Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH3:34][O:35][P:36]([CH:39]([NH:43][C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[CH:40]([CH3:42])[CH3:41])(=O)[OH:37].[CH3:54][O:55][C:56](=[O:70])[CH:57]([OH:69])[CH2:58][CH2:59][CH2:60][NH:61][C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63].CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:54][O:55][C:56](=[O:70])[CH:57]([O:69][P:36]([CH:39]([NH:43][C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[CH:40]([CH3:42])[CH3:41])([O:35][CH3:34])=[O:37])[CH2:58][CH2:59][CH2:60][NH:61][C:62]([O:64][C:65]([CH3:67])([CH3:66])[CH3:68])=[O:63]
Reactant: COP(=O)(O)C(NC(=O)OCc1ccccc1)C(C)C
Reactant: COC(=O)C(O)CCCNC(=O)OC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(CCCNC(=O)OC(C)(C)C)OP(=O)(OC)C(NC(=O)OCc1ccccc1)C(C)C
Yield: 68.7 %

Procedure:
A solution of PyBOP (2.1 g, 4.0 mmol) in DMF (3 mL) was added to a mixture of (1-benzyloxycarbonylamino-2-methyl-propyl)-phosphonic acid monomethyl ester (1.0 g, 3.32 mmol) and 5-tert-butoxycarbonylamino-2-hydroxy-pentanoic acid methyl ester (865 mg, 3.5 mmol) in DMF (4 mL) under argon. DIPEA (2.28 mL, 13.3 mmol) was added dropwise and the mixture was stirred over night. Ethyl acetate was added and the mixture was washed with 10% KHSO4, satd. NaHCO3 and brine and dried. Concentration under reduced pressure followed by chromathography (heptane/EtOAc, 1:1→1:6) gave 2-[(1-benzyloxycarbonylamino-2-methyl-propyl)-methoxy-phosphinoyloxy]-5-tert-butoxycarbonylamino-pentanoic acid methyl ester (1.21 g, 69%).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[H-].[Na+].Cl[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=1.Cl>CCCCCC.CN(C=O)C>[OH:4][CH2:3][CH2:2][CH2:1][O:5][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=1
Reactant: OCCCO
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: OCCCOc1ccc(C(F)(F)F)cn1
Reaction time: 1 h
Yield: 43.5 %

Procedure:
A mixture of 12.6 g of 1,3-propanediol and 100 ml of N,N-dimethylformamide was stirred under a nitrogen stream, to which 3.30 g of an oily mixture containing 60% sodium hydride was added in small portions at room temperature over 30 minutes. After further stirring continued at room temperature for 1 hour, 20 ml of a DMF solution of 10.0 g of 2-chloro-5-trifluoromethylpyridine was added dropwise over 40 minutes. After further stirring continued under a nitrogen stream at room temperature overnight, 100 ml of about 2 N diluted hydrochloric acid was added over 15 minutes to stop the reaction. The reaction mixture was extracted twice with toluene at a total volume of 500 ml. The combined toluene layer was successively washed with diluted hydrochloric acid and aqueous sodium bicarbonate solution, dried with magnesium sulfate, and concentrated to obtain an oily product. The oily product was dissolved in 300 ml of hexane by heating, followed by recrystallization, which afforded 5.3 g of 2-(3-hydroxypropyloxy)-5-trifluoromethylpyridine as almost pure crystals (44% yield), m.p. 46.6° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:18][CH2:17][CH2:16][C:15]3=[O:19])[CH:11]=[C:10]([C:20](O)=[O:21])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][C:24]1[N:29]=[CH:28][C:27]([C@H:30]([NH2:32])[CH3:31])=[CH:26][N:25]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:23][C:24]1[N:29]=[CH:28][C:27]([C@H:30]([NH:32][C:20]([C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[CH:13]=[C:12]([N:14]3[CH2:18][CH2:17][CH2:16][C:15]3=[O:19])[CH:11]=2)=[O:21])[CH3:31])=[CH:26][N:25]=1
Reactant: Cc1ncc([C@@H](C)N)cn1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(N3CCCC3=O)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3cnc(C)nc3)cc(N3CCCC3=O)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-(2-oxopyrrolidin-1-yl)biphenyl-3-carboxylic acid (58.0 mg, 0.000167 mol) in N,N-dimethylformamide (1 mL, 0.01 mol) was added (R)-1-(2-methylpyrimidin-5-yl)ethanamine (50.0 mg, 0.000364 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (150.0 mg, 0.0003945 mol) and N,N-diisopropylethylamine (150.0 uL, 0.0008612 mol). The reaction mixture was stirred for 16 hours at 25° C. Checked LC/MS, the reaction was completed. The DMF reaction solution was directly applied to prep. HPLC. The final product was yield a light color foam.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]2[C:13]=1[C:12]1[C@@H:11]([CH2:14][CH:15]([OH:18])[C:16]#[N:17])[CH2:10][CH2:9][C:8]=1[S:7]2.[C:19]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:20].N1C=CN=C1>CN(C=O)C.C(Cl)Cl>[Si:23]([O:18][CH:15]([CH2:14][C@H:11]1[CH2:10][CH2:9][C:8]2[S:7][C:6]3[C:13](=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=3)[C:12]1=2)[C:16]#[N:17])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#CC(O)C[C@H]1CCc2sc3ncnc(Cl)c3c21
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC(C#N)C[C@H]1CCc2sc3ncnc(Cl)c3c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
To a solution of 3-[(3R)-12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]-2-hydroxypropanenitrile (170 mg, 0.61 mmol, 1.00 equiv) in 5 mL of distilled DMF was added tert-butyl(chloro)dimethylsilane (138 mg, 0.92 mmol, 1.50 equiv) and imidazole (124 mg, 1.82 mmol, 3.00 equiv) at room temperature under nitrogen. The resulting solution was stirred for 2 h at ambient temperature and diluted with DCM (30 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 236 mg (99%) of 2-[(tert-butyldimethylsilyl)oxy]-3-[(3R)-12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]propanenitrile as a white solid. MS: m/z 395 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH2:31][CH2:30][C@@:15]23[C:16]4[CH:17]=[C:18]([O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:20][C:21]=4[CH2:22][C@@H:9]1[C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14]3)(OC(C)(C)C)=O.O1CCOCC1.Cl.C(Br)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[CH2:1]([N:8]1[CH2:31][CH2:30][C@@:15]23[C:16]4[CH:17]=[C:18]([O:23][C:24](=[O:29])[C:25]([CH3:27])([CH3:26])[CH3:28])[CH:19]=[CH:20][C:21]=4[CH2:22][C@@H:9]1[C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14]3)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(OC(=O)C(C)(C)C)cc13
Reactant: BrCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Oc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(Cc1ccccc1)CC3
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
To a solution of compound 31 (5 mg, 0.012 mmol) in dry CH2Cl2 (0.2 ml) was added 4 M HCl dioxane solution (0.5 mL) and the mixture stirred for 2 h at 0° C. Solvent was evaporated under reduced pressure. The crude amine salt 32 was dissolved in CH2Cl2 (0.5 ml) and to it were slowly added benzyl bromide (2 μL, 0.020 mmol) and TEA (9 μL, 0.064 mmol) at 0° C. After 4 h stirring, the reaction mixture was concentrated under reduced pressure. The crude product was purified on a silica gel column chromatography (3:1 n-Hexane/EtOAc) to give a colorless oil (4 mg, 80% yield): 1H NMR (300 MHz, CDCl3) 0.91˜1.74 (m, 18H); 1.89 (m, J=12.6 Hz, 1H); 2.07˜2.21 (m, 1H), 2.29˜2.48 (m, 2H); 2.63˜2.69 (m, 1H); 2.87 (s, 1H); 3.09 (d, J=18.3 Hz, 1H); 3.68 (dd, J=13.4 Hz, 2H); 6.82˜6.93 (m, 2H); 7.15 (d, J=8.3 Hz, 1H); 7.25˜7.38 (m, 5H).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([NH2:14])[CH:12]=2)[NH:7][N:6]=1.[F:15][C:16]1[C:24]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])=[CH:23][CH:22]=[C:21]([F:32])[C:17]=1[C:18](O)=[O:19].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[F:15][C:16]1[C:24]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:27])=[O:28])=[CH:23][CH:22]=[C:21]([F:32])[C:17]=1[C:18]([NH:14][C:11]1[CH:12]=[C:13]2[C:5]([O:4][CH2:3][CH2:2][F:1])=[N:6][NH:7][C:8]2=[N:9][CH:10]=1)=[O:19]
Reactant: Nc1cnc2[nH]nc(OCCF)c2c1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(OCCF)c3c2)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-(2-fluoroethoxy)-1H-pyrazolo[3,4-b]pyridin-5-amine (0.020 g, 0.10 mmol), 2,6-difluoro-3-(propylsulfonamido)benzoic acid (0.031 g, 0.11 mmol), EDCI (0.021 g, 0.11 mmol), and HOBt (0.017 g, 0.11 mmol) in DMF (6 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl, saturated aqueous NaHCO3 and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure to give 2,6-difluoro-N-(3-(2-fluoroethoxy)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide. The crude material was purified by silica gel flash column chromatography (5% 7N NH3-MeOH in CH2Cl2) to afford 2,6-difluoro-N-(3-(2-fluoroethoxy)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (41 mg, 88% yield). LRMS (ACPI pos) m/e 458.1 (M+1). 1H-NMR (400 MHz, d6-DMSO) δ 12.68 (s, 1H), 11.12 (s, 1H), 9.73 (br s, 1H), 8.58 (d, 1H), 8.54 (d, 1H), 7.55 (q, 1H), 7.27 (t, 1H), 4.90 (m, 1H), 4.78 (m, 1H), 4.63 (m, 1H), 4.55 (m, 1H), 3.12 (t, 2H), 1.76 (m, 2H), 0.99 (t, 3H); 19F NMR (376 MHz, DMSO) δ−117.3, −122.6, −223.1.
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([CH2:17][CH:18]([CH3:20])[CH3:19])[N:5]([P:13]([CH3:16])([CH3:15])=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:22][O:23][K].Cl>>[OH:23][NH:22][C:3](=[O:2])[C@H:4]([N:5]([P:13]([CH3:16])([CH3:15])=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:17][CH:18]([CH3:20])[CH3:19]
Reactant: NO[K]
Reactant: COC(=O)[C@@H](CC(C)C)N(Cc1ccccc1)P(C)(C)=O
Agent: Cl
Product: CC(C)C[C@H](C(=O)NO)N(Cc1ccccc1)P(C)(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-(Dimethylphosphinyl)-N-benzyl-D-leucine methyl ester (158 mg, 0.51 mmol) is treated with a solution of NH2OK (2.8 mL, 1.76M in methanol) prepared as described in Fieser and Fieser, Vol. 1, p. 478). The reaction is allowed to stir 3 hours at room temperature at which time is determined complete by TLC. The reaction mixture is neutralized with 1M aqueous HCl; the volatiles are removed until the product oils out. Methanol is then added followed by water dropwise until the solution appears cloudy. The crystals are collected by filtration to give N-hydroxy-2(R)-[[dimethylphosphinyl]benzylamino]-4-methyl-pentanamide as a colorless solid: MS-IS m/z 313 [M+H]+, 335 [M+Na]+, 357 [M+K]+. (R2 =isobutyl, R1 =benzyl, R3 =methyl, R4 =phenyl).
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C@H:16]([C:24]([O:26][CH2:27]C)=[O:25])[N:15](S(C4C=CC(C)=CC=4)(=O)=O)[C:14]3=[O:39])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Mg]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C@H:16]([C:24]([O:26][CH3:27])=[O:25])[NH:15][C:14]3=[O:39])=[CH:11][CH:12]=2)=[CH:40][CH:41]=1
Reactant: CCOC(=O)[C@H]1[C@H](c2ccccc2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C(=O)N1S(=O)(=O)c1ccc(C)cc1
Agent: [Mg]
Solvent: CO
Product: COC(=O)[C@@H]1NC(=O)N(c2ccc(Oc3ccc(Cl)cc3)cc2)[C@H]1c1ccccc1
Temperature: 80 °C

Procedure:
To a solution of (4R,5S)-ethyl 1-(4-(4-chlorophenoxy)phenyl)-2-oxo-5-phenyl-3-tosylimidazolidine-4-carboxylate (15.0 mg, 0.025 mmol) in MeOH (0.5 mL) is added magnesium powder (6.2 mg, 0.25 mmol). The reaction mixture is heated in a sealed tube at 80° C. for 1 h. After cooling down to room temperature, the mixture is quenched with saturated NH4Cl aqueous solution (5 mL) and extracted with EtOAc (3×3 mL). The combined organic layer is concentrated and purified by preparatory TLC to provide the title compound; 1H NMR (CDCl3, 400 MHz) δ 7.39-7.32 (m, 7H), 7.23 (d, 2H), 6.86 (m, 4H), 5.43 (d, 1H), 5.26 (br, 1H), 4.08 (d, 1H), 3.87 (s, 3H); HPLC-MS calculated for C23H19ClN2O4 (M+H+) 423.1, found 423.1.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[CH2:30]([OH:32])[CH3:31].C([O:37]C)(C)(C)C>C(O)(=O)C>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[C:30]([O-:37])(=[O:32])[CH3:31]
Reactant: COC(C)(C)C
Reactant: CCO
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: CC(=O)O
Product: CC(=O)[O-]
Temperature: 50 °C

Procedure:
Sunitinib base (3 g) was dissolved in acetic acid (6 ml) and absolute ethanol (6 ml) by stirring for 10 min at 20° C. and the solution was heated to 50° C. Then methyl tert-butyl ether (60 ml) was added within 30 min with stirring, the mixture was cooled to −10° C. After 16 h at −10° C. the solid was filtered, washed with 2×20 ml of MTBE, dried on filter for one hour obtaining a red solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@H:4]([C@@H:19]([CH3:21])[OH:20])[NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([O:16][CH3:17])[CH:8]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[CH3:17][O:16][C:9]1[CH:8]=[C:7]([C:6]2[O:20][CH:19]([CH3:21])[CH:4]([C:3]([O:2][CH3:1])=[O:22])[N:5]=2)[CH:12]=[CH:11][C:10]=1[N+:13]([O-:15])=[O:14]
Reactant: COC(=O)[C@@H](NC(=O)c1ccc([N+](=O)[O-])c(OC)c1)[C@@H](C)O
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: COC(=O)C1N=C(c2ccc([N+](=O)[O-])c(OC)c2)OC1C
Yield: 85 %

Procedure:
The same operation as in Example (97b) was performed using N-(3-methoxy-4-nitrobenzoyl)threonine methyl ester obtained in Example (105a) (4.49 g, 14.4 mmol), the Burgess reagent (3.94 g, 16.5 mmol) and THF (50 mL). Purification by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 1/2, 1/1, 1/2) gave 3.6 g of the title compound as a light yellow solid (85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH:19](=O)[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[OH:22]>>[OH:22][C:21]1[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=1[CH:19]=[C:13]1[C:12]2[C:16](=[CH:17][C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:10][CH:11]=2)[NH:15][C:14]1=[O:18]
Reactant: O=Cc1ccccc1O
Reactant: COc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Product: COc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2ccccc2O)c1

Procedure:
6-(3-Methoxyphenyl)-1,3-dihydroindol-2-one was condensed with salicylaldehyde using method B to give 3-(2-hydroxybenzylidene)-6-(3-methoxyphenyl)-1,3-dihydro-indol-2-one as a yellow solid which was reducted using method E to give 0.03 g (66%) of 3-(2-hydroxy-benzyl)-6-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as a white solid.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([C:24]([F:27])([F:26])[F:25])([C:5]1[NH:6][C:7]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:9]=1)[NH2:4].ClC1C=CC=C(C(OO)=[O:38])C=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[F:29][C:2]([F:28])([F:1])[C:3]1([C:24]([F:25])([F:26])[F:27])[C:5](=[CH:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:38])[NH:6][C:7]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[N:4]1
Reactant: NC(c1cc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)[nH]1)(C(F)(F)F)C(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C(C=C1NC(c2ccc(F)cc2)=NC1(C(F)(F)F)C(F)(F)F)c1ccc(F)cc1
Temperature: 25 °C
Yield: 19.6 %

Procedure:
To a solution of α,α-bis(trifluoromethyl)-4,5-bis(4-fluorophenyl)-1H-pyrrole-2-methanamine (5.0 g, 0.012 mole) in chloroform (100 mL) was added portionwise, m-chloroperbenzoic acid (MCPBA, 4.09 g, 0.024 mole). The reaction mixture was refluxed under nitrogen for one hour. Then additional MCPBA (2.05 g, 0.012 mole) was added and the mixture was refluxed for 1 hour. The solution was cooled to room temperature and poured into saturated sodium bicarbonate (200 ml). The organic layer was washed successively with saturated sodium bicarbonate solution, 10% sodium sulfite solution, water, and saturated sodium chloride solution, dried over magnesium sulfate and evaporated under vacuum. The residue was columned in silica gel eluted with hexane-ethyl acetate 20:1 then 10:1 to give the 2-[4,4-bis(trifluoromethyl)-2-(4-fluorophenyl)-4,5-dihydro-1H-imidazol-5-ylidene]-1-(4-fluorophenyl)-1-ethanone (1.02 g, 20%) as a yellow solid: mp 121°-123°; MS m/e 435 (M+ +H); 1H NMR (CDCl3 /TMS) δ 6.73(s,1H,C=CH), 7.17-7.30(m,4H,Harom), 8.00-8.10(m,4H,Harom), 11.80(s,1H,NH). Another product, N[2-(4-fluorophenyl)-4,5-dihydro-1-methyl-5,5-bis(trifluoromethyl)-1H-imidazol-5-yl]-N-methylacetamide (2.09 g, 56%) was also isolated as a solid: mp 114°-115°; MS m/e 437 (M+ +H); 1H NMR (CDCl3 /TMS) δ 2.57(s,2H,NH2), 3.87(s,1H,NH), 6.77(s,1H,C=CH), 6.90-7.03(m,4H,Harom), 7.23-7.40(m, 2H,Harom), 7.15-7.17(m,2H,Harom).
Reaction SMILES: O/[CH:2]=[C:3]1\[C:4](=[O:13])[NH:5][C:6]2[C:11]\1=[C:10]([CH3:12])[CH:9]=[CH:8][CH:7]=2.O/C=C1\C(=O)NC2C\1=CC=CC=2.[NH2:26][C:27]1[CH:31]=[CH:30][NH:29][N:28]=1>O1CCCC1>[CH3:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:3](=[CH:2][NH:26][C:27]1[CH:31]=[CH:30][NH:29][N:28]=1)[C:4](=[O:13])[NH:5]2
Reactant: Nc1cc[nH]n1
Reactant: Cc1cccc2c1/C(=C/O)C(=O)N2
Agent: O=C1Nc2ccccc2/C1=C/O
Solvent: C1CCOC1
Product: Cc1cccc2c1C(=CNc1cc[nH]n1)C(=O)N2

Procedure:
The named compound is prepared by substituting E & Z-3-[(hydroxy)-methylene]-4-methyl-1,3-dihydro-indol-2-one for E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-4-methyl-1,3-dihydro-indol-2-one (0.110 gms.) is reacted with 0.18 mL of 3-aminopyrazole by refluxing in tetrahydrofuran (2.5 mL).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([NH:25][CH2:26][C:27]#[CH:28])=[O:24])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2]>C(#N)C.[Au](Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:24][C:27]([CH3:28])=[CH:26][N:25]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[O:16])[CH2:14]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: C#CCNC(=O)C1CC(c2ccc(CC)cc2)CN(C(=O)N2CCOCC2)C1
Agent: Cl[Au](Cl)Cl
Solvent: CC#N
Product: CCc1ccc(C2CC(c3ncc(C)o3)CN(C(=O)N3CCOCC3)C2)cc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
50 mg (0.13 mmol) of the compound from Example 199A were initially charged in 0.5 ml of acetonitrile, and 2 mg (0.01 mmol) of gold trichloride were added. The reaction mixture was stirred at 50° C. for 16 h, concentrated and purified by preparative HPLC. Yield: 10 mg (15% of theory).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16](/[CH:19]=[CH:20]/OC)[CH:15]=[CH:14]2)(C(C)(C)C)(C)C.BrN1C(=O)CCC1=O.[CH3:31][O:32][CH2:33][CH2:34][O:35][C:36]1[CH:41]=[CH:40][N:39]=[C:38]([NH2:42])[CH:37]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[CH3:31][O:32][CH2:33][CH2:34][O:35][C:36]1[CH:41]=[CH:40][N:39]2[C:19]([C:16]3[CH:15]=[CH:14][C:13]4[C:18](=[C:9]([OH:8])[CH:10]=[CH:11][CH:12]=4)[N:17]=3)=[CH:20][N:42]=[C:38]2[CH:37]=1
Reactant: COCCOc1ccnc(N)c1
Reactant: CO/C=C/c1ccc2cccc(O[Si](C)(C)C(C)(C)C)c2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C1CCC(=O)N1Br
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COCCOc1ccn2c(-c3ccc4cccc(O)c4n3)cnc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.7 %

Procedure:
(E)-8-(tert-butyldimethylsilyloxy)-2-(2-methoxyvinyl)quinoline (1.90 g, 6.02 mmol) was dissolved in a solution of THF (20 mL) and water (3 mL). N-bromosuccinimide (1.13, 6.32 mmol) was added to the reaction mixture. After the reaction was judged to be complete (monitored by MS), 4-(2-methoxyethoxy)pyridin-2-amine 1.01 g, 6.02 mmol) was added. The reaction was then heated to reflux for 5 hours and then cooled to ambient temperature. To the reaction mixture was added 10 ml of 1.0 M tetrabutylammonium fluoride in THF. The reaction mixture was stirred at ambient temperature for 1 hour and then diluted with water. The mixture was extracted with 1:4 isopropyl acetate:dichloromethane. The combined organic phase was dried (sodium sulfate), filtered and condensed under reduced pressures. The residue was purified by flash chromatography, eluting with gradient from 100% EtOAc to 10% MeOH (w/6% NH4OH)/EtOAc to obtain 700 mg of the desired product as a red solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:11]([O-])=O)=[C:4]([OH:10])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.NN>CCO.C(OCC)(=O)C.[Ru]>[NH2:11][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([O:8][CH3:9])=[CH:5][C:4]=1[OH:10]
Reactant: COc1cc(O)c([N+](=O)[O-])c(Cl)c1
Agent: [Ru]
Agent: NN
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(O)c(N)c(Cl)c1
Temperature: 85 °C
Yield: 76 %

Procedure:
To 3-chloro-5-methoxy-2-nitrophenol, synthetic method A [1], (200 mg) in 95% EtOH (10 mL) was added 5% Ru/C (20 mg) and hydrazine (0.36 mL). The mixture was placed in an oil bath and heated to 85° C. for 2 h. After reaction cooled, the mixture was diluted with ethyl acetate and filtered through a pad of celite and concentrated. Flash chromatography on silica gel eluting with 30% ethyl acetate-hexane afforded 138 mg (76%) of the title compound as a solid. MS: 174 (MH+), HPLC tR: 0.84 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[C@H:13]1[C@H:8]([CH2:9][CH2:10][CH2:11][CH2:12]1)[N:7]=[C:6]2[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=1.Cl.O>CO.[Fe]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[C@H:13]1[C@H:8]([CH2:9][CH2:10][CH2:11][CH2:12]1)[N:7]=[C:6]2[C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=1
Reactant: COc1cc2c(cc1OC)[C@@H]1CCCC[C@@H]1N=C2c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1OC)[C@@H]1CCCC[C@@H]1N=C2c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8.5 g of (+/-)-cis-8,9-dimethoxy-6-(4-nitrophenyl)-1,2,3,4,4a,10b-hexahydrophenanthridine are dissolved in 200 ml of methanol, and the solution is treated with 5 ml of concentrated hydrochloric acid, 20 ml of water and 800 mg of iron powder and stirred overnight at RT. The reaction mixture is filtered, the filtrate is concentrated, the residue is extracted with sodium hydrogencarbonate solution/ethyl acetate, and the organic phase is dried using sodium sulfate and concentrated. The residue is chromatographed on silica gel using a mixture of toluene/dioxane/triethylamine in the ratio 40:20:2. After concentration of the corresponding eluate fractions, 5.5 g (70.5% of theory) of the title compound of m.p. 159.5-161° C. are obtained.