Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([CH3:16])([CH3:15])[O:9][SiH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1.C([Li])CCC.[F:22][C:23]1[CH:34]=[CH:33][C:26]([C:27](N(OC)C)=[O:28])=[CH:25][CH:24]=1>CCOCC>[C:11]([SiH2:10][O:9][C:8]([CH3:16])([CH3:15])[C:6]1[CH:7]=[C:2]([C:27]([C:26]2[CH:33]=[CH:34][C:23]([F:22])=[CH:24][CH:25]=2)=[O:28])[CH:3]=[N:4][CH:5]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CON(C)C(=O)c1ccc(F)cc1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cncc(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)[SiH2]OC(C)(C)c1cncc(C(=O)c2ccc(F)cc2)c1
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
To a solution of 3-bromo-5-(tert-butyl-dimethyl-silanyloxymethyl)-pyridine (1G) (1.0 g, 3.3 mmol) in 15 mL of ether at −75° C., is added n-butyl lithium (1.4 mL, 3.6 mmol, 2.5M in hexane) drop wise. After being stirred at −75° C. for 30 minutes, a solution of 4-fluoro-N-methoxy-N-methyl-benzamide (0.69 g, 3.8 mmol) in 5 mL of ether is added to the reaction solution drop wise. After being stirred at −75° C. for 1 hour, the reaction solution is warmed to room temperature in 1 hour, and quenched by addition of 10 mL of water. The mixture is extracted with 2×15 mL of EtOAc. After concentration, the crude product is purified by chromatography (heptane 90%, EtOAc 10%) to give [5-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-3-yl]-(4-fluoro-phenyl)-methanone (1H) (0.79 g, Yield 69%) as colorless liquid. MS (ESI) m/e 346 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:21]=3[C:14]([C:15]3[C:20]=2[C:19]=1[CH:18]=[CH:17][CH:16]=3)=[CH:13][CH:12]=[CH:11]4.[C:22]1([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[N+](C1C=CC=CC=1)([O-])=O>[Cu]>[C:29]1([N:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[CH:7]=[CH:8][CH:9]=[C:10]5[C:21]=4[C:14]([C:15]4[C:20]=3[C:19]=2[CH:18]=[CH:17][CH:16]=4)=[CH:13][CH:12]=[CH:11]5)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Brc1ccc2c3cccc4cccc(c5cccc1c52)c43
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Product: c1ccc(N(c2ccccc2)c2ccc3c4cccc5cccc(c6cccc2c63)c54)cc1
Reaction time: 40 h

Procedure:
The following compounds were introduced into a vessel: (a) 3-bromoperylene; (b) diphenylamine; (c) potassium carbonate; (d) copper power; and (e) nitrobenzene. Then, the mixture was stirred at 200 degrees centigrade for 40 hours. After reaction has finished, nitrobenzene was removed under a reduced pressure. Then, chlorofom was added to the mixture, and filtered for removing inorganic materials. A filtrate was condensed, and then, impurities were removed by silica gel column chromatography employing ligroin. As a result, there was obtained a target material, 3-diphenylaminoperylene.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]=2[CH3:19])=[CH:7][CH:6]=[CH:5][N:4]=1.[OH-].[Na+]>CCO.O>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=2[CH3:19])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COC(=O)c1ccc(-c2cccnc2OC)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ncccc1-c1ccc(C(=O)O)cc1C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Methyl 4-bromo-3-methylbenzoate (Intermediate 17, step 1) (2 g; 8.73 mmol; 1 eq.), 2-methoxypyridin-3-ylboronic acid (1.47 g; 9.60 mmol; 1.10 eq.), K2CO3 (6.03 g; 43.65 mmol; 5 eq.), Pd(PPh3)4 (1.01 g; 0.87 mmol; 0.10 eq.) were taken up in toluene (10 mL) and water (10 mL) under N2 atmosphere. The reaction mixture was purged with vacuum, then degassed with N2 and refluxed for 24 hours. The reaction mixture was cooled to RT, filtered over a pad of celite and washed with toluene (100 mL). The filtrate was concentrated to afford a yellow oil which was taken in EtOAc (100 mL). The organic layer was washed with a saturated aqueous solution of NaHCO3 solution, water and brine, dried over MgSO4 and concentrated affording methyl 4-(2-methoxypyridin-3-yl)-3-methyl benzoate as a yellow oil (2.4 g, HPLC (Method A) Rt 4.02 min). A solution of methyl 4-(2-methoxypyridin-3-yl)-3-methylbenzoate (2.50 g; 9.72 mmol; 1 eq.) in EtOH (75 mL) at RT was treated with sodium hydroxide (5.83 mL; 5 M; 29.15 mmol; 3 eq.). The reaction mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated to give a brown solid, which was taken up in water (50 mL) and the aqueous phase was washed twice with EtOAc. The aqueous phase was acidified with HCl cc to pH 2. Then it was concentrated (volume divided by 3) and the suspension was filtered affording the title compound as a beige solid. 1H NMR (DMSO-d6, 300 MHz) δ 12.96 (br s, 1H), 8.28-8.26 (dd, J=5.07 Hz, 1.86 Hz, 1H), 7.89 (m, 1H), 7.84-7.82 (dd, J=7.94 Hz, 1.52 Hz, 1H), 7.64-7.62 (dd, J=7.26 Hz, 1.86 Hz, 1H), 7.31-7.29 (d, J=7.94 Hz, 1H), 7.16-7.12 (m, 1H), 3.90 (s, 3H), 2.15 (s, 3H). LC/MS (Method A): 241.9 (M−H)−. HPLC (Method A) Rt 3.19 min (Purity: 99.1%).
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)[NH:4][CH:5]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:4]2[CH:5]=[N:1][N:2]=[C:3]2[C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(CCl)cc1
Reactant: c1cc(-c2nnc[nH]2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cnnc2-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.3 %

Procedure:
A mixture of 4-(4H-1,2,4-triazol-3-yl)pyridine (0.56 g, 3.8 mmol), PMBCl (0.66 g, 4.2 mmol), and K2CO3 (2.12 g, 15.3 mmol) in DMF (10 mL) was stirred for 4 h at room temperature. The reaction mixture was then diluted with water and extracted with DCM. The combined organic layers were washed with water three times, dried with Na2SO4, filtered and concentrated. The crude product was purified by column chromatography to give 4-(4-(4-methoxybenzyl)-4H-1,2,4-triazol-3-yl)pyridine (0.60 g).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=1)[CH2:10][NH:11][C@H:12]([C:14]([NH:16][C@H:17]([C:21]([NH:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH3:13])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C@@H:9]([CH2:28][C:29]1[CH:30]=[C:31]([F:36])[CH:32]=[C:33]([F:35])[CH:34]=1)[CH2:10][NH:11][C@H:12]([C:14]([NH:16][C@H:17]([C:21]([NH:23][CH2:24][CH:25]([CH3:26])[CH3:27])=[O:22])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH3:13]
Reactant: CC(C)CNC(=O)[C@@H](NC(=O)[C@H](C)NC[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CNC(=O)[C@@H](NC(=O)[C@H](C)NC[C@@H](N)Cc1cc(F)cc(F)c1)C(C)C

Procedure:
N-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propyl]-L-alanyl-N1-isobutyl-L-valinamide (377 mg, 0.735 mmol) is stirred with 1.5 mL of trifluoroacetic acid and 3 mL of dichloromethane for 25 min. It is then concentrated on a rotary evaporator and then neutralized with several mL of saturated aqueous sodium bicarbonate. The product is taken up in ethyl ether containing about 1% methanol, washed with several more mL of bicarbonate solution and with brine, and then dried over Na2SO4. Concentration afforded a quantitative yield of the title compound as a yellow solid. HRMS (ESI) calcd for C21H34F2N4O2+H1 413.2728, found 413.2730.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[C:15](=[O:26])[N:14]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1)[C:13]2=[O:38].CCN(CC)CC>C(Cl)Cl>[CH3:37][O:36][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][C:31]=1[O:34][CH3:35])[CH2:27][N:14]1[C:13](=[O:38])[C:12]2[C:17](=[CH:18][CH:19]=[C:10]([CH2:9][NH:8][C:1](=[O:3])[CH3:2])[CH:11]=2)[N:16]([CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:15]1=[O:26]
Reactant: COc1ccc(Cn2c(=O)c3cc(CN)ccc3n(C3CCOCC3)c2=O)cc1OC
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2c(=O)c3cc(CNC(C)=O)ccc3n(C3CCOCC3)c2=O)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
0.066 g of acetic anhydride is added at 0° C. to a solution of 0.23 g of the compound obtained in Step 12.2 and 0.11 g of Et3N in 5 ml of DCM. The mixture is stirred at room temperature for 2 hours. The organic phase is washed with saturated NH4Cl solution, filtered and evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a DCM/MeOH mixture from (99/1, v/v) to (95/5, v/v) to give 0.195 g of the expected product.
Reaction SMILES: [N:1]1([CH2:6][CH:7]=O)[CH:5]=[CH:4][N:3]=[CH:2]1.[Br-].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]([CH:40]=[CH:41][C:42]=2[C:43]([O:45][CH3:46])=[O:44])[CH2:20][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[N:1]1([CH2:6][CH:7]=[CH:20][C:19]2[CH:40]=[CH:41][C:42]([C:43]([O:45][CH3:46])=[O:44])=[C:17]([C:14]3[CH:13]=[CH:12][C:11]([F:10])=[CH:16][CH:15]=3)[CH:18]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=CCn1ccnc1
Reactant: COC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C=CCn2ccnc2)cc1-c1ccc(F)cc1
Yield: 93 %

Procedure:
A solution of 2-(imidazol-1-yl)acetaldehyde (2.6 g; 0.018 mmol), 3-(4-fluorophenyl)-4-methoxycarbonylbenzyl triphenylphosphonium bromide (5.4 g; 0.09 mmol), potassium carbonate (1.38 g; 0.01 mmol) and 18 crown-6 (0.1 g; 0.37 mmol) in THF (150 ml) was stirred under argon atmosphere at ambient temperature overnight. After filtration of the insoluble material and evaporation to dryness, the residue was purified by flash chromatography eluting with a mixture of dichloromethane/ethanol (98/2) to give methyl 4-[3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate as a mixture of E and Z isomers. Yield: 93%.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([CH:9](O)[CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[N:16]2[CH2:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[OH-].[Na+]>>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[C:10]2/[CH:11]([N:16]3[CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:13][CH2:14][CH2:15]/2)=[CH:7][CH:8]=1
Reactant: OC(c1ccc(C(F)(F)F)cc1)C1CCCCC1N1CCC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: FC(F)(F)c1ccc(/C=C2\CCCCC2N2CCC2)cc1
Reaction time: 0.33 h

Procedure:
A 0.4 g (1.3 mmole) portion of 1-[2-[[4-(trifluoromethyl)phenyl](hydroxy)methyl]cyclohexyl]azetidine, from step A above was added during 5 min to 4 ml of ice cooled sulfuric acid. The mixture was stirred in ice for 20 min. The resulting mixture was poured into ice, basified with sodium hydroxide, and extracted with six 30 ml portions of chloroform. The chloroform extracts were combined and dried with magnesium sulfate and evaporated to give 0.173 g of (±)-(E)-1-[2-[[4-(trifluoromethyl)phenyl]methylene]cyclohexyl]azetidine. The crystalline p-toluenesulfonic acid salt of this azetidine derivative was prepared, mp 135°-136° C. UV λmax(ε)219 sh (17,350) 222 (17,400) 227 sh (15,250) 246 (11,750) IR,NH Rf 3000b, 2600, 1660 C=C, 1615, 1575, 1495, 1325 SO3 /CF3, 1230, 1215, 1175, 1125, 1065, 1035, 1010, 814 aromatic, 805, 680. NMR (d6DMSO)δ7.75, 7.1 (2d, 4H, aromatic of TSA), 7.6-7.4 (m, 4H, aromatic), 4.1-3.8 (m, 5H, --CH--N(CH2)--CH2 move upfield with addition of NaOH, 2.6-211 (m, 4H, CH2 --C=C+C+CH2 -- of azetidine), 2.3 (s, 3H, CH3), 1.9-1.45 (m,6H, CH2 's).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:13]([Si:17](Cl)([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].N1C=CN=C1.O>C(Cl)Cl>[CH2:22]([Si:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[O:1][C:2]1[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCC[Si](Cl)(CCCC)CCCC
Reactant: CCOC(=O)c1ncccc1O
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CCCC[Si](CCCC)(CCCC)Oc1cccnc1C(=O)OCC
Reaction time: 8 h
Yield: 49.7 %

Procedure:
A mixture of ethyl 3-hydroxypicolinate (15 g, 900 mmol), tributylsilyl chloride (16.23 g, 110 mmol), imidazole (8.0 g, 120 mmol) in methylene chloride was stirred overnight under a nitrogen atmosphere. Water was added and the methylene chloride layer was separated and concentrated in vacuo. Purification on a silica gel column using ethyl acetate-hexane (1:4) as the eluant gave ethyl 3-(tributylsilyloxy)picolinate as a solid (20 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Cl:9][C:3]1[C:2]([NH:1][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([Cl:8])[N:6]=[CH:5][N:4]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1c(Cl)ncnc1Cl
Product: O=C(Nc1c(Cl)ncnc1Cl)c1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 5-amino-4,6-dichloropyrimidine (1.15 g, 0.00701 mol) and benzoyl chloride (1.0 mL, 0.0086 mol) was heated at 100° C. overnight. The reaction was cooled and the residue was triturated with diethyl ether, filtered and collected to obtain 1.6 g (85%).
Reaction SMILES: [Cl:1][CH:2]=[CH:3][CH2:4][CH2:5]Cl.[C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)#[N:8].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:5][CH:4]=[CH:3][CH2:2][Cl:1])=[CH:11][CH:10]=1)#[N:8]
Reactant: N#Cc1ccc(O)cc1
Reactant: ClC=CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(OCC=CCCl)cc1

Procedure:
1,4-Dichlorobutene (750 g; 5 mol) was added to a stirred suspension of 4-cyanophenol (119.12 g; 1 mol) and K2CO3 (345 g; 2.5 mol) in MeCN (1000 mL) and the reaction mixture was refluxed for 4 h. The reaction mixture was filtered and concentrated. The residue was dissolved in di-iso-propyl ether (2000 mL) and after 24 h the precipitate was filtered off. The filtrate was concentrated giving the sub-title compound as a yellow oil which solidified upon standing (186 g; 0.89 mol).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][CH2:20][Cl:21]>>[Cl:21][CH2:20][CH2:19][CH2:18][O:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)=[CH:6][CH:7]=1
Reactant: ClCCCBr
Reactant: Oc1ccc(C=Cc2cccc(Cl)c2)cc1
Product: ClCCCOc1ccc(/C=C/c2cccc(Cl)c2)cc1
Yield: 86.3 %

Procedure:
The procedures of Example 1 were followed using 4-hydroxy-3'-chlorostilbene (5.0 g, 23 mmol) and 1-bromo-3-chloropropane (4.4 mL, 43 mmol) to give 6.1 g (87%) of (E)-4-chloropropoxy-3'-chlorostilbene as an amber oil. 1NMR (CDCl3): δ7.66-6.72(m,10H), 4.11(t,2H), 3.72(t,2H), 2.22(m,2H).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16](F)[CH:15]=1>CN(C=O)C>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([NH:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:15]=1
Reactant: NC1CCCC1
Reactant: N#Cc1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cl)cc1NC1CCCC1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
Cyclopentylamine and potassium carbonate were added to a DMF solution of 4-chloro-2-fluorobenzonitrile, followed by stirring at 100° C. for 12 hours. By post-treating the reaction liquid, 4-chloro-2-(cyclopentylamino)benzonitrile was obtained.
Reaction SMILES: C1(C[N:8]([CH2:23][CH:24]([CH:26]2[CH2:31][CH2:30][C:29]3[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:28]=3[O:27]2)[OH:25])[CH2:9][CH:10]([CH:12]2[CH2:17][CH2:16][C:15]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:14]=3[O:13]2)[OH:11])C=CC=CC=1>[Pd].C(O)(=O)C>[NH:8]([CH2:23][CH:24]([CH:26]1[CH2:31][CH2:30][C:29]2[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:28]=2[O:27]1)[OH:25])[CH2:9][CH:10]([CH:12]1[CH2:17][CH2:16][C:15]2[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:14]=2[O:13]1)[OH:11]
Reactant: OC(CN(Cc1ccccc1)CC(O)C1CCc2cc(F)ccc2O1)C1CCc2cc(F)ccc2O1
Agent: [Pd]
Solvent: CC(=O)O
Product: OC(CNCC(O)C1CCc2cc(F)ccc2O1)C1CCc2cc(F)ccc2O1
Temperature: 30 °C
Reaction time: 4 h

Procedure:
The mixture of (±)-[2R*[1S*,5S*(S*)]]-α,α′-[phenylmethyliminobis (methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] (48 gm), acetic acid (480 gm) and 5% palladium on charcoal (19 gm) was taken into a hydrogenation flask and subjected to hydrogenation under a hydrogen gas pressure of 1.5 kg/cm2 for 3 hours at 25-40° C. Then the reaction mixture was filtered on hi-flo and washed with acetic acid (55 gm). The solvent was distilled off completely under reduced pressure and then co-distilled twice with ethyl acetate (each time 60 ml). To the resulting mass, ethyl acetate (480 ml) was added, refluxed for 1 hour and then cooled to 25-35° C. The reaction mass was stirred for 4 hours, again cooled to 0-10° C. and stirred for 1 hour 30 minutes. Filtered the material and washed with ethyl acetate (60 ml). The resulting wet cake was stirred with methanol (850 ml) and 25% monomethyl amine (60 ml) for 1 hour at 25-35° C., cooled to 0-10° C. and then stirred for 1 hour at 0-10° C. Filtered the material and washed with methanol (60 ml) to give 40.5 gm of (±)-[2R*[1S*,5S*(S*)]]-α,α′-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] (Nebivolol) (HPLC purity: 99.2%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]1([CH3:18])[CH2:14][O:13][C:12]([CH2:15][O:16][CH3:17])=[N:11]1>>[C:2]1([CH:1]=[C:15]([C:12]2[O:13][CH2:14][C:10]([CH3:18])([CH3:9])[N:11]=2)[O:16][CH3:17])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCC1=NC(C)(C)CO1
Reactant: O=Cc1ccccc1
Product: COC(=Cc1ccccc1)C1=NC(C)(C)CO1

Procedure:
Benzaldehyde was reacted with 4,4-dimethyl-2-methoxymethyl-2-oxazoline (derived from methoxyacetic acid) to produce 2-(2-phenyl-1-methoxyethenyl)-4,4-dimethyl-2-oxazoline (P-1907), b.p. 122 (0.3 mm)-125 (0.26 mm).
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:15]=[C:16](B(O)O)[CH:17]=[N:18][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:24]1[CH:25]=[C:26]([C:30]2[N:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:33]3[CH:41]=[CH:42][CH:43]=[CH:44][C:32]=3[N:31]=2)[CH:27]=[N:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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:35]1([N:34]2[C:33]3[CH:41]=[CH:42][CH:43]=[CH:44][C:32]=3[N:31]=[C:30]2[C:26]2[CH:25]=[C:24]([C:16]3[CH:17]=[N:18][CH:19]=[C:14]([N:12]4[C:13]5[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=5[C:6]5[C:11]4=[CH:10][CH:9]=[CH:8][CH:7]=5)[CH:15]=3)[CH:29]=[N:28][CH:27]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: OB(O)c1cncc(-n2c3ccccc3c3ccccc32)c1
Reactant: Brc1cncc(-c2nc3ccccc3n2-c2ccccc2)c1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: c1ccc(-n2c(-c3cncc(-c4cncc(-n5c6ccccc6c6ccccc65)c4)c3)nc3ccccc32)cc1
Temperature: 90 °C
Yield: 49 %

Procedure:
A mixture of (5-(9H-carbazol-9-yl)pyridin-3-yl)boronic acid (2C) (0.90 g, 3.1 mmol), 2-(5-bromopyridin-3-yl)-1-phenyl-1H-benzo[d]imidazole (1F) (0.856 g, 3.1 mmol), Pd(PPh3)4 (0.18 g, 0.155 mmol) and potassium carbonate (1.07 g, 7.8 mmol) in dioxane/water (20 mL/5 mL) was degassed and heated at about 90° C. overnight under argon atmosphere. The whole was poured into ethyl acetate (100 mL), then washed with brine (50 mL). The organic phase was collected and dried over Na2SO4, absorbed on silica gel, then purified by flash column (dichloromethane/methanol 40:1) to give a light yellow solid (0.78 g), which was purified again by flash column (silica gel, dichloromethane/methanol 50:1) followed by recrystallization in dichloromethane/methanol to give HTH-2, a light yellow solid (0.60 g, 38% yield).
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@@H:26]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:27]=[O:28])[CH2:10][O:11][CH2:12][C@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][Mg]Br.C(OCC)C>C(Cl)Cl>[CH2:1]([O:8][C@H:9]([C@@H:26]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C@H:27]([OH:28])[CH3:37])[CH2:10][O:11][CH2:12][C@H:13]([NH:18][C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: COC(=O)[C@H](COC[C@H](OCc1ccccc1)[C@H](C=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)[C@H](COC[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H](C)O)NC(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a solution of (S)-methyl 3-((2S,3R)-2,3-bis(benzyloxy)-4-oxobutoxy)-2-((tert-butoxycarbonyl)amino)propanoate (0.980 g, 1.95 mmol) in DCM (18.61 ml) at −78° C. was added a 3.0 M solution of methylmagnesium bromide in diethyl ether (Et2O) (1.30 ml, 3.91 mmol) and the reaction was stirred at −70° C. for 1 h, warmed slowly to −20° C. over 2 h, and then quenched at −20° C. with H2O. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO4, filtered, and the filtrate was concentrated and purified by flash chromatography (SiO2, hexanes/EtOAc gradient) to yield the title compound as a colorless oil (0.475 g, 47%): 1H NMR (400 MHz, CDCl3) δ 7.37-7.27 (m, 10H), 5.43 (d, J=8.6 Hz, 1H), 4.71 (d, J=14.0 Hz, 1H), 4.69 (d, J=14.4 Hz, 1H), 4.55 (dd, J=11.5, 2.6 Hz, 2H), 4.49-4.41 (m, 1H), 3.96-3.84 (m, 2H), 3.75 (dd, J=10.1, 5.0 Hz, 1H), 3.72 (s, 3H), 3.71-3.63 (m, 3H), 3.32-3.29 (m, 1H), 2.26 (d, J=6.3 Hz, 1H), 1.45 (s, 9H), 1.14 (d, J=6.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 171.20, 155.58, 138.36, 138.21, 128.59, 128.53, 128.21, 128.07, 128.05, 127.89, 82.88, 80.16, 78.55, 74.94, 73.18, 71.71, 71.34, 67.04, 54.16, 52.58, 28.46, 20.30; ESIMS m/z 516.3 ([M−H]−).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](OC)=[CH:7][C:8](=[O:13])[C:9]([Cl:12])([Cl:11])[Cl:10])(=[O:3])[CH3:2].[Cl:16][C:17]1[C:18]([NH:23][NH2:24])=[N:19][CH:20]=[CH:21][CH:22]=1>C(O)C>[C:1]([O:4][CH2:5][C:6]1[CH2:7][C:8]([OH:13])([C:9]([Cl:10])([Cl:11])[Cl:12])[N:23]([C:18]2[C:17]([Cl:16])=[CH:22][CH:21]=[CH:20][N:19]=2)[N:24]=1)(=[O:3])[CH3:2]
Reactant: COC(=CC(=O)C(Cl)(Cl)Cl)COC(C)=O
Reactant: NNc1ncccc1Cl
Solvent: CCO
Product: CC(=O)OCC1=NN(c2ncccc2Cl)C(O)(C(Cl)(Cl)Cl)C1
Reaction time: 3 h

Procedure:
27.5 g (0.1 mol) of 5,5,5-trichloro-2-methoxy-4-oxopent-2-en-1-yl acetate and 14.4 g (0.1 mol) of 3-chloro-2-hydrazinopyridine were initially charged in 200 ml of ethanol, and the mixture was stirred at 25° c. for 3 h. The precipitate was filtered off and washed with cyclohexane.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl.Cl[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:16]1([CH2:15][CH2:14][O:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1cccc(O)c1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(OCCN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 60.6 %

Procedure:
A mixture of methyl 3-hydroxybenzoate (8.0 g, 56 mmol) and 4-(2-chloroethyl)-morpholine hydrochloride (15.7 g, 84 mmol) and potassium carbonate (11.5 g, 83 mmol) in toluene (50 ml) was heated at reflux. After 4 days, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with water and then extracted with dilute hydrochloric acid. The acidic layer was separated, basified with 5 N sodium hydroxide and the product was extracted into ethyl acetate. The organics were removed in vacuo and the residue was purified by flash chromatography (elution gradient 3% acetone/methylene chloride) to give methyl 3-(2-morpholin-4-ylethoxy)benzoate (9.0 g) as an oil.