Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:8]2[CH:4]([CH2:5][CH:6]=[C:7]2[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.C(C1N(C(C(OCC2C=CC=CC=2)=O)=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C(=O)C1)C=C.[C:57]1([SH:63])[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[O:1]=[C:2]1[N:8]2[CH:4]([CH2:5][CH:6]([S:63][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[CH:7]2[C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:3]1
Reactant: Sc1ccccc1
Reactant: O=C(OCc1ccccc1)C1=CCC2CC(=O)N12
Agent: C=CCC1CC(=O)N1C(C(=O)OCc1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)C1C(Sc2ccccc2)CC2CC(=O)N21

Procedure:
Crude benzyl 7-oxo-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate prepared from an ethyl acetate solution of 4-allyl-1-(1-benzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)azetidin-2-one (1.00 g) by ozonolysis and cyclisation was dissolved in dry dimethylformamide (5 ml) treated successively with thiophenol (0.20 ml) and potassium carbonate (0.133 g) with stirring. After a period of 1 hour the solution was concentrated under reduced pressure and the residue treated with ethyl acetate. It was then washed with brine, dried over sodium sulphate and concentrated. Chromatography on silica gel 60 (<230 mesh) eluting with 60°-80° petroleum ether/ethyl acetate 7:3 grading to 6:4 gave two fractions containing diastereoisomers of the title compound. The least polar fraction (0.183 g) was an approximately 4:1 mixture of isomers A (5) and B (6); νmax (CHCl3) 3000, 1760 and 1740 (sh); τ(CDCl3) for major isomer A (5), 2.6-2.9 (10H, m, phenyls), 4.88 (2H, s, benzyl CH2), 5.26 (1H, d, J7 Hz, C2-H), ca 5.90 (1H, br m, C5-H), 6.10 (1H, td, J9 and 7 Hz, C3-H), 6.69 (1H, dd, J16 and 5 Hz, C6-H), 7.32 (1H, dd, J16 and 21/2 Hz, C6-H), 7.73 (1H, dd, J9 and 7 Hz, C4-H) and 7.77 (1H, dd, J9 and 4 Hz, C4-H); minor isomer B (6) had 5.62 (d, J 5 Hz, C2-H); (M+ for mixture at m/e 353.1102. C20H19NO3S requires 353.1085). The more polar fraction (0.102 g) was isomer C (8) which could be crystallized from diethyl ether; m.p. 84°-85°; νmax (CHCl3) 3000, 1765 and 1740 cm-1 ; τ(CDCl3) 2.6-2.9 (10H, m, phenyls), 4.81 (2H, s, benzyl CH2), 5.84 (1H, d, J7 Hz, C2-H), 6.04 (1H, ddd, J12, 7 and 5 Hz, C3-H), 6.2-6.5 (1H, m, C5-H), 6.90 (1H, dd, J16 and 4 Hz, C6-H), 7.19 (1H, dd, J16 and 21/2 Hz, C6-H), 7.64 (1H, dt, J12 and 5 Hz, C4-H) and 7.95 (1H, td, J12 and 10 Hz, C4-H); (Found; C, 68.1; H, 5.6; N, 3.9% C20H19NO3S requires C, 68.0; H, 5.4 and N, 4.0%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[C:15]#[C:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([N:34]=[C:35]=[O:36])=[O:33])=[CH:27][CH:26]=1.COC1C=CC(CNC2N=CN=C(OC3C=CC(NC(NC(=O)CC4C=CC(F)=CC=4)=O)=CC=3F)C=2)=CC=1.[ClH:75]>>[ClH:75].[ClH:75].[F:1][C:2]1[CH:3]=[C:4]([NH:23][C:35]([NH:34][C:32](=[O:33])[CH2:31][C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=2)=[O:36])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[C:15]#[C:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccncc2C#Cc2cccnc2)c(F)c1
Agent: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Agent: Cl
Product: O=C(Cc1ccc(F)cc1)NC(=O)Nc1ccc(Oc2ccncc2C#Cc2cccnc2)c(F)c1
Yield: 38 %

Procedure:
The title compound was prepared from 3-fluoro-4-(3-(2-(pyridin-3-yl)ethynyl)pyridin-4-yloxy)benzenamine (22 mg, 0.072 mmol) and 0.3 M solution of 2-(4-fluorophenyl)acetyl isocyanate in toluene (Compound D of Example 11, 0.50 mL, 0.15 mmol) in a manner similar to Step D of Example 33. Purification of the reaction mixture by flash column chromatography on SiO2 eluting with 0-100% EtOAc/CH2Cl2 gave a white solid which was converted to the hydrochloride in a manner similar to Step D of Example 33 to give the title compound (15 mg, 38%) as a white solid. 1H NMR (DMSO-d6) δ 11.04 (s, 1H), 10.59 (s, 1H), 8.76 (s, 1H), 8.74 (d, 1H, J=1.1 Hz), 8.60 (dd, 1H, J=5.6, 1.1 Hz), 8.45 (d, 1H, J=6.1 Hz), 7.98 (d, 1H, J=7.7 Hz), 7.80 (d, 1H, J=12.1 Hz), 7.47-7.45 (m, 1H), 7.41 (s, 2H), 7.36-7.34 (m, 2H), 7.16 (dd, 2H, J=8.8, 8.9 Hz), 6.78 (d, 1H, J=5.5 Hz), 3.74 (s, 2H); MS (ESI+): 485.13 m/z.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[C:14]([NH2:16])=[O:15].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.N1CCCCC1>C(O)C>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[N:1][C:2]2[NH:6][N:5]=[C:4]([NH:7][C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[C:3]=2[C:14]([NH2:16])=[O:15])=[CH:21][CH:20]=1
Reactant: NC(=O)c1c(Nc2cccnc2)n[nH]c1N
Reactant: COc1ccc(C=O)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(C=Nc2[nH]nc(Nc3cccnc3)c2C(N)=O)cc1
Yield: 50 %

Procedure:
5-amino-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide (1.0 g) was suspended in 10 mL of ethanol and 4-methoxybenzaldehyde (559 mg, 1.0 eq.) and piperidine (0.10 eq, 47 μL) was added. Stirred the reaction at reflux until starting material was absent and confirmed by HPLC. After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 5-((4-methoxybenzylidene)amino)-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide as a yellow to orange powder. The product was washed with ethanol to remove any excess 4-methoxybenzaldehyde. Product was allowed to dry under vacuum for 1 hr (800 mg, 50% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:21])[C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:9]([NH:19][CH3:20])=[CH:8][N:7]=1.CCN(C(C)C)C(C)C.[F:31][C:32]([F:47])([F:46])[C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[C:36](Cl)=[O:37]>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:21])[C:6]1[N:7]=[CH:8][C:9]([N:19]([CH3:20])[C:36](=[O:37])[C:35]2[CH:34]=[C:33]([C:32]([F:47])([F:46])[F:31])[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=2)=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH:11]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnc(N(C)CCOC)cc1-c1ccccc1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(C)c1cc(-c2ccccc2C)c(N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Reaction time: 1 h
Yield: 32.9 %

Procedure:
A solution of N2-(2-methoxyethyl)-N2,N5-dimethyl-4-o-tolylpyridine-2,5-diamine (32 mg, 0.11 mmol) and DIPEA (43 μL, 0.25 mmol) in CH2Cl2 (1 mL) was treated with 3,5-bis-trifluoromethylbenzoyl chloride (46 mg, 0.17 mmol, CAS RN 1271-19-8). After stirring for 1 h, the reaction mixture was loaded directly onto a silica gel column. Elution with 25% EtOAc in n-hexane afforded the title compound as a yellow solid (19 mg, 33%). MS (ESI): m/z=526.2 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH3:18])=[CH:13][CH:12]=1)=[O:10].NO.[OH-].[K+].CO>C1COCC1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:17]([CH3:18])[C:14]2[CH:13]=[CH:12][C:11]([S:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:27])=[O:2])=[O:10])=[CH:16][CH:15]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)CCCCCS(=O)c1ccc(N(C)Cc2ccc(Cl)cc2)cc1
Agent: NO
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(Cc1ccc(Cl)cc1)c1ccc(S(=O)CCCCCC(=O)O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of the 6-(4-((4-chlorobenzyl)-methylamino)-benzenesulfinyl)-hexanoic acid methyl ester (1.6 g, 4.0 mmol) in distilled THF (25 mL) containing 50% aqueous hydroxylamine (2.6 mL, 40 mmol) was added at 0° C. a solution of potassium hydroxide in methanol (1M, 8 mL, 8 mmol) in a dropwise manner. After stirring at 0° C. for 1 h, distilled water (25 mL) was added and the mixture was made neutral by dropwise addition of concentrated hydrochloric acid (10 M) at 0° C. The aqueous solution was extracted with ethyl acetate (2×50 mL) and the combined extracts were washed with brine (100 mL), dried over anhydrous MgSO4, filtered and evaporated to dryness. The solid residue was recrystallised from acetone/40-60° C. petroleum ether to give the title compound (867 mg, 53%) as a white powder, mp 109-111° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:11])[CH:3]=1.Cl.[CH3:13][O:14][NH:15][CH3:16].CC(C)N=C=NC(C)C>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:15]([O:14][CH3:13])[CH3:16])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: CNOC
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Into a 1000-mL round-bottom flask, was placed a solution of 4-bromo-2-fluorobenzoic acid (50 g, 229.36 mmol, 1.00 equiv) in dichloromethane (600 mL), N-methoxymethanamine hydrochloride (25 g, 257.73 mmol, 1.10 equiv). To the resulting mixture was added DIC (32 g, 253.97 mmol, 1.10 equiv) at 0° C. The resulting solution was stirred for 4 h at room temperature. The reaction was then quenched by the addition of water (500 mL). The solids were filtered out. The resulting solution was extracted with DCM (2×300 mL) and the organic layers combined. The resulting mixture was washed with water (2×300 mL), and sodium carbonate (1×300 mL). The resulting mixture was washed with brine (1×300 mL), then dried over anhydrous sodium sulfate and concentrated under vacuum to yield 4-bromo-2-fluoro-N-methoxy-N-methylbenzamide as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[CH2:11]([NH2:16])[C:12]([CH3:15])([CH3:14])[CH3:13]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:16][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[S:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)CN
Reactant: Fc1ccc(N=C=S)cc1
Solvent: ClCCl
Product: CC(C)(C)CNC(=S)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a solution of 4-fluoro-phenylisothiocyanate (1.00 g, 6.53 mmol) in dichloromethane (20 mL) at room temperature was added neopentylamine (1.00 mL, 8.5 mmol) and the reaction was stirred overnight at room temperature. The mixture was concentrated in vacuo and the resulting residue was triturated with diethyl ether and filtered to afford 1.42 g (90%) of 1-(4-fluoro-phenyl)-3-(2,2-dimethylpropyl)-thiourea as a white solid which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[O:26]1[CH2:31][CH2:30][CH:29](O)[CH2:28][CH2:27]1>>[C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[C:9](=[O:10])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:29]2[CH2:30][CH2:31][O:26][CH2:27][CH2:28]2)=[CH:13][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OC1CCOCC1
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(O)cc1)c1ccc(Cl)cc1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OC2CCOCC2)cc1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared from rac-[1-(4-chloro-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and tetrahydro-4H-pyran-4-ol in analogy to Example 9c): MS (ISN): 444.3 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:12][N:11]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C1C(=O)N([Cl:24])C(=O)C1>CC#N>[Cl:24][C:9]1[C:10]([C:13]([F:14])([F:15])[F:16])=[N:11][NH:12][C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Fc1cccc(-c2cc(C(F)(F)F)n[nH]2)c1
Solvent: CC#N
Product: Fc1cccc(-c2[nH]nc(C(F)(F)F)c2Cl)c1

Procedure:
Following protocol L, 5-(3-fluorophenyl )-3-trifluoromethyl-1H-pyrazole was treated with NCS in CH3CN to yield the title compound.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10].N(OC(C)(C)C)=O.N[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>N1C=CC=CC=1>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([O:1][N:2]2[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]2([CH3:11])[CH3:10])[CH:21]=1
Reactant: Nc1cccnc1
Reactant: CC1(C)CCCC(C)(C)N1O
Agent: CC(C)(C)ON=O
Solvent: c1ccncc1
Product: CC1(C)CCCC(C)(C)N1Oc1cccnc1
Yield: 51.2 %

Procedure:
The procedure of Example 1 is repeated using 1.95 g (12.5 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperidine, 3.90 g (38 mmol) of tert-butyl nitrite, 7.6 mg (0.0125 mmol) of (S,S)-(+)-N,N-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(II), 120 mL of pyridine and 2.35 g (25 mmol) of 3-aminopyridine at 70° C. The crude product obtained is purified by vacuum flash chromatography (heptane) to give 1.5 g of the title compound as a colorless oil in 50.8% yield. The structure is confirmed by 1Hnmr and mass spectrographic analyses.
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[N:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Temperature: 45 °C
Reaction time: 2 h
Yield: 648.9 %

Procedure:
To a solution of 8-bromo-3-methyl-1H-purine-2,6(3H,7H)-dione (10.8 g, 4.42 mmol) in DMF (200 mL) was added 1-(bromomethyl)-4-chlorobenzene (10 g, 4.86 mmol) followed by potassium carbonate (9.16 g, 6.63 mmol). The resulting mixture was stirred at 45° C. for 2 h. The mixture was diluted with ethyl acetate (300 mL) and washed with brine (200 mL). The layers were separated and the organic slurry was filtered and the filter cake was washed with ice cold ethanol, dried under vacuum to give 8-bromo-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (10.6 g, 64.9% yield) as white solid. LCMS retention time 1.637 min; LCMS MH+ 369.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[C:8]([OH:13])=[C:7]([C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[O:18])[C:6](=[O:20])[C:5]2([CH3:22])[CH3:21].[OH:23]OS([O-])=O.[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[C:8](=[O:13])[C:7]([C:14](=[O:19])[CH2:15][CH2:16][C:17]([OH:23])=[O:18])=[C:6]([OH:20])[C:5]2([CH3:22])[CH3:21]
Reactant: O=S([O-])OO
Reactant: CC1(C)C(=O)C(C(=O)CCC=O)=C(O)c2cc(Cl)c(Cl)cc21
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)C(O)=C(C(=O)CCC(=O)O)C(=O)c2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Yield: 100.6 %

Procedure:
A mixture of 4-(6,7-dichloro-1-hydroxy-4,4-dimethyl-3-oxo-3,4-dihydronaphthalen-2-yl)-4-oxobutanal (0.22 g, 0.64 mmol) in 6 mL DMF was stirred at room temperature and treated with oxone (0.36 mL, 0.64 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was quenched with 50 mL H2O and adjusted to pH=5 with concentrated HCl. The solid was collected by filtration and washed with 20 mL H2O. The crude was dried under high vacuum to give 0.23 g white solid. MS m/e: 357 (M+H)+. Calculated for C16H14Cl2O5: 356.
Reaction SMILES: [Cu]C#N.[Cl-].[Li+].[CH2:6]([Zn]CC)[CH3:7].[F:11][C:12]1[C:13](/[C:22](/I)=[CH:23]/[C:24](=O)[C:25]2[NH:26][CH:27]=[CH:28][CH:29]=2)=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[CH2:15]2>C1COCC1>[CH2:6]([C:22]1[CH:23]=[C:24]([C:25]2[NH:26][CH:27]=[CH:28][CH:29]=2)[C:15]2[C:16](=[O:21])[NH:17][C:18]3[C:14]=2[C:13]=1[C:12]([F:11])=[CH:20][CH:19]=3)[CH3:7]
Reactant: O=C1Cc2c(ccc(F)c2/C(I)=C/C(=O)c2ccc[nH]2)N1
Reactant: CC[Zn]CC
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To a suspension of copper(I) cyanide (Aldrich, 27 mg, 0.3 mmol) and lithium chloride (Fluka, 25.5 mg, 0.6 mmol) in dry THF (2 mL) was added diethylzinc (Aldrich, 1.0 M solution in n-hexane, 3.0 mL, 3.0 mmol), under argon, at −20° C. and the reaction mixture was stirred for 30 minutes at the same temperature. The light green reaction mixture was then cooled to −78° C. and treated dropwise with a solution of (Z)-5-fluoro-4-[1-iodo-3-oxo-3-(1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-one (from Example 8 above) (79.2 mg, 0.2 mmol) in dry THF (4 mL). After stirring at the same temperature for 1 hour, the reaction mixture was allowed to warm up slowly to room temperature overnight, then heated under reflux for 3 hours. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were successively washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude product which was further purified by preparative TLC (silica gel, 20% ethyl acetate in hexanes) to afford 5-ethyl-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 10.6 mg, 18.9%).
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([OH:14])[CH:6]=1.N1C=CN=C1.[CH:20]([Si:23](Cl)([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])([CH3:22])[CH3:21]>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)C>[CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([O:14][Si:23]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:20]([CH3:22])[CH3:21])[CH:6]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CON=Cc1ccc([N+](=O)[O-])c(O)c1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CON=Cc1ccc([N+](=O)[O-])c(O[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To a solution of 3-hydroxy-4-nitrobenzaldehyde O-methyloxime (5.0 g, 25 mmol) in N,N-dimethylformamide (40 mL) is added imidazole (1.8 g, 27 mmol), followed by triisopropylsilyl chloride (6.0 mL, 28 mmol), and 4-(dimethylamino)pyridine (catalytic amount). After stirring overnight at room temperature, the reaction mixture is diluted with diethyl ether (200 mL) and then washed twice with water and once with saturated aqueous sodium chloride solution. The organic phase is then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude solid is purified by flash chromatography (hexanes/ethyl acetate) to give 4-nitro-3-[(triisopropylsilyl)oxy]benzaldehyde O-methyloxime as a white solid (6.2 g, 70%).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:11][C@H:12]1[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:15]([N:21]2[CH:29]=[N:28][C:27]3[C:22]2=[N:23][C:24]([C:31]#[N:32])=[N:25][C:26]=3Cl)[O:14][C@@H:13]1[CH2:33][O:34][C:35](=[O:37])[CH3:36])(=[O:10])[CH3:9].[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([CH:45]([C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=2)[CH2:46][NH2:47])=[CH:41][CH:40]=1>C(#N)C>[C:8]([O:11][C@H:12]1[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:15]([N:21]2[CH:29]=[N:28][C:27]3[C:22]2=[N:23][C:24]([C:31]#[N:32])=[N:25][C:26]=3[NH:47][CH2:46][CH:45]([C:42]2[CH:43]=[CH:44][C:39]([Cl:38])=[CH:40][CH:41]=2)[C:48]2[CH:49]=[CH:50][C:51]([Cl:54])=[CH:52][CH:53]=2)[O:14][C@@H:13]1[CH2:33][O:34][C:35](=[O:37])[CH3:36])(=[O:10])[CH3:9]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NCC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccc(Cl)cc4)c4ccc(Cl)cc4)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 16 h
Yield: 91.7 %

Procedure:
Triethylamine (0.2 ml, 1.14 mmol) was added to a stirred solution of (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-chloro-2-cyano-9H-purin-9-yl)tetrahydro-3-furanyl acetate (500 mg, 1.14 mmol) (Preparation 45) and 2,2-bis(4-chlorophenyl)ethanamine (919 mg, 1.2 mmol) (J. Am. Chem. Soc., 1983, 105 (10), 3138) in acetonitrile (5 ml) at room temperature. The reaction mixture was stirred for 16 hours. The solvent was then removed under reduced pressure and the residue was dissolved in dichloromethane (20 ml). The solution was washed with water (10 ml) and saturated sodium chloride solution (10 ml), dried over anhydrous magnesium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:(99:1 by volume) increasing in polarity to dichloromethane:methanol (98.5:1.5 by volume). The solvent was removed under reduced pressure to give the title compound (698 mg) as a foam.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[N:16]1[CH:20]=[N:19][C:18]([CH3:21])=[N:17]1.C(N(C(C)C)CC)(C)C.[Cl:31][C:32]1[N:33]=[C:34](Cl)[C:35]2[CH2:40][CH2:39][CH:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:36]=2[N:37]=1>C(#N)C>[Cl:31][C:32]1[N:33]=[C:34]([N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=2[N:16]2[CH:20]=[N:19][C:18]([CH3:21])=[N:17]2)[C:35]2[CH2:40][CH2:39][CH:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:36]=2[N:37]=1
Reactant: CNCCCOc1cc([N+](=O)[O-])ccc1-n1cnc(C)n1
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)CC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCCN(C)c2nc(Cl)nc3c2CCC3c2ccccc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.2 %

Procedure:
To a solution of N-methyl-3-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)propan-1-amine (Preparation L, 1.20 g, 4.15 mmol) in acetonitrile (50 mL) was added diisopropylethylamine (0.731 g, 5.66 mmol) followed by 2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation R, 1 g, 3.77 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was taken up in dichloromethane (10 mL) and silica (2 g). The resultant slurry of the compound on silica was subjected to flash chromatography using a Teledyne Isco instrument (12 g RediSep silica column, 50% ethyl acetate in pet-ether) to get 2-chloro-N-methyl-N-(3-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)propyl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (1.2 g, 61.2%) as a light yellow solid. LC-MS (M+H)+=518.2. 1H NMR (400 MHz, CDCl3) δ ppm 8.95 (1H, s), 8.05-7.93 (3H, m), 7.30-7.11 (5H, m), 4.35-4.31 (2H, m), 4.18-4.14 (1H, m), 3.87-3.70 (2H, s), 3.28 (3H, s), 3.21-3.07 (2H, m), 2.54-2.50 (1H, m), 2.27-2.24 (2H, m), 2.01-1.98 (1H, m).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:11])=[C:7]([CH:10]=1)[CH:8]=[O:9])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>>[C:25]([Si:22]([CH3:24])([CH3:23])[O:21][CH2:20][CH2:19][O:11][C:6]1[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:10][C:7]=1[CH:8]=[O:9])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CCc1ccc(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1ccc(OCCO[Si](C)(C)C(C)(C)C)c(C=O)c1
Yield: 92 %

Procedure:
In a manner similar to the method described in example 130a, 5-ethyl-2-hydroxy-benzaldehyde (4.75 g, 31.7 mmol) was reacted with K2CO3 (13.1 g, 95.1 mmol) and (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (9.09 g, 38.0 mmol) to give 2-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-5-ethyl-benzaldehyde as dark brown oil (9.0 g, 92.7%).