Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[F:20])[O:11][C:10](=[O:21])[NH:9]2)[CH:5]=[N:6][CH:7]=1.[C:22]([Si](C)(C)C)#[CH:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[F:20][C:14]1[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=1[C@H:12]1[O:11][C:10](=[O:21])[NH:9][C@@H:8]1[C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:22]#[CH:23])[CH:3]=1
Reactant: O=C1N[C@H](c2cncc(Br)c2)[C@@H](c2cc(F)ccc2F)O1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Product: C#Cc1cncc([C@H]2NC(=O)O[C@@H]2c2cc(F)ccc2F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a slurry of (4R,5R)-4-(5-bromopyridin-3-yl)-5-(2,5-difluorophenyl)oxazolidin-2-one (1.00 g, 2.82 mmol) in triethylamine (30 mL) was bubbled nitrogen for 20 min at which time ethynyltrimethylsilane (0.557 mL, 3.94 mmol) was added with continued nitrogen bubbling for 5 min before adding bis(triphenylphosphine) palladium (II) chloride (0.148 g, 0.211 mmol), triphenylphosphine (0.133 g, 0.507 mmol), and copper (I) iodide (0.161 g, 0.845 mmol) together in 1 portion. After 5 min additional bubbling of nitrogen, the vessel was capped and placed in a 70° C. bath. After 18 h, the vessel was cooled to ambient temperature, concentrated in vacuo dissolved in ethyl acetate, washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to a black tar which was dissolved in methanol (30 mL). Potassium carbonate (0.428 g, 3.10 mmol) was added and after 30 min, the reaction was concentrated and dissolved in ethyl acetate, washed with water, brine, dried over MgSO4, filtered and concentrated in vacuo to a black tar which was loaded with dichloormethane onto a 40 g silica gel cartridge. Elution with 5 to 75% EtOAc/Hex over 6 column volumes then 75% EtOAc over 2 column volumes. Fractions containing the main peak were concentrated to (4R,5R)-5-(2,5-difluorophenyl)-4-(5-ethynylpyridin-3-yl)oxazolidin-2-one (766 mg; 91%) as a yellow oil which crystallized upon standing. 1H NMR (500 MHz, CDCl3) δ ppm 8.75 (1H, d, J=1.83 Hz), 8.52 (1H, d, J=2.14 Hz), 7.87 (1H, t, J=1.98 Hz), 7.17-7.24 (1H, m), 6.98-7.15 (2H, m), 5.52 (2H, d, J=5.49 Hz), 4.80 (1H, d, J=5.80 Hz), 3.30 (1H, s). Mass Spectral Anal. Calcd. for [M+H]+ C16H10F2N2O2: 301.07. found 301.01.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]2[C:3]=1[CH2:4][CH:5]([CH2:14]C)[C:6]2=[O:13].C([O-])(=[O:18])C.[Na+].CCOC(C)=O>C(O)(=O)C>[CH3:12][O:11][C:8]1[CH:7]=[C:3]([CH2:4][CH:5]([CH3:14])[C:6]([OH:13])=[O:18])[CH:2]=[CH:10][CH:9]=1
Reactant: CC(=O)[O-]
Reactant: CCC1Cc2c(Br)ccc(OC)c2C1=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1cccc(CC(C)C(=O)O)c1
Yield: 73.5 %

Procedure:
A mixture of the indanone (5c, 29.7 g, 0.110 mol), sodium acetate (15.0 g, 0.183 mol), 10% palladium-coal (3.01 g) in acetic acid (300 ml) was hydrogenated at atmospheric pressure. The catalyst was filtered off and the solvent evaporated. The residue was partitioned between water and AcOEt and the aqueous layer was extracted with AcOEt. The combined organic layers were washed with water, 5% NaHCO3 and brine, dried, filtered and evaporated. The crude product was purified by recrystallization from hexane:AcOEt to give the pure titled compound (15.7 g, 3 steps yield 51%), mp, 67-69° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[NH2:22][CH:23]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:24]([N:26]([CH3:28])[CH3:27])=[O:25]>>[CH3:27][N:26]([CH3:28])[C:24]([CH:23]([NH:22][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25]
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CN(C)C(=O)C(N)c1ccccc1
Agent: Cl
Product: CN(C)C(=O)C(NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)c1ccccc1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and 2-amino-N,N-dimethyl-2-phenylacetamide hydrochloride (CAN 1214036-19-7) as starting materials. MS (EI): m/e=445.1 [M+H]+.
Reaction SMILES: C[Mg]I.C([O:6][CH2:7][CH3:8])C.[CH2:9](OCC)C.[Br:14][C:15]1[N:20]=[C:19](C(OC)=O)[CH:18]=[CH:17][CH:16]=1.Cl>O>[Br:14][C:15]1[N:20]=[C:19]([C:7]([OH:6])([CH3:8])[CH3:9])[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1cccc(Br)n1
Reactant: CCOCC
Agent: C[Mg]I
Agent: Cl
Solvent: O
Product: CC(C)(O)c1cccc(Br)n1

Procedure:
In a nitrogen atmosphere, 30 mL of 3 M methylmagnesium iodide/diethyl ether was added to 300 mL of diethyl ether solution of 8.72 g of methyl 6-bromopyridine-2-carboxylate. Water and 2 N hydrochloric acid were added to the reaction liquid, and extracted with ethyl acetate. This was washed with aqueous saturated sodium hydrogencarbonate solution and saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure to obtain 8.51 g of crude 2-(6-bromo-2-pyridinyl)-2-propanol as a yellow oily substance.
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.[NH2:10][C@H:11]([C:13]([OH:15])=[O:14])[CH3:12].[NH2:16][C@H:17]([C:28](O)=[O:29])[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1>>[NH2:16][C@H:17]([C:28]([NH:10][C@@H:11]([C:13]([OH:15])=[O:14])[CH3:12])=[O:29])[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: C[C@H](N)C(=O)O
Agent: c1ccc2[nH]ccc2c1
Product: C[C@@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
NMR (1H) in DMSO-d6 10.88 (1H, s) NH indole, 8.20 (1H, broad s) NH Ala, 7.58 (1H, d) H4 indole, 7.32 (1H, d) H7 indole, 7.16 (1H, s) H2 indole, 7.05 (1H, t) H6 indole, 6.97 (1H, t) H5 indole, 4.05 (1H, broad q) Hα Ala, 3.73 (1H, dd) Hα Trp, 3.12 (1H, dd) HβA Trp, 2.88 (1H, dd) HβB Trp, 1.12 (1H, t) CH3 Ala
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([CH3:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:4]=1C=O.ClC1C=CC=C(C(OO)=[O:22])C=1.[OH-].[K+].Cl>ClCCl.O>[CH3:1][O:2][C:3]1[C:10]([CH3:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:4]=1[OH:22]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(C=O)c(OC)c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(O)c(OC)c1C
Reaction time: 1 h

Procedure:
To 416 mmol of 2,4-dimethoxy-3-methyl-benzaldehyde dissolved in 200 ml of dichloromethane there are added 624 mmol of meta-chloroperbenzoic acid. The reaction mixture is heated at reflux for 5 hours before being filtered. The filtrate is washed three times using 200 ml of saturated NaHCO3 solution each time and then dried over magnesium sulphate. After evaporating off the solvent, the crude product is taken up in 400 ml of methanol. 624 mmol of 10% KOH solution are added. The mixture is stirred for one hour and is then adjusted to pH=4 using 1N hydrochloric acid solution. After stirring for one hour, the volume is reduced to ⅓. The crude product is taken up in 400 ml of water and extracted with dichloromethane. The organic phases are collected and dried. After evaporating off the solvents, the residue obtained is purified by chromatography on a silica column (eluant: cyclohexane/ethyl acetate 90/10) to yield the expected product.
Reaction SMILES: [S:1]([N:11]([C:18]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:19]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28])=[O:21])[CH2:12][C:13](=[O:17])[N:14]([CH3:16])[CH3:15])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH3:16][N:14]([CH3:15])[C:13]([CH:12]1[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])([OH:21])[C:19]2[C:18](=[CH:32][CH:31]=[C:30]([Cl:33])[CH:29]=2)[N:11]1[S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2])=[O:17]
Reactant: Cc1ccc(S(=O)(=O)N(CC(=O)N(C)C)c2ccc(Cl)cc2C(=O)c2ccccc2Cl)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2c3ccc(Cl)cc3C(O)(c3ccccc3Cl)C2C(=O)N(C)C)cc1
Yield: 12.7 %

Procedure:
1.5 g of the compound prepared in step B are refluxed in DCM for 24 hours in the presence of 900 mg of DBU. The mixture is chromatographed on a silica column using a DCM/AcOEt mixture (95/5, v/v) as the eluent. 190 mg of the expected product are obtained after recrystallization from isopropyl ether.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4](I)=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.C(N(CC)CC)C.[H][H]>C(O)C.[C].[Pd]>[Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=[N+]([O-])c1nc(Cl)[nH]c1I
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1c[nH]c(Cl)n1
Yield: 83.7 %

Procedure:
2-Chloro-5-iodo-4-nitroimidazole (545 mg) was dissolved in ethanol (10 ml), then triethylamine (840 μl) and 10% palladium-carbon (54 mg) were added, the reaction mixture was subjected to hydrogenation at hydrogen pressure of 4 kg/cm2 by use of Pearl reduction equipment, there was obtained 2-chloro-4-nitroimidazole (246 mg, yield: 83.4%) as colorless solid matter.
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[N:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[C:46](Cl)=[O:47]>>[N:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[C:46]([O:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1)=[O:47]
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Reactant: O=C(Cl)c1ccccn1
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3ccccn3)CN2C1=O
Yield: 35.6 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and picolinoyl chloride (94 mg, 0.53 mmol). The final trituration (diethyl ether/hexane) and filtration gave 42 mg (54%) of 18-(picolinoyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 99.8% pure (HPLC), MS m/z 672 (M−H)−, HRMS: calcd. 674.2860 and found 674.2861 (M+H)+, mp 164-166° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][C:3](=O)[CH2:2]1.[C:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])[NH:9][NH2:10].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:10][NH:9][C:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:2]1
Reactant: O=C1CCCOC1
Reactant: CC(C)(C)OC(=O)NN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NNC1CCCOC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Dihydro-2H-pyran-3(4H)-one (100 mg, 1.00 mmol), tert-butyl carbazate (145 mg, 1.10 mmol, 1.1 equiv) and acetic acid (0.280 mL, 4.99 mmol, 5 equiv) were combined in 1,2-dichloroethane (3 mL), stirred at ambient temperature for 10 minutes and treated with sodium triacetoxyborohydride (296 mg, 1.34 mmol, 1.4 equiv). After stirring for 1 hour, the mixture was poured into water and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo to provide the titled compound.
Reaction SMILES: C([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]2[OH:25])[C:12]([CH3:27])([CH3:26])[CH2:11]1)(=O)C1C=CC=CC=1.[OH-].[K+]>CO>[OH:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]2[OH:25])[C:12]([CH3:27])([CH3:26])[CH2:11]1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OC1CCCCC1O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1O

Procedure:
The title compound is prepared by heating the compound prepared in Example 34 in a solution of potassium hydroxide in methanol.
Reaction SMILES: Br.[Al].ClC(Cl)=[CH:5][C@@H:6]1[C@H:8]([C:9]([OH:11])=[O:10])[C:7]1([CH3:13])[CH3:12].Cl.[CH2:16]([Br:18])[Br:17]>>[Br:17][C:16]([Br:18])=[CH:5][CH:6]1[CH:8]([C:9]([OH:11])=[O:10])[C:7]1([CH3:13])[CH3:12]
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)O
Reactant: BrCBr
Agent: Br
Agent: Cl
Agent: [Al]
Product: CC1(C)C(C=C(Br)Br)C1C(=O)O
Reaction time: 0.33 h

Procedure:
Anhydrous hydrogen bromide gas was introduced through a pipet (below the liquid level in the flask) to a stirred suspension of a small portion of aluminum shot in methylene bromide (250 ml) at 60°. The temperature was maintained at 60°-65° by heating or cooling as required during the portionwise addition of the aluminum shot (9.67 g, 0.358 mole total). The flow of HBr was maintained until all the aluminum had reacted to produce a cloudy brown mixture. The temperature of the reaction mixture was then reduced to 0°-5°, and a solution of cis-3-(2,2-dichlorovinyl)2,2-dimethylcyclopropanecarboxylic acid (50.0 g, 0.24 mole) in methylene bromide was added dropwise over a period of an hour to the vigorously stirred mixture under a nitrogen atmosphere. The reaction mixture was allowed to stir for 1 hour 20 minutes at 0.5°; then a flow of nitrogen was passed through the reaction mixture at reduced pressure (20 mm) for 11/2 hours. The entire reaction mixture was then poured slowly into a mixture of ice and 1 N hydrochloric acid and extracted twice with diethyl ether. The combined ethereal solution was dried over anhydrous magnesium sulfate, and the ether was removed under reduced pressure, affording a gray-brown solid, which was dried in a vacuum oven, affording 3-(2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylic acid (70.7 g). The crude product was recrystallized from hexane and sublimed. The cis-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylic acid thus obtained was 93% pure by glc analysis.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=2[F:15])=[O:6])[CH2:3][CH2:2]1.[C:16](O)(=[O:21])[CH2:17][C:18](O)=[O:19].C(OC(=O)C)(=O)C.C(Cl)(=O)C>O.C1(C)C=CC=CC=1>[CH:1]1([N:4]2[C:18](=[O:19])[CH2:17][C:16](=[O:21])[N:7]([C:8]3[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=3[F:15])[C:5]2=[O:6])[CH2:2][CH2:3]1
Reactant: O=C(Nc1ccc(I)cc1F)NC1CC1
Reactant: O=C(O)CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CC(=O)N(C2CC2)C(=O)N1c1ccc(I)cc1F
Temperature: 60 °C
Reaction time: 3 h
Yield: 82.3 %

Procedure:
To 1-cyclopropyl-3-(2-fluoro-4-iodophenyl)urea 48 (61.0 g) obtained in Step 1 and malonic acid 4 (19.9 g) were added acetic anhydride (300 ml) and acetyl chloride (27.2 ml), and the mixture was stirred under a nitrogen atmosphere at 60° C. for 3 hrs. After allowing to cool to room temperature, the reaction mixture was added dropwise to water-toluene [2:1 (volume ratio), 900 ml] with stirring. The precipitated crystals were collected by filtration and dried to give 1-cyclopropyl-3-(2-fluoro-4-iodophenyl)pyrimidine-2,4,6-trione 49 (60.9 g, yield 82%) as pale-yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[CH:9]=[CH:10]/[CH:11]=O.[N:13]([CH2:16][C:17]([O:19][CH2:20]C)=[O:18])=[N+:14]=[N-:15].O>CO>[N:13](/[C:16](=[CH:11]\[CH:10]=[CH:9]\[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])/[C:17]([O:19][CH3:20])=[O:18])=[N+:14]=[N-:15]
Reactant: COc1ccccc1/C=C/C=O
Reactant: CCOC(=O)CN=[N+]=[N-]
Solvent: CO
Solvent: O
Product: COC(=O)/C(=C/C=C/c1ccccc1OC)N=[N+]=[N-]
Temperature: -20 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
28%-Sodium metholate-methanol solution (4.4 ml) was diluted with methanol (5 ml), and cooled to −20° C. A solution of (2E)-3-(2-methoxyphenyl)prop-2-enal (2.4 g) and ethyl azidoacetate (7.5 g) in methanol (8 ml) was added over 30 min, and the mixture was stirred at −10° C. for 1 hr and at room temperature for 2 hr. The reaction mixture was poured into water and extracted with ether. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:4) was concentrated under reduced pressure to give methyl(2Z,4E)-2-azido-5-(2-methoxyphenyl)penta-2,4-dienoate (3.6 g). A part (3.5 g) thereof was dissolved in chloroform (10 ml), zinc iodide (214 mg) was added and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into water, and extracted with 1,2-dichloroethane. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:4) was concentrated under reduced pressure to give the object product (3.26 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([F:11])[CH:4]=1)[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[C:5]([F:11])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C#N)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCc1ccc(CN)c(F)c1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
A solution of 4-ethyl-2-fluoro-benzonitrile (1.19 g, 8.0 mmol) in ether (70 mL) was cooled in an ice bath. To the cold, stirred solution was added LiAlH4 (600 mg, 16 mmol). The suspension was then heated to reflux. After several hours at reflux, the suspension was allowed to cool to ambient temperature and was quenched by the careful addition of H2O (600 μL), followed by 15% aqueous NaOH (600 μL), and finally H2O (1.8 mL). The resulting suspension was filtered, and the solids were washed thoroughly with ether. The filtrate was concentrated under reduced pressure to afford 4-ethyl-2-fluoro-benzylamine (1.16 g, 95% yield) as a liquid. This material was used for the subsequent amide formation without further purification. 1H-NMR (400 MHz, CDCl3): δ 7.21 (1H, app t, J=7.6 Hz), 6.96-6.86 (2H, m), 3.85 (2H, s), 2.63 (2H, q, J=7.6 Hz), 1.22 (3H, t, J=7.6 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12](S(C2C=NC=CC=2)(=O)=O)[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:31]2[CH:32]=[C:27]([F:26])[CH:28]=[CH:29][C:30]=2[F:33])[NH:12][CH:11]=1)[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: OB(O)c1cc(F)ccc1F
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(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+]
Product: CN(Cc1c[nH]c(-c2cc(F)ccc2F)c1)C(=O)OC(C)(C)C

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (2,5-difluorophenyl)boronic acid (220 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (220 mg), the title compound was obtained as a colorless oil (yield 135 mg, 60%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[Br:9][C:10]1[N:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl>[Br:9][C:10]1[N:15]=[CH:14][C:13]([CH2:16][N:6]2[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]2)=[CH:12][CH:11]=1
Reactant: CCN1CCNCC1
Reactant: O=Cc1ccc(Br)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCN1CCN(Cc2ccc(Br)nc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.7 %

Procedure:
Add neat 1-ethylpiperazine (5.6 kg) to a mixture of 6-bromo-pyridine-3-carbaldehyde (8.3 kg) and DCM (186 kg). Then, add sodium triacetoxyborohydride (10.9 kg) in portions and stir at 20-30° C. for 12 h. Quench the reaction into a mixture of DCM (36 kg) and aqueous solution of sodium hydroxide 2 N (46 kg). Separate the layers and extract twice the aqueous layer with DCM (24×2 kg). Combine the organic layers, wash with brine (50×2 kg) and remove the solvent under vacuum to afford 11.5 kg of the title compound. MS (ES+): m/z=285 (M+H)+.
Reaction SMILES: C(C1C2NC3C(=CC=CC=3)C=2C=CC=1)C(C)C.CC1(C)C(C)(C)OB(C2C=CC(CCC[C:35]3[CH:36]=[CH:37][C:38]4[N:39]([CH2:66][CH:67]([CH3:69])[CH3:68])[C:40]5[C:45]([C:46]=4[CH:47]=3)=[CH:44][C:43](CCCC3C=CC(B4OC(C)(C)C(C)(C)O4)=CC=3)=[CH:42][CH:41]=5)=CC=2)O1.BrC1C=CC=C(Br)N=1.C([O-])([O-])=O.[K+].[K+]>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].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.O.C1COCC1>[CH3:68][CH:67]([CH3:69])[CH2:66][N:39]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:45]=2[C:46]2[C:38]1=[CH:37][CH:36]=[CH:35][CH:47]=2
Reactant: CC(C)Cn1c2ccc(CCCc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2c2cc(CCCc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)ccc21
Agent: [Pd]
Agent: Brc1cccc(Br)n1
Agent: CC(C)Cc1cccc2c1[nH]c1ccccc12
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Cn1c2ccccc2c2ccccc21
Temperature: 85 °C
Reaction time: 48 h
Yield: 175.3 %

Procedure:
Polymer 1—poly(iso-butylcarbazole-co-biphenylpyridine). Into a mixture of 36 (0.200 g, 0.281 mmol), 2,6-dibromopyridine (0.067 g, 0.281 mmol), Pd2(dba)3 (6.4 mg, 7.0 μmol), tri(o-tolyl)phosphine (8.6 mg, 28 μmol) and K2CO3 (0.387 g, 2.81 mmol) was added THF (4.2 mL) and H2O (1.4 mL). The reaction mixture was stirred at 85° C. under dark for 48 hours before cooling to room temperature. The aqueous solution was removed with a pipette. The organic phase was diluted with chloroform, and washed with 5% aqueous NaCN solution till no further bleaching occurs. The organic solution was concentrated and precipitated in methanol and then in hexane. The collected solid was subjected to Soxhlet extraction with methanol, hexane and acetone to yield Polymer 1 as a white solid (0.11 g, 69%). 1H NMR (400 MHz, CDCl3, 298 K): δ(ppm) 8.05-8.03 (d, J=8 Hz, 4H), 7.88 (s, 1H), 7.71-7.66 (m, 1H), 7.58-7.57 (m, 2H), 7.36-7.20 (m, 7H), 4.01-3.99 (d, 2H), 2.85-2.81 (t, 4H), 2.76-2.72 (t, 4H), 2.35-2.28 (m, 1H), 2.11-2.02 (m, 4H), 0.95-0.93 (d, 6H). MW=80,100, Mn=21,900.