Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[O:8][C:9](I)=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:3]=12.[F:18][C:19]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[CH:30][C:20]=1[O:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>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.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[O:8][C:9]([C:32]3[CH:31]=[CH:30][C:20]([O:21][CH2:22][CH2:23][N:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]4)=[C:19]([F:18])[CH:33]=3)=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:3]=12
Reactant: Clc1ccnc2oc(I)c(-c3ccccc3)c12
Reactant: CC1(C)OB(c2ccc(OCCN3CCCCC3)c(F)c2)OC1(C)C
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: O
Solvent: CC#N
Product: Fc1cc(-c2oc3nccc(Cl)c3c2-c2ccccc2)ccc1OCCN1CCCCC1
Temperature: 80 °C
Reaction time: 23 h

Procedure:
A resealable tube was charged with 4-chloro-2-iodo-3-phenylfuro[2,3-b]pyridine 6d (0.100 g, 0.281 mmol), 1-(2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)piperidine 201 (0.200 g, 0.576 mmol), sodium carbonate (0.074 g, 0.703 mmol), acetonitrile (4 mL), and water (1 mL). Tetrakis(triphenylphosphine)palladium (0) (0.032 g, 0.028 mmol) was added and the system was purged with argon. The tube was sealed and the mixture stirred at 80° C. for 23 h. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a brown oil. Purification via preparative thin layer chromatography (eluting with 95:5:0.5 dichloromethane/methanol/ammonium hydroxide) afforded 4-chloro-2-(3-fluoro-4-(2-(piperidin-1-yl)ethoxy)phenyl)-3-phenylfuro[2,3-b]pyridine 6f as a yellow orange oil. MS (MH+) 451.1; Calculated 450 for C26H24ClFN2O2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][C:13](OC(C)=O)=[O:14]>>[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)[C:13]([CH3:12])=[O:14]
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(CC(=O)O)cc1

Procedure:
The mixture of 100 g (4-amino-phenyl)-acetic acid and 200 ml acetanhydride is heated at the steam cone for 15 minutes and evaporated. The residue is stirred with 500 ml hot water until complete dissolution occurs. The solution is cooled and the precipitate formed filtered off, to yield the (4-acetamino-phenyl)-acetic acid melting at 168°-170°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1Cl)([O-:3])=[O:2].[CH2:15]([CH2:17][NH2:18])[OH:16]>O>[N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[NH:18][CH2:17][CH2:15][OH:16])([O-:3])=[O:2]
Reactant: NCCO
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(NCCO)c([N+](=O)[O-])c1

Procedure:
0.35 mol (76 g) of 2,6-dinitro-4-methylchlorobenzene is added gradually, in the course of 10 minutes, whilst stirring, to 150 ml of ethanolamine, the reaction medium being cooled as necessary so as not to exceed 75° C. When the addition has ended, the stirring is maintained for 5 minutes and the reaction medium is then poured into 600 g of iced water. The expected product precipitates. It is filtered off, washed with water and then recrystallised from ethanol. After drying in vacuo, it melts at 131° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:66]=[CH:65][C:53]2[NH:54][C:55]([C@@H:57]([NH2:64])[CH2:58][C:59]3[CH:63]=[CH:62][S:61][CH:60]=3)=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:49][C:50]1[CH:66]=[CH:65][C:53]2[NH:54][C:55]([C@@H:57]([NH:64][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH2:58][C:59]3[CH:63]=[CH:62][S:61][CH:60]=3)=[N:56][C:52]=2[CH:51]=1
Reactant: N[C@@H](Cc1ccsc1)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)N[C@@H](Cc2ccsc2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-2-(thiophen-3-yl)ethylamine in tetrahydrofuran. Yield: %; Rf value: 0.38 (silica gel: dichloromethane/ethanol=9:1); C26H25ClN4O2S (493.03); mass spectrum: (M+H)+=493/495 (chlorine isotope).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([C:12](=O)[CH:13]([CH3:19])[CH2:14][C:15](OC)=[O:16])=[CH:11][C:6]=2[S:5][CH2:4][C:3]1=[O:21].[NH2:22][NH2:23]>C(O)C>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[CH:13]([CH3:19])[CH2:14][C:15](=[O:16])[NH:22][N:23]=3)=[CH:11][C:6]=2[S:5][CH2:4][C:3]1=[O:21]
Reactant: NN
Reactant: COC(=O)CC(C)C(=O)c1ccc2c(c1)SCC(=O)N2C
Solvent: CCO
Product: CC1CC(=O)NN=C1c1ccc2c(c1)SCC(=O)N2C

Procedure:
Methyl 4-(3,4-dihydro-4-methyl-3-oxo-1,4[2H]-benzothiazin-7-yl)-4-oxo-3-methylbutyrate (1.7 g) was heated at reflux overnight with 0.3 ml of hydrazine in 50 ml of ethanol. Filtration gave a white powder which was chromatographed on silica gel eluted with 5% methanol in methylene chloride, yielding 110 mg of the named compound, mp 193°-194.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)=[N:7]1.[C:31]([CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)#[N:32]>>[CH3:11][C:10]1[N:6]([CH2:5][C:4]2[CH:3]=[C:2]([N:36]3[CH2:37][CH2:38][CH:33]([C:31]#[N:32])[CH2:34][CH2:35]3)[CH:30]=[CH:29][CH:28]=2)[N:7]=[C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=1
Reactant: N#CC1CCNCC1
Reactant: Cc1cc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(Br)c1
Product: Cc1cc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(N2CCC(C#N)CC2)c1

Procedure:
Analogously to the process described in Example 8, 150 mg (0.313 mmol) of the compound from Example 1A and 69 mg (0.626 mmol) of 4-cyanopiperidine were used to obtain 68 mg (43% of theory) of the title compound.
Reaction SMILES: CC1(C)[O:7][C:6](=[O:8])[CH:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:4](=[O:20])[O:3]1>[OH-].[Na+]>[F:17][C:16]([F:18])([F:19])[C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][CH:5]([C:6]([OH:8])=[O:7])[C:4]([OH:20])=[O:3]
Reactant: CC1(C)OC(=O)C(Cc2cccc(C(F)(F)F)c2)C(=O)O1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(Cc1cccc(C(F)(F)F)c1)C(=O)O
Temperature: 25 °C

Procedure:
A solution of 2,2-dimethyl-5-(3-(trifluoromethyl)benzyl)-1,3-dioxane-4,6-dione (4.0 g, 13.23 mmol, Intermediate 15: step a) in 40% aqueous NaOH (20 mL) was heated in a 93° C. oil bath for 48 hours. The mixture was then cooled to room temperature and extracted with EtOAc. The aqueous layer was acidified to pH 2 with 6 N aqueous HCl then extracted with EtOAc (2×). The combined EtOAc extracts were washed with H2O followed by brine and dried over Na2SO4. The mixture was filtered, solvent was removed under reduced pressure and crude product purified by chromatography (10% MeOH/0.2% HOAc mixture in DCM) to afford the title compound as an off-white solid.
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.NC1C=CNN=1.[NH2:32][C:33]1[CH:37]=[C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[NH:35][N:34]=1>O1CCCC1>[CH3:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:3](=[CH:2][NH:32][C:33]1[CH:37]=[C:36]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[NH:35][N:34]=1)[C:4](=[O:13])[NH:5]2
Reactant: Cc1cccc2c1/C(=C/O)C(=O)N2
Reactant: Nc1cc(-c2ccccc2)[nH]n1
Agent: Nc1cc[nH]n1
Agent: O=C1Nc2ccccc2/C1=C/O
Solvent: C1CCOC1
Product: Cc1cccc2c1C(=CNc1cc(-c3ccccc3)[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 and substituting 3-amino-5-phenylpyrazole for 3-aminopyrazole 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 0.2398 gms. 3-amino-5-phenylpyrazole by refluxing in tetrahydrofuran (2.5 mL).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.[O:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][OH:23])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CC(N(C)C)=O>[I:8][C:5]1[CH:6]=[CH:7][C:2]([O:23][CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:3][CH:4]=1
Reactant: OCc1ccccc1Oc1ccccc1
Reactant: Clc1ccc(I)cn1
Solvent: CC(=O)N(C)C
Product: Ic1ccc(OCc2ccccc2Oc2ccccc2)nc1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
To a solution of 2-chloro-5-iodopyridine in dimethylacetamide (2 ml), 300 mg of potassium tert-butoxy and 535 mg of (2-phenoxyphenyl)methanol were added, and the reaction solution was stirred at 110° C. for 4 hours. The reaction solution was cooled, then diluted with a saturated saline solution, extracted with diethyl ether, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate/hexane (0:100-10:90)) to afford the title compound as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([CH3:18])[C:10]=1[F:19])C1C=CC=CC=1.[CH3:20]OC(OC)N(C)C>[Pd]>[F:19][C:10]1[C:9]([OH:8])=[CH:14][CH:13]=[C:12]2[C:11]=1[CH:18]=[CH:20][NH:15]2
Reactant: COC(OC)N(C)C
Reactant: Cc1c([N+](=O)[O-])ccc(OCc2ccccc2)c1F
Agent: [Pd]
Product: Oc1ccc2[nH]ccc2c1F
Temperature: 180 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
1-Benzyloxy-2-fluoro-3-methyl-4-nitrobenzene (5 g, 19 mmol) is dissolved N,N-dimethylformamide dimethyl acetal (15 mL) and heated in a microwave reactor at 180° C. in a sealed vial for 1 hour. The solution is then concentrated under reduced pressure. The resulting residue is dissolved in THF and Pd/C (1.0 g, 10%, 0.95 mmol) is added. The mixture is stirred under a hydrogen atmosphere at room temperature for 16 h before being filtered through a pad of Celite® and concentrated. The residue is separated by FCC (EtOAc/heptane from 0 to 40%) to give 4-fluoro-1H-indol-5-ol (1.5 g, 52% yield). MS (ESI) m/z 152.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 11.02 (br. s., 1H), 8.79 (s, 1H), 7.26 (t, J=2.78 Hz, 1H), 7.00 (d, J=8.59 Hz, 1H), 6.75 (t, J=8.46 Hz, 1H), 6.34 (m, 1H).
Reaction SMILES: Cl[C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4].[C:8]([OH:12])([CH3:11])([CH3:10])[CH3:9].N1C=CC=CC=1.O>CC(OC)(C)C>[CH3:6][O:5][C:3](=[O:4])[C:2]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:7]
Reactant: COC(=O)C(=O)Cl
Reactant: CC(C)(C)O
Solvent: c1ccncc1
Solvent: O
Solvent: COC(C)(C)C
Product: COC(=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of methyl chlorooxoacetate in TBME (1 mmol/ml) was added at 0-5° C. tert-butanol (1.5 equiv.), followed by dropwise addition of pyridine (1.5 equiv.). The resulting mixture was stirred at room temperature for 20 h. Water (15 vol.) was added, the mixture was extracted with TBME twice. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum to give a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[N:5]2.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:19]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[N:5]2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]c2ccc(O)cc2nc1-c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccc(OCc3ccccc3)cc2nc1-c1cccs1

Procedure:
The quinoxalin-2-one of the present example is prepared treating 6-hydroxy-3-thiophen-2-yl-1H-quinoxalin-2-one from Example 43 in DMF with bromomethyl benzene in the presence of K2CO3 at a temperature between 25° C. to 80° C. The resulting reaction mixture, after workup and purification, affords 6-benzyloxy-3-thiophen-2-yl-1H-quinoxalin-2-one.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([B:10]([OH:12])[OH:11])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[C:13]([O:19][CH2:20]Cl)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:13]([O:19][CH2:20][N:1]1[C:9]2[C:4](=[C:5]([B:10]([OH:12])[OH:11])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: OB(O)c1cccc2[nH]ncc12
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCn1ncc2c(B(O)O)cccc21
Temperature: 30 °C

Procedure:
A mixture of 1H-indazol-4-ylboronic acid (0.2 g, 1.227 mmol), chloromethyl pivalate (554 mg, 3.68 mmol) and K2CO3 (509 mg, 3.68 mmol) in dry DMF (10 mL) was heated to 30° C. for 16 hours. Reaction was quenched with water and product extracted with ethyl acetate (150 mL), then washed with water (3×20 mL) and brine (2×20 mL), then dried over Na2SO4, filtered and concentrated. The product (114 mg, crude) was obtained and used into next step without further purification. LCMS: (M+Na)+=299.
Reaction SMILES: C([Si](OCCO[CH2:12][CH2:13][O:14][CH2:15][CH2:16]Cl)(C)C)(C)(C)C.[I-].[Na+].[I-].C[C:22](=[O:25])[CH2:23][CH3:24]>>[CH2:15]([O:14]/[CH:13]=[CH:12]/[CH2:24][CH2:23][CH2:22][OH:25])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)OCCOCCOCCCl
Reactant: CCC(C)=O
Agent: [I-]
Agent: [Na+]
Product: CCO/C=C/CCCO

Procedure:
tert-Butyl-{2-[2-(2-chloro-ethoxy)-ethoxy]-ethoxy}-dimethyl-silane was converted to the corresponding iodide by refluxing with 5 equiv of NaI in 2-butanone for 6 h. This was then alkynylated and deprotected by the same process described above to provide E-5-Ethoxy-pent-4-en-1-ol: 1H NMR (500 MHz) 4.02 (q, J=6.8, 2H, H2C(5″)); 3.74–3.70 (m, 2 H, HCO); 3.68–3.66 (m, 2H, HCO); 3.64–3.60 (m, 4H, HCO); 3.54 (t, J=7.3, 2H, H2CO)); 2.49 (t, J=6.3, 1H, OH); 2.41 (t, J 7.3, 2H, H2CO); 1.33 (t, J=7.3, 3H, H3C(6″)); 13C NMR (100 (M+NH4); 186.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[Br:12]Br>O1CCOCC1>[Br:12][CH2:10][C:9]([C:3]1[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=1[F:1])=[O:11]
Reactant: BrBr
Reactant: CC(=O)c1ccc(O)cc1F
Solvent: C1COCCO1
Product: O=C(CBr)c1ccc(O)cc1F
Reaction time: 3 h
Yield: 62 %

Procedure:
To a stirred solution of 1-(2-fluoro-4-hydroxyphenyl)-1-ethanone (2.56 g, 16.6 mmol) in dioxane (4 ml) was added a solution of bromine (2.70 g, 16.9 mmol) in dioxane (15 ml) dropwise, and the mixture was stirred for 3 hours. The volatile was evaporated in vacuo, and the residue was used for next reaction without purification. (2.4 g, 62% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)=[CH:6][C:5]=1[NH:21][CH2:22][P:23](=[O:30])([O:27]CC)[O:24]CC)([O-:3])=[O:2].C[Si](C)(C)Br>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][N:12]=2)=[CH:6][C:5]=1[NH:21][CH2:22][P:23](=[O:24])([OH:27])[OH:30])([O-:3])=[O:2]
Reactant: CCOP(=O)(CNc1cc(Oc2ccc(C(F)(F)F)cn2)ccc1[N+](=O)[O-])OCC
Agent: C[Si](C)(C)Br
Product: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cn2)cc1NCP(=O)(O)O
Temperature: 20 °C
Reaction time: 18 h

Procedure:
A mixture of 3 g of diethyl N-[2-nitro-5-(5-trifluoromethyl-2-pyridyloxy)phenyl]-aminomethylphosphonate and 5 g of trimethylbromosilane is stirred for 18 hours at 20° C. Excess trimethylbromosilane is removed by evaporation and the residue is then taken up in ethanol and the solution is concentrated, affording 2.51 g (96.9% of theory) of the title compound with a melting point of 94° C. (decompos.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](O)([CH3:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[N-:13]=[N+:14]=[N-:15]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([CH3:11])[CH2:10][N:13]=[N+:14]=[N-:15])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(C)(C)O)c1
Reactant: [N-]=[N+]=[N-]
Product: COc1cccc(C(C)CN=[N+]=[N-])c1
Yield: 19 %

Procedure:
Ethyl 3-methoxybenzoate (10 g, 56 mmol) was dissolved in 55 mL ether, cooled to −78° C., and treated with 55 mL 3.0 M methylmagnesium bromide in ether. The reaction was warmed to room temperature, stirred overnight, and excess reagent was quenched by addition of water and 6 M H2SO4 to the reaction at 0° C. 8.2 g (49 mmol, 89%) of 2-(3-methoxyphenyl)propan-2-ol was obtained as a colorless oil. NMR (1H, CDCl3): 7.25 (m, 1H), 7.07 (m, 2H), 6.79 (m, 1H), 3.80 (s, 3H), 1.56 (s, 6H). The alcohol (8.2 g, 49 mmol) was converted to the azide by the method reported in J. Org. Chem. 1993, 58, 5886. 1.8 g (9.4 mmol, 19%) of 2-(3-methoxyphenyl)propylazide was obtained. NMR (1H, CDCl3) 7.5-6.7 (m, 4H), 3.8 (s, 3H), 1.55 (s, 6H). The azide (1.8 g, 9.4 mmol) was reduced to the amine with catalytic 10% Pd/C, H2 (40 psi), and 5 mL conc. HCl in 75 mL ethanol. 1.5 g (9.3 mmol, 99%) of 2-(3-methoxyphenyl)propyl-2-amine was obtained as an oil. MS (Cl) m/z 166 (MH+). The amine was converted to the amide with (R,R)-2-phenylcyclopropanecarboxylic acid, then reduced to the amine using the method in example 2.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][CH3:10])=[N:7][CH:8]=1.Br[C:12]1[CH:21]=[C:20]2[C:22](=[O:41])[N:23]([C@H:27]3[CH2:32][CH2:31][CH2:30][CH2:29][C@@H:28]3[O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[C:24]([CH3:26])([CH3:25])[C:19]2=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2>O1CCCC1.[Cl-].[NH4+].[Zn].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Si:34]([O:33][C@H:28]1[CH2:29][CH2:30][CH2:31][CH2:32][C@@H:27]1[N:23]1[C:24]([CH3:26])([CH3:25])[C:19]2[C:20](=[CH:21][C:12]([CH2:2][C:3]3[CH:8]=[N:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=3)=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[C:22]1=[O:41])([C:37]([CH3:40])([CH3:38])[CH3:39])([CH3:36])[CH3:35]
Reactant: COc1ccc(CCl)cn1
Reactant: CC1(C)c2c(cc(Br)c3cccnc23)C(=O)N1[C@H]1CCCC[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(Cc2cc3c(c4ncccc24)C(C)(C)N([C@H]2CCCC[C@@H]2O[Si](C)(C)C(C)(C)C)C3=O)cn1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-(chloromethyl)-2-methoxypyridine (0.117 g, 0.745 mmol) in 0.3 mL of tetrahydrofuran under an atmosphere of nitrogen was added Rieke zinc (0.76 M, 0.98 mL, 0.74 mmol). The mixture was heated at 90° C. for 2 h and then cooled to 0° C. 5-Bromo-8-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]-9,9-dimethyl-8,9-dihydro-7H-pyrrolo[3,4-h]quinolin-7-one (0.075 g, 0.15 mmol) and bis(tri-tert-butylphosphine)palladium(0) (2.3 mg, 0.0045 mmol) were added and the mixture was stirred at ambient temperature for 30 min. The mixture was diluted with saturated aqueous ammonium chloride and extracted 2× with dichloromethane. The combined organic extracts were washed with brine, dried with magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC followed by purification via silica gel chromatography, eluting with 0-10% methanolic ammonium hydroxide (10%) in dichloromethane, to provide 8-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]-5-[(6-methoxypyridin-3-yl)methyl]-9,9-dimethyl-8,9-dihydro-7H-pyrrolo[3,4-h]quinolin-7-one.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:22]1[S:23][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][N:26]=1.CI.[C:34](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]([CH3:34])[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:22]1[S:23][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][N:26]=1
Reactant: CCOC(=O)c1cnc(-c2cc3cccc(NS(=O)(=O)c4cccs4)c3n2COC)s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3n2COC)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
A mixture of ethyl 2-{1-(methoxymethyl)-7-[(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazole-5-carboxylate (2.19 g), methyl iodide (0.57 mL), potassium carbonate (0.95 g) and N,N-dimethylformamide (20 mL) was stirred at room temperature overnight. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried to give the title compound (2.18 g, yield 97%) as pale-yellow crystals. melting point 142-143° C.
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]([F:20])([F:19])[C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[O:11].[B]1OC2C(=CC=CC=2)O1.Cl>C(OCC)(=O)C.ClCCl>[F:20][C:9]([F:8])([F:19])[C@@H:10]([C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)[OH:11]
Reactant: O=C(c1ccc(F)cc1)C(F)(F)F
Agent: Cl
Agent: [B]1Oc2ccccc2O1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O[C@H](c1ccc(F)cc1)C(F)(F)F
Temperature: 25 °C
Yield: 87.1 %

Procedure:
To a −78° C. toluene (25 mL)/dichloromethane (25 mL) solution of 2,2,2,4′-tetrafluoroacetophenone (2.5 g, 13.01 mmol) and 1M S-CBS catalyst (1.3 mL, 1.3 mmol) was added freshly distilled catecholborane (1.66 mL, 15.62 mmol). The reaction mixture was maintained at −78° C. for 16 h at which time 4N HCl (5 mL in dioxane) was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was diluted with ethyl acetate and washed with a saturated brine solution. The organic layer was dried over magnesium sulfate, filtered and concentrated to provide a solid. The solid was suspended in hexanes and filtered off. The hexanes filtrate containing the desired product was concentrated and the residue subjected to flash chromatography (10 hexanes: 1 ethylacetate) to provide the title compound as colorless oil (2.2 g, 87% yield). The ratio of enantiomers was determined to be 95:5 by chiral HPLC (Chiralcel OD column, 95 hexanes: 5 isopropanol mobile phase. Ret. time major product 6.757 min. Ret. time minor isomer 8.274 min.).