Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:17]=[CH:18]/[C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][O:36][C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=4)=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)=[O:20])[CH:5]=[C:6]([CH3:16])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][N:10]=1.[F:44][C:45]1[CH:46]=[C:47]([CH:50]=[CH:51][C:52]=1[CH3:53])[CH2:48]Br.C([O-])([O-])=O.[K+].[K+]>O>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:17]=[CH:18]/[C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][O:36][C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=4)=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)=[O:20])[CH:5]=[C:6]([CH3:16])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:48][C:47]2[CH:50]=[CH:51][C:52]([CH3:53])=[C:45]([F:44])[CH:46]=2)=[CH:11][N:10]=1
Reactant: Cc1cc(/C=C/C(=O)N2CCN(Cc3ccc(CCOc4ccc(Cl)cc4)cc3)CC2)cc(Cl)c1Oc1ccc(O)cn1
Reactant: Cc1ccc(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccc(COc2ccc(Oc3c(C)cc(/C=C/C(=O)N4CCN(Cc5ccc(CCOc6ccc(Cl)cc6)cc5)CC4)cc3Cl)nc2)cc1F
Reaction time: 4 h

Procedure:
To a solution of (E)-3-{3-chloro-4-[(5-hydroxypyridin-2-yl)oxy]-5-methyl-phenyl}-1-(4-{4-[2-(4-chlorophenoxy)ethyl]benzyl}piperazin-1-yl)prop-2-en-1-one (400 mg) was added 3-fluoro-4-methylbenzyl bromide (144 mg) and K2CO3 (134 mg) at room temperature, then the reaction mixture was stirred for 4 hours. The reaction mixture was diluted with H2O and extracted with AcOEt. The organic layer was washed with water and saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt) to afford (E)-3-[3-chloro-4-({5-[(3-fluoro-4-methylbenzyl)oxy]pyridin-2-yl}oxy)-5-methylphenyl]-1-(4-{4-[2-(4-chlorophenoxy)ethyl]benzyl}piperazin-1-yl)prop-2-en-1-one as a colorless amorphous (430 mg).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[CH:19]1[CH2:25][C:24](=O)[O:23][C:21](=[O:22])[CH2:20]1.[ClH:27]>ClCCl.O1CCOCC1>[ClH:27].[N:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][C:24]=1[CH2:25][CH:19]([C:10]1[CH:11]=[CH:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=1)[CH2:20][C:21]([OH:23])=[O:22]
Reactant: O=C1CC(c2ccc3ccccc3c2)CC(=O)O1
Reactant: Nc1ccccc1N
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(O)CC(Cc1nc2ccccc2[nH]1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,2-Phenylenediamine (54 mg) and 3-(2-naphthyl)glutaric anhydride (120 mg) were dissolved in dichloromethane (2 ml) with heating. The solution was stirred at rt for 1 h. The precipitate formed was collected by suction filtration, washed with dichloromethane, and dried to give a mixture of regioisomeric amides (131 mg) as colourless solid. This solid was dissolved in 1,4-dioxane (1 ml) with heating, and 4M HCl in 1,4-dioxane (1 ml) was added. The solution was heated to reflux for 1 h. After removal of the solvent the residue was triturated with acetone to give 4-(2-benzimidazolyl)-3-(2-naphthyl)butanoic acid HCl (100 mg) as colourless solid.
Reaction SMILES: C([CH:5]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:14]3[CH:15]=[CH:16][CH:17]=[C:7]([C:8]=23)[S:6]1(=[O:19])=[O:18])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[S:6]1(=[O:18])(=[O:19])[C:7]2=[CH:17][CH:16]=[CH:15][C:14]3=[CH:13][CH:12]=[CH:11][C:9](=[C:8]23)[NH:10][CH2:5]1
Reactant: CC(C)(C)C1Nc2cccc3cccc(c23)S1(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S1(=O)CNc2cccc3cccc1c23
Reaction time: 22 h

Procedure:
0.06 g of 2-tert-butyl-2,3-dihydro-naphtho[1,8-de][1,3]thiazin-1,1-dioxide is dissolved in 1 mL of dichloromethane and 0.02 mL of trifluoroacetic acid is added. Then the mixture is stirred for a total of 22 hours at reflux temperature and for 96 hours at ambient temperature, while during this period a total of 0.07 mL of trifluoroacetic acid is added. The reaction mixture is evaporated down in vacuo and purified by chromatography. Yield: 0.034 g; m.p.: 206° C.–207° C.
Reaction SMILES: C(C1[O:5]C1)Cl.[C:6]1([O:16][CH3:17])[C:7](=[CH:9][CH:10]=[C:11]([CH:15]=1)[CH:12]=[CH:13][CH3:14])[OH:8].[OH-].[Na+]>C(O)C>[O:5]1[C:12](=[CH:13][CH3:14])[C:11]2[CH:15]=[C:6]([O:16][CH3:17])[C:7]([OH:8])=[CH:9][C:10]1=2
Reactant: CC=Cc1ccc(O)c(OC)c1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC=C1Oc2cc(O)c(OC)cc21

Procedure:
To manufacture this combination Epichlorohydrin was mixed with isoeugenol and NaOH dissolved in ethanol and boiled to reflux for 2–6 hours. Ethanol was then removed from the resulting mixture and the mixture was passed through silica gel column eluted with n-hexane and ethyl acetate, and dried with reduced pressure, to obtain 4-epoxy isoeugenol.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19](I)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].Cl>CN(C)C=O>[CH2:19]([O:1][C:2]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCI
Reactant: COC(=O)c1ccc(I)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCCCCOc1cc(I)ccc1C(=O)OC

Procedure:
A mixture of methyl 2-hydroxy-4-iodobenzoate (25 g, 90 mmol), caesium carbonate (35.2 g, 108 mmol) and n-heptyl iodide (19.2 ml, 117 mmol), in 500 ml of dimethylformamide (DMF) is stirred for 10 hours at room temperature. The solution is neutralized by addition of 2N hydrochloric acid solution. The desired product is extracted by addition of ethyl acetate. The organic phase is washed with water, dried with magnesium sulfate and concentrated using a rotary evaporator. After evaporation of the solvent, 33.84 g (100%) of the expected compound are recovered in the form of a brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1.[H-].[Na+].[CH2:20]([CH:22]1[O:24][CH2:23]1)Cl.O>CN1CCCC1=O>[CH2:20]([O:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1)[CH:22]1[O:24][CH2:23]1
Reactant: O=C1c2ccccc2C(=O)c2cc(O)ccc21
Reactant: ClCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C1c2ccccc2C(=O)c2cc(OCC3CO3)ccc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
112.1 g (0.5 mole) of 2-hydroxyanthraquinone are dissolved in 500 ml of N-methylpyrrolidone, and 12 g (0.5 mole) of sodium hydride are added in portions. When the evolution of gas has ended, 46.37 ml (0.5 mole) of epichlorohydrin are added dropwise at 70° C. and stirring is continued at 70° C. for a further 8 hours. 1.5 liters of water are then added, the mixture is filtered and the filter cake is dried in vacuo. After drying, the product is boiled up again in 1 liter of N,N-dimethylformamide with 10 g of active charcoal and filtered hot. The crystals which precipitate on cooling to 0° C. are separated off by filtration and dried under a high vacuum. 69.45 g (50.57% of theory) of 2-anthraquinonyl glycidyl ether are obtained;
Reaction SMILES: [F:1][C:2]1([F:48])[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]5[O:27][C:26]([NH:28]CC6C=CC(OC)=CC=6)=[N:25][N:24]=5)[CH:21]=4)[N:16]([S:38]([C:41]4[CH:47]=[CH:46][C:44]([CH3:45])=[CH:43][CH:42]=4)(=[O:40])=[O:39])[CH:15]=3)[CH:11]=[N:10][CH:9]=2)[CH2:4][CH2:3]1>C(O)(C(F)(F)F)=O.O1CCOCC1>[F:48][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]5[O:27][C:26]([NH2:28])=[N:25][N:24]=5)[CH:21]=4)[N:16]([S:38]([C:41]4[CH:47]=[CH:46][C:44]([CH3:45])=[CH:43][CH:42]=4)(=[O:40])=[O:39])[CH:15]=3)[CH:11]=[N:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cncc(N5CCC(F)(F)CC5)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(N4CCC(F)(F)CC4)n3)c3cc(-c4nnc(N)o4)ccc32)cc1
Yield: 72.2 %

Procedure:
A solution of 5-(3-(6-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (590 mg) in TFA (5 mL) was heated in a microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 110° C. for 20 min. The volatiles were removed under reduced pressure. The brown residue was diluted with EtOAc and washed with 0.5 N NaOH. The EtOAc layer was concentrated. The off white solid was stirred with 5 mL Et2O, filtered, rinsed with 2×5 ml of Et2O to give 350 mg of crude material of 5-(3-(6-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine that was used without further purification. A glass microwave reaction vessel was charged with the above obtained 5-(3-(6-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (350 mg) in p-dioxane (3 mL) followed by 1 N NaOH (2 mL). The reaction was heated in a microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 105° C. for 20 min. The mixture was partitioned between 5 mL of H2O and 50 mL of EtOAc. The EtOAc layer was concentrated and the residue purified on a reverse phase HPLC, using a gradient of 10-90% [0.1% TFA in MeCN] in [0.1% TFA in H2O]. The desired fractions were collected, concentrated, the residue was extracted with EtOAc and washed with 0.5 N NaOH to give 5-(3-(6-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl)-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (20 mg, 5%) as an off white crystalline solid. MS (ESI, pos. ion) 398.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 11.93 (1H, br. s.), 8.85 (1H, d, J=1.2 Hz), 8.45 (1H, s), 8.29 (1H, s), 8.19 (1H, s), 7.67 (1H, m), 8.57 (1H, d, J=8.6 Hz), 7.06 (2H, br. s.), 3.89 (4H, t, J=5.6 Hz), 2.12 (4H, m).
Reaction SMILES: [C:1]1([C@H:7]([CH2:9][OH:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:18][CH2:19][C:20](Cl)=[O:21]>C(Cl)Cl>[Cl:18][CH2:19][C:20]([NH:8][C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:9][OH:10])=[O:21]
Reactant: O=C(Cl)CCl
Reactant: N[C@@H](CO)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N[C@@H](CO)c1ccccc1
Reaction time: 0.33 h

Procedure:
To a solution of (R)-2-phenylglycinol (10 g, 73 mmol) and triethylamine (10.2 mL, 73 mmol) in CH2Cl2 (500 mL) at 0° C. was slowly added chloroacetyl chloride (5.8 mL, 73 mmol). After 20 min, the reaction mixture was quenched with saturated aqueous NaHCO3 (150 mL) and extracted with CH2Cl2 (2×250 mL). The combined organic extracts were washed with 10% citric acid, then brine, then dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=214 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:31][NH2:32].Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:18])[NH:32][CH2:31][C:30]3[CH:33]=[CH:34][C:35]([Cl:36])=[C:28]([Cl:27])[CH:29]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: NCc1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCc4ccc(Cl)c(Cl)c4)cc3)c(Cl)cc21
Reaction time: 16 h
Yield: 94.2 %

Procedure:
4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1) (51.5 mg, 0.137 mmol), in 1:1 DMF:DCM (0.1 M) was sequentially treated with 3,4-dichlorobenzylamine (26.5 mg, 0.150 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31.4 mg, 0.164 mmol), and 1-Hydroxy-7-azabenzotriazole (5.58 mg, 0.0410 mmol) at ambient temperature. After 16 hours the reaction was applied directly to a silica gel column and eluted with a gradient (15% to 60%) of ethyl acetate-hexanes to provide the title compound (69.0 mg, 0.129 mmol, 94.4% yield) as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl[CH2:13][C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][N:15]=1>>[F:23][C:20]([F:21])([F:22])[C:19]1[C:14]([CH2:13][N:1]2[C:9]3[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=3)[CH:3]=[N:2]2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: FC(F)(F)c1cccnc1CCl
Reactant: O=Cc1ccc2[nH]ncc2c1
Product: O=Cc1ccc2c(cnn2Cc2ncccc2C(F)(F)F)c1

Procedure:
1-(3-Trifluoromethyl-pyridin-2-ylmethyl)-1H-indazole-5-carbaldehyde was prepared from 1H-Indazole-5-carbaldehyde and 2-Chloromethyl-3-trifluoromethyl-pyridine following General Procedure A.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:33]([C@@H:35]([O:37]C(=O)C)[CH3:36])=[O:34]>>[OH:37][C@@H:35]([CH3:36])[C:33]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:34]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1
Product: C[C@H](O)C(=O)N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from cis-4-(2-cyclopropylmethoxy-4-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A156) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Cl[CH2:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([O:33][CH3:34])[CH:26]=1>>[CH3:34][O:33][C:27]1[CH:26]=[C:25]([CH:30]=[C:29]([O:31][CH3:32])[CH:28]=1)[CH2:24][N:15]1[C:16]([CH3:19])([CH3:20])[C:17](=[O:18])[N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:22])[CH:12]=2)[C:14]1=[O:21]
Reactant: COc1cc(CCl)cc(OC)c1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Product: COc1cc(CN2C(=O)N(c3cnn(Cc4c(C)noc4C)c3)C(=O)C2(C)C)cc(OC)c1

Procedure:
Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and 1-(chloromethyl)-3,5-dimethoxybenzene. MS 454 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.3 μM.
Reaction SMILES: B(F)(F)F.CCOCC.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:15]=O.[CH2:22]([SH:26])[CH2:23][CH2:24][SH:25]>C(Cl)Cl>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:15]2[S:26][CH2:22][CH2:23][CH2:24][S:25]2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: SCCCS
Reactant: COc1ccc(C=O)cc1OC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(C2SCCCS2)cc1OC

Procedure:
The first step in the process for making Justicidin P can be conducted by adding boron trifluoride etherate (BF3.Et2O) to a solution containing 3,4-dimethoxybenzaldehyde and 1,3-propanedithiol in methylene chloride. After a suitable reaction time, the mixture is washed with a NaOH solution and a saturated solution of NaCl. The product is dried and then recovered by evaporation under reduced pressure.
Reaction SMILES: [ClH:1].Cl.Cl.[CH:4]1([NH:7][C:8]([C:10]2[C:18]3[CH:17]=[C:16]([C:19]4[C:24]([Cl:25])=[CH:23][N:22]=[C:21]([NH:26][CH2:27][CH2:28][CH2:29][N:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)[N:20]=4)[S:15][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[O:9])CC1.CNC(C1C2C=C(C3C([Br:56])=CN=C([Cl:57])N=3)SC=2C=CC=1)=O>>[ClH:25].[ClH:57].[ClH:1].[CH3:4][NH:7][C:8]([C:10]1[C:18]2[CH:17]=[C:16]([C:19]3[C:24]([Br:56])=[CH:23][N:22]=[C:21]([NH:26][CH2:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[N:20]=3)[S:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)=[O:9]
Reactant: CN1CCN(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Reactant: CNC(=O)c1cccc2sc(-c3nc(Cl)ncc3Br)cc12
Agent: Cl
Product: CNC(=O)c1cccc2sc(-c3nc(NCCCN4CCN(C)CC4)ncc3Br)cc12

Procedure:
Using the method of 2-{5-chloro-2-[3-(4-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide tri-hydrochloride, the title compound is synthesized from 2-(5-bromo-2-chloro-pyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid methylamide and isolated as a yellow solid. ES+(m/z) 517 (79Br) and 519 (81Br) [M(free base)+H].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[Cl:12][C:13]1[C:22](Cl)=[N:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:12][C:13]1[C:22]([NH:11][S:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)(=[O:9])=[O:10])=[N:21][C:20]2[C:15]([N:14]=1)=[CH:16][CH:17]=[CH:18][CH:19]=2
Reactant: NS(=O)(=O)c1cccc(F)c1
Reactant: Clc1nc2ccccc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1nc2ccccc2nc1Cl)c1cccc(F)c1
Temperature: 135 °C
Yield: 84.6 %

Procedure:
3-fluorobenzenesulfonamide (250 mg, 1.4 mmol), 2,3-dichloroquinoxaline (284.1 mg, 1.4 mmol) and dry K2CO3 (198.4 mg, 1.4 mmol) are dissolved in dry DMF (0.8 ml) and heated up to 135° C. in a sealed tube for 2.5 h. When TLC confirms the completion of the reaction, the reaction mixture is cooled down to rt and quenched by addition of water (4 ml) and AcOH (0.03 ml). The residue obtained is triturated and the resulting solid is filtered and washed with water until neutral pH then dried under vacuum to afford 400 mg (83%) of the title compound as an off white solid. 1H NMR (DMSO-d6) δ 12.8-10.9 (br s, 1H), 8.05-7.62 (m, 7H), 7.54 (td, J=2.0, 8.5 Hz, 1H). HPLC (max plot) 94%; Rt 3.79 min. LC/MS: (ES+): 338.1, (ES−): 336.1.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:18]=[CH:17][C:8](/[CH:9]=[N:10]/[S@@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])=[C:7]([F:19])[CH:6]=1)([F:4])[CH3:3].[CH3:20][Mg]Br>C(Cl)Cl>[F:1][C:2]([C:5]1[CH:18]=[CH:17][C:8]([C@@H:9]([NH:10][S:11]([C:13]([CH3:14])([CH3:15])[CH3:16])=[O:12])[CH3:20])=[C:7]([F:19])[CH:6]=1)([F:4])[CH3:3]
Reactant: C[Mg]Br
Reactant: CC(F)(F)c1ccc(/C=N/[S@](=O)C(C)(C)C)c(F)c1
Solvent: ClCCl
Product: C[C@H](NS(=O)C(C)(C)C)c1ccc(C(C)(F)F)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (R,E)-N-(4-(1,1-difluoroethyl)-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (497 mg, 1.706 mmol) in DCM (9.59 mL) was added methylmagnesium bromide (3M in diethylether; 1.20 mL) at 0° C. The reaction mixture was allowed to stir for 1 hr at 0° C., gradually allowed to warm to room temperature and stirred for 1 hr at room temperature. The mixture was cooled to 0° C., additional methylmagnesium bromide (3M in diethylether; 0.5 mL) was added and stirring was continued for 30 min at 0° C. The reaction mixture was carefully quenched with saturated aqueous ammonium chloride solution (6 mL) and diluted with water (20 mL). The separated aqueous phase was extracted with DCM (30 mL). The combined organic layers were washed with brine (50 mL), concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 24 g, heptane/ethyl acetate] providing N—((S)-1-(4-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (349 mg) as a white solid. LCMS m/z 308.2 (M+H)+, Rt 0.91 min.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:12]=[CH:13][CH:14]=2)CCCCC1.[S:26]1[CH:30]=[CH:29][N:28]=C1C=O.[BH4-].[Na+]>CO>[S:26]1[CH:30]=[CH:29][N:28]=[C:1]1[CH2:7][NH:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH:12]=[CH:13][CH:14]=1
Reactant: O=Cc1nccs1
Reactant: CC(C)(C)OC(=O)NCCCc1cccc(NCC2CCCCC2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCc1cccc(NCc2nccs2)c1
Reaction time: 18 h

Procedure:
A-3 Molecular seives were added to a solution of aniline 17 (0.4 g, 1.6 mmol) and thiazole-2-carbaldehyde (0.18 g, 1.6 mmol) in MeOH. The reaction mixture was stirred for 18 h and then NaBH4 (0.121 g, 3.2 mmol) was added and the reaction mixture was stirred for overnight. The reaction mixture was filtered through Celite, concentrated under reduced pressure Purification by column chromatography (100-200 silica mesh, 20% EtOAc in hexane) gave tert-butyl 3-(3-(thiazol-2-ylmethylamino)phenyl)propylcarbamate as a brown oil. Yield (0.17 g, 31%); 1H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J=3.2 Hz, 1H), 7.56 (d, J=3.2 Hz, 1H), 6.96 (t, J=7.6 Hz, 1H), 6.80 (bs, 1H), 6.45-6.38 (m, 4H), 4.55 (d, J=6.0 Hz, 2H), 2.91 (q, J=6.4 Hz, 2H), 2.39 (t, J=7.2 Hz, 2H), 1.59 (quintet, J=7.2 Hz, 2H), 1.37 (s, 9H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=2)[C@H:10]([CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[Cl:29][C:30]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33]>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]([NH:21][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:30]=3[Cl:29])[CH:18]=[CH:19][CH:20]=2)[CH:10]([CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CN(Cc2ccccc2)CC[C@@H]1Oc1cccc(N)c1
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC1CN(Cc2ccccc2)CCC1Oc1cccc(NC(=O)c2ccc(F)cc2Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine racemic 3-(1-benzyl-cis-3-methyl-piperidin-4-yloxy)-phenylamine (preparation 41, 0.80 g, 2.7 mmol), 1,4-dioxane (20 mL), and 2-chloro-4-fluoro-benzoyl chloride (0.625 g, 3.24 mmol), stir and heat at reflux. After 2 hr., cool to ambient temperature. Dilute with methanol and load the resulting solution on 210 g SCX columns. Wash each with methanol (2×50 mL). Elute product from each column with 2M ammonia/methanol (2×50 mL). Combine and concentrate the eluents. Purify residue by silica gel flash chromatography eluting with 5% (2M NH3/methanol)/methylene dichloride to obtain the title compound as a racemic mixture (1.07 g, 87.7%). Resolve using a Chiralpak AD™ 4.6×250 mm column eluting at 1.0 mL/min. with 10% absolute ethanol/90% Heptane with 0.2% DMEA to obtain of the title compound (0.524 g, 49.0%). Mass spectrum (electrospray): m/z=453.2 (M+1); 1H NMR (CDCl3): 7.85 (bs, 1H), 7.8 (dd, 1H), 7.45 (s, 1H), 7.3 (m, 7H), 7.1 (m, 1H), 7.0 (m, 1H), 6.75 (dd, 1H), 4.4 (m, 1H), 3.5 (m, 2H), 2.5 (m, 2H), 2.4 (m, 2H), 2.1 (m, 2H), 1.8 (m, 1H), 1.0 (d, 3H).
Reaction SMILES: Br[C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:11]=[O:12])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[N:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[CH3:14][O:13][C:3]1[C:2]([C:18]2[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=2)=[CH:10][C:6]2[CH:7]=[CH:8][O:9][C:5]=2[C:4]=1[CH:11]=[O:12]
Reactant: OB(O)c1ccncc1
Reactant: COc1c(Br)cc2ccoc2c1C=O
Product: COc1c(-c2ccncc2)cc2ccoc2c1C=O

Procedure:
From 5bromo-6-methoxybenzofuran-7-carbaldehyde (350 mg) and pyridine-4-boronic acid (0.21g).