Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]4[O:20][CH2:19][CH2:18][N:17]([C:21]([N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]5[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[O:22])[CH2:16][C:15]=4[CH:35]=3)[CH:9]=[CH:10][C:4]=2[N:3]=1>C(O)C.CO>[CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]4[O:20][CH2:19][CH2:18][N:17]([C:21]([N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]5[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[O:22])[CH2:16][C:15]=4[CH:35]=3)[CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Cc1nc2ccc(-c3ccc4c(c3)CN(C(=O)N3CCCCC3c3ccccc3)CCO4)cc2[nH]1
Solvent: CCO
Solvent: CO
Product: Cc1nc2ccc(-c3ccc4c(c3)CN(C(=O)N3CCCC[C@@H]3c3ccccc3)CCO4)cc2[nH]1

Procedure:
Prepared by chiral preparative HPLC separation of racemic 7-(2-methyl-1H-benzimidazol-6-yl)-4-[(2-phenylpiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepine (example 1) using a SHIMADZU LC-20AD apparatus equipped with a Chiralpak AD-H, 25 cm×4.6 mm column using a mobile phase of ethanol:methanol 1:1 and flow rate of 18.0 mL/min and detection at 220 nm. The isomer with retention time 11.20 min. was assigned as the (R)-enantiomer. Chiral analytical HPLC was carried out using a SHIMADZU LC-20AD apparatus equipped with a Chiralpak AD-H, 25 cm×4.6 mm column using a mobile phase of ethanol:methanol 1:1 and flow rate of 0.7 mL/min with detection at 254/220 nm. This isomer gave a retention time 9.51 min and ee>99%. MS (EI) C29H30N4O2: 467 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])/[C:11](=[CH:20]/[CH3:21])/[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH3:22].[BH4-].[Na+]>C1COCC1>[NH2:22][CH:20]([CH:11]1[CH2:10][C@@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]1[OH:19])[CH3:21]
Reactant: N
Reactant: C/C=C1\C[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(N)C1C[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc2C1O
Reaction time: 2 h
Yield: 78.7 %

Procedure:
To a solution of (S,E)-4-(3,4-dichlorophenyl)-2-ethylidene-3,4-dihydronaphthalen-1(2H)-one (42) (0.60 g, 1.89 mmol) in THF (8 mL) at ambient temperature was added ammonia solution (2.0 M in MeOH, 2.83 mL, 5.67 mmol). The reaction mixture was stirred for 4 h before NaBH4 (0.14 g, 3.78 mmol) was added. The reaction mixture was stirred for 2 h before being quenched by a saturated solution of NH4Cl (8 mL). The product was extracted with diethyl ether (30 mL×2), dried and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane/0.1% DEA=1:7 to 1:5) to give (4S)-2-(1-aminoethyl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-ol (43) (0.50 g, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:3]=1N.N([O-])=O.[Na+].S(=O)(=O)(O)O.CN(C)C1C=CC=CC=1.Cl.[C:30]([O:33]C(=O)C)(=[O:32])C>C(O)(=O)C.S(=O)(=O)(O)N.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:3]=1[C:30]([OH:33])=[O:32]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1cccc(Cl)c1N
Agent: Cl
Agent: NS(=O)(=O)O
Agent: O=N[O-]
Solvent: CN(C)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCc1cccc(Cl)c1C(=O)O
Temperature: 6 °C
Reaction time: 0.5 h
Yield: 113.2 %

Procedure:
3.60 g (21.2 mmol) of 2-chloro-6-ethylaniline in 60 ml of acetic acid is introduced into a reaction vessel and the clear, colourless solution is cooled to 6° C. At that temperature, 3.64 g (22.7 mmol) of a 43% aqueous sodium nitrite solution are added and then, in the course of 15 minutes, a solution of 4.32 g (42.4 mmol) of sulfuric acid (96%) in 7 ml of acetic acid is added dropwise. The resulting dark-red solution is then stirred for 30 minutes. When a diazo colour test, for example using dimethylaniline-coated indicator paper, is positive and a colour spot test, e.g. using KI indicator paper moistened with aqueous 1N hydrochloric acid solution, is negative, 15 mg of sulfamic acid are added and then, at a temperature of 10° C., 8.7 ml (91.6 mmol) of acetic anhydride are added. The reaction mixture is then transferred to a glass autoclave and rinsed with 20 ml of acetic acid. At a temperature of 20° C. the autoclave is flushed out three times with nitrogen and then flushed out three times with CO. 220 mg of Pd2(dba)3.CHCl3 (0.212 mmol) in 5 ml of acetic acid are then metered in using a cannula at a CO pressure of 1 bar, then a CO pressure of 8 bar is applied and the reaction mixture is stirred overnight at 45° C. When the pressure has been released, the resulting suspension is filtered and the acetic acid filtrate is concentrated by evaporation under reduced pressure using a rotary evaporator; 1M aqueous hydrochloric acid solution is added to the organic phase that remains and extraction is carried out three times with toluene. The combined organic phases are evaporated under reduced pressure using a rotary evaporator, yielding 4.43 g of crude product with a target compound content of 75% according to HPLC. Purification by means of vacuum distillation (b.p. 130-135° C./0.01 mbar) yields 3.31 g (yield 85% of theory) of the desired target compound.
Reaction SMILES: [OH:1][C:2]([CH3:33])([CH3:32])[CH2:3][CH2:4][CH2:5][CH2:6]/[CH:7]=[C:8](/[C:10]1[CH:11]=[C:12]([CH:29]=[CH:30][CH:31]=1)[O:13][CH2:14][C:15]1[CH:16]=[C:17]([C:25](OC)=[O:26])[C:18](=[CH:23][CH:24]=1)[C:19](OC)=[O:20])\[CH3:9].[BH4-].[Li+]>>[OH:26][CH2:25][C:17]1[CH:16]=[C:15]([CH:24]=[CH:23][C:18]=1[CH2:19][OH:20])[CH2:14][O:13][C:12]1[CH:11]=[C:10](/[C:8](/[CH3:9])=[CH:7]/[CH2:6][CH2:5][CH2:4][CH2:3][C:2]([CH3:32])([OH:1])[CH3:33])[CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc(COc2cccc(/C(C)=C/CCCCC(C)(C)O)c2)cc1C(=O)OC
Agent: [BH4-]
Agent: [Li+]
Product: C/C(=C\CCCCC(C)(C)O)c1cccc(OCc2ccc(CO)c(CO)c2)c1

Procedure:
In a manner similar to Example 53(e), by reacting 204 mg (0.46 mmol) of dimethyl 4-[3-((E)-7-hydroxy-1,7-dimethyloct-1-enyl)phenoxymethyl]-phthalate (prepared in a manner similar to Examples 72(a-c)) with 30 mg (1.4 mmol) of lithium borohydride, a colourless oil is obtained (m=146 mg; Y=82%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[OH:18])[O:9][C:6]2=[N:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:1][CH:2]([F:19])[CH2:3][O:18][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:12]=1[C:10]1[O:9][C:6]2[C:5]([N:11]=1)=[CH:4][C:3]([C:2]([F:19])([F:1])[F:20])=[CH:8][N:7]=2
Reactant: Oc1cnccc1-c1nc2cc(C(F)(F)F)cnc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)COc1cnccc1-c1nc2cc(C(F)(F)F)cnc2o1
Temperature: 60 °C
Yield: 52.5 %

Procedure:
To a mixture of 0.31 g of 4-(6-trifluoromethyl-oxazolo[5,4-b]pyridin-2-yl)pyridin-3-ol, 0.23 g of potassium carbonate and 3 ml of DMF, a mixture of 0.50 g of trifluoromethanesulfonate(2,2-difluoroethyl)ester and 7 ml of DMF was added at room temperature, and then stirred while heating at 60° C. for six hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.10 g of 2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-6-trifluoromethyl-oxazolo[5,4-b]pyridine (hereinafter, referred to as “active compound 162”).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][C:6]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)(O)[CH2:5]1)[CH:2]=[CH2:3].[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+]>Cl>[CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]=[C:6]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCCC(O)(c2cccc3[nH]ccc23)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCN1CCC=C(c2cccc3[nH]ccc23)C1
Yield: 52.6 %

Procedure:
A solution of 14 g of the product of Example 27 in 400 ml of hydrochloric acid was refluxed for 4 hours and the mixture was iced and made alkaline with sodium hydroxide. Potassium carbonate was added to the mixture which was then extracted with ethyl acetate. The organic phase was dried and evaporated to dryness under reduced pressure and the 12.7 g of residue were chromatographed over silica gel. Elution with a 9-1 chloroform-acetone mixture yielded 6.85 g of 4-[1-(2-propenyl)-1,2,5,6-tetrahydropyridin-3-yl]-1H-indole with an Rf=0.15.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=[O:2].[F:24][C:25]1[C:32]([F:33])=[C:31]([F:34])[C:30]([F:35])=[C:29]([F:36])[C:26]=1[CH2:27]Br>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([O:3][CH2:27][C:26]4[C:29]([F:36])=[C:30]([F:35])[C:31]([F:34])=[C:32]([F:33])[C:25]=4[F:24])=[O:2])([CH2:9][CH2:8]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Fc1c(F)c(F)c(CBr)c(F)c1F
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)OCc3c(F)c(F)c(F)c(F)c3F)(CC1)CC2
Yield: 89.7 %

Procedure:
In a similar manner to Example 8, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (30.0 mg) and 2,3,4,5,6-pentafluorobenzyl bromide (26.6 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-(2,3,4,5,6-pentafluorobenzyl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (41.9 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][N:13]=2)[CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.[NH4+].[Cl-]>C(O)C.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([NH:11][C:12]2[N:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:15]=[CH:14][N:13]=2)[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)cc(Nc2nccc(C(F)(F)F)n2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1cc(Br)cc(Nc2nccc(C(F)(F)F)n2)c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
N-(3-Bromo-5-nitrophenyl)-4-(trifluoromethyl)pyrimidin-2-amine (4.76 g, 13.11 mmol) was dissolved in ethanol (131 ml) and saturated solution of NH4Cl (1 mL) was added followed by Fe (3.66 g, 65.5 mmol). The reaction mixture was stirred at 80° C. for 30 minutes then cooled to room temperature. The solution was filtered through a short pad of silica gel and eluted with EtOAc. The phase were separated, the organics were dried, filtered, concentrated under reduced pressure to afford 5-bromo-N-[4-(trifluoromethyl)pyrimidin-2-yl]benzene-1,3-diamine as a beige powder.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li]CCCC.[CH2:11]([CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16]I)[CH2:12][CH2:13][CH3:14].O>C1COCC1>[CH2:11]([CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCC(CI)CCCC
Reactant: c1ccsc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCC(CCCC)Cc1cccs1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of thiophene (5.71 g, 67.9 mmol) in dry THF (60 mL) was cooled to −78° C. under nitrogen. A solution of n-BuLi (26.0 mL, 2.5 M, 65.0 mmol) was then added dropwise. After addition, the reaction mixture was stirred at −78° C. for additional 1 hour, before a solution of 2-butyloctyliodide (16.0 g, 54.0 mmol) in dry THF (30 mL) was added slowly. This mixture was stirred at −78° C. for 1 hour, and then allowed to warm to room temperature slowly and stirred at room temperature for 38 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ether. The organic layer was washed with water and brine, dried over MgSO4, and concentrated on a rotary evaporator. The residue was subjected to column chromatography on silica gel with hexane as the eluent, leading to a colorless oil as the product (4.95 g, 36.3%).
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[N:19]=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O.O>[Cl:24][C:21]1[N:20]=[N:19][C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:25])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)=[CH:23][CH:22]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccc(Cl)nn3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccc(Cl)nn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Yield: 54.4 %

Procedure:
To a solution of [6-(6-chloro-pyridazin-3-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.2 g, 0.55 mmol) in THF:H2O (1:1, 10 mL) at 0° C. was added a solution of LiOH (0.026 g, 1.10 mmol) in water (1 mL). The solution was allowed to warm to room temperature over 3 hours then acidified to pH 2 with 1N HCl (1 mL) at 0° C. and concentrated in vacuo. The residue was purified by preparative HPLC to give [6-(6-chloro-pyridazin-3-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid (0.1 g, 54%). 1H NMR (400 MHz, DMSO): δ 9.21 (s, 1H), 7.96 (d, J=9.2 Hz, 1H), 7.60 (d, J=9.2 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.15 (d, J=1.6 Hz, 1H), 5.52 (dd, J=2.4, 9.2 Hz, 1H), 3.10 (dd, J=2.0, 15.6 Hz, 1H), 2.31 (s, 3H), 2.18-2.12 (m, 1H). MS (ESI) m/z=333 [M−H]−.
Reaction SMILES: C([O:8][C:9]1[C:10]([CH:15]=[CH:16][CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>C(O)C.CCOC(C)=O.[Pd]>[OH:8][C:9]1[C:10]([CH2:15][CH2:16][CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc(CC=Cc2ncccc2OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CCCc2ncccc2O)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 77.2 %

Procedure:
Methyl 4-[3-(3-benzyloxy-2-pyridyl)prop-2-enyl]benzoate (1.5 g, 4.2 mmol) was dissolved in ethanol (5 ml) and EtOAc (15 ml), treated with 10% palladium on carbon (0.15 g) and placed under a hydrogen atmosphere. The mixture was stirred at ambient temperature for 10 hours and filtered and evaporated to give methyl 4-[3-(3-hydroxy-2-pyridyl)propyl]benzoate as a yellow oil (0.88 g, 77%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].[CH2:14]([CH2:21][C:22](=O)[C:23]([OH:25])=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([BH3-])#N.[Na+].Cl>CO>[C:23]([CH:22]([NH:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13])[CH2:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([OH:25])=[O:24]
Reactant: O=C(O)C(=O)CCc1ccccc1
Reactant: NC1CCc2ccccc2NC1=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C(O)C(CCc1ccccc1)NC1CCc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 3-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (8.0 g) and benzylpyruvic acid (18.0 g) in methanol (450 ml) was stirred at room temperature under nitrogen for 30 minutes. Sodium cyanoborohydride (4.5 g) was added, and the resulting solution stirred at room temperature for 48 hours. Concentrated hydrochloric acid (7 ml) was added dropwise during 10 minutes and stirring was maintained for an additional 1 hour. The reaction mixture was evaporated to dryness, dichloromethane (150 ml) was added, and the mixture stirred for 30 minutes. The solid was filtered off, stirred with water (100 ml) for 15 minutes, then filtered, washed with water (50 ml), and dried to give 3-(1-carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one, m.p. 173°-175° as a mixture of isomers.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10]CC)=[O:9])=[C:4]([CH3:15])[C:3]=1[NH:16][CH2:17][C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH:21]=[CH:20][C:19]=1[F:31].[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH3:15])[C:3]=1[NH:16][CH2:17][C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH:21]=[CH:20][C:19]=1[F:31]
Reactant: CCOC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(OCC(=O)O)ccc(F)c1NCc1cc(-c2cccc(F)c2)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a solution of ethyl 2-[4-fluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]-2-methyl-phenoxy]acetate (200 mg, 0.466 mmol, 1.0 eq) in THF (8 mL) was added NaOH (1M aqueous solution, 4 mL, 4.0 mmol, 9.0 eq) at 0° C. The reaction mixture was stirred at room temperature for 1 h, then the organic solvent removed under reduced pressure and the aqueous solution diluted with water and adjusted to pH 4-6 by addition of diluted HCl. The precipitate that formed was collected by filtration, washed with water and dried in vacuo to give the title compound (I(m)) as a solid (150 mg, 80%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19].O>C(OCC)(=O)C>[C:18]([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2])(=[O:20])[CH3:19]
Reactant: CC(C)c1ccccc1O
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccccc1C(C)C
Reaction time: 1 h

Procedure:
2-Isopropylphenol (5.0 kg, 36.7 mol) is dissolved in ethyl acetate (20.8 L) and to this is added triethylamine (4.48 kg, 44.1 mmol). This solution is cooled to -12° and to this is added acetyl chloride (3.15 kg, 40.2 tool) over a period of 2.5 hours keeping the temperature below -10°. Triethylamine hydrochloride precipitates immediately. After the addition is complete stirring is continued for 1 hour at 15° at which time a solid mass is formed. This is dissolved by the addition of water (12L). After separation of the layers the organic layer is further washed with water (233 12L) and evaporated in vacuo (50°, 2 Torr) and then at 70°, 2 Torr to give 2-isopropyl-phenyl acetate as a residual amber oil.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCc1ccc(-c2ccc(OC)cc2)cc1
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
To a solution of ethyl 3-(4′-methoxybiphenyl-4-yl)propanoate (0.35 g, 1.2 mmol) in dichloromethane was added borontribromide (0.4 g, 1.6 mmol) at 0° C. and stirred at RT for 30 min, Reaction quenched with ethanol and diluted with water and extracted with dichloromethane, organic layer was washed with NaHCO3, water and brine solution and dried over sodium sulphate then concentrated to white solid (0.27 g, Yield: 83.3%): 1H NMR (300 MHz, CDCl3): δ 9.49 (s, 1H), 7.43-7.48 (t, 4H), 7.23-7.26 (d, 2H), 6.81-6.84 (d, 2H), 4.01-4.08 (m, 2H), 2.83-2.88 (t, 2H), 2.59-2.64 (t, 2H), 1.13-1.18 (t, 3H).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[O:5]=[S:6]1(=[O:32])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][N:9]([C:17]2[CH:26]=[C:25]([S:27](Cl)(=[O:29])=[O:28])[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH3:31])[CH:23]=3)[N:18]=2)[CH2:8][CH2:7]1>ClCCl.C(N(CC)CC)C>[NH2:3][CH2:2][CH2:1][NH:4][S:27]([C:25]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH3:31])[CH:23]=2)[N:18]=[C:17]([N:9]2[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:6](=[O:32])(=[O:5])[CH2:7][CH2:8]2)[CH:26]=1)(=[O:28])=[O:29]
Reactant: NCCN
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(S(=O)(=O)Cl)c2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(S(=O)(=O)NCCN)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 3.1 %

Procedure:
To a cooled solution of ethane-1,2-diamine (320 mg, 5.4 mmol) in dichloromethane (50 mL) was added triethylamine (3 drops) followed by 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinoline-4-sulfonyl chloride (the filtrate from the above step) at 0° C. The resulting mixture was stirred at room temperature for 16 hours and concentrated in vacuo. The residue was purified by preparative HPLC to afford 56.38 mg of the desired product (yield of three steps was 3.1%). MS (ESI+) [(M+H)+] 461, 1H NMR (400 MHz, CD3OD) δ ppm 8.11 (s, 1 H), 7.99-7.97 (d, J=8.4 Hz, 1 H), 7.85-7.83 (d, J=7.6 Hz, 1 H), 7.67-7.63 (m, 3 H), 7.49-7.45 (m, 2 H), 5.25 (s, 2 H), 4.76-4.03 (m, 2 H), 3.63-3.59 (t, 2 H), 3.03-3.00 (m, 4 H), 2.46 (s, 3 H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[CH2:16]([O:20][CH2:21][CH2:22][CH2:23][NH2:24])[CH2:17][CH2:18][CH3:19].O>CC(C)=O>[CH2:16]([O:20][CH2:21][CH2:22][CH2:23][NH:24][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:9])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCOCCCN
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Solvent: O
Solvent: CC(C)=O
Product: CCCCOCCCNC(c1ccccc1)C(O)c1ccccc1
Temperature: 140 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A mixture of trans-stilbene oxide (1.96 g, 0.010 mole) and 3-(n-butyloxy)-1-propylamine (3.93 g, 0.030 mole) was heated at 140° C. for 5 hrs. After standing at ambient temperature for 18 hr, the mixture was dissolved in acetone (20 ml) and the solution poured into water (120 ml). The solid which formed was collected by filtration and dried under ambient conditions to yield 3.24 g of slightly wet solid (>100%). Recrystallization from tolueneisooctane gave 1.70 g of a white solid, m.p. 82°-84° C.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Cl)Cl.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[CH3:8][C:7]1[C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3][CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Br
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc([N+](=O)[O-])cnc1-c1ccccc1
Yield: 96.4 %

Procedure:
In a schlenck tube, a mixture of 2-bromo-3-methyl-5-nitropyridine (4.6 mmol, 1.0 g), phenylboronic acid (4.6 mmol, 0.560 g), PdCl2dppf.DCM (0.47 mmol, 0.4 g), Cs2CO3 (13.8 mmol, 4.5 g) in a dioxane/water 4:1 mixture (18 ml) was heated at 100° C. for 14 hours, under argon atmosphere. The solvent was evaporated and the crude mixture was extracted between water and ethyl acetate. The solid residue was purified by chromatography over SiO2 eluting with hexane/ethyl acetate mixtures affording 3-methyl-5-nitro-2-phenylpyridine (0.95 g, yield 97%) as major product.