Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[F:24][C:25]1[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.ClCCl.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:26]2[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH3:32])[C:25]=2[F:24])[CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Reactant: COc1cccc(B(O)O)c1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: COc1cccc(Cc2cccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)c2)c1F
Yield: 50.8 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-(2-fluoro-3-methoxybenzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.080 g; 0.230 mmol), 2-fluoro-3-methoxyphenylboronic acid (0.041 g; 0.241 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride, complex with dichloromethane (0.018 g; 0.023 mmol), sodium carbonate (0.049 g; 0.461 mmol), sodium iodide (0.069 g; 0.461 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.051 g (50%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[Cl:21][C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1>>[Cl:21][C:22]1[CH:23]=[C:24]([S:28]([N:8]2[C:9]3[C:5](=[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])[C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[CH:6]=[CH:7]2)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2S(=O)(=O)c2cccc(Cl)c2)c1CN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 11.3 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 3-chlorobenzene-1-sulfonyl chloride (23 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification using preparative HPLC/UV (System B) afforded the title product (3 mg, 10%) as a white solid. MS (ESI+) for C18H19ClN2O3S m/z 379 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH:18]([CH3:20])[CH3:19])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:21]=1.[C:22]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[C:28]([F:30])[CH:29]=1)#[N:23]>>[F:30][C:28]1[CH:29]=[C:24]([CH:25]=[C:26]([C:2]2[CH:3]=[CH:4][C:5]3[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH:18]([CH3:20])[CH3:19])([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)[C:6]=3[CH:21]=2)[CH:27]=1)[C:22]#[N:23]
Reactant: N#Cc1cc(F)cc(B(O)O)c1
Reactant: CC(C)C1(c2cccs2)OCC(=O)Nc2ccc(Br)cc21
Product: CC(C)C1(c2cccs2)OCC(=O)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21

Procedure:
Prepared from 7-bromo-5-isopropyl-5-thien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3-cyano-5-fluorobenzeneboronic acid using the coupling procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.07 (s, 1H), 8.03 (s, 1H), 7.90 (m, 1H), 7.84 (m, 1H), 7.77 (m, 2H), 7.51 (dd, J=5.0, 1.2 Hz, 1H), 7.24 (d, J=8.5 Hz, 1H), 7.04 (m, 2H), 4.20 (d, J=14.4 Hz, 1H), 3.96 (d, J=14.4 Hz, 1H), 2.90 (m, 1H), 0.92 (t, J=6.4 Hz, 6H); MS (ES) m/z 407 (M+H)+.
Reaction SMILES: N[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[BrH:13].N([O-])=O.[Na+]>C(#N)C.O>[Br:13][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: Nc1ccc2c(c1)C(=O)NCC2
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C1NCCc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a solution of 7-amino-3,4-dihydro-1(2H)-isoquinolinone, (0.77 g, 4.77 mmol)(for a synthesis see Girard, Yves; Atkinson, Joseph G.; Belanger, Patrice C.; Fuentes, Jose J.; Rokach, Joshua; Rooney, C. Stanley; Remy, David C.; Hunt, Cecilia A J. Org. Chem. (1983), 48(19), 3220) in acetonitrile (10 ml) at 0° C. was added 48% aqueous HBr (10 ml, precooled to 0° C.). The mixture was stirred at 0° C. for 0.5 h before addition of a solution of NaNO2 (0.379 g, 5.49 mmol) in water (2 ml) over 0.4 h. The reaction was then stirred at 0° C. for 0.5 h and then CuBr (0.822 g, 5.726 mmol) was added portionwise over 10 min. The reaction mixture was then warmed to room temperature, stirred at room temperature for 0.5 h and then at 70° C. for 1 h. The reaction mixture was then cooled to 0° C., water (60 ml) was added and the mixture stirred at 0° C. for 1 h before filtering and drying in vacuo. The residue was dissolved in 10% methanol/dichloromethane, dried with magnesium sulphate and evaporated to give the desired product (0.679 g, 63%).
Reaction SMILES: C(OC([NH:11][C@H:12]([CH2:29][P:30]([O:34][CH3:35])([O:32][CH3:33])=[O:31])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][C:23]2=[O:28])=[CH:18][CH:17]=1)=[O:14])=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:11][C@H:12]([CH2:29][P:30]([O:32][CH3:33])([O:34][CH3:35])=[O:31])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][C:23]2=[O:28])=[CH:18][CH:17]=1)=[O:14]
Reactant: [H][H]
Reactant: COP(=O)(C[C@@H](NC(=O)OCc1ccccc1)C(=O)Nc1ccc(N2CCOCC2=O)cc1)OC
Agent: [Pd]
Solvent: CO
Product: COP(=O)(C[C@@H](N)C(=O)Nc1ccc(N2CCOCC2=O)cc1)OC
Yield: 93.2 %

Procedure:
5.3 The mixture of 0.39 g (0.78 mmol) of (S)-2-(benzyloxycarbonyl-amino)-N-[4-(3-oxomorpholin-4-yl)phenyl]-3-(dimethoxyphosphoryl)-propionamide and 0.4 g of 5% palladium/carbon in 30 ml of methanol is hydrogenated until hydrogen is no longer taken up. The reaction mixture is subsequently filtered off, and the filtrate is evaporated to dryness, giving 0.27 g of (S)-2-amino-N-[4-(3-oxomorpholin-4-yl)phenyl]-3-(dimethoxyphosphoryl)propionamide as colourless oil, ESI 371.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH:9]1([CH:15]=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.O>CS(C)=O>[CH:9]1([CH:15]2[O:16][CH2:4]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=CC1CCCCC1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C1CCC(C2CO2)CC1
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
Sodium hydride (4.5 g, 187.5 mmol) and trimethylsulfoxonium iodide (41.25 g, 187.5 mmol) were combined in a 3-neck flask equipped with a mechanical stirrer and an addition funnel. Dimethyl sulfoxide (DMSO) was added slowly, over a 30 min period, until 200 mL had been added. Gas was evolved throughout the addition. A solution of cyclohexane carboxaldehyde (21.8 mL, 180 mmol) in 50 mL of DMSO was added dropwise to the reaction mixture over a 15 min period. The reaction mixture was heated to 55° C. and stirred at 55° C. for 30 min. The reaction mixture was cooled to ambient temperature and poured into 500 mL of water. The aqueous solution was extracted with 3×100 mL of diethyl ether. The combined ether extracts were washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product was distilled (44° C., 0.1 mm) to give 14 g (62% yield) of 1-cyclohexyl ethylene oxide as a clear colorless liquid.
Reaction SMILES: [CH:1](=O)[CH2:2][CH3:3].[O:5]=[C:6]([CH3:19])[CH2:7][C:8]([O:10][CH2:11][CH2:12][O:13][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])=[O:9].N1CCCCC1.Cl>O>[C:6]([C:7](=[CH:1][CH2:2][CH3:3])[C:8]([O:10][CH2:11][CH2:12][O:13][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])=[O:9])(=[O:5])[CH3:19]
Reactant: CCC=O
Reactant: C=C(C)C(=O)OCCOC(=O)CC(C)=O
Agent: Cl
Solvent: O
Solvent: C1CCNCC1
Product: C=C(C)C(=O)OCCOC(=O)C(=CCC)C(C)=O
Temperature: 0 °C
Reaction time: 0.02 h

Procedure:
To a magnetically stirred, 1000 mL, round bottom flask were added 200 mL of propionaldehyde and 587 mL 2-(methacryloyloxy)ethyl 3-oxobutanoate. The reaction mixture was cooled to 0° C., in an ice bath, and then 3 to 5 mL of piperidine was added dropwise over one minute. The mixture was stirred at 0° C., for 2 hours, and then allowed to warm to room temperature over the course of 2-2.5 hours. To the reaction mixture was slowly added 30 mL of 3N HCl, over about one minute, to neutralize the piperdine. The mixture was poured into a separatory funnel, and then 150 mL of deionized water was added. The mixture was shaken, and then the aqueous layer was separated and disposed of. The reaction mixture was washed three more times with 150 mL of deionized water, each time, and then dried over MgSO4. The reaction mixture was filtered, and then stabilized with 10 mass ppm of 4-hydroxy-TEMPO. The dried reaction mixture was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]([C:23]3[CH:33]=[CH:32][C:26]([C:27](OCC)=[O:28])=[CH:25][C:24]=3[CH3:34])[CH2:19][CH:20]([CH3:22])[CH3:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:35])[O:4][N:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)C>C1COCC1.ClCCl.CO>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]([C:23]3[CH:33]=[CH:32][C:26]([CH2:27][OH:28])=[CH:25][C:24]=3[CH3:34])[CH2:19][CH:20]([CH3:22])[CH3:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:35])[O:4][N:3]=1
Reactant: CCOC(=O)c1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)c(C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: Cc1cc(CO)ccc1N(CC(C)C)S(=O)(=O)c1ccc(OCc2c(C)noc2C)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 4-(4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-isobutylphenylsulfonamido)-3-methylbenzoate (40 mg, 0.080 mmol) in THF (5 mL) stirred under nitrogen at 0° C. was added a solution of LiAlH4 1M in diethyl ether (0.160 mL, 0.160 mmol) dropwise. The reaction mixture was stirred at 0° C. for 30 minutes. The reaction was then allowed to warm up to room temperature and stirred for 2 hours. The reaction mixture was diluted with dichloromethane (10 mL). The organic phase was washed with water 10 mL, and saturated brine 10 mL, dried using a hydrophobic frit and concentrated under a stream of nitrogen in the Radleys blowdown apparatus to give the crude product. The crude was dissolved in 1:1 MeOH:DMSO 1 mL and purified by mass directed autoprep on a Sunfire C18 column using acetonitrile:water with a formic acid modifier. The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus to give the required product, 23.6 mg colorless oil which solidified. LCMS (M+1) 459, RT 1.14 mins.
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]([O:20]C(C)(C)C)=[O:19])=[C:10]1[CH3:25])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].O1CCCC1.CO>O>[C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]([OH:20])=[O:19])=[C:10]1[CH3:25])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)OC(C)(C)C)c2ccccc2n1C(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)c2ccccc2n1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.6 %

Procedure:
A mixture of tert-butyl 1-benzoyl-2-methyl-1H-indole-3-carboxylate (440 mg, 1.3 mmol), lithium hydroxide monohydrate (276 mg, 6.6 mmol), tetrahydrofuran (12 mL), methanol (4 mL) and water (4 mL) was stirred at room temperature for 4 hours. The mixture was concentrated, acidified to pH 2 with concentrated hydrochloric acid and extracted with ethyl acetate (20 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 1-benzoyl-2-methyl-1H-indole-3-carboxylic acid (260 mg, 72%). LRMS (M+H) m/z: calcd 279.13. found 279.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].C(Br)C=C.[CH2:21]([O:24]CC=C)[CH:22]=[CH2:23].C(C1C=C(C=C(Br)C=1O)C#N)C=C.ClC1C=C(C=CC=1)C(OO)=O>C1(C)C=C(C)C=C(C)C=1>[Br:1][C:2]1[C:9]2[O:10][CH:22]([CH2:21][OH:24])[CH2:23][C:8]=2[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1
Reactant: C=CCOCC=C
Reactant: N#Cc1ccc(O)c(Br)c1
Agent: C=CCc1cc(C#N)cc(Br)c1O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Solvent: Cc1cc(C)cc(C)c1
Solvent: C=CCBr
Product: N#Cc1cc(Br)c2c(c1)CC(CO)O2

Procedure:
Treatment of 3-bromo-4-hydroxybenzonitrile (10.0 g, 50.0 mmol) with potassium carbonate (27.9 g, 200 mmol) and allyl bromide (7.96 g, 66.0 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-5-bromo-4-hydroxybenzonitrile. Treatment of 3-allyl-5-bromo-4-hydroxybenzonitrile (4.63 g, 19.0 mmol) with 3-chloroperoxybenzoic acid (6.2 g, 35.93 mmol, 77%) followed by potassium carbonate (6.56 g, 47.5 mmol) generally according to the procedure described for Intermediate 9 afforded 1.30 g (426) of (±)-7-bromo-2-(hydroxymethyl)-2,3-dihydro-1-benzofuran-5-carbonitrile. Treatment of (±)-7-bromo-2-(hydroxymethyl)-2,3-dihydro-1-benzofuran-5-carbonitrile (1.3 g, 5.0 mmol) with p-toluenesulfonyl chloride (1.02 g, 5.4 mol) generally according to the procedure described for Intermediate 10 gave 1.5 g (72%) of (±)-(7-bromo-5-cyano-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Treatment of (±)-(7-bromo-5-cyano-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.73 mmol) and 2-methylphenylboronic acid (0.3 g, 2.20 mmol) generally according to the procedure described for Intermediate 35 afforded 0.33 g, (99%) of (±)-[5-cyano-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.26 g, 4.0 mmol) generally according to the procedure described for Intermediate 98 afforded 0.17 g (74%) of (±)-2-(azidomethyl)-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-5-carbonitrile. Treatment of the azide with polymer-supported triphenylphosphine (0.24 g, 0.67 mmol) according to the procedure described in Example 154 afforded 0.118 g (53%) of (±)-2-(aminomethyl)-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-5-carbonitrile as a white solid, hydrochloride salt. mp 127-129° C.
Reaction SMILES: [CH:1]1([C:4](O)=O)[CH2:3][CH2:2]1.P(=O)(O)(O)O.[NH2:12][C:13]1[C:18]([NH2:19])=[C:17]([CH3:20])[CH:16]=[CH:15][N:14]=1.[OH-].[K+]>O>[CH:1]1([C:4]2[NH:12][C:13]3=[N:14][CH:15]=[CH:16][C:17]([CH3:20])=[C:18]3[N:19]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)C1CC1
Reactant: Cc1ccnc(N)c1N
Agent: O=P(O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1ccnc2[nH]c(C3CC3)nc12
Temperature: 130 °C
Reaction time: 12 h

Procedure:
30 ml of cyclopropanecarboxylic acid and 70 ml of phosphoric acid (85%) were added to 15 g of 2,3-diamino-4-methylpyridine, and the mixture was stirred at an internal temperature of 130° C. for 12 hr. The reaction mixture was cooled, poured into a solution of 140 g of potassium hydroxide in 420 ml of water and then extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by column chromatography (chloroform:ethanol=97:3). The yield was 14.1 g, and the product was recrystallized from ethyl acetate-isopropyl ether to prepare the title compound in a pure form having a melting point of 203° to 204° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([O:10][CH3:11])=[O:9])=[C:5]([CH3:7])[N:6]=1.[S:12](Cl)([CH3:15])(=[O:14])=[O:13]>N1C=CC=CC=1>[S:12]([NH:1][C:2]1[S:3][C:4]([C:8]([O:10][CH3:11])=[O:9])=[C:5]([CH3:7])[N:6]=1)([CH3:15])(=[O:14])=[O:13]
Reactant: COC(=O)c1sc(N)nc1C
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)c1sc(NS(C)(=O)=O)nc1C

Procedure:
To a mixture of methyl 2-amino-4-methylthiazole-5-carboxylate (3.72 g) and pyridine (25 ml) was added mesyl chloride (1.6 ml) over the period of 5 minutes under cooling with stirring, and the mixture was stirred for 1 hour at ambient temperature and for 3 hours for 40° C. After the reaction mixture was concentrated, ethyl acetate (50 ml) and tetrahydrofuran (20 ml) were added to the residue and the mixture was adjusted to pH 3 with diluted hydrochloric acid. The separated organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was pulverised with diethyl ether to give methyl 2-mesylamino-4-methylthiazole-5-carboxylate (3.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:17])([C:13]([F:16])([F:15])[F:14])[O:8][CH:7](O)[CH2:6]2.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:17])([C:13]([F:16])([F:14])[F:15])[O:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CC(O)OC2(C)C(F)(F)F
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)CCOC2(C)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
To a solution of 6-methoxy-1-methyl-1-trifluoromethyl-isochroman-3-ol (8.36 g, 31.9 mmol) in dichloromethane (84 mL) was added triethylsilane (15.3 mL, 95.8 mmol) followed by trifluoroacetic acid (14.7 mL, 191 mmol). The reaction was stirred at room temperature for 2 hours and was poured into 1N aqueous sodium hydroxide (250 mL). The organic layer was separated and washed with 1N aqueous sodium hydroxide (100 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated to afford 6-methoxy-1-methyl-1-trifluoromethyl-isochromanas an oil (6.88 g, 88%). 1H NMR (300 MHz, CDCl3) δ1.69 (s, 3), 2.85-2.90 (m, 2), 3.85 (s, 3), 3.90-3.98 (m, 1), 4.14-4.21 (m, 1), 6.72 (d, 1, J=2.6), 6.85 (dd, 1, J=8.7, 2.6), 7.31 (d, 1, J=8.7). 13C NMR (100 MHz, CDCl3) δ23.25, 29.42, 55.19, 61.37, 76.10 (q, J=27.4), 112.84, 113.43, 124.85, 125.96 (q, J=289), 127.86, 136.49, 158.98. IR2946, 2839, 1738, 1611, 1505, 1162, 1137, 1101 cm−1. Analysis calculated for C12H13F3O2: C, 58.54; H, 5.32. Found: C, 58.27; H, 5.35.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]2[C:18]3[CH:19]=[CH:20][C:21]([O:23][CH2:24][O:25][CH3:26])=[CH:22][C:17]=3[O:16][CH2:15][C:14]2([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][O:36][CH3:37])=[CH:30][CH:29]=2)[CH3:27])[CH:10]=[CH:11][CH:12]=1.[I-:38].[Na+].O>C(C(C)=O)C>[I:38][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]2[C:18]3[CH:19]=[CH:20][C:21]([O:23][CH2:24][O:25][CH3:26])=[CH:22][C:17]=3[O:16][CH2:15][C:14]2([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][O:36][CH3:37])=[CH:30][CH:29]=2)[CH3:27])[CH:10]=[CH:11][CH:12]=1
Reactant: [I-]
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2c2cccc(OCCCCCl)c2)cc1
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: O
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2c2cccc(OCCCCI)c2)cc1
Temperature: 25 °C
Yield: 96.4 %

Procedure:
(3RS,4RS)-4-[3-(4-Chlorobutyloxy)phenyl]-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methyl-2,3-dihydro-4H-benzopyran (300 mg, 0.57 mmol) and sodium iodide (260 mg, 1.73 mmol) were dissolved in methyl ethyl ketone (30 ml) and then refluxed for 12 hours. The reaction mixture was cooled to room temperature and then water was added thereto. The reaction solution was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure to remove the organic solvent. The concentrate was separated by column chromatography (n-hexane:ethyl acetate=4:1) to obtain 340 mg (yield: 97%) of the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5](Cl)[S:4][N:3]=1.CC1(C)C(C)(C)OB([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Br:1][C:2]1[N:6]=[C:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[C:18]([C:26]([F:27])([F:29])[F:28])[CH:17]=2)[S:4][N:3]=1
Reactant: Clc1nc(Br)ns1
Reactant: CC(C)Oc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(Br)ns2)cc1C(F)(F)F
Temperature: 80 °C
Yield: 52.9 %

Procedure:
To a solution of 3-bromo-5-chloro-1,2,4-thiadiazole (604 mg), 4,4,5,5-tetramethyl-2-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,2-dioxaborolane (D42) (500 mg) and tripotassium phosphate (964 mg) in N,N-dimethylformamide (DMF) (3 mL) and water (0.600 mL) stirred under nitrogen at room temperature was added PdCl2(dppf)-CH2Cl2 adduct (618 mg). The reaction mixture was sealed and heated under microwave at 80° C. for 1 h. The reaction mixture was concentrated and the residue was purified by column chromatography to give 3-bromo-5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,2,4-thiadiazole (D45) (294 mg) as a white solid. MS (ES): C12H10BrF3N2OS requires 366. found 367.2 (M+H+).
Reaction SMILES: C([N:8]([C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:20])[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)(C(OCC)=O)=O.[N+:26]([O-:29])(O)=[O:27]>C(O)(=O)C.C(OC(=O)C)(=O)C>[C:19]([NH:8][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][C:12]=2[N+:26]([O-:29])=[O:27])[CH:17]=[CH:18][C:9]=1[NH:8][C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:20])([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C(=O)N(C(=O)C(=O)OCC)c1ccc2ccccc2c1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)Nc1ccc2cccc([N+](=O)[O-])c2c1NC(=O)C(=O)OCC
Temperature: 0 °C

Procedure:
A partial suspension of 1 2-diethoxalylaminonaphthalene (1,79 g, 5 mmol) in 7 ml of acetic acid and 7 ml of acetic anhydride was treated dropwise with a solution of nitric acid (1.8 ml, 43 mmol, d 1.52) in 7 ml of acetic acid, with stirring at 0° C. The resulting solution was stirred at 0° C. for 11/2 h and then poured on 150 ml of ice/water. The yellow precipitate was isolated, dried and recrystallized from ethanol with decolourising carbon giving 0.67 g (33%) of the required compound, m.p. 173-175° C.,1H-NMR (CDCl3 +DMSO-d6), 1,43 (t,J=7 Hz, 6H,2 CH3), 4.40 (q,J=7Hz, 2H, CH2), 4.42 (q,J=7Hz, 2H, CH2), 7.3-8.4 (m, 5H, ArH).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:18][CH2:19][CH:20]1[CH2:22][CH2:21]1.C1C(=O)N([Br:30])C(=O)C1>C(Cl)(Cl)(Cl)Cl.O>[NH2:1][C:2]1[C:3]([O:18][CH2:19][CH:20]2[CH2:21][CH2:22]2)=[CH:4][C:5]([C:8]2([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][C:7]=1[Br:30]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1(c2ccc(N)c(OCC3CC3)c2)CCCC1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)C1(c2cc(Br)c(N)c(OCC3CC3)c2)CCCC1
Temperature: 25 °C
Yield: 75.2 %

Procedure:
To a stirred solution of ethyl 1-(4-amino-3-(cyclopropylmethoxy)phenyl)cyclopentanecarboxylate (1.2 g, 4.0 mmol) in dry CCl4 (60 mL), NBS (0.427 g, 3.2 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 at room temperature to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography to yield ethyl 1-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)cyclopentanecarboxylate (920 mg) as a yellow solid.