Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:25]1[CH:29]=[CH:28][C:27]([C:30]2[S:34][CH:33]=[C:32]([S:35](Cl)(=[O:37])=[O:36])[CH:31]=2)=[N:26]1.C(N(CC)CC)C>>[O:25]1[CH:29]=[CH:28][C:27]([C:30]2[S:34][CH:33]=[C:32]([S:35]([N:22]3[CH2:23][CH2:24][CH:19]([C:10]4[C:9]5[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=[C:7]([C:1]6[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=6)[CH:8]=5)[NH:12][CH:11]=4)[CH2:20][CH2:21]3)(=[O:37])=[O:36])[CH:31]=2)=[N:26]1
Reactant: O=S(=O)(Cl)c1csc(-c2ccon2)c1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)c[nH]c12
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)c4csc(-c5ccon5)c4)CC3)c[nH]c12

Procedure:
Following the general procedure in example 267, 5-(phenyl)-3-(4-piperidinyl)-1H-indole-7-carboxamide (32 mg, 0.1 mmol), 5-(3-isoxazolyl)-3-thiophenesulfonyl chloride (37.5 mg, 0.15 mmol) and triethylamine (0.06 mL, 0.3 mmol) were reacted to form the desired product which was purified by Gilson HPLC (CH3CN/Water, 0.1% TFA) (11.7 mg, 22%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12](=O)[CH2:11][CH2:10][CH:9]([N+:14]([O-])=O)[CH2:8][C:7]=2[CH:17]=1.[H][H]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][CH:9]([NH2:14])[CH2:8][C:7]=2[CH:17]=1
Reactant: [H][H]
Reactant: COc1ccc2c(c1)CC([N+](=O)[O-])CCC2=O
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CC(N)CCC2
Yield: 94.1 %

Procedure:
A solution of 2-methoxy-8-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (0.20 g) in acetic acid (2 ml) was hydrogenated at 4 atm hydrogen atmosphere over 10% palladium on carbon (0.20 g). After removing the catalyst, the pH of the solution was adjusted to 12 with sodium hydroxide solution and the solution was extracted with ethyl acetate. The extract was washed with brine, dried over potassium carbonate, and evaporated in vacuo to give 3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-amine (153 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[C:19]1([S:25]([O-:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Na+]>>[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][S:25]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:27])=[O:26]
Reactant: O=S([O-])c1ccccc1
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Agent: [Na+]
Product: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccccc3)c(C)o2)cc1
Yield: 83.7 %

Procedure:
Reaction of chloride 2 (267 mg, 1.0 mmol) and sodium benzenesulfinate (173 mg, 1.1 mmol) gave benzoate 16 (311 mg, 84%) as a white powder: mp (EtOAc) 159-161° C.; 1H NMR (CDCl3) δ 8.07 (ddd, J=8.7, 1.9, 1.5 Hz, 2H, H-2, H-6), 7.91 (ddd, J=8.7, 1.9, 1.5 Hz, 2H, H-3, H-5), 7.82 (ddd, J=8.2, 2.0, 1.2 Hz, 2H, H-2′, H-6′), 7.64 (tt, J=7.5, 1.2 Hz, 1H, H-4′), 7.52 (br dd, J=8.2, 7.5 Hz, 2H, H-3′, H-5′), 4.32 (s, 2H, CH2SO2), 3.94 (s, 3H, OCH3), 2.32 (s, 3H, CH3); MS m/z 372.3 (MH+, 100%). Anal. calcd for C19H17NO5S: C, 61.44; H, 4.61; N, 3.77. Found: C, 61.75; H, 4.62; N, 3.75%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Br:9][CH2:10][CH2:11][CH2:12][CH2:13]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][CH2:12][CH2:11][CH2:10][Br:9])=[CH:4][CH:3]=1
Reactant: BrCCCCBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: BrCCCCOc1ccc(Br)cc1

Procedure:
A solution of 4-bromophenol (3 g) and 1,4-dibromobutane (6.2 ml) in N,N-dimethylformamide (30 ml) was treated with potassium carbonate (2.89 g) at room temperature for 27 hours. The mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, filtered, and evaporated. The residue was purified by silica gel chromatography (25:1 hexane-ethyl acetate elution) to give 1-bromo-4-(4-bromobutoxy)benzene (3.09 g).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=[O:5])#[N:2].P(Cl)(Cl)(Cl)(Cl)Cl.Cl.[Cl:14][C:15]1[C:20](O)=[C:19]([Cl:22])[C:18]([Cl:23])=[C:17]([Cl:24])[C:16]=1[Cl:25]>ClCCl.C(OCC)C>[Cl:14][C:15]1[C:20]([O:5][C:4](=[O:6])[CH2:3][C:1]#[N:2])=[C:19]([Cl:22])[C:18]([Cl:23])=[C:17]([Cl:24])[C:16]=1[Cl:25]
Reactant: N#CCC(=O)O
Reactant: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: N#CCC(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Temperature: 25 °C

Procedure:
8.5 g (0.1 mole) of cyano acetic acid are dissolved in 350 ml. of ethylether and cooled to 0° C. 20.1 g. (0.1 mole) of phosphorus pentachloride are added. The cooling is stopped and the temperature is slowly raised to room temperature. When the HCl evolution ceases the solvent is distilled off in vacuo. The residue containing the formed cyanoacetic acid chloride and phosphoroxychloride is taken up in 50 ml. of dichloromethane and 26 g. (0.1 mole) of pentachlorophenol and 11 ml. (0.1 mole) of N,N'-dimethylaniline are added dropwise in 300 ml. of dichloromethane.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH2:6][N:7]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:10]=3[C:11]=2[N:12]=1.[CH3:25][O-:26].[Na+]>CO>[Cl:17][C:15]1[CH:14]=[CH:13][C:10]2[C:11]3[N:12]=[C:2]([O:26][CH3:25])[N:3]=[CH:4][C:5]=3[CH2:6][N:7]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9]=2[CH:16]=1
Reactant: C[O-]
Reactant: Fc1ccccc1C1=NCc2cnc(Cl)nc2-c2ccc(Cl)cc21
Agent: [Na+]
Solvent: CO
Product: COc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Reaction time: 18 h

Procedure:
To 25 ml of methanol was added 1.0 g (0.0279 mol) of 2,9-dichloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine and 0.18 g (0.00335 mol) of sodium methoxide. The reaction was stirred for 18 hr, and evaporated to dryness. The solid was dissolved in 50 ml of dichloromethane and washed with 40 ml of water, dried and evaporated to dryness. The oil was crystallized and recrystallized from ether/petrol and then from ether to give white prisms, mp 137°-141° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:28]([NH:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:29])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: O=C=Nc1ccccc1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 10 mL round-bottomed flask, 3-(aminomethyl)-7-chloro-1-phenylquinolin-4(1H)-one (intermediate D) (0.05 g, 0.176 mmol), phenyl isocyanate (20.9 mg, 19.2 μL, 0.176 mmol) and N,N-diisopropylethylamine (68.1 mg, 92.0 μL, 0.527 mmol) were combined with CH2Cl2 (3 mL). The reaction mixture was stirred at room temperature for 1 hr. The crude product was purified using preparative reverse-phase HPLC, giving 1-(7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-3-phenyl-urea. MS calcd. for C23H19ClN3O2 [(M+H)+] 404.1 obsd. 403.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH:6]=[CH:7][C:8]([OH:10])=[O:9].[OH-].[Na+].[H][H]>[Ni].O>[CH3:1][O:2][C:3]1[CH2:4][CH:5]([CH:11]=[CH:12][CH:13]=1)[CH:6]=[CH:7][C:8]([OH:10])=[O:9]
Reactant: [H][H]
Reactant: COc1cccc(C=CC(=O)O)c1
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC1=CC=CC(C=CC(=O)O)C1
Yield: 89.8 %

Procedure:
A mixture of m-methoxycinnamic acid (100 g, 0.56 mole), water (1 L), and NaOH (22.4 g, 0.56 mole), in the presence of Raney nickel catalyst (20 g, #30), was hydrogenated under 3 atmospheres H2 pressure until the theoretical uptake of hydrogen was observed. The solution was filtered, cooled to 0°, and concentrated HCl was added until acidic pH was achieved. The solid was filtered, washed with water, dried (in-vacuo) to yield 90.6 g white solid, (90%); M+ 180.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:18][Si](CC)(CC)CC)[CH2:16]I)=[CH:11][C:10]=1[NH:26][S:27]([CH3:30])(=[O:29])=[O:28])C1C=CC=CC=1.[NH2:31][CH2:32][CH2:33][C:34]1[CH:57]=[CH:56][C:37]([NH:38][CH:39]2[CH2:44][CH2:43][N:42]([C:45]([NH:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])=[O:46])[CH2:41][CH2:40]2)=[CH:36][CH:35]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:48]([NH:47][C:45]([N:42]1[CH2:41][CH2:40][CH:39]([NH:38][C:37]2[CH:36]=[CH:35][C:34]([CH2:33][CH2:32][NH:31][CH2:16][C@H:15]([OH:18])[C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:11]=3)=[CH:57][CH:56]=2)[CH2:44][CH2:43]1)=[O:46])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Reactant: CC[Si](CC)(CC)O[C@@H](CI)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)cc2)CC1

Procedure:
N-(2-(Benzyloxy)-5-{(1R)-2-iodo-1-[(triethylsilyl)oxy]ethyl}phenyl)methanesulfonamide (E. J. Corey and J. O. Link, J. Org. Chem., 1991, 56, 422 and WO 9737646) (1.0 g, 1.93 mmol) was refluxed in anhydrous tetrahydrofuran (30 mL) with 4-[4-(2-aminoethyl)anilino]-N-octyl-1-piperidinecarboxamide (1.48 g, 3.98 mmol) and N,N-diisopropylethylamine (0.69 mL). The reaction was stirred at reflux for 7 days. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel Merck-60 (eluant: 20:1 chloroform-methanol containing 2% triethylamine) to furnish the title compound (0.92 g, 1.14 mmol).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[CH:12][C:11]([NH2:14])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.N1C=CC=CC=1.[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([N+:33]([O-:35])=[O:34])=[C:28]([CH:32]=1)[C:29](Cl)=[O:30]>ClCCl>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([N+:33]([O-:35])=[O:34])=[C:28]([CH:32]=1)[C:29]([NH:14][C:11]1[CH:12]=[CH:13][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=2)[N:10]=1)=[O:30]
Reactant: Nc1ccn(-c2cccc(C(F)(F)F)c2)n1
Reactant: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccn(-c2cccc(C(F)(F)F)c2)n1)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of 1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine (520 mg, 2.29 mmol, 1.00 equiv) in dichloromethane (5 mL), pyridine (540 mg, 6.84 mmol, 3.00 equiv), and 5-chloro-2-nitrobenzoyl chloride (500 mg, 2.27 mmol, 1.00 equiv). The resulting solution was stirred for 1 h at room temperature. The resulting mixture was washed with 2×50 mL of water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (10:1). This resulted in 800 mg (85%) of product as a yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1([O:11][C@H:10]([CH2:12][O:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9][C@H:7]1[OH:8])[OH:6].N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:1][O:2][CH2:3][CH2:4][C:5]1([O:11][C@H:10]([CH2:12][O:13][C:14](=[O:21])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:9][C@H:7]1[O:8][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[OH:6]
Reactant: COCCC1(O)O[C@H](COC(=O)c2ccccc2)C[C@H]1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COCCC1(O)O[C@H](COC(=O)c2ccccc2)C[C@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of (2-methoxyethyl)-5-O-benzoyl-3-deoxy-D-xylofuranose (example 122) (9.59 g, 32.40 mmol) and imidazole (3.980 g, 58.47 mmol) in DMF (40 mL ) at room temperature was added t-butyldimethylsilyl chloride (6.35 g, 42.12 mmol). The solution was stirred for 3 h and saturated NaHCO3 wasadded. The mixture was concentrated under vacuo. The residue was then partitioned between ether (100 mL) and water (50 mL). The aqueous phase was further extracted with ether (2×50 mL). The combined extracts were washed with brine (2×50 mL) dried (MgSO4) and concentrated to give the title compound (13.3 g, 100%)
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:18]N(C=O)C.IC.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:15])([F:16])[F:17])=[CH:7][C:3]=1[C:4]([O:6][CH3:18])=[O:5]
Reactant: Cc1c(C(=O)O)cc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Product: COC(=O)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a stirred solution of 2-methyl-3-nitro-5-(trifluoromethyl)benzoic acid (1 equiv.) in DMF (3 ml per 1 mmol), iodomethane (4 equiv.) and sodium carbonate (4 equiv.) were added. The resulting reaction mixture was stirred at 60° C. for 8 h. On completion, reaction mixture was filtered and the inorganic solid residue washed with ethyl acetate. The combined filtrate was concentrated under vacuum till dryness and the residue re-dissolved in ethyl acetate before washing with 5% sodium bicarbonate solution followed by 5M HCl solution, the organic layer was finally washed with brine, dried over sodium sulfate and concentrated to afford pure methyl 2-methyl-3-nitro-5-(trifluoromethyl)benzoate (yield 90-95%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][CH2:30][O:31][C:24]=3[CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][CH2:30][O:31][C:24]=4[CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: FC(F)(F)c1cc2c(NCc3ccc4c(c3)OCCO4)nc(Cl)nc2s1
Reactant: c1c[nH]cn1
Product: FC(F)(F)c1cc2c(NCc3ccc4c(c3)OCCO4)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-trifluoromethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-trifluoromethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].F[C:25]1[C:26]([C:31]2[N:36]=[C:35]([CH3:37])[N:34]=[C:33]([NH2:38])[CH:32]=2)=[N:27][CH:28]=[CH:29][N:30]=1>C1COCC1>[NH2:38][C:33]1[N:34]=[C:35]([CH3:37])[N:36]=[C:31]([C:26]2[C:25]([NH:1][C:2]3[CH:3]=[C:4]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=3)=[N:30][CH:29]=[CH:28][N:27]=2)[CH:32]=1
Reactant: CS(=O)(=O)Nc1cc(N)cnc1Cl
Reactant: Cc1nc(N)cc(-c2nccnc2F)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(N)cc(-c2nccnc2Nc2cnc(Cl)c(NS(C)(=O)=O)c2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 5.3 %

Procedure:
To a solution of N-(5-amino-2-chloropyridin-3-yl)methanesulfonamide (Example 330, Step 2) (0.091 g, 0.413 mmol) in THF (2.5 mL) at 0° C. was added NaHMDS (1.0 M solution in THF) (1.876 mL, 1.876 mmol). After the addition, the reaction mixture continued to stir at 0° C. under N2 for 30 min. 6-(3-fluoropyrazin-2-yl)-2-methylpyrimidin-4-amine (0.077 g, 0.375 mmol) was added into the reaction mixture. The reaction mixture continued to stir at 0° C. for 10 min and was then slowly warmed up to RT. After 1 hour, the reaction mixture was partitioned between pH 7 buffer (1M TRIS-HCl) and CH2Cl2. The aqueous layer was extracted with CH2Cl2 (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by HPLC (10-90% CH3CN and H2O with 0.1% NH4OH, flow rate equal to about 5 mL/min). The fractions containing the desired product were concentrated under a vacuum. The material was further purified by chromatography through a silica gel column (4 g), eluting with a gradient of 0% to 10% MeOH in CH2Cl2, to provide N-(5-((3-(6-amino-2-methyl-4-pyrimidinyl)-2-pyrazinyl)amino)-2-chloro-3-pyridinyl)methanesulfonamide (0.0080 g, 0.020 mmol, 5.24% yield) as a yellow solid. m/z (ESI, +ve) 407.0 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 10.12 (s, 1H); 8.85 (s, 2H); 8.35 (s, 1H); 8.23-8.30 (m, 1H); 7.22 (s, 1H); 6.87 (br. s., 1H); 3.14 (s, 3H); 2.42 (s, 3H).
Reaction SMILES: Cl.[O:2]=[C:3]1[C:11]2([CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:20]C(=O)OC(C)(C)C)[CH:17]=3)[CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1>CCOC(C)=O>[NH2:20][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[CH2:12][C:11]1([C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:4][C:3]1=[O:2])[CH2:19]2
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
HCl(g) was bubbled through a solution of (±)-tert-butyl (2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-indol]-5-yl)carbamate from Step C (19.0 mg, 0.054 mmol) in EtOAc (5 mL) for 15 min. The reaction mixture was stirred at ambient temperature for 1 h and then concentrated in vacuo to give the title compound as the hydrochloride salt. MS: m/z 251 (M+1).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Br[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:12]([O:15][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:11][CH2:10][CH2:9][CH2:14][CH3:13]
Reactant: CCCCCCBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCOc1ccc(Br)cc1

Procedure:
A solution of 1-bromohexane (60 g) in acetone (150 ml) is added dropwise to a stirred mixture of 4-bromphenol (71 g) and K2CO3 (120 g) in acetone 600 ml) at room temperature. The stirred mixture is heated under reflux for 43 hrs (i.e. until glc revealed complete reaction). The product is extracted into ether twice, and the combined ethereal extracts are washed with water, 5% NaOH water and dried (MgSO4). The solvent is removed in vacuo and the residue was distilled (bp=100°-110° C. at 0.1 mm Hg) to yield a colourless liquid.
Reaction SMILES: Br[C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[NH:8][C:9]([C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[C:31]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32]>>[C:31]([C:35]1[CH:40]=[CH:39][C:38]([C:2]2[CH:3]=[CH:4][C:5]([CH2:6][C:7]3[NH:8][C:9]([C:20]4[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=4)=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[N:11]=3)=[CH:29][CH:30]=2)=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: O=[N+]([O-])c1ccc(-c2[nH]c(Cc3ccc(Br)cc3)nc2-c2ccc(Cl)cc2Cl)cc1
Product: CC(C)(C)c1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)c(-c4ccc([N+](=O)[O-])cc4)[nH]3)cc2)cc1

Procedure:
2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-5-(4-nitro-phenyl)-1H-imidazole (prepared according to general procedure A) (1.0 g, 2 mmol) was treated as described in general procedure G using 4-tert-butylphenylboronic acid (712 mg, 4 mmol) to give 2-(4′-tert-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-5-(4-nitro-phenyl)-1H-imidazole, which was treated as described in general procedure L using 2-(trimethylsilyl)ethoxymethyl chloride (0.7 mL, 4 mmol) to give 2-(4′-tert-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-5-(4-nitro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H -imidazole.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[C:26](O)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:26](=[O:33])[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: O=C(O)c1ccccc1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)c1ccccc1

Procedure:
The title compound, white solid (24.1 mg, 69.4%), MS (ISP) m/z=435.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (29.4 mg, 0.080 mmol) and benzoic acid.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]([OH:14])=[O:13].[F:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:2]2[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=2[C:12]([OH:14])=[O:13])=[CH:18][CH:17]=1
Reactant: Cn1nc(C(F)(F)F)c(C(=O)O)c1Cl
Reactant: Fc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cn1nc(C(F)(F)F)c(C(=O)O)c1Sc1ccc(F)cc1
Reaction time: 4 h
Yield: 35 %

Procedure:
A mixture of 5-chloro-1-methyl-3-trifluoromethylpyrazole-4-carboxylic acid (2.0 g), 4-fluorothiophenol (1.66 g) and anhydrous potassium carbonate (3.26 g) was heated under reflux in acetonitrile with stirring for 4 hours. After filtration the filtrate was evaporated, acidified with dilute hydrochloric acid and extracted with ethyl acetate. The combined extract was dried (anydrous magnesium sulphate), filtered and evaporated in vacuo. Recrystallisation from ether/hexane gave 5-(4-fluorophenylthio)-1-methyl-3-trifluoromethylpyrazole-4-carboxylic acid (0.98 g) m.p. 190°-193.7° C. as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(COC)OC>[N+:9]([C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1)([O-:11])=[O:10]
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1ncc(-c2ccccc2)cc1[N+](=O)[O-]
Yield: 46.4 %

Procedure:
A mixture of 5-bromo-3-nitropyridine-2-amine (10 g), phenylboronic acid (8.39 g), tetrakis(triphenylphosphine)palladium(0) (5.3 g), 2N aqueous sodium carbonate solution (100 ml) and dimethoxyethane (500 ml) was heated under reflux under an argon atmosphere for 5 hr. The insoluble material was removed by filtration, and the filtrate was concentrated, diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated. The obtained crude crystals were washed with diethyl ether to give the title compound (4.58 g, yield 46%) as yellow crystals. purity 80%. M+H: 216.