Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].[N+](=[CH2:12])=[N-]>C(Cl)Cl>[Br:1][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([O:5][CH3:12])=[O:4]
Reactant: C=[N+]=[N-]
Reactant: CC(C)CC(Br)C(=O)O
Solvent: ClCCl
Product: COC(=O)C(Br)CC(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-bromo-4-methylpentanoic acid (9.86 mmol, 1.31 g) in CH2Cl2 (100 mL), was added slowly a solution of diazomethane until no bubbles appears. The mixture was stirred at r.t. for 0.25 h. The volatiles were removed under reduced pressure to leave a yellow liquid. The crude methyl ester was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.[N+:12]([CH3:15])([O-:14])=[O:13].[OH-].[Na+]>>[F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[CH:15][N+:12]([O-:14])=[O:13]
Reactant: COc1ccc(F)c(C=O)c1
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(F)c(C=C[N+](=O)[O-])c1
Yield: 58.6 %

Procedure:
2-Fluoro-5-methoxy-benzaldehyde (4 g, 25.95 mmol) was reacted with nitro methane (1.58 g, 25.95 mmol), 10N NaOH (2.2 mL, 27.24 mmol) to afford 3 g of the product (58.7% yield).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][N:8]1[CH2:22][CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:11]2=[CH:12][CH:13]=[C:14]3[C:18]([NH:17][C:16](=O)[C:15]3=O)=[C:10]2[CH2:9]1.O>C(OCC)C.O1CCCC1>[CH3:7][N:8]1[CH2:22][CH:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:11]2=[CH:12][CH:13]=[C:14]3[C:18]([NH:17][CH:16]=[CH:15]3)=[C:10]2[CH2:9]1
Reactant: CN1Cc2c(ccc3c2NC(=O)C3=O)C(c2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN1Cc2c(ccc3cc[nH]c23)C(c2ccccc2)C1

Procedure:
20 g (0.524 mol) of LiAlH4 are suspended in 400 ml of absolute diethyl ether at room temperature, with stirring, while flushing with nitrogen and in the absence of moisture. 550 ml of absolute tetrahydrofuran are then added, followed by 34 g (0.116 mol) of 8-methyl-6-phenyl-6,7,8,9-tetrahydro-1H-pyrido[4,3-g]indole-2,3-dione in portions. The reaction mixture is subsequently stirred at room temperature for 31/2 hours. To dissociate the reaction complex, a solution of 42 ml of H2O in 160 ml of tetrahydrofuran is added dropwise, with cooling. The inorganic solid is filtered off and the filtrate is freed from the solvent on a rotary evaporator. The residue is chromatographed on silica gel 60 with an eluent mixture of: ethyl acetate and 8.3% of MeOH. The pure substance is dried in a desiccator over P2O5 at 60° C. under a water pump vacuum.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:10]1([N:16]2[C:20]3([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:19](=[O:26])[NH:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:27]([OH:30])(=[O:29])C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+:44]>C1COCC1.O>[C:27](=[O:29])([OH:9])[O-:30].[Na+:44].[Br:1][C:2]1[C:7]([CH2:8][N:23]2[CH2:22][CH2:21][C:20]3([N:16]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH2:17][NH:18][C:19]3=[O:26])[CH2:25][CH2:24]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: CC(=O)O
Reactant: O=Cc1cccnc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C([O-])O
Product: O=C1NCN(c2ccccc2)C12CCN(Cc1cccnc1Br)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 2-bromo-pyridine-3-carbaldehyde(0.68 g, 3.6 mmol) were added 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (0.846 g, 3.6 mmol), and acetic acid(1.1 g, 18 mmol) in THF (40.0 ml) and sodium triacetoxyborohydride (1.55 g, 7.3 mmol) and the resulting reaction mixture stirred at room temperature overnight. Water (50 ml) was added and the reaction mixture solution was extracted with ethyl acetate three times. The combined organic layers were dried over MgSO4. The solvent was removed and the resulting residue was purified over silica gel column eluted with methylene chloride (97%), methanol(2%), acetic acid(1%) and then with saturated sodium bicarbonate solution to yield 8-(2-bromo-pyridin-3-ylmethyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one as a white solid.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:22]=[CH:21][C:9]([C:10]([CH2:12]P(=O)(OCC)OCC)=[O:11])=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH:23]([CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:27][CH2:26]1)=O.O>O1CCCC1>[CH2:31]([N:28]1[CH2:29][CH2:30][CH:25]([CH:23]=[CH:12][C:10]([C:9]2[CH:8]=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:22][CH:21]=2)=[O:11])[CH2:26][CH2:27]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCOP(=O)(CC(=O)c1ccc([N+](=O)[O-])cc1)OCC
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(C=CC1CCN(Cc2ccccc2)CC1)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.17 h
Yield: 56.5 %

Procedure:
Under ice cooling, 0.40 g of 64% sodium hydride was added to 3.03 g of diethyl (4-nitrobenzoylmethyl)phosphonate dissolved in 30 ml of tetrahydrofuran. After about 10 minutes, 4.07 g of 4-formyl-1-benzylpiperidine was added to the mixture. The mixture was stirred under ice cooling for 30 minutes and then stirred at room temperature for about 16 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained residue was applied to silica gel column chromatography to obtain 1.99 g of the title compound as pale yellow crystal.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[N+](C1C=CC([O:42][C:43](=O)[O:44][CH:45]2[CH:52]3[CH:48]([O:49][CH2:50][CH2:51]3)[O:47][CH2:46]2)=CC=1)([O-])=O.CCN(C(C)C)C(C)C>C(#N)C.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:21][CH2:22][CH:23]([NH:26][C:43]([O:44][CH:45]2[CH:52]3[CH:48]([O:49][CH2:50][CH2:51]3)[O:47][CH2:46]2)=[O:42])[CH2:24][CH2:25]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC(N)CC1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1COC2OCCC12
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC(NC(=O)OC2COC3OCCC23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-[(4-amino-cyclohexyl)-(trans-4-methylcyclohexanecarbonyl)-amino]-5-(3,3-dimethyl-but-1ynyl)thiophene-2-carboxylic acid methyl ester (0.40 g, 0.873 mmol) in ACN (5.0 mL) was cooled to 0° C. and carbonic acid hexahydro-furo[2,3-b]furan-3-yl ester 4-nitro-phenyl ester (0.295 g, 1.0 mmol) was added, followed by DIEA (391 μL, 2.18 mmol) and DMAP (cat). The reaction mixture was warmed to rt, and stirred for 1 h. The solvent was removed under reduced pressure and the crude reaction mixture was partitioned between EtOAc and 2N K2CO3(aq). The layers were separated and the organics washed repeatedly with 2N K2CO3(aq). Both epimers of 5-(3,3-Dimethyl-but-ynyl)-3-[[4-(hexahydro-furo[2,3-b]furan-3-yloxycarbonylamino)-cyclohexyl]-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester were isolated by reverse phase HPLC and carried forward wet into the next reaction.
Reaction SMILES: [Cl:1][C:2]([F:15])([F:14])[C:3]1([C:10]([Cl:13])([F:12])[F:11])[O:7][CH:6]([CH2:8][OH:9])[CH2:5][O:4]1.[O-:16][C:17]#[N:18].[Na+].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:13][C:10]([F:11])([F:12])[C:3]1([C:2]([Cl:1])([F:14])[F:15])[O:7][CH:6]([CH2:8][O:9][C:17](=[O:16])[NH2:18])[CH2:5][O:4]1
Reactant: N#C[O-]
Reactant: OCC1COC(C(F)(F)Cl)(C(F)(F)Cl)O1
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)OCC1COC(C(F)(F)Cl)(C(F)(F)Cl)O1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
A sample of 15 grams of 2,2-bis(chlorodifluoromethyl)-4-hydroxymethyl-1,3-dioxolane (0.055 mols) is dissolved in 75 ml methylene chloride and 7.16 grams of sodium cyanate (0.11 mols) is added. Trifluoroacetic acid, 12.6 grams (0.11 mols) is added dropwise with stirring at 23°-33° C. The temperature is then raised to 40° C. and stirring continued for 18 hours. The product is filtered and the filtrate washed with water until neutral. Vacuum stripping gives a quantitative yield of crude products which solidified partly. Filtration and recrystallization from a mixture of benzene-hexane and once from cyclohexane yields 2,2-bis(chlorodifluoromethyl)-4-carbamoyloxymethyl-1,3-dioxolane (m.p. 56°-57° C.)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#N)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:17].[Na+].[OH2:19]>CCO>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]([OH:19])=[O:17])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: [OH-]
Reactant: N#Cc1ccc(OCc2ccccc2)nc1
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1ccc(OCc2ccccc2)nc1
Temperature: 90 °C
Reaction time: 20 h
Yield: 96 %

Procedure:
To a stirred solution of 6-benzyloxy-nicotinonitrile (100 mg, 0.47 mmol) in a mixture of EtOH (5 mL) and water (5 mL), was added NaOH (95.1 mg, 2.3 mmol) and the resulting mixture was stirred at 90° C. for 20 hrs. The mixture was evaporated under reduced pressure. The residue was diluted with cold water, adjusted the pH to 3 and extracted with EtOAc. The organic layer was washed with saturated brine solution and dried over Na2SO4. The organic layer was then concentrated under reduced pressure to afford 105 mg (96% yield) of 6-benzyloxy-nicotinic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])[C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1.C1C=C(Cl)C=C(C(OO)=[O:31])C=1.CCCCCC.C(OCC)(=O)C>ClCCl>[Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([C:15]3[C:16]([F:22])=[CH:17][CH:18]=[CH:19][C:20]=3[F:21])[C:4]=2[N:5]=[C:6]([S:8]([CH3:9])=[O:31])[N:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)c1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.4 %

Procedure:
To the compound 4-chloro-8-(2,6-difluorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (1.70 g, 5.0 mmol) in dichloromethane (100 mL) was added mCPBA (1.16 g, 7.5 mmol). The mixture was stirred at rt for 10 min. Chromatography with hexane/ethyl acetate afforded the title compound (1.59 g, 89%). LC-MS m/z 356 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH:9]([C:18]([O:20]CC)=[O:19])[CH2:10][CH:11]=[CH:12][CH2:13][C:14]([O:16]C)=[O:15].C([O:25][C:26](=[O:32])[CH2:27][CH2:28][C:29](Cl)=[O:30])C.Cl>C(Cl)Cl.O>[OH:32][C:26](=[O:25])[CH2:27][CH2:28][C:29]([NH:8][CH:9]([C:18]([OH:20])=[O:19])[CH2:10][CH:11]=[CH:12][CH2:13][C:14]([OH:16])=[O:15])=[O:30]
Reactant: CCOC(=O)CCC(=O)Cl
Reactant: CCOC(=O)C(N)CC=CCC(=O)OC
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)CC=CCC(NC(=O)CCC(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
338 mg of triethylamine were added at ambient temperature to 583 mg of 1-methyl 7-ethyl 6-amino-3-heptenedioate prepared as in Example 5D in 50 ml of methylene chloride and after the mixture was cooled to +5° C., 483 mg of ethyl4-chloro-4-oxo-butanoate were added. The mixture was stirred for 1 hour at ambient temperature and 25 ml of water and 1 ml of 2N hydrochloric acid were added. Extraction was done with methylene chloride and the extract was washed with salt water, then with sodium bicarbonate solution, dried and the solvents were evaporated. The residue was chromatographed on silica and elution with cyclohexane - ethylene acetate (1-1) yielded 750 mg of the expected product.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:19]1[CH:20]=[C:21]([NH:25][C:26]([O:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][C:32]=2[CH3:40])=[O:27])[CH:22]=[CH:23][CH:24]=1)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C:42]1[CH:43]=[C:44]2[C:49](=[CH:50][CH:51]=1)[C:48]([N:52]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])=[N:47][CH:46]=[CH:45]2.O.[C:68]([OH:72])(=[O:71])[CH:69]=O>>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:19]1[CH:20]=[C:21]([NH:25][C:26]([O:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH:69]([NH:41][C:42]3[CH:43]=[C:44]4[C:49](=[CH:50][CH:51]=3)[C:48]([N:52]([C:53]([O:55][C:56]([CH3:57])([CH3:58])[CH3:59])=[O:54])[C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])=[N:47][CH:46]=[CH:45]4)[C:68]([OH:72])=[O:71])=[CH:33][C:32]=2[CH3:40])=[O:27])[CH:22]=[CH:23][CH:24]=1)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Reactant: CCOC(=O)C[C@@H](NC(=O)OCc1ccccc1)c1cccc(NC(=O)OCCc2ccc(B(O)O)cc2C)c1
Reactant: O=CC(=O)O
Solvent: O
Product: CCOC(=O)C[C@@H](NC(=O)OCc1ccccc1)c1cccc(NC(=O)OCCc2ccc(C(Nc3ccc4c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc4c3)C(=O)O)cc2C)c1
Yield: 44 %

Procedure:
Using a procedure analogous to that used to prepare 2D, 39E (440 mg, 0.8 mmol) was reacted with Intermediate 1 and glyoxylic acid monohydrate to afford 39F (538 mg, 44%) as a brown oil. MS (ESI) m/z 920.6 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11]N.[Cl:13][C:14]1[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20](=O)[CH3:21])=[CH:16][CH:15]=1>CC#N.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]2[C:3]=1[NH:11][C:20]([CH3:21])=[C:19]2[O:18][C:17]1[CH:16]=[CH:15][C:14]([Cl:13])=[CH:24][CH:23]=1
Reactant: CC(=O)COc1ccc(Cl)cc1
Reactant: NNc1cc([N+](=O)[O-])ccc1Br
Solvent: O
Solvent: CC#N
Product: Cc1[nH]c2c(Br)ccc([N+](=O)[O-])c2c1Oc1ccc(Cl)cc1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
A mixture of the compound from (i) (2.4 g) and 1-(4-Chloro-phenoxy)-propan-2-one (1.65 g) in MeCN (20 ml) and water (5 ml) was stirred for 16 h. The volatiles were removed in vacuo. AcOH (50 ml) was added and the reaction heated at 75° C. for 72 h. The volatiles were evaporated under reduced pressure and the residue was purified by chromatography on silica eluting with 5% ethylacetate/iso-hexane. Yield 0.34 g
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:11])[NH:9][N:10]=[C:4]2[C:3]=1[I:12].C(N(CC)C(C)C)(C)C.[CH3:22][O:23][CH2:24]Cl>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:11])[N:9]([CH2:22][O:23][CH3:24])[N:10]=[C:4]2[C:3]=1[I:12]
Reactant: O=c1[nH]nc2c(I)c(Br)ccn12
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCn1nc2c(I)c(Br)ccn2c1=O
Temperature: 20 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
To a solution of 7-bromo-8-iodo-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (1.0 g, 2.94 mmol) in DMF (10 mL) and N,N-diisopropylethylamine (2.6 mL, 14.7 mmol) at 20° C. was added chloromethyl methyl ether (473 mg, 5.9 mmol). The resulting reaction mixture was stirred for an additional 3 h at 20° C. and then quenched by addition of H2O (25 mL). The quenched reaction mixture was extracted with Et2O/EtOAc (2:1, 3×50 mL). The combined organic extract was washed with saturated aqueous NaHCO3 solution (30 mL), then brine (30 mL), dried over MgSO4, filtered and concentrated in vacuo to obtain the title compound as a light yellow solid (1.1 g, 2.86 mmol). MS: [M+H]+=384.0. 1H NMR (400 MHz, CDCl3) δ 3.46 (s, 3H), 5.34 (s, 2H), 6.68 (d, J=7.15 Hz, 1H), 7.65 (d, J=7.15 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:3]([F:12])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[C:13]([O-:16])(=[O:15])[CH3:14].[Br-].[C:18]([Zn+2])([CH3:21])([CH3:20])[CH3:19]>O1CCCC1.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>[C:18]([O:15][C:13](=[O:16])[CH2:14][C:2]1[C:3]([F:12])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)[Zn+2]
Reactant: Fc1c(Br)ccc2ncccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1ccc2ncccc2c1F
Temperature: 120 °C
Yield: 70.6 %

Procedure:
To a solution of 6-bromo-5-fluoro-quinoline (1.0 g, 4.5 mmol) in tetrahydrofuran (1 mL) was added a solution of tert-butylzincbromide acetate (9 mmol, 20 mL, 10.4 M in tetrahydrofuran) followed by Pd(PPh3)4 (0.52 g, 0.45 mmol). The mixture was heated in a microwave reactor for 30 min at 120° C. The reaction mixture was quenched with a saturated ammonium chloride (60 mL), and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography to afford the title compound (0.83 g, 71%). 1H-NMR (CDCl3, 300 MHz): 8.9 (d, 1H), 8.4 (d, 1H), 7.8 (d, 1H), 7.6 (m, 1H), 7.5 (m, 1H), 3.7 (d, 2H), 1.4 (s, 9H).
Reaction SMILES: [Te].[BH4-].[Na+].[CH3:4][O:5][C:6]([C:8]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:10]2([CH2:15][CH2:14][N:13]([C:16](=[O:41])[CH:17]([NH:27][C:28](=[O:40])[C:29]([NH2:39])([CH3:38])[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:18][O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:12][CH2:11]2)[CH:9]=1)=[O:7].C(Cl)Cl.C(OCC)(=O)C>C(O)C>[CH3:4][O:5][C:6]([CH:8]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:10]2([CH2:15][CH2:14][N:13]([C:16](=[O:41])[CH:17]([NH:27][C:28](=[O:40])[C:29]([NH2:39])([CH3:38])[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])[CH2:18][O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:12][CH2:11]2)[CH2:9]1)=[O:7]
Reactant: COC(=O)C1=CC2(CCN(C(=O)C(COCc3ccccc3)NC(=O)C(C)(N)CC(=O)OC(C)(C)C)CC2)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Agent: [Te]
Solvent: ClCCl
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)C1CC2(CCN(C(=O)C(COCc3ccccc3)NC(=O)C(C)(N)CC(=O)OC(C)(C)C)CC2)c2ccccc21
Yield: 90.9 %

Procedure:
To a suspention of Tellurium (52.6 mg, 0.412 mmol) in ethanol (2.0 ml) was added sodiumborohydride (36.6 mg, 0.99 mmol) and the mixture was refluxed for 10 minutes. A solution of the title compound from Example 3, Step E (100 mg, 0.165 mg) in ethanol (1.0 ml) was cannulated into the reaction mixture at room temperature. The reaction mixture was then stirred over night, filtered and concentrated. The residue was dissolved in ethyl acetate and 1 N KOH was added. The aqueous layer was then extracted with ethyl acetate (3×1 vol). The organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. Flash chromatography (silica gel, methylene chloride/ethyl acetate 2:1) gave the title compound (91 mg, 0.15 mmol) as a clear glass.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([N:7]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:3][CH:2]=1.[I:26]N1C(=O)CCC1=O>C(O)(=O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[I:26][C:16]1[CH:17]=[CH:18][C:19]2[N:7]([C:4]3[CH:5]=[CH:6][C:1]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:2][CH:3]=3)[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: O=C1CCC(=O)N1I
Reactant: c1ccc(-c2ccc(-n3c4ccccc4c4ccccc43)cc2)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Ic1ccc2c(c1)c1ccccc1n2-c1ccc(-c2ccccc2)cc1
Reaction time: 24 h
Yield: 98.8 %

Procedure:
3.2 g (10 mmol) of 9-(4-biphenylyl)carbazole was dissolved in a mixed solution of 200 mL of glacial acetic acid, 200 mL of toluene, and 50 mL of ethyl acetate. 2.3 g (10 mmol) of N-iodosuccinimide was slowly added thereto. The mixture was stirred overnight (for about 24 hours) and then washed with water, a sodium thiosulfate water solution, and a saturated sodium chloride solution. Magnesium sulfate was added thereto to remove water and filtered to obtain a filtrate. The filtrate was concentrated, mixed with acetone and hexane, and then recrystallized with ultrasonic wave. This was filtered to obtain a residue. The residue was collected and dried. 4.4 g (yield: 98%) of 3-iodo-9-(4-biphenylyl)carbazole, which was beige powder, was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]([C:14]1[N:19]=[C:18](C(O)=O)[CH:17]=[C:16]([CH3:23])[N:15]=1)[CH2:12][CH3:13].[N:24]1([C:30](N)=O)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.B.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C.C(O)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]([C:14]1[N:19]=[C:18]([CH2:30][N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[CH:17]=[C:16]([CH3:23])[N:15]=1)[CH2:12][CH3:13]
Reactant: CCN(c1nc(C)cc(C(=O)O)n1)c1ccc(C(C)C)cc1Br
Reactant: NC(=O)N1CCOCC1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCN(c1nc(C)cc(CN2CCOCC2)n1)c1ccc(C(C)C)cc1Br
Temperature: 25 °C
Yield: 39 %

Procedure:
To a solution of 2-(N-(2-bromo-4-(2-propyl)phenyl)-N-ethylamino)-6-methylpyrimidine-4-carboxylic acid, morpholine amide (750 mg, 1.72 mmol) in anhydrous tetrahydrofuran (1.4 mL) at ambient temperature under a nitrogen atmosphere was added a solution of borane in tetrahydrofuran (1 M, 3.6 mL, 3.6 mmol) dropwise and the reaction mixture was heated at reflux temperature for 20 h. After cooling to room, acetic acid (3.5 mL) was slowly added and the mixture was heated at reflux for 30 min. After being cooled to ambient temperature, the reaction mixture was poured into a 3 N NaOH solution and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Column chromatography (ethyl acetate) afforded the title compound as an oil (300 mg, 39% yield, Rf 0.3): NMR (CDCl3, 300 MHz) 7.5 (s, 1H), 7.2 (d, 1H, J=7), 7.15 (d, 1H, J=7), 6.5 (s, 1H), 4.3-4.1 (m, 1H), 3.8-3.6 (m, 7H), 3.5-3.3 (m, 2H), 2.9 (septet, 1H, J=7), 2.55-2.35 (br m, 3H), 2.35-2.25 (m, 2H), 1.3 (d, 6H, J=7), 1.2 (t, 3H, J=7); CI-HRMS: calcd: 433.1603 (M+H), found: 433.1586.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([C:14]1[CH:23]=[N:22][C:21]2[C:16](=[CH:17][C:18]([F:25])=[C:19]([F:24])[CH:20]=2)[N:15]=1)[CH2:11][C:12]#[CH:13]>>[F:24][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[F:25])[N:15]=[C:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1)[CH:23]=[N:22]2
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCc1cnc2cc(F)c(F)cc2n1
Product: FCc1cccc(C#CCCc2cnc3cc(F)c(F)cc3n2)n1
Reaction time: 0.25 h
Yield: 13.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 108(C), from 2-bromo-6-(fluoromethyl)-pyridine (70 mg, 0.37 mmol) and 2-but-3-ynyl-6,7-difluoro-quinoxaline (80 mg, 0.37 mmol). Microwave conditions: 120° C. for 15 minutes. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 16 mg (50 μmol, 14%) of 6,7-difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)quinoxaline as a yellow solid (M.P.: 134.9-138.5° C.).