Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(OC(OC)=O)=O.[C:10]1([CH:16]([CH3:18])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.S(=O)(=O)(O)O.[C:24]1([OH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[C:16]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[OH:30])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:18])[CH3:17]
Reactant: Oc1ccccc1
Reactant: CC(C)c1ccccc1
Agent: COC(=O)OC(=O)OC
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CC(C)(c1ccccc1)c1ccccc1O

Procedure:
A stock solution containing 6 wt% DMPC, 15 wt% cumene and 50 ppm sulfuric acid with the balance composed of equimolar phenol and acetone was distributed among several melting point capillary tubes which were subsequently sealed and heated for various lengths of time in a stirred oil bath. The tubes were then quickly cooled by immersion in an ice bath and the contents were analyzed by gas chromatography. The amount of AMS formed increased with time up to a maximum yield and then declined as increased amounts of AMS dimers and cumylphenol were formed. Table II records the maximum AMS yield obtained at each temperature, as well as the heating time required to reach that yield. It is clear from the data of Table II that the best yields of AMS were obtained at temperatures over 90° C., e.g., 120° and 130° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=O)=[CH:4][CH:3]=1.C=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CCCC)CCCC)CCC.CC1C=CC(C)=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: C=Cc1ccccc1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccc(C)cc1
Solvent: CCCCN(CCCC)CCCC
Product: Brc1ccc(C=Cc2ccccc2)cc1
Yield: 51 %

Procedure:
0.448 g (2 millimols) of palladium acetate, 43.88 g (0.2 mol) of 4-bromobenzoyl chloride, 26 g (0.25 mol) of styrene and 37.06 g (0.2 mol) of tri-n-butylamine in 200 mol of p-xylene are stirred for 4 hours at 120° C. After the reaction mixture has been extracted by shaking with 2 N HCl and 2 N NaOH, and dried over magnesium sulfate, the crude product is chromatographed in toluene on silica gel, and is recrystallised from n-hexane. 26.43 g (51% of theory) of 4-bromostilbene are obtained as pale yellow crystals of melting point 137.7° C.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[C:15]=1[F:22].[C:23](=[O:25])=[O:24]>C1COCC1>[Br:13][C:14]1[C:15]([F:22])=[C:16]([F:21])[C:17]([F:20])=[C:18]([CH:19]=1)[C:23]([OH:25])=[O:24]
Reactant: O=C=O
Reactant: Fc1ccc(Br)c(F)c1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1cc(Br)c(F)c(F)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of diisopropylamine (10.14 g, 100.20 mmol) in THF (100 mL) was added n-BuLi (40.08 mL, 2.5 M in hexane, 100.20 mmol) at −78° C. under nitrogen atmosphere. The stirring was maintained at this temperature for 1 h. Then a solution of 1-bromo-2,3,4-trifluorobenzene (17.62 g, 83.50 mmol) in THF (120 mL) was added. After stirring for 1 h at −78° C., the mixture was transferred to a bottle with dry ice. The mixture was stirred overnight at room temperature. The reaction was quenched with 10% aqueous HCl and pH was adjusted to 1-2. The mixture was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL) sequentially, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the desired product (20.12 g, 94.5% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.95 (s, 1H), 7.97 (m, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[C@@H:27]([C:28](O)=[O:29])[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH:28]([C@H:27]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][N:18]1[C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])=[O:29]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@@H]1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@@H]1C=O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
To a solution of oxalyl dichloride (1.14 g, 9 mmol) in dichloromethane (30 mL) was added dimethyl sulfoxide (1.4 g, 18 mmol) at −78° C. After stirring at −78° C. for 20 min, to the mixture was added a solution of (R)-tert-butyl3-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (Step A (2), 1.32 g, 5 mmol) in dichloromethane (30 mL) and stirred at −78° C. for 30 to 45 min. Then triethylamine (36 mmol) was added and the reaction mixture was warmed up to rt over 2 h. Saturated sodium carbonate solution was added and extracted with dichloromethane. The solvent was removed and the crude mixture was purified by silica gel Flash chromatography to give the title compound: 1.2 g (90% yield). 1H NMR (CDCl3, 500 MHz) δ 1.48 (9H, d, J=35 Hz), 3.06-3.62 (2H, m), 4.45-4.81 (3H, m), 7.09-7.19 (4H, m), 9.48 (1H, d, J=25 Hz).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([NH2:20])=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)[CH2:3][CH2:2]1.I.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](SC)=[NH:28]>C(O)C.O.C(=O)([O-])[O-].[Na+].[Na+]>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([NH:20][C:27]([C:23]4[S:22][CH:26]=[CH:25][CH:24]=4)=[NH:28])=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)[CH2:3][CH2:2]1
Reactant: CSC(=N)c1cccs1
Reactant: Nc1ccc2c(c1)CCCN2CCCN1CCOCC1
Agent: I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N=C(Nc1ccc2c(c1)CCCN2CCCN1CCOCC1)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
To a stirred solution of 1-(3-morpholinopropyl)-1,2,3,4-tetrahydroquinolin-6-amine (190 mg, 0.690 mmol) in ethanol (10 ml) under argon was added methyl thiophene-2-carbimidothioate hydroiodide (393 mg, 1.380 mmol). The resulting suspension was then stirred overnight at room temperature. The mixture was then diluted with water and sodium carbonate and extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated, then chromatographed in ethyl acetate, followed by 5-10% (2M NH3 in MeOH) in dichloromethane, giving the desired N-(1-(3-morpholinopropyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboximidamide 72 (132 mg, 0.343 mmol, 49.8% yield). 1H NMR (DMSO-d6) δ 7.67 (d, J=3 Hz, 1H), 7.56 (d, J=4.8 Hz, 1H), 7.09-7.06 (m, 1H), 6.56 (brs, 2H), 6.49 (s, 1H), 6.33 (brs, 2H), 3.60-3.56 (m, 4H), 3.26-3.17 (m, 4H), 2.66 (t, J=6.3 Hz, 2H), 2.34-2.28 (m, 6H), 1.89-1.81 (m, 2H), 1.69-1.63 (m, 2H). EI-MS (m/z, %) 384 (100, MH+), 270 (52). HPLC purity: 99%.
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[O:5][CH2:6][CH:7]([OH:10])[CH2:8][NH2:9])#[N:2].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].[CH2:23](Cl)[CH:24]([OH:26])[CH3:25]>C(O)C>[C:1]([C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[O:5][CH2:6][CH:7]([OH:10])[CH2:8][NH:9][CH2:23][CH:24]([CH3:25])[OH:26])#[N:2]
Reactant: N#Cc1ccccc1OCC(O)CN
Reactant: CC(O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: CC(O)CNCC(O)COc1ccccc1C#N

Procedure:
A mixture consisting of 0.3 gm (about 0.0015 mol) of 1-(2'-cyano-phenoxy)-2-hydroxy-3-amino-propane, 5 ml of absolute ethanol, 0.21 gm (0.002 mol) of sodium carbonate, 30 mgm of potassium iodide and 0.189 gm (0.002 mol) of propylene chlorohydrin was refluxed for 20 hours, accompanied by stirring. Thereafter, the reaction mixture was worked up in conventional manner, and the isolated raw reaction product was purified by chromatography in a silicagel column, yielding the free base 1-(2'-cyano-phenoxy)-2-hydroxy-3-[(2"-methyl-2"-hydroxy-ethyl)-amino]-propane.
Reaction SMILES: [C:1]1([S:7][CH:8]2[CH2:12][C:11](=[O:13])[O:10][C:9]2=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[O:13]=[C:11]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[S:7][CH:8]([C:9]([OH:10])=[O:14])[CH2:12]1
Reactant: O=C1CC(Sc2ccccc2)C(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1CC(C(=O)O)Sc2ccccc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 47.4 %

Procedure:
Crude 3-phenylsulfanyl-dihydro-furan-2,5-dione (20 g, 91 mmol) was dissolved in CH2Cl2 (30 ml) and cooled to 0° C. Aluminum chloride (18.16 g, 136 mmol) was added and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was diluted with CH2Cl2 (1000 ml) and poured into ice-cooled conc HCl (1000 ml). The phases were separated and the aqueous phase was extracted with CH2Cl2(×3). The combined organic phases were washed with water, dried (MgSO4) and evaporated to a brown solid. The solid was triturated with Et2O to give 8.98 g of 4-oxo-thiochroman-2-carboxylic acid as a pale brown solid. 1H NMR (DMSO) δ 7.96 (1H, dd), 7.20-7.60 (3H, m), 4.40 (1H, dd), 3.20-3.33 (2H, m).
Reaction SMILES: CC(C)([O-])C.[K+].C1(C)C=CC(S([CH2:16][N+:17]#[C-])(=O)=O)=CC=1.[CH2:20]([O:27][C:28]1[C:32]([CH:33]=O)=[CH:31][N:30]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>C(COC)OC.CO>[CH2:20]([O:27][C:28]1[C:32]([CH2:33][C:16]#[N:17])=[CH:31][N:30]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1cn(-c2ccccc2)nc1OCc1ccccc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Solvent: COCCOC
Product: N#CCc1cn(-c2ccccc2)nc1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 67.3 %

Procedure:
To a mixture of potassium t-butoxide (3.82 g) and dimethoxyethane (20 ml) was added a solution of p-toluenesulfonylmethyl isocyanide (3.51 g) in dimethoxyethane (20 ml) and the mixture was stirred at −78° C. for 5 min. Then a solution of 3-benzyloxy-1-phenyl-1H-pyrazole-4-carbaldehyde (4.73 g) in dimethoxyethane (80 ml) was added. After stirring at said temperature for 1 hr, the mixture was stirred for 1 hr. while raising the temperature to room temperature. To the obtained mixture was added methanol (100 ml), and the mixture was refluxed for 1 hr. After cooling, the reaction solution was poured into saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 3-benzyloxy-1-phenyl-1H-pyrazol-4-ylacetonitrile (3.31 g, yield 67%). was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). The crystals were recrystallized from tetrahydrofuran-hexane. melting point: 102–103° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[N:5][C:4]=1[C:14]([N:16]([CH2:38][CH:39]([CH3:41])[CH3:40])[C@H:17]1[CH2:22][C@@H:21]([C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:24])[CH2:20][N:19]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:18]1)=[O:15].[C:42]1(O)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[CH3:40][CH:39]([CH3:41])[CH2:38][N:16]([C:14]([C:4]1[N:5]=[N:6][N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[CH2:2][O:1][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:15])[C@H:17]1[CH2:22][C@@H:21]([C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:24])[CH2:20][N:19]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[CH2:18]1
Reactant: Oc1ccccc1
Reactant: CC(C)CN(C(=O)c1nnn(-c2ccccc2)c1CO)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)CN(C(=O)c1nnn(-c2ccccc2)c1COc1ccccc1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 148.1 %

Procedure:
tert-Butyl (3S,5R)-3-[{[5-(hydroxymethyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (205 mg), phenol (70 mg) and triphenylphosphine (190 mg) were dissolved in toluene (5 ml), diisopropyl azodicarboxylate (40% toluene solution, 365 mg) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated brine, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted to with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object product (344 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C[Si]([C:11]#[C:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17])(C)C.Cl>CO>[C:12]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17])#[CH:11]
Reactant: C[Si](C)(C)C#Cc1cccc(C#N)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
Add potassium carbonate (0.138 g, 1 mmol) to a solution of 3-trimethylsilanylethynylbenzonitrile from PREPARATION 5 (2.0 g, 10.1 mmol) in methanol (50 mL). Stir the mixture at room temperature for 20 min and add a 10% aqueous hydrochloric acid solution (4 mL). Concentrate to a reduced volume, add diethyl ether and water and separate the phases. Wash once the aqueous phase with diethyl ether. Combine the organic phases, dry over sodium sulfate and concentrate to obtain the title compound as a solid (1.17 g, 92%).
Reaction SMILES: [CH2:1]1[NH:3][CH2:2]1.[NH2:4][C@@H:5]([CH2:9][CH2:10][C:11]([NH:13][C@H:14]([C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])[CH2:15][SH:16])=[O:12])[C:6]([OH:8])=[O:7]>O>[NH2:3][CH2:2][CH2:1][S:16][CH2:15][C@@H:14]([C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])[NH:13][C:11](=[O:12])[CH2:10][CH2:9][C@@H:5]([C:6]([OH:8])=[O:7])[NH2:4]
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Reactant: C1CN1
Solvent: O
Product: NCCSC[C@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)NCC(=O)O
Temperature: 25 °C

Procedure:
There are added over a 5 minute period 1.29 g of ethylene imine, freshly distilled, to a solution of 30 millimoles of glutathione in 150 cc of water. The resulting mixture is stirred for ten minutes at ambient temperature and then concentrated to dryness. The resulting solid residue is triturated and washed successively with benzene, ethanol and acetone. The white product thus obtained (9.5 g) melts around 200° with decomposition.
Reaction SMILES: [C:1]1([CH:7]2[CH2:13][C:12](=[O:14])[O:11][C:9](=[O:10])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CN.[CH2:18]([N:20](CC)CC)C>C1COCC1>[CH3:18][NH:20][C:9]([CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:13][C:12]([OH:11])=[O:14])=[O:10]
Reactant: CCN(CC)CC
Reactant: O=C1CC(c2ccccc2)CC(=O)O1
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)CC(CC(=O)O)c1ccccc1
Reaction time: 1.5 h
Yield: 89 %

Procedure:
A solution of 3-phenylglutaric anhydride (500 mg, 2.63 mmol) in THF was added to a mixture of methylamine hydrochloride (266 mg, 3.94 mmol) and triethylamine (1.1 mL, 0.80 g, 7.9 mmol) in 4.0 mL of THEF. After 1.5 h, additional methylamine hydrochloride (177 mg, 2.62 mmol) and triethylamine (0.36 mL, 0.26 g, 2.6 mmol) were added and stirring was continued overnight at room temperature. The reaction was partitioned between 50 mL of ethyl acetate and 25 mL of 2.0 N aqueous HCl. The aqueous layer was extracted with 2×25 mL of ethyl acetate. The combined ethyl acetate layers were washed with 50 mL of brine, dried over sodium sulfate, and evaporated to give 518 mg of the title compound as a white solid. 1NMR (400 MHz, CD3OD): δ 7.29-7.22 (m, 4H), 7.20-7.14 (m, 1H), 3.58 (tt, 1H, J=9, 7 Hz), 2.68 (dd, 1H, J=15, 7 Hz), 2.59 (dd, 1H, J=15, 9 Hz), 2.57 (s, 3H), 2.55 (dd, 1H, J=15, 7 Hz), 2.44 (dd, 1H, J=15, 9 Hz). Mass spectrum (NH3 /CI): m/z=222 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9]Br.[I-].[Na+].[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19]>O1CCCC1.C(Cl)Cl>[C:18]([NH:22][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][C:3]1[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:2]=1[F:1])([CH3:21])([CH3:20])[CH3:19]
Reactant: Fc1ccc(Br)cc1COCCCCBr
Reactant: CC(C)(C)N
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)NCCCCOCc1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-(2-fluoro-5-bromobenzyloxy)butyl bromide (400 mg, 1.18 mmol) in tetrahydrofuran (6 ml) was treated with sodium iodide (242 mg, 1.6 mmol). The resulting mixture was stirred at ambient temperature. After 1.5 hours, the sodium bromide was removed by filtration, and the filtrate concentrated. The residue was treated with a tetrahydrofuran solution of tert-butylamine (1.24 ml, 11.8 mmol). The progress of the reaction was monitored by thin layer chromatography. The resulting mixture was stirred for about 19 hours at ambient temperature. The reaction mixture was diluted with methylene chloride, and washed with saturated sodium bicarbonate. The organic fraction was dried over sodium sulfate and the solvents were removed in vacuo. The desired title intermediate was further purified by radial chromatography.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]([NH2:13])[CH3:12])=[CH:2]1.[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O>>[F:14][C:15]1[CH:16]=[C:17]([CH:18]2[C:2]3[NH:1][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]=3[CH2:10][CH:11]([CH3:12])[NH:13]2)[CH:20]=[CH:21][CH:22]=1
Reactant: O=Cc1cccc(F)c1
Reactant: CC(N)Cc1c[nH]c2ccccc12
Product: CC1Cc2c([nH]c3ccccc23)C(c2cccc(F)c2)N1

Procedure:
In addition, the compounds in Example 15(5) and Example 15(6) were prepared by separating diastereomer mixture which was obtained by reacting [2-(1H-indol-3-yl)-1-methylethyl]amine with 3-fluorobenzaldehyde, by column chromatography on silica gel.
Reaction SMILES: [NH2:1][C@H:2]([CH2:15][F:16])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[NH:13])=[O:12])=[CH:7][CH:6]=1)[OH:4].C([O:19][C:20](=O)[CH:21]([Cl:23])[Cl:22])C>>[Cl:22][CH:21]([Cl:23])[C:20]([NH:1][C@H:2]([CH2:15][F:16])[C@H:3]([OH:4])[C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH3:14])(=[NH:13])=[O:12])=[CH:9][CH:10]=1)=[O:19]
Reactant: CCOC(=O)C(Cl)Cl
Reactant: CS(=N)(=O)c1ccc([C@@H](O)[C@H](N)CF)cc1
Product: CS(=N)(=O)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.4 %

Procedure:
To a solution of (1R,2S)-2-amino-3-fluoro-1-(4-(S-methylsulfonimidoyl)phenyl)propan-1-ol (76 mg, 0.308 mmol) Methanol (5 mL) is added TEA (0.047 mL, 0.462 mmol) followed by addition of ethyldichloroacetate (0.048 mL, 0.308 mmol) The resulting reaction mixture is stirred at room temperature for 16 h. Solvent is evaporated in vacuo to get crude which is purified by combi-flash chromatography using 0.6% MeOH in DCM as an eluent to get 40 mg of the compound which is re-purified by prep HPLC to afford title compound (25 mg) white solid. 1H-NMR (400 MHz, DMSO) δ: 3.0 (s, 3H), 4.19-4.25 (m, 2H), 4.28-4.32 (m, 0.5H), 4.40-4.44 (m, 0.5H), 4.56-4.59 (m, 0.5H), 4.67-4.71 (m, 0.5H), 4.96 (bs, 1H), 6.12 (d, 1H, J=3.6 Hz), 6.47 (d, 1H, J=1.88 Hz), 7.56 (d, 2H, J=8.28 Hz), 7.54 (d, 2H, J=8.28 Hz), 8.82 (d, 1H, J=8.28 Hz). LC-MS (m/z): M+H=357.0.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][O:8][CH:7]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[O:6][CH2:5]1)[CH2:2][CH3:3].C([Li])CCC.Br[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1.O>C1COCC1.CCCCCC.[Cl-].[Zn+2].[Cl-]>[CH2:1]([CH:4]1[CH2:5][O:6][CH:7]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[C:12]([F:17])[CH:11]=2)[O:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: Clc1ccc(Br)cc1
Reactant: CCCC1COC(c2cc(F)cc(F)c2)OC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC1COC(c2cc(F)c(-c3ccc(Cl)cc3)c(F)c2)OC1
Temperature: -60 °C
Reaction time: 0.83 h
Yield: 56.3 %

Procedure:
5-Propyl-2-(3,5-difluorophenyl)-1,3-dioxane (5.0 g; 20.6 mmol), which had been synthesized in Step 1 of Example 1, was dissolved in THF (50 ml), and the solution was cooled to -60° C. in a nitrogen atmosphere. A solution (16.1 ml; 25.8 mmol) of 1.60M n-butyl lithium in hexane was added dropwise thereto so that the temperature of the mixture did not exceed -55° C. The mixture was stirred for 50 minutes with the temperature being maintained below -55° C. Subsequently, a solution (51.6 ml; 25.8 mmol) of 0.5M zinc chloride in THF was added dropwise so that the temperature of the mixture did not exceed -50° C. Thereafter, the mixture was warmed to room temperature and stirred for 30 minutes. Tetrakistriphenylphosphine palladium (0.5 g) and 1-bromo-4-chlorobenzene (4.94 g; 25.8 mmol) were added, and the mixture was refluxed for 3 hours. Water (100 ml) was added to the resultant reaction mixture, and the material produced was extracted with toluene. The extract was sequentially washed with saturated ammonium chloride solution, saturated sodium bicarbonate solution and saturated brine and dried over magnesium sulfate. Subsequently, the solvent was evaporated. The residue was purified by column chromatography (eluent: toluene). The solvent was evaporated, and the residue was recrystallized twice from heptane, to thereby obtain 4.10 g (11.6 mmol) of 5-propyl-2-(4-(4-chlorophenyl)-3,5-difluorophenyl)-1,3-dioxane. The yield of this compound from 5-propyl-2-(3,5-difluorophenyl)-1,3-dioxane was 56.3%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=2)=[CH:13][CH:12]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:18]=2)=[CH:15][CH:16]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=Cc1cccc(-c2ccc(Cl)cc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Fc1ccc(CNCc2cccc(-c3ccc(Cl)cc3)c2)cc1
Reaction time: 4 h
Yield: 62.7 %

Procedure:
To a homogeneous mixture of (4-fluorophenyl)methanamine (2.5 mL, 21.8 mmol) and 4′-chlorobiphenyl-3-carbaldehyde (Aldrich, 3.6 g, 16.8 mmol) in anhydrous dichloroethane (25 mL), under nitrogen atmosphere, was added acetic acid (1.2 mL, 21.0 mmol). The mixture was stirred at room temperature for 13.5 h before sodium triacetoxyborohydride (5.0 g, 23.5 mmol) was added. After 4 h, (4-fluorophenyl)methanamine (2.5 mL, 21.8 mmol) was added and the stirring continued. After an additional 5 h of stirring, the reaction was quenched with 1 N aq. NaOH solution (50 mL) then extracted twice with chloroform. The organic extracts were combined, washed with saturated aqueous NaHCO3 and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (Merck KGaA, 230-400 mesh particle size) eluting with 0-70% ethyl acetate in hexane, to afford the title compound (3.43 g, 59%) as a colorless oil. MS (ESI): 326.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:6]=1[Cl:14])[CH:2]=[CH2:3].[OH-].[Na+]>C(O)C>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([CH:8]=[CH:7][C:6]=1[Cl:14])[NH2:11])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc([N+](=O)[O-])ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=CCOc1cc(N)ccc1Cl
Temperature: 0 °C

Procedure:
A suspension of 1.0 g of 3A and 5.3 g of stannous chloride dihydrate in 10 mL of absolute ethanol was heated for 1 hour. The resulting mixture was poured into 100 g of ice, then sufficient 10% aqueous sodium hydroxide solution was added, with stirring, to bring the pH of the mixture to 10. The mixture was extracted with ethyl acetate, then with ether. The combined extracts were washed with water, then brine, then dried (Na2SO4) and stripped of the solvents, to give 3-(allyloxy)-4-chloroaniline (3B), as a brown oil.