Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13](O)=[O:14])=[CH:4][CH:3]=1.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[OH:32]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[OH:32])=[O:14])=[CH:6][CH:7]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: O=C(O)c1cnc(CCc2ccccn2)c(-c2ccc(Cl)cc2)c1
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(CCc2ccccn2)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 5d, using 5-(4-chloro-phenyl)-6-(2-pyridin-2-yl-ethyl)-nicotinic acid and (1R,2R)-2-amino-cyclohexanol as starting materials, LC at 215 nm; Rt 3.10: 98%, m/z (ES+): 436.4 (M+H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:30]=[CH:29][C:9]([C:10]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21][C:19]3=[O:20])[CH2:14][CH2:13]2)=[O:11])=[CH:8][CH:7]=1.[C:31](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:31][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:30]=[CH:29][C:9]([C:10]([N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21][C:19]3=[O:20])[CH2:16][CH2:17]2)=[O:11])=[CH:8][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(c1ccc(-c2ncc[nH]2)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ccnc1-c1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.5 %

Procedure:
To a solution of 1-{1-[4-(2-imidazolyl)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (1.0 g) and potassium carbonate (0.35 g) in dimethylformamide (10 ml) is added methyl iodide (0.16 ml) under ice-cooling, and the mixture is stirred at room temperature overnight. Further, to the mixture are added methyl iodide (0.16 ml) and potassium carbonate (0.3 g), and the mixture is stirred at room temperature for 8 hours. The mixture is poured into ice-water, extracted with ethyl acetate, washed with water and dried over sodium sulfate. After concentrated under reduced pressure, the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=25:1) and recrystallized from ethyl acetate to give 1-{1-[4-(1-methyl-2-imidazolyl)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (0.15 g) as colorless scales, m.p. 177°-179° C.
Reaction SMILES: Br[C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:13])=[N:7]2.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C1(P(C2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=C(C3C4C(=CC=CC=4)C=CC=3)C3C(C=2)=CC=CC=3)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[F:12][C:11]1[C:2]([N:17]2[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]2)=[C:3]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([CH3:13])[CH:5]=[CH:4]2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccc2c(Br)c(F)ccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2cc3ccccc3c(-c3cccc4ccccc34)c2P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc2c(N3CCN(C(=O)OC(C)(C)C)CC3)c(F)ccc2n1
Temperature: 120 °C
Reaction time: 20 h
Yield: 65.8 %

Procedure:
A mixture of 5-bromo-6-fluoro-2-methylquinoline (Chem. Pharm. Bull., 1989, 37(8), 2103-8, 0.285 g), 1,1-dimethylethyl 1-piperazinecarboxylate (0.265 g, 1.2 equiv.), Pd(OA)2 (15 mol %, 0.04 g), bis(diphenylphosphino)-1,1′-binaphthyl (BINAP, 30 mol %, 0.221 g), cesium carbonate (1.5 equiv. 0.580 g) and toluene (3.5 mL) were stirred at 120° C. for 20 h in a sealed tube. The mixture was cooled to room temperature and partitioned between ethyl acetate and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. This crude product was purified by flash chromatography [SiO2; DCM-MeOH (99:1)→(90:10)] to afford the title compound as colourless solid (0.270 g, 65% yield).
Reaction SMILES: [CH:1]1([CH:4]([OH:45])[CH2:5][O:6][C@H:7]2[CH2:12][CH2:11][C@H:10]([N:13]3[C:18](=[O:19])[C:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:33]5[NH:37][C:36](=[O:38])[O:35][N:34]=5)=[CH:23][CH:22]=4)=[C:16]([CH2:39][CH2:40][CH3:41])[N:15]4[N:42]=[CH:43][CH:44]=[C:14]34)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O>[CH:1]1([C:4](=[O:45])[CH2:5][O:6][C@H:7]2[CH2:8][CH2:9][C@H:10]([N:13]3[C:18](=[O:19])[C:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:33]5[NH:37][C:36](=[O:38])[O:35][N:34]=5)=[CH:23][CH:22]=4)=[C:16]([CH2:39][CH2:40][CH3:41])[N:15]4[N:42]=[CH:43][CH:44]=[C:14]34)[CH2:11][CH2:12]2)[CH2:2][CH2:3]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)C3CC3)CC2)c2ccnn12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)C3CC3)CC2)c2ccnn12
Reaction time: 2 h

Procedure:
To a solution of 4-[trans-4-(2-cyclopropyl-2-hydroxyethoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one (0.25 g) in methylene chloride (3 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (0.35 g), and the mixture was stirred for 2 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred for 30 min. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.21 g, 83%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:19][C:18]3[C:20]([C:25]4[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:32])=[CH:21][C:22]([F:24])=[CH:23][C:17]=3[CH2:16][CH:15]=[CH:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pt](=O)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:19][C:18]3[C:20]([C:25]4[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:32])=[CH:21][C:22]([F:24])=[CH:23][C:17]=3[CH2:16][CH2:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C=CCc3cc(F)cc(-c4c(Cl)cccc4Cl)c3O2)cc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCCc3cc(F)cc(-c4c(Cl)cccc4Cl)c3O2)cc1
Yield: 86.5 %

Procedure:
A solution (R)-(9-(2,6-dichlorophenyl)-7-fluoro-2,5-dihydrobenzo[b]oxepin-2-yl)methyl 4-methylbenzene-sulfonate (0.7 g, 1.4 mmol) in ethyl acetate/ethanol (10/10 mL) was added platinum (IV) oxide (0.2 g) and the mixture hydrogenated at 45 psi of hydrogen for 14 hours. The reaction mixture was then filtered through celite and the filtrate concentrated under reduced pressure. Chromatography with 10–30% ethyl acetate in hexanes afforded 0.60 g (85%) of (R)-(9-(2,6-dichlorophenyl)-7-fluoro-2,3,4,5-tetrahydrobenzo[b]oxepin-2-yl)methyl 4-methylbenzene-sulfonate as a colorless oil. [α]D25=+24.81° (c=6.6 mg/0.7 mL MeOH); MS (ES) m/z 512.1 ([M+NH4]+).
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]([CH2:28][CH3:29])[C:19]4[C:24]([CH:25]=3)=[C:23]([Cl:26])[C:22]([Cl:27])=[CH:21][CH:20]=4)=[O:16])=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:30]([O:34][C:35](=[O:43])[C:36]1[CH:41]=[CH:40][C:39](Br)=[CH:38][CH:37]=1)([CH3:33])([CH3:32])[CH3:31].CC(C)([O-])C.[Na+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:30]([O:34][C:35](=[O:43])[C:36]1[CH:41]=[CH:40][C:39]([N:5]2[CH2:6][CH2:7][N:2]([C:8]3[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]4[N:18]([CH2:28][CH3:29])[C:19]5[C:24]([CH:25]=4)=[C:23]([Cl:26])[C:22]([Cl:27])=[CH:21][CH:20]=5)=[O:16])=[CH:10][CH:9]=3)[CH2:3][CH2:4]2)=[CH:38][CH:37]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CCn1c(C(=O)Nc2ccc(N3CCNCC3)cc2)cc2c(Cl)c(Cl)ccc21
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: CCn1c(C(=O)Nc2ccc(N3CCN(c4ccc(C(=O)OC(C)(C)C)cc4)CC3)cc2)cc2c(Cl)c(Cl)ccc21
Temperature: 100 °C
Yield: 49.1 %

Procedure:
A mixture containing 4,5-dichloro-1-ethyl-1H-indole-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide hydrochloride (110 mg, 0.24 mmol), dioxane (6 mL), 4-bromo-benzoic acid tert-butyl ester (160 mg, 0.62 mmol), sodium tert-butoxide (128 mg, 1.33 mmol), Pd2(dba)3 (20 mg, 5% mol) and X-PHOS ligand (35 mg) was stirred under Ar, and heated for 2 hours at 100° C. The mixture was concentrated to dryness. The residue was taken up in 50 mL of EtOAc and washed with 50 mL of water, brine and dried with anhydrous sodium sulfate. The solvent was removed and the residue was triturated with methanol followed by hexanes. The solid was filtered to give 4-(4-{4-[(4,5-dichloro-1-ethyl-1H-indole-2-carbonyl)-amino]-phenyl}-piperazin-1-yl)-benzoic acid tert-butyl ester (70 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[N:18][CH3:19])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]2.[BH4-].[Na+]>C(O)(C)C>[OH:1][CH2:2][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([CH2:17][NH:18][CH3:19])=[C:11]2[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]2
Reactant: CN=Cc1c2ccccc2c(CO)c2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CNCc1c2ccccc2c(CO)c2ccccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 84.9 %

Procedure:
10-(hydroxymethyl)-9-((methylimino)methyl)anthracene (1.00 g, 4.0 mmol) was slurried in 25 mL isopropanol. NaBH4 (0.454 g, 12.0 mmol) was added as a solid and the solution was stirred at room temperature for 72 h. The mixture was filtered on a sintered-glass frit and the solvent was removed under reduced pressure to yield 10 as a bright yellow powder (0.853 g, 86% yield): 1H NMR (300.13 MHz, CD3OD) δ2.55 (s, 3H), 4.64 (s, 2H), 5.56 (s, 2H), 7.55 (m, 4H), 8.38 (m, 2H), 8.50 (m, 2H); 13C-{1H} NMR (75.4 MHz, CD3OD) δ133.4, 133.0, 131.6, 131.5, 126.9, 126.7, 126.2, 125.7, 57.2, 47.9, 36.5.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:16](=[CH:17][C:18]=1[N:19]1[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH:21]([CH3:32])[CH2:20]1)[N:15]1[C:6](=[N:7][C:8]3[C:13]([C:14]1=[O:33])=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]2=[O:34].C(Cl)(Cl)Cl>C(Cl)Cl.FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:16](=[CH:17][C:18]=1[N:19]1[CH2:24][CH2:23][NH:22][CH:21]([CH3:32])[CH2:20]1)[N:15]1[C:6](=[N:7][C:8]3[C:13]([C:14]1=[O:33])=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]2=[O:34]
Reactant: CC1CN(c2cc3c(cc2F)C(=O)c2nc4ccccc4c(=O)n2-3)CCN1C(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CN(c2cc3c(cc2F)C(=O)c2nc4ccccc4c(=O)n2-3)CCN1
Yield: 75 %

Procedure:
A solution of 8-fluoro-9-(3-methyl-4-t-butyloxycarbonylpiperazinyl)-indolo[2,1-b]quinazoline-6-12-dione (0.19 g, 0.4 mmol) (from Example 53) in methylene chloride (7 mL) and trifluoroacetic acid (7 mL) was stirred for 1 h. Chloroform was added and the chloroform/methylene chloride solution was washed with saturated sodium bicarbonate. The organic layer was separated, dried and concentrated to give a solid. Purification of the crude product by silica gel chromatography (chloroform eluent) gave the title compound in 75% yield: mp 225°-227° C.; 1H NMR (300 MHz, CDCl3) δ 8.40 (d, 1H), 8.18 (d, 1H), 8.03 (d, 1H), 7.85 (t, 1H), 7.65 (t, 1H) 7.50 (d, 1H), 4.3 (m, 1H), 3.86-3.76 (m, 2H), 3.13-3.04 (m, 4H), 2.8 (t, 1H) 1.75 (s, 3H).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([F:17])[CH:16]=1)[NH:13][C:12](=O)[CH:11]=[CH:10]2>>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([F:17])[CH:16]=1)[N:13]=[C:12]([Cl:3])[CH:11]=[CH:10]2
Reactant: O=c1ccc2cc(Br)cc(F)c2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1cc(Br)cc2ccc(Cl)nc12

Procedure:
Using the POCl3 procedure from INTERMEDIATE 4 Step B, 6-bromo-8-fluoroquinolone was converted to the title compound: LC6: 3.42 min. (M+H) 260.
Reaction SMILES: C(OC(=O)C)(=[O:3])C.OO.[CH3:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([NH2:17])[CH2:12]1.C(OO)(=O)C>S(=O)(=O)(O)O.C(Cl)Cl>[N:17]([CH:13]1[CH2:14][CH2:15][CH2:16][CH:11]([CH3:10])[CH2:12]1)=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC1CCCC(N)C1
Agent: CC(=O)OO
Agent: O=S(=O)(O)O
Agent: OO
Solvent: ClCCl
Product: CC1CCCC(N=O)C1
Temperature: 0 °C
Reaction time: 10 h
Yield: 19.5 %

Procedure:
1-Nitroso-3-methylcyclohexane dimer was prepared as follows: Acetic anhydride (55 g) was added over a 30-minute period, to a solution of 12.2 ml of 90% hydrogen peroxide and one drop of concentrated sulfuric acid in 50 ml of methylene chloride, while the temperature was maintained at 0° C. This solution was then added slowly to 22.8 g of 3-methylcyclohexylamine in 75 ml of methylene chloride while the temperature was maintained at 15° C. After the addition of the peracetic acid solution was completed, the reaction mixture was allowed to warm to room temperature and stirred an additional 10 hours. The solution was extracted with 200 ml of water, 100 ml of cold 15% ammonium hydroxide, 100 ml of 10% sulfuric acid and 100 ml of water, and dried over anhydrous magnesium sulfate. The methylene chloride was removed by distillation to leave a pale blue solid. This solid was recrystallized from methanol-water to give 5.0 g of 1 -nitroso-3-methylcyclohexane dimer as a white solid, mp 81°-83° C. The structure was confirmed by IR, UV and NMR spectra.
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([C:7]#[C:8][C:9](Cl)=[O:10])=[CH:3][CH:2]=1.[Cl:18][C:19]1[CH:32]=[C:31]([NH2:33])[CH:30]=[CH:29][C:20]=1[O:21][CH2:22][CH2:23][N:24]([CH2:27][CH3:28])[CH2:25][CH3:26].ClCCl.CO.N>>[Cl:18][C:19]1[CH:32]=[C:31]([NH:33][C:9](=[O:10])[C:8]#[C:7][C:4]2[CH:5]=[CH:6][C:1]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:2][CH:3]=2)[CH:30]=[CH:29][C:20]=1[O:21][CH2:22][CH2:23][N:24]([CH2:27][CH3:28])[CH2:25][CH3:26]
Reactant: O=C(Cl)C#Cc1ccc(-c2ccccc2)cc1
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CCN(CC)CCOc1ccc(NC(=O)C#Cc2ccc(-c3ccccc3)cc2)cc1Cl

Procedure:
Prepared analogously to Example 4.1.d. from biphenyl-4-ylpropynoic acid chloride and [2-(2-chloro-4-aminophenoxy)ethyl]diethylamine. Yield: 0.28 g (31.3% of theory); melting point: 105° C.-108° C.; C27H27ClN2O2 (M=446.98); calc.: molecular ion peak (M+H)+: 447/449; found: molecular ion peak (M+H)+: 447/449; Rf value: 0.5 (silica gel, dichloromethane/methanol/ammonia (9:1:0.1)).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[NH:6][C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]([CH:23]([F:25])[F:24])([CH:14](OC(C)C)[O:15][CH:16]([CH3:18])[CH3:17])[C:4]=2[CH:3]=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[NH:6][C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]([CH:23]([F:24])[F:25])([CH2:14][O:15][CH:16]([CH3:18])[CH3:17])[C:4]=2[CH:3]=1
Reactant: CC(C)OC(OC(C)C)C1(C(F)F)c2cc(Cl)ccc2Nc2ncccc21
Solvent: O=C(O)C(F)(F)F
Product: CC(C)OCC1(C(F)F)c2cc(Cl)ccc2Nc2ncccc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Method NNN To a stirred solution 7-chloro-5-(difluoromethyl)-5-diisopropoxymethyl-5,10-dihydrobenzo[b][1,8]naphthyridine (94) (50 mg, 0.13 mmol) in trifluoroacetic acid (2 mL) at room temperature was added borane-methyl sulfide complex (36 μL, 0.38 mmol). After 14 h at room temperature, the reaction mixture was quenched with 1.0 N NaOH and extracted with EtOAc (3×). The combined layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting yellow residue was taken up in MeOH (3 mL), acidified with 4 N HCl in dioxane (100 μL), and stirred at room temperature for 3 hours. The solution was quenched with saturated aqueous NaHCO3 (50 mL) and extracted with EtOAc (3×). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue afforded 95 in quantitative yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[F:12][C:13]1[C:20]([F:21])=[C:19]([C:22]([F:25])([F:24])[F:23])[C:18]([F:26])=[C:17]([F:27])[C:14]=1[CH2:15]Br>CN(C=O)C>[N+:9]([C:4]1[CH:3]=[C:2]([NH:1][CH2:15][C:14]2[C:17]([F:27])=[C:18]([F:26])[C:19]([C:22]([F:23])([F:25])[F:24])=[C:20]([F:21])[C:13]=2[F:12])[CH:7]=[CH:6][C:5]=1[OH:8])([O-:11])=[O:10]
Reactant: Nc1ccc(O)c([N+](=O)[O-])c1
Reactant: Fc1c(F)c(C(F)(F)F)c(F)c(F)c1CBr
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(NCc2c(F)c(F)c(C(F)(F)F)c(F)c2F)ccc1O
Yield: 40.1 %

Procedure:
According to the similar procedure in Synthesis Example 1, by using 4-amino-2-nitrophenol (1.00 g, 6.49 mmole), DMF (30 ml), TEA (0.5 ml), and 2,3,5,6-tetrafluoro-4-trifluoromethylbenzyl bromide (1.30 g, 7.78 mmole), 1.00 g (40.0% yield) of 2-nitro-4-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)phenol was obtained as a reddish solid.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.C([Sn](CCCC)(CCCC)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)CCC.[F-].[Cs+].CO.C(Cl)Cl>O1CCOCC1.CN(C=O)C.[Cu]I.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>[CH3:22][C:3]1[C:2]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1Cl
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1-c1ccccn1
Temperature: 140 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
A solution of 2-(3-chloro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 425; 38.0 mg, 0.122 mmol), 2-(tributylstannyl)pyridine (Aldrich; 0.043 mL, 0.134 mmol), CuI (2.314 mg, 0.012 mmol), cesium fluoride (36.9 mg, 0.243 mmol), and Pd(PPh3)4 (Strem Chemicals, Inc.; 7.02 mg, 6.08 μmol) in a mixture of 1,4-dioxane (2.0 mL) and DMF (2.0 mL) was stirred in a sealed tube under argon at 140° C. for 1 h. The reaction mixture was then concentrated onto silica gel and chromatographically purified (silica gel, 50-100% EtOAc/hexanes, then 0-10% MeOH/DCM) to provide 2-(2-methyl-3-(pyridin-2-yl)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (31.2 mg, 0.088 mmol, 72% yield) as a brown solid. 1H NMR (400 MHz, CDCl3) δ ppm 12.20 (1H, br. s.), 8.85 (1H, d, J=4.5 Hz), 8.09 (1H, dd, J=7.4, 1.0 Hz), 7.94-8.01 (1H, m), 7.90 (2H, d, J=8.2 Hz), 7.74-7.81 (1H, m), 7.50 (1H, ddd, J=7.3, 4.9, 1.1 Hz), 7.25 (1H, br. s.), 5.32 (1H, br. s.), 3.63 (2H, td, J=6.8, 2.1 Hz), 2.97 (3H, s), 2.94 (2H, t, J=6.8 Hz). m/z (ESI, +ve) 356.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([F:29])[C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][N:11]2[CH:14]([CH3:20])[C:15]([O:17]CC)=O)=[CH:7][CH:6]=1.[NH3:30]>CO>[Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:22]=[C:21]([F:29])[C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][N:11]2[CH:14]([CH3:20])[C:15]([NH2:30])=[O:17])=[CH:7][CH:6]=1
Reactant: N
Reactant: CCOC(=O)C(C)n1ncc2ccc(Oc3c(F)cc(C(F)(F)F)cc3Cl)cc21
Solvent: CO
Product: CC(C(N)=O)n1ncc2ccc(Oc3c(F)cc(C(F)(F)F)cc3Cl)cc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl 2-[6-(2-chloro-4-trifluoromethyl-6-flourophenoxy)indazol-1-yl]propionate (0.41 g) (prepared as in Example 1) was dissolved in methanol (25cm3), 880 ammonia (15cm3) added and the mixture stirred at room temperature for 18 hours. The white precipitate was collected by filtration and the solvent removed from the filtrate under vacuum. The residue was purified by flash chromatography (SiO2 ; EtOAc) to give compound 19, 2-[6-(2-chloro-4-trifluoromethyl-6-fluorophenoxy)indazol-1-yl]propionamide as a white solid; total yield=250 mgs. m.pt 171°-172.5 ° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[N:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:20]([CH3:32])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:33][CH3:34])(=[O:10])=[O:9])=[C:4]([Cl:35])[CH:3]=1.[O:36]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37]1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C(OCC)(=O)C>[Cl:35][C:4]1[CH:3]=[C:2]([C:38]2[CH:39]=[CH:40][O:36][CH:37]=2)[CH:7]=[CH:6][C:5]=1[S:8]([NH:11][C:12]1[N:17]=[C:16]([N:18]2[CH2:23][C@H:22]([CH3:24])[N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:20]([CH3:32])[CH2:19]2)[CH:15]=[CH:14][C:13]=1[O:33][CH3:34])(=[O:10])=[O:9]
Reactant: COc1ccc(N2C[C@@H](C)N(C(=O)OC(C)(C)C)[C@@H](C)C2)nc1NS(=O)(=O)c1ccc(Br)cc1Cl
Reactant: CC1(C)OB(c2ccoc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COc1ccc(N2C[C@@H](C)N(C(=O)OC(C)(C)C)[C@@H](C)C2)nc1NS(=O)(=O)c1ccc(-c2ccoc2)cc1Cl
Yield: 116 %

Procedure:
1,1-Dimethylethyl (2R,6S)-4-[6-{[(4-bromo-2-chlorophenyl)sulfonyl]amino}-5-(methyloxy)-2-pyridinyl]-2,6-dimethyl-1-piperazinecarboxylate (D13) (0.15 g, 0.254 mmol), 2-(3-furanyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.0739 g, 0.381 mmol), Palladium dichloride di-triphenylphosphine (9.0 mg, 0.0127 mmol), sodium carbonate (0.053 g, 0.508 mmol) were heated in DME (2 mL) and water (1 mL) at 120° C. in the microwave for 20 minutes. The reaction was then diluted with ethyl acetate (50 mL) and washed with saturated sodium hydrogen carbonate (2×30 mL) and brine (30 mL). The organic layer was dried (MgSO4) and evaporated to give a yellow oil which was purified by chromatography [silica gel, eluting with 0 to 60% Ethyl acetate/pentane]. Product fractions evaporated to give a pale yellow foam (D15) (0.170 g) MS (ES+) m/e 577/579 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@@H:7](O)[CH2:6][N:5]1C(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:37]([C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=1)([O-:39])=[O:38].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[O:46][C:43]1[CH:44]=[CH:45][C:40]([N+:37]([O-:39])=[O:38])=[CH:41][CH:42]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CCCN1Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of N-Boc-trans-4-hydroxyproline methyl ester (10.0 g, 41 mmol) 150 mL of anhydrous THF at 0° C. under N2 was added triphenylphosphine (12.7 g, 48 mmol) and 4-nitrophenol (6.7 g, 48 mmol). To this mixture was added diethylazodicarboxylate (7.7 mL, 48 mmol) dropwise over a 30 minute period. The mixture was warmed to room temperature. After stirring for 2 days, the solvent was removed in vacuo, and the crude oil treated successively with 200 mL portions of toluene and ether to remove triphenylphosphine oxide and diethylazodihydrazide by crystallization. The resulting oil was then chromatographed (SiO2, 15-50% ethyl acetate/hexanes) to provide 5.2 g (34%) of N-Boc-4-(cis)-(4-nitrophenoxy-L-proline methyl ester as a light yellow oil.