Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([N:12]2[CH2:18][CH:17]3[O:19][CH:14]([CH2:15][CH2:16]3)[CH2:13]2)[N:3]=1.[OH:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][N:8]1[C:6]2=[N:7][C:2]([C:25]3[CH:26]=[C:21]([OH:20])[CH:22]=[CH:23][CH:24]=3)=[N:3][C:4]([N:12]3[CH2:18][CH:17]4[O:19][CH:14]([CH2:15][CH2:16]4)[CH2:13]3)=[C:5]2[CH:10]=[N:9]1
Reactant: OB(O)c1cccc(O)c1
Reactant: Cn1ncc2c(N3CC4CCC(C3)O4)nc(Cl)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cn1ncc2c(N3CC4CCC(C3)O4)nc(-c3cccc(O)c3)nc21
Temperature: 120 °C

Procedure:
A mixture of 3-(6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (95 mg, 0.34 mmol), 3-hydroxyphenylboronic acid (70 mg, 0.51 mmol), and tetrakis(triphenylphosphine)palladium(0) (39 mg, 10 mol %) in toluene/ethanol (1:1, 3 mL) and 2 M aqueous sodium carbonate solution (2 mL) was heated in a Smith process vial in the microwave reactor for one hour at 120° C. The cooled mixture was partitioned between ethyl acetate and water. The aqueous phase was acidified with 1 M aqueous hydrochloric acid and then extracted three times with ethyl acetate. The combined extracts were washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution. The extracts were then dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude residue was purified via reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 90% acetonitrile to provide, after concentration, 3-[1-methyl-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenol. MS (ES+): 338.0 (M+H)+
Reaction SMILES: [CH2:1]([N:8]([CH2:13][C:14]1[C:19](Cl)=[N:18][C:17]([Cl:21])=[CH:16][N:15]=1)[CH2:9][C@@H:10]([OH:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].O>C1COCC1>[CH2:1]([N:8]1[CH2:13][C:14]2[N:15]=[CH:16][C:17]([Cl:21])=[N:18][C:19]=2[O:12][C@@H:10]([CH3:11])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](O)CN(Cc1ccccc1)Cc1ncc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1CN(Cc2ccccc2)Cc2ncc(Cl)nc2O1
Reaction time: 2 h
Yield: 51.8 %

Procedure:
To a solution of (2S)-1-{benzyl[(3,5-dichloropyrazin-2-yl)methyl]amino}propan-2-ol (3.48 g) in THF (50 mL) was added sodium hydride (513 mg) under ice-cooling, and the mixture was stirred for 2 hr under ice-cooling. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (solvent gradient: 5→20% ethyl acetate/hexane) to give the title compound (1.60 g, 52%) as a pale-yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:20])[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:21]([C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=1)[C:26]([O:28][CH3:29])=[O:27])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.C(O)(=O)C.CCOC(C)=O>[C:15]([O:14][C:13]([NH:12][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C@H:3]([OH:20])[CH2:2][NH:1][CH2:21][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=1)[C:26]([O:28][CH3:29])=[O:27])=[O:19])([CH3:17])([CH3:16])[CH3:18]
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(CNC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
A solution of tert-butyl (2S,3R)-4-amino-3-hydroxy-1-phenylbutan-2-ylcarbamate (200 mg, 0.713 mmol) in THF was added methyl 3-formylbenzoate (117.1 mg, 0.713 mmol) and stirred for 30 min at room temperature. NaB(OAc)3H (302.5 mg, 1.43 mmol) was then added portionwise in 30 min, finally 5 drops of acetic acid was added and the resulting mixture was stirred at the same temperature overnight. The reaction mixture was diluted with EtOAc, and washed with saturated aqueous NaHCO3. The organic layer was separated and dried (MgSO4). Concentration in vacuo was followed by purification with flash chromatography to give the desired product as a white solid (300 mg, % yield). 1H NMR (CDCl3): d: 7.999 (m, 2H), 7.589 (m, 1H), 7.451 (m, 1H), 7.254 (m, 5H), 3.956 (s, 3H), 3.892 (m, 3H), 3.549 (m, 1H), 3.040-2.850 (m, 2H), 2.793 (m, 2H), 1.374 (s, 9H).
Reaction SMILES: CC1(C)[O:6][C@H:5]2[C:7](=[O:51])[O:8][C@H:9]([CH2:10][O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][C:21]5[C:27](=[O:28])[NH:26][C:25]6[CH:29]=[C:30]([CH2:33][CH2:34][O:35][C:36]7[CH:41]=[CH:40][C:39]([N:42]8[CH2:47][CH2:46][O:45][CH2:44][CH2:43]8)=[CH:38][CH:37]=7)[CH:31]=[CH:32][C:24]=6[NH:23][C:22]=5[CH:48]=4)=[CH:14][C:13]=3[O:49][CH3:50])[C@H:4]2[O:3]1.FC(F)(F)C(O)=O>ClCCl>[OH:3][C@H:4]1[C@@H:5]([OH:6])[C:7](=[O:51])[O:8][C@@H:9]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]3[C:27](=[O:28])[NH:26][C:25]4[CH:29]=[C:30]([CH2:33][CH2:34][O:35][C:36]5[CH:41]=[CH:40][C:39]([N:42]6[CH2:43][CH2:44][O:45][CH2:46][CH2:47]6)=[CH:38][CH:37]=5)[CH:31]=[CH:32][C:24]=4[NH:23][C:22]=3[CH:48]=2)=[CH:14][C:13]=1[O:49][CH3:50]
Reactant: COc1cc(-c2ccc3c(c2)Nc2ccc(CCOc4ccc(N5CCOCC5)cc4)cc2NC3=O)ccc1OC[C@H]1OC(=O)[C@@H]2OC(C)(C)O[C@H]12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2ccc3c(c2)Nc2ccc(CCOc4ccc(N5CCOCC5)cc4)cc2NC3=O)ccc1OC[C@H]1OC(=O)[C@H](O)[C@@H]1O
Temperature: 25 °C

Procedure:
A mixture of Example 642B (11.2 mg, 0.016 mmol) in dichloromethane (1 mL) was treated with trifluoroacetic acid (50 μL, 0.65 mmol) and stirred at room temperature. The reaction mixture was then concentrated and purified by preparative HPLC. MS (ESI) m/e 668 (M+H)+; 1H NMR (300 MHz, DMSO-d6) 9.74 (s, 1H), 7.84 (s, 1H), 7.73 (d, J=8.3 Hz, 1H), 7.25 (d, J=1.5 Hz, 1H), 7.22 (d, J=1.8 Hz, 1H), 7.15-1.19 (m, 2H), 7.07 (d, J=8.3 Hz, 1H), 6.85-6.96 (m, 7H), 4.73 (d, J=5.5 Hz, 1H), 4.59 (t, J=3.4 Hz, 1H), 4.25-4.29 (m, 3H), 4.05 (t, J=6.8 Hz, 2H), 3.86 (s, 3H), 3.75-3.85 (m, 2H), 3.73-3.75 (m, 4H), 3.03-3.05 (m, 4H), 2.87 (t, J=6.6 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][NH:12][CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1.BrC1C=C2C3(CCNC3)CN(C(NC3SC(Cl)=CN=3)=O)C2=CC=1.CC1(C)[O:52][C@@H:51]([C:53](O)=[O:54])[CH2:50][O:49]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:50](=[O:49])[C@H:51]([OH:52])[CH2:53][OH:54])[CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1
Reactant: CC1(C)OC[C@H](C(=O)O)O1
Reactant: O=C(Nc1ncc(Cl)s1)N1CC2(CCNC2)c2cc(Cl)ccc21
Agent: O=C(Nc1ncc(Cl)s1)N1CC2(CCNC2)c2cc(Br)ccc21
Product: O=C([C@H](O)CO)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Example 19 and Step 2 of Example 117, with the exceptions that the 5-chloro-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide obtained as an intermediate of Example 39 was used instead of 5-bromo-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide, and that (R)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid was used instead of N-Boc glycine.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[CH2:20]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[CH2:9]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH2:22][C:21]([OH:25])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:20]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1CCCN(C(=O)OCc2ccccc2)C1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCCC(O)(c2ccccc2)C1
Reaction time: 0.5 h
Yield: 29.4 %

Procedure:
To a solution of 9 ml (9 mmol) phenylmagnesium bromide (1M solution in THF) in THF (13 ml) was added a solution of 1.5 g (6.00 mmol) 3-oxo-piperidine-1-carboxylic acid benzyl ester (commercial) in THF (5 ml) at room temperature over a period of 15 minutes. The mixture was stirred for 30 minutes and then quenched under ice bath cooling with a 20% ammonium chloride solution (4 ml). The organic layer was decanted and the residue was extracted once with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude oil was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 50%) to provide 0.55 g (30%) of the title compound as a white solid. MS (m/e): 312.0 (M+H+)
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:23]=[CH:22][C:21]3[CH:20]4[S:24](=[O:26])(=[O:25])[CH:16]([CH2:17][CH2:18][CH2:19]4)[C:15]=3[CH:14]=2)[N:3]=1.[NH2:27][CH2:28][C:29]1[C:30]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])=[N:31][CH:32]=[CH:33][CH:34]=1.C(N(C(C)C)CC)(C)C>CC(O)(C)C.ClC(Cl)C>[O:25]=[S:24]1(=[O:26])[CH:20]2[CH2:19][CH2:18][CH2:17][CH:16]1[C:15]1[CH:14]=[C:13]([NH:12][C:4]3[N:3]=[C:2]([NH:27][CH2:28][C:29]4[C:30]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])=[N:31][CH:32]=[CH:33][CH:34]=4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=3)[CH:23]=[CH:22][C:21]=12
Reactant: O=S1(=O)C2CCCC1c1cc(Nc3ncc(C(F)(F)F)c(Cl)n3)ccc12
Reactant: CN(c1ncccc1CN)S(C)(=O)=O
Solvent: CC(C)(C)O
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ncccc1CNc1nc(Nc2ccc3c(c2)C2CCCC3S2(=O)=O)ncc1C(F)(F)F)S(C)(=O)=O
Temperature: 85 °C
Reaction time: 2 h
Yield: 17.7 %

Procedure:
A mixture of C6 (51 mg; 0.126 mmol) and 1:1 (vol:vol) t-BuOH/dichloroethane (500 μL) was added to a mixture of N-(3-Aminomethyl-pyridin-2-yl)-N-methyl-methanesulfonamide (38 mg, 0.139 mmol) and diisopropyl ethylamine (66 μL, 0.378 mmol). The reaction mixture was heated to 85° C. in a sealed vial. After two hours, the hot reaction mixture was loaded directly onto silica under reduced pressure, purified via chromatography (99:1:0.1 CHCl3:CH3OH:NH4OH), and concentrated under reduced pressure to provide 1 as a white solid (13 mg, 0.0223 mmol, 18%). LC/MS (Method F) r.t.=2.26 min.; m/z 583.2. HPLC r.t.=6.40 min.
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[NH:6])C.[C:23]([NH:31][NH2:32])(=O)[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]4[NH:6][C:23]([C:24]5[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=5)=[N:31][N:32]=4)[CH:8]=3)[NH:12][N:11]=2)=[CH:21][CH:20]=1
Reactant: NNC(=O)c1ccncc1
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Agent: Cl
Product: Fc1ccc(-c2n[nH]c3ccc(-c4nnc(-c5ccncc5)[nH]4)cc23)cc1
Yield: 15.4 %

Procedure:
The procedure described in example 119 using ethoxy[3-(4-fluorophenyl)(1H-indazole-5-yl)]methanimine hydrochloride (200 mg, 0.62 mmol), triethylainine (0.25 mL, 1.86 mmol) and isonicotinic acid hydrazide (171.42 mg, 1.25 mmol) was followed to yield the title compound (34 mg, 15% yield). 1H NMR (DMSO-d6) δ 13.6 (s, 1H), 8.78-8.82 (m, 3H), 8.05-8.25 (m, SH), 7.8 (d, 1H), 7.45 (t, 2H), ES-MS (m/z) 357 [M+1]−.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.[CH2:26]([NH2:28])[CH3:27]>>[CH2:26]([NH:28][C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])[CH3:27]
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccncc3)noc2C)nn1
Reactant: CCN
Product: CCNC(=O)c1ccc(OCc2c(-c3ccncc3)noc2C)nn1
Yield: 33 %

Procedure:
As described for example 69, 6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid ethyl ester (100 mg, 0.29 mmol) was converted, using ethylamine (2 M solution in THF) instead of isopropylamine, to the title compound (33 mg, 33%) which was obtained as a white solid. MS: m/e=340.1 [M+H]−.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]([OH:27])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:28][C:29]1[CH:30]=[C:31]([C:35](=[N:37]O)[NH2:36])[CH:32]=[CH:33][CH:34]=1>>[F:28][C:29]1[CH:30]=[C:31]([C:35]2[N:37]=[C:25]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[O:27][N:36]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: NC(=NO)c1cccc(F)c1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)no2)C1

Procedure:
250 mg (about 0.52 mmol) of the compound from Example 49A and 89 mg (0.58 mmol) of 3-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 26 mg (10% of theory).
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH3:10])=[C:7]([N+]([O-])=O)[CH:6]=[CH:5][N:4]=1)#[N:2].[CH3:14][O-:15].[Na+].[Na]>CO.O>[C:1]([C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:15][CH3:14])[CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: C[O-]
Reactant: COc1c([N+](=O)[O-])ccnc1C#N
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: O
Product: COc1ccnc(C#N)c1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
3 g (0.017 moles) of 2-cyano-3-methoxy-4-nitropyridine obtained in Example a) and a sodium methoxide solution prepared from 0.77 g (0.033 moles) of sodium and 65 ml of methanol are stirred at ambient temperature for 4 hours. There is added 100 ml of water, the methanol is eliminated and the aqueous phase is extracted with dichloromethane. The organic phase is washed with water, dried, concentrated and the residue chromatographed (ethyl acetate/heptane, 1:1) to obtain 1.96 g (72% yield) of a white solid (MP=133° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)[CH:2]=1.[CH3:16][O:17][C:18]([CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:19]>C(Cl)(Cl)Cl>[CH3:16][O:17][C:18](=[O:19])/[CH:20]=[CH:12]/[C:11]1[CH:14]=[CH:15][C:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Cc2cccnc2)cc1
Solvent: ClC(Cl)Cl
Product: COC(=O)/C=C/c1ccc(Cc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 45.3 %

Procedure:
A mixture of 200 mg of 4-(3-pyridylmethyl)benzaldehyde (prepared as described in Reference Example 1), 0.14 g of methoxycarbonylmethylenetriphenylphosphorane and 5 ml of chloroform was stirred at room temperature for 3 days, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride as eluent to give 48 mg of the title compound having the following physical characteristics:
Reaction SMILES: C([O:5][CH2:6][C@@:7]12[CH2:34][O:33][C@@H:9]([C@:10]([SiH](C3C=CC=CC=3)C3C=CC=CC=3)([N:12]3[CH:19]=[CH:18][C:16](=[O:17])[NH:15][C:13]3=[O:14])[O:11]1)[C@@H:8]2[OH:35])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:34]1[C@@:7]2([CH2:6][OH:5])[C@@H:8]([OH:35])[C@H:9]([C@H:10]([N:12]3[CH:19]=[CH:18][C:16](=[O:17])[NH:15][C:13]3=[O:14])[O:11]2)[O:33]1
Reactant: CC(C)(C)OC[C@]12CO[C@H]([C@@H]1O)[C@@](n1ccc(=O)[nH]c1=O)([SiH](c1ccccc1)c1ccccc1)O2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=c1ccn([C@@H]2O[C@@]3(CO)CO[C@@H]2[C@@H]3O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
Compound 12 (13.2 g, 26.7 mmol) was dissolved in anhydrous THF (60 mL). To this mixture was added tetrabutylammonium fluoride (TBAF, 29.4 mmol, 29.4 mL of a 1 M solution in THF). After stirring at room temperature for 2 hours, mixture was concentrated in vacuo to ˜15 mL and then eluted through a short silica gel column with 10% methanol in CH2Cl2. Eluate was concentrated to a pale solid, which was washed on a glass frit with a minimal amount of ice-cold methanol. The remaining solid was dried in vacuo to yield 5.78 g (84%) of 13 as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[CH:8]=[CH:7]2.[CH3:19][C:20]([O:22][CH2:23][C@H:24]1[O:29][C@H:28](Br)[C@H:27]([O:31][C:32]([CH3:34])=[O:33])[C@@H:26]([O:35][C:36]([CH3:38])=[O:37])[C@@H:25]1[O:39][C:40]([CH3:42])=[O:41])=[O:21].[OH-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.C(Cl)Cl>[C:32]([O:31][C@@H:27]1[C@@H:26]([O:35][C:36](=[O:37])[CH3:38])[C@H:25]([O:39][C:40](=[O:41])[CH3:42])[C@@H:24]([CH2:23][O:22][C:20](=[O:21])[CH3:19])[O:29][C@H:28]1[O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[CH:8]=[CH:7]2)(=[O:33])[CH3:34]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Cc1ccc(Cn2ccc3cccc(O)c32)cc1
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3ccn(Cc4ccc(C)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.4 %

Procedure:
To a mixture of 7-hydroxy-1-(4-methylbenzyl)-1H-indole (1.36 g), acetobromo-α-D-glucose (2.59 g) and benzyltri-(n-butyl)ammonium chloride (1.79 g) in methylene chloride (20 mL) was added 5 mol/L aqueous sodium hydroxide solution (3.4 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was purified by column chromatography on aminopropylated silica gel (eluent: n-hexane/ethyl acetate 1/1), and purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1-2/1) to give 7-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1-(4-methylbenzyl)-1H-indole (1.25 g). The obtained 7-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1-(4-methylbenzyl)-1H-indole (0.3 g) was dissolved in methanol (2 mL). To the solution was added sodium methoxide (28% methanol solution, 0.05 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by column chromatography on silica gel (eluent: methylene chloride/methanol=5/1) to give the title compound (0.19 g).
Reaction SMILES: [C:1]([CH:4]([CH2:15][C:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])(=O)[CH3:2].C([O-])(=O)C.[NH4+:28]>C(O)(=O)C.O>[CH3:2][C:1]1[NH:28][C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15][C:4]=1[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: [NH4+]
Reactant: CC(=O)C(CC(=O)c1ccccc1)C(=O)OCc1ccccc1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1[nH]c(-c2ccccc2)cc1C(=O)OCc1ccccc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A 6.00 g portion of benzyl 2-acetyl-4-oxo-4-phenylbutanoate was dissolved in a mixture of 54 ml acetic acid and 5.4 ml water, and 14.9 g of ammonium acetate was added, followed by stirring at 100° C. for 1 hour. After evaporation of the solvent under a reduced pressure and subsequent addition of ethyl acetate-water, the ethyl acetate layer was washed with a 1 M sodium hydroxide aqueous solution and saturated brine, followed by drying with anhydrous sodium sulfate. Then, the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:5-1:4) to obtain 3.84 g of benzyl 2-methyl-5-phenyl-1H-pyrrole-3-carboxylate as a light purple solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2.C([OH:20])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn]>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][C:12](=[O:20])[NH:13]2
Reactant: Fc1cccc(F)c1-c1cccc2[nH]ccc12
Reactant: CCO
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2c(F)cccc2F)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To the suspension of 4-(2,6-difluoro-phenyl)-1H-indole (9.5 g, 41.4 mmol) in t-BuOH: ethanol: acetic acid (262 mL: 155 mL: 81 mL) was added pyridinium tribromide (40.28 g, 126 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added more acetic acid (200 mL). Zinc dust (14.2 g, 217 mmol) was added to the reaction mixture portionwise. After stirring for one hour, the unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (5×), sat. NaHCO3 (2×), brine (3×), dried over Na2SO4, concentrated, triturated with ether to give 7.1 g (70%) of 4-(2,6-difluoro-phenyl)-1,3-dihydro-indol-2-one as a white solid.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@@:14]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH3:25])[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:4]1.[Si](OC[C@@H]1[C@@H](C2C=CC=CC=2)CNC1)(C(C)(C)C)(C)C>CCCCCC.CCOC(C)=O>[CH:2]([C@H:3]1[C@@H:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][N:5]([C@@:14]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH3:25])[C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[CH2:4]1)=[O:1]
Reactant: C[C@](C(=O)OCc1ccccc1)(c1ccccc1)N1C[C@@H](CO)[C@@H](c2ccccc2)C1
Agent: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C[C@](C(=O)OCc1ccccc1)(c1ccccc1)N1C[C@@H](C=O)[C@@H](c2ccccc2)C1

Procedure:
The title compound was prepared from 2-(R)-(3-(S)-hydroxymethyl-4-(S)-phenylpyrrolidin-1-yl)-2-(phenyl)propionic acid, benzyl ester (from Step B) using a procedure analogous to that described in preparation of Aldehyde 1. For the title compound: RF: 0.46 (4:1 v/v hexane/EtOAc); 1H NMR (300 MHz, CDCl3) δ1.73 (s, 3H), 2.95-3.10 (m, 3H), 3.33 (m, 1H), 3.50-3.63 (m, 2H), 5.25 (s, 2H), 7.12-7.38 (m, 15H), 9.62 (d, J=1.6 Hz).