Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([C:18]2[C:19]([CH3:25])=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=2)[CH:10]=[C:11]2[C:16]=1[NH:15][C:14](=[O:17])[CH:13]=[CH:12]2.[CH2:26]=[O:27].[Cl-].[NH4+]>CCCCCC.C1COCC1>[OH:27][CH2:26][C:7]1[CH:8]=[C:9]([C:18]2[C:19]([CH3:25])=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=2)[CH:10]=[C:11]2[C:16]=1[NH:15][C:14](=[O:17])[CH:13]=[CH:12]2
Reactant: C=O
Reactant: Cc1ccc(-c2cc(Br)c3[nH]c(=O)ccc3c2)c(C)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(CO)c3[nH]c(=O)ccc3c2)c(C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of n-butyl lithium [1.04 cm3 of a 1.6M solution in n-hexane] was added at -70° to a stirred solution of 8-bromo-6-[2,6-dimethyl-pyrid-3-yl]-2-(1H)-quinolone (0.25 g) in THF (20 cm3) under nitrogen. After 2 hours, gaseous formaldehyde [generated by sublimation of paraformaldehyde (0.3 g)] was passed over the solution, and, after stirring for a further 10 minutes, the mixture was allowed to warm to room temperature. Saturated ammonium chloride solution (10 cm3) was then added and the mixture was extracted with chloroform (3×50 cm3). The combined and dried (MgSO4) organic extracts were evaporated and the residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with dichloromethane:methanol, 19:1. Combination and evaporation of the appropriate fractions afforded 8-hydroxymethyl-6-[2,6-dimethylpyrid-3-yl]-2-(1H)-quinolone. 0.1H2O, m.p. 218.5°-221° (0.094 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]([N:8]1[C@H:11]([S:12]SC2SC3C=CC=CC=3N=2)[CH2:10][C:9]1=[O:23])=[C:5]([CH3:7])[CH3:6].[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(O)(=O)C.[Zn]>[CH3:1][O:2][C:3](=[O:24])[C:4]([N:8]1[C@H:11]([S:12][C:25](=[O:27])[CH3:26])[CH2:10][C:9]1=[O:23])=[C:5]([CH3:6])[CH3:7]
Reactant: COC(=O)C(=C(C)C)N1C(=O)C[C@H]1SSc1nc2ccccc2s1
Reactant: CC(=O)OC(C)=O
Agent: [Zn]
Solvent: CC(=O)O
Product: COC(=O)C(=C(C)C)N1C(=O)C[C@H]1SC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1 g of zinc powder is added in portions over a period of one hour to a solution, stirred under nitrogen and in an ice bath, of 380 mg (1 mmol) of 2-[(4R)-4-(benzthiazol-2-yl-dithio)-2-oxoazetidin-1yl]-3-methylcrotonic acid methyl ester in 3 ml of acetic anhydride and 5 ml of glacial acetic acid. The reaction mixture is further stirred for one hour at room temperature, filtered and concentrated in vacuo. The residue is taken up in methylene chloride and washed in succession with 25% aqueous ammonium chloride solution and aqueous sodium bicarbonate solution. The combined aqueous phases are reextracted with methylene chloride, all the methylene chloride phases are combined, dried with sodium sulphate and concentrated in vacuo. The residue is chromatographed over 40 g of silica gel (deactivated with 10% water) with toluene and toluene/ethyl acetate (19:1) and yields the optically pure title compound having a melting point of 78°-80°;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)[CH2:9][N:8]([C:23]3[C:24]4[C@H:31]([CH3:32])[CH2:30][CH2:29][C:25]=4[N:26]=[CH:27][N:28]=3)[C:5]2=[CH:6][CH:7]=1.[ClH:33]>C(Cl)Cl.O1CCOCC1>[ClH:1].[ClH:33].[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[CH2:9][N:8]([C:23]3[C:24]4[C@H:31]([CH3:32])[CH2:30][CH2:29][C:25]=4[N:26]=[CH:27][N:28]=3)[C:5]2=[CH:6][CH:7]=1
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(Cl)ccc43)c21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H]1CCc2ncnc(N3CC4(CCNCC4)c4cc(Cl)ccc43)c21
Reaction time: 8 h
Yield: 73 %

Procedure:
A solution of (R)-tert-butyl 5-chloro-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (30 mg, 0.066 mmol) in DCM was treated with 4N HCl in dioxane (0.5 mL) The reaction was stirred at about room temperature overnight. The reaction was concentrated and triturated with ether (×2) to yield (R)-5-chloro-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]dihydrochloride (21 mg, 73%). LCMS (APCI+) m/z 355, 357 [M+H]+; Rt=2.09 min.
Reaction SMILES: [Cl:1][C:2](Cl)(Cl)[S:3]Cl.[CH3:7][C:8]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:9]=1[C:10]([NH2:12])=[NH:11].[OH-].[Na+]>ClCCl.O>[Cl:1][C:2]1[S:3][N:12]=[C:10]([C:9]2[C:8]([CH3:7])=[CH:16][C:15]([CH3:17])=[CH:14][C:13]=2[CH3:18])[N:11]=1
Reactant: ClSC(Cl)(Cl)Cl
Reactant: Cc1cc(C)c(C(=N)N)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)c(-c2nsc(Cl)n2)c(C)c1
Reaction time: 1 h
Yield: 99.1 %

Procedure:
2.2 g of trichloromethanesulfenyl chloride are introduced into a solution of 2 g of 2,4,6-trimethyl benzamidine in 16 ml of dichloromethane under an inert atmosphere at about -20° C., followed by the slow addition of 2 g of NaOH dissolved in 3.2 ml of water at about -10° C. After 1 hour at about -5° C., the precipitate formed is isolated and the organic phase is separated and washed with 6 ml of water. After being dried over K2CO3, it is concentrated under reduced pressure to give 2.8 g of the desired product in the form of an oil, which may be used without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1.C([O-])(=O)C.[Na+].[Br:15]Br.[OH-].[Na+]>C(O)(=O)C>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[N:4][C:5]=1[Br:15]
Reactant: COc1ccc(N)cn1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc(N)c(Br)n1
Reaction time: 0.33 h
Yield: 39.5 %

Procedure:
A stirred mixture of 2-methoxy-5-aminopyridine (10 g, 0.081 mol, 1.0 equiv) and sodium acetate (6.6 g, 0.081 mol, 1.0 equiv) in 60 mL of acetic acid was treated dropwise with bromine (12.9 g, 0.081 mol, 1.0 equiv). After 20 minutes, the reaction mixture was poured into 1000 mL of 10% aqueous sodium hydroxide solution and extracted with three 250 mL portions of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and evaporated to dryness. Chromatography on SiO2 (20% hexanes in dichloromethane) gave 5-amino-6-bromo-2-methoxypyridine (6.5 g, 40% yield) as a purple solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH:7]([N:16]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([N+:27]([O-])=O)[CH:23]=3)[N:18]=[C:17]2[CH2:30][CH2:31][CH3:32])[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1>CCOC(C)=O.[Pd]>[NH2:27][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([CH2:30][CH2:31][CH3:32])[N:16]([CH:7]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:34][CH:33]=1)[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:25]2=[O:26]
Reactant: CCCc1nc2ccc([N+](=O)[O-])cc2c(=O)n1C(c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1nc2ccc(N)cc2c(=O)n1C(c1ccc(OC)cc1)c1ccc(OC)cc1
Yield: 71.9 %

Procedure:
A solution of 12.1 g (26.0 mmol) of 3-(4,4'-dimethoxybenzhydryl)-2-propyl-6-nitro-quinazolin-4(3H)-one dissolved in 250 ml of EtOAc was hydrogenated under atmospheric pressure over three days in the presence of three portions of 1.2 g of 10% Pd/C. added daily. The mixture was filtered through celite and concentrated in vacuo to give an oil. The product was purified by flash chromatography over silica gel eluting with 50% EtOAc/hexanes to give 7.8 g (18.7 mmol) of the amine. 72% yield. 1H-NMR (CDCl3):0.82 (t, 3H, J=7.2 Hz), 1.49 (bm, 2H), 2.61 (t, 2H, J=7.81 Hz), 3.79 (s, 6H), 3.90 (bs, 2H), 6.85 (d, 4H, J=8.8 Hz), 7.08 (dd, 1H, J=2.8, 8.7 Hz), 7.20 (d, 4H, J=8.4 Hz), 7.42 (d, 1H, J=2.7 Hz), 7.47 (d, 1H, J=8.7 Hz).
Reaction SMILES: [CH3:1][CH:2]([NH2:12])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8](Cl)=[CH:7][CH:6]=1.[C:13](C1C=CC(CCC(=O)C)=CC=1)#[N:14]>>[CH3:1][CH:2]([NH2:12])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:13]#[N:14])=[CH:7][CH:6]=1
Reactant: CC(N)CCc1ccc(Cl)cc1
Reactant: CC(=O)CCc1ccc(C#N)cc1
Product: CC(N)CCc1ccc(C#N)cc1

Procedure:
Using the procedure of Example 3 (a) with 4-(4-cyanophenyl)-2-butanone in place of 4-(4-chlorophenyl)-2-butanone, distillation under reduced pressure gave 1-methyl-3-(4-cyanophenyl)propylamine (b.p. 106°-112°/0.2 mm).
Reaction SMILES: S([O-])(O[O-])(=O)=[O:2].[K+].[K+].[C:9]([C:12]1[CH:35]=[CH:34][C:15]([O:16][CH2:17][C:18]2[CH:19]=[C:20]([S:24][C:25]3[CH:26]=[N:27][CH:28]=[C:29]([CH:33]=3)[C:30]([OH:32])=[O:31])[CH:21]=[CH:22][CH:23]=2)=[C:14]([CH3:36])[C:13]=1[OH:37])(=[O:11])[CH3:10].Cl>O.CO>[C:9]([C:12]1[CH:35]=[CH:34][C:15]([O:16][CH2:17][C:18]2[CH:19]=[C:20]([S:24]([C:25]3[CH:26]=[N:27][CH:28]=[C:29]([CH:33]=3)[C:30]([OH:32])=[O:31])=[O:2])[CH:21]=[CH:22][CH:23]=2)=[C:14]([CH3:36])[C:13]=1[OH:37])(=[O:11])[CH3:10]
Reactant: O=S(=O)([O-])O[O-]
Reactant: CC(=O)c1ccc(OCc2cccc(Sc3cncc(C(=O)O)c3)c2)c(C)c1O
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(=O)c1ccc(OCc2cccc(S(=O)c3cncc(C(=O)O)c3)c2)c(C)c1O
Temperature: 25 °C
Reaction time: 36 h
Yield: 14.6 %

Procedure:
Add a 0.5 M solution of potassium peroxymonosulfate (0.61 g, 1.00 mmol) in water (2.0 mL) to a solution of 5-(3-((4-acetyl-3-hydroxy-2-methylphenoxy)methyl)phenylthio)nicotinic acid (205 mg, 0.50 mmol) in methanol (7.5 mL) at 0° C. Allow the solution to warm to room temperature and stir for 1.5 d. Add water and 2.2 mL of 2.0 M HCl to the mixture. Extract the mixture with EtOAc. Dry, filter and concentrate. Recrystallize the residue from a mixture of CH2Cl2 and hexanes to give a light yellow solid. Purify the yellow solid by flash chromatograhpy on silica gel eluting with a mixture of acetone, hexanes, and acetic acid (50:50:1 to 90:10) to afford the title compound (31 mg, 15%): 1H NMR (d6-DMSO) δ 2.01 (s, 3H), 2.58 (s, 3H), 5.33 (s, 2H), 6.67 (d, J=9.0 Hz, 1H), 7.61-7.63 (m, 2H), 7.77 (d, J=9.0 Hz, 1H), 7.81-7.83 (m, 1H), 7.88 (s, 1H), 8.49 (t, J=2.0 Hz, 1H), 9.08 (d, J=2.0 Hz, 1H), 9.12 (d, J=2.0 Hz, 1H), 12.84 (s, 1H); MS (APCI-neg mode) m/z (rel intensity): 424 (M−H, 100%).
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]([CH2:15][C:16]([O:18]CC2C=CC=CC=2)=[O:17])[C:5]1=[O:26])=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]([CH2:15][C:16]([OH:18])=[O:17])[C:5]1=[O:26]
Reactant: [N-]=[N+]=NC1CCc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CCO
Product: NC1CCc2ccccc2N(CC(=O)O)C1=O

Procedure:
A solution of 3-azido-1-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (14.0 g, 0.04 mol) in ethanol (300 ml) was hydrogenated for 25 hours on a Parr shaker at 45 psi at room temperature using 5% Pd-C (2.0 g) as catalyst. The catalyst was filtered off and the solvent removed under reduced pressure. The residue was dissolved in water (500 ml) and the solution extracted with dichloromethane (2×400 ml). The aqueous solution was filtered, and evaporated under reduced pressure. Ethanol (50 mol) was added and the solution evaporated under reduced pressure. More ethanol (50 ml) was added, and the evaporation repeated. The residue was recrystallized from ethanol/ethyl acetate to give 3-amino-1-carboxymethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one, m.p. 147°-150°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:12]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:14])[CH2:11][C:10](=O)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.P(Br)(Br)([Br:24])=O.C(=O)([O-])O.[Na+]>C(#N)C>[Br:24][C:10]1[CH2:11][CH:12]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:14])[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]=1
Reactant: O=P(Br)(Br)Br
Reactant: CCCCCOC(=O)C1CC(=O)NN1c1ncccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCCCCOC(=O)C1CC(Br)=NN1c1ncccc1Cl
Reaction time: 0.08 h
Yield: 137.5 %

Procedure:
A mixed solution comprising 1.2 g of pentyl 2-(3-chloropyridin-2-yl)-5-oxopyrazolidine-3-carboxylate, 0.59 g of phosphorus oxybromide and 18 ml of acetonitrile was gradually heated, and 25 minutes later, the mixed solution was refluxed with heating for one hour. After the reaction liquid was stood to cool, it was slowly added to a saturated sodium hydrogen carbonate aqueous solution, followed by stirring for 5 minutes. The mixed liquid was subjected to extraction with ethyl acetate, and the organic layer was washed with a sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1 to 8/2) to obtain 1.06 g of the desired product (melting point: 39 to 42° C.) in the form of pale yellow crystals.
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[OH2:26]>CN(C=O)C.Cl[Cu].Cl[Pd]Cl>[Br:19][C:16]1[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@:4]([CH2:1][C:2](=[O:26])[CH3:3])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:9][C:8]2=[O:10])[CH3:12])=[CH:18][CH:17]=1
Reactant: O
Reactant: C=CC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Solvent: CN(C)C=O
Product: CC(=O)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Yield: 58 %

Procedure:
To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (20 g, 50 mmol) and CuCl (12.4 g, 125 mmol) in dry DMF (50 mL) was added H2O (12 mL) and PdCl2 (2.66 g, 15 mmol) at 0˜−5° C. After addition, the mixture was allowed to warm to rt gradually for 48 h under O2. After TLC showing the stating material had disappeared, the solid was filtered off. Water (200 mL) and EtOAc (50 mL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (3×40 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by column chromatography to give (S)-3-((S)-1-(4-bromo-phenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazinan-2-one (12 g, 58%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([NH2:10])[CH2:7][CH2:8][CH2:9][C:2]1=2.Cl.[O-:12][C:13]#[N:14].[K+]>O>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([NH:10][C:13]([NH2:14])=[O:12])[CH2:7][CH2:8][CH2:9][C:2]1=2
Reactant: N#C[O-]
Reactant: NC1CCCc2sccc21
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)NC1CCCc2sccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A sample of 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine (19.9 grams) is cooled in a flask, and a solution of 12 ml. of 12 N hydrochloric acid in 50 ml. of water is slowly added. Subsequently, at about 20° C., a solution of 11.7 grams of potassium cyanate in 80 ml. of water is added in 0.5 hour. The mixture is stirred at room temperature for one hour and then warmed to 60° C. and kept at this temperature for 0.5 hour. After standing overnight at room temperature, the product is collected and washed with water to afford 21 grams, melting point 206° C. to 209° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=3Br)[S:9][C:5]=2[CH:4]=1.[C:21](=O)([O-])[O-].[K+].[K+].CB(O)O>C1(C)C=CC=CC=1.C(OC(=O)C)C.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>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=3[CH3:21])[S:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2nc(-c3cccc(OC)c3Br)sc2c1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB(O)O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc2nc(-c3cccc(OC)c3C)sc2c1
Temperature: 100 °C
Yield: 63.2 %

Procedure:
To a solution of 6-methoxy-2-(2-bromo-3-methoxy-phenyl)-benzothiazole (0.128, 0.366 mmol) in dry toluene (4 mL) was added potassium carbonate (0.404 g, 2.92 mmol), methylboronic acid (88 mg, 1.47 mmol) and tetrakis(triphenylphosphine)palladium (42 mg, 0.036 mmol). The mixture was heated to 100° C. for 3 h, then cooled to room temperature. The mixture was diluted with ethylacetate and washed with water, saturated sodium carbonate and brine. After chromatographic purification gave 6-methoxy-2-(2-methyl-3-methoxy-phenyl)-benzothiazole (66 mg, 63% yield) as a white solid. Mass spec: MH+=286.
Reaction SMILES: FC1C(F)=CC(C2C=CC(OCC3C=CC=C4C=3C=CN4C(=O)CCC(O)=O)=CC=2)=C(OC)C=1.[F:35][C:36]1[C:41]([F:42])=[CH:40][C:39]([C:43]2[CH:48]=[CH:47][C:46]([O:49][CH2:50][C:51]3[CH:59]=[CH:58][CH:57]=[C:56]4[C:52]=3[CH:53]=[CH:54][NH:55]4)=[CH:45][CH:44]=2)=[C:38]([O:60][CH3:61])[CH:37]=1.[CH3:62][C:63]1([CH3:70])[CH2:68][C:67](=[O:69])[O:66][C:64]1=[O:65]>>[F:35][C:36]1[C:41]([F:42])=[CH:40][C:39]([C:43]2[CH:48]=[CH:47][C:46]([O:49][CH2:50][C:51]3[CH:59]=[CH:58][CH:57]=[C:56]4[C:52]=3[CH:53]=[CH:54][N:55]4[C:67](=[O:69])[CH2:68][C:63]([CH3:70])([CH3:62])[C:64]([OH:66])=[O:65])=[CH:45][CH:44]=2)=[C:38]([O:60][CH3:61])[CH:37]=1
Reactant: CC1(C)CC(=O)OC1=O
Reactant: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc3[nH]ccc23)cc1
Agent: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc3c2ccn3C(=O)CCC(=O)O)cc1
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc3c2ccn3C(=O)CC(C)(C)C(=O)O)cc1

Procedure:
4-[4-(4′,5′-Difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-2,2-dimethyl-4-oxo-butyric acid was synthesized by a procedure similar to 4-[4-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-4-oxo-butyric acid from starting materials 4-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-1H-indole and 2,2-dimethyl-succinic anhydride to yield the product as a white solid (13 mg, 27%). LC-MS (ES) calculated for C28H25F2NO5, 493.2; found m/z 494 [M+H]+.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.CON(C)[C:35](=[O:43])[C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[N:38][CH:37]=1>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([C:35]([C:36]3[CH:37]=[N:38][C:39]([CH3:42])=[CH:40][CH:41]=3)=[O:43])=[N:3][CH:4]=[C:5]([Cl:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: CON(C)C(=O)c1ccc(C)nc1
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)c1ccc(C)nc1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 33.7 %

Procedure:
To a solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (90 mg, 0.2 mmol) in 2.0 mL of THF under nitrogen atmosphere at −78° C. was added drop-wise 0.3 mL (0.6 mmol) of isopropylmagnesium chloride. The mixture was then stirred for 10 min at −78° C. followed by warming to room temperature and stirred at that temperature for 30 min. The mixture was cooled to 0° C. (ice water) and a solution of N-methoxy-6,N-dimethyl-nicotinamide (72mg, 0.4 mmol) in 1 mL of THF was added. The mixture was stirred at room temperature for 3 hours, quenched with 1M HCl and neutralized with 1M NaOH until pH was 9. The mixture was extracted with ethyl acetate, dried and concentrated. The residue was purified by flash column (silica gel, 50% ethyl acetate in hexane) to afford 36 mg of 4-chloro-N-[5-chloro-2-(6-methyl-pyridine-3-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide as an off white solid. MS: (M+H)/z=534.0.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[CH:18]=3)[CH:13]=2)[C:8]=1[Cl:26])[CH3:2].[C:28](Cl)(=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[C:18]=3[C:28](=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32])[CH:13]=2)[C:8]=1[Cl:26])[CH3:2]
Reactant: CCOC(=O)COc1ccc2cc(-c3cc4ccccc4s3)ccc2c1Cl
Reactant: CCCCC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCC(=O)c1c(-c2ccc3c(Cl)c(OCC(=O)OCC)ccc3c2)sc2ccccc12
Temperature: 25 °C
Yield: 2.1 %

Procedure:
A mixture of yielded (6-benzo[b]thiophen-2-yl-1-chloro-naphthalen-2-yloxy)-acetic acid ethyl ester (2.7 g, 6.8 mmol), valeryl chloride (3.9 mL, 33 mmol) in four portions and tin (IV) chloride (6.4 mL, 56 mmol)in four portions in chloroform (55 mL) was refluxed for five hours. It was then allowed to cool to ambient temperature and poured into ice water. It was diluted with additional chloroform and washed with water and brine. It was then dried with anhydrous magnesium sulfate, filtered and solvent evaporated. The residue was purified three times by flash chromatography (Biotage apparatus) using (1) 25–60% methylene chloride in hexane, (2) 20–40% 1,2-dichloroethane in hexane and (3) 2.5–7.5% methyl t-butyl ether in hexane. It was then purified by HPLC using 92% acetonitrile (0.1% trifluoroacetic acid) in water as the mobile phase. Evaporating the solvent and extracting with ethyl acetate, washing with water and brine, drying with anhydrous magnesium sulfate, filtering, concentrating and drying in vacuo at 60° C. for 20 minutes yielded [1-chloro-6-(3-pentanoyl-benzo[b]thiophen-2-yl)-naphthalen-2-yloxy]-acetic acid ethyl ester as an olive gum (0.0702 g, 2.14%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:6]([C:8](OCC)=[O:9])[N:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1>[CH:8]([C:6]1[N:7]=[C:3]([NH:2][CH3:1])[S:4][C:5]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[O:9]
Reactant: CCOC(=O)c1nc(NC)sc1-c1ccncc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CNc1nc(C=O)c(-c2ccncc2)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
To a solution of ethyl 2-methylamino-5-(4-pyridyl)-4-thiazolecarboxylate (2.6 g) in dry tetrahydrofuran (120 ml) was added lithium aluminum hydride (0.38 g) at -10° C. with stirring, which was continued at -10°~-3° C. for 30 minutes. The reaction mixture was poured into ice-water and the resultant solution was acidified to pH 1.0 with 10% hydrochloric acid. The insoluble material was filtered off. The filtrate was adjusted to pH 7.0 with 20% aqueous solution of potassium carbonate and extracted with a mixture of ethyl acetate and tetrahydrofuran. The organic extract was concentrated in vacuo. The precipitate was collected by filtration, washed with ethyl acetate and dried in vacuo to give 4-formyl-2-methylamino-5-(4-pyridyl)thiazole (0.8 g). mp 243°-245° C. (dec.).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:23])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[NH3:24]>C(Cl)Cl>[NH2:24][CH2:2][C:3]1[C:4]([F:23])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1
Reactant: N#Cc1cc(Oc2c(Cl)ccc(CBr)c2F)cc(C(F)(F)F)c1
Reactant: N
Solvent: ClCCl
Product: N#Cc1cc(Oc2c(Cl)ccc(CN)c2F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of 3-{[3-(bromomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(trifluoromethyl)benzonitrile (5.00 g, 12.24 mmol) in DCM (15 ml) was added dropwise to ammonia (7.0 M solution in MeOH) (69.9 ml, 490 mmol) and the mixture was stirred overnight at rt. The solvent was removed and the crude material was neutralized to give 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(trifluoromethyl)benzonitrile (4.22 g, 12.24 mmol, 100% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.24 (d, 2H), 8.15 (s, 1H), 7.76 (d, 2H), 7.62-7.69 (m, 1H), 7.54-7.61 (m, 1H), 4.12 (s, 2H).