (M+1): 189.1.