Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]1.[C:11](=[O:14])([O-])[O-:12].[K+].[K+]>C1COCC1.O>[CH3:10][O:9][C:7]([C@@H:4]1[CH2:5][CH2:6][C@H:2]([NH:1][C:11](=[O:14])[O:12][C:4]([CH3:7])([CH3:5])[CH3:3])[CH2:3]1)=[O:8]
Reactant: COC(=O)[C@@H]1CC[C@H](N)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CC[C@H](NC(=O)OC(C)(C)C)C1
Reaction time: 24 h
Yield: 172.7 %

Procedure:
Boc-anhydride (2.90 ml, 13.1 mmol) was added to a solution of (1R,3S)-methyl 3-aminocyclopentanecarboxylate (1.70 g, 11.9 mmol) and potassium carbonate (3.29 g, 23.8 mmol) in THF (10 ml), water (20 ml) and stirred for 24 h. The reaction mixture was extracted with DCM (2×50 ml). The combined organic layer was washed with water (20 ml), brine solution (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under vacuo to afford 2.5 g (87%) of tert-butyl (1S,3R)-3-(methoxycarbonyl)cyclopentylcarbamate as a colorless liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[N+:10]([O-])([OH:12])=[O:11]>ClC(Cl)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[C:4]([OH:9])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(O)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CC(Cl)Cl
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(O)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
3-fluoro-4-methylphenol (3.66 g, 29.0 mmol) was dissolved in dichloroethane (32 mL) and tetrabutylammonium bromide (0.935 g, 2.90 mmol) was added. Nitric acid 70% (3.7 mL, 58 mmol) was diluted with water (33 mL) to make a 7% nitric acid solution. This solution was added to the reaction mixture which was then stirred at room temperature for 4 h at which time the reaction was judged complete by TLC. The reaction was poured into water and extracted with dichloromethane (3×). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was absorbed onto silica gel and purified by chromatography on SiO2 to give 5-fluoro-4-methyl-2-nitrophenol as a yellow solid (2.83 g, 57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.10 (s, 1 H), 7.89 (d, J=8.1 Hz, 1 H), 6.85 (d, J=11.0 Hz, 1 H), 2.13 (s, 3 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28].[CH:29]1(Br)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[CH:29]1([O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=2[C:15]2[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=2[OH:28])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: BrC1CCCCC1
Reactant: CCOC(=O)CCc1ccc(O)c(-c2cc(CCC(=O)OCC)ccc2O)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(O)c(-c2cc(CCC(=O)OCC)ccc2OC2CCCCC2)c1
Yield: 11.7 %

Procedure:
To 5 ml of a DMF solution containing 200 mg (0.5181 mmol) of 2,2'-dihydroxy-5,5'-bis (2-ethoxycarbonylethyl) biphenyl and 644.5 μl (5.181 mmol) of cyclohexyl bromide, there were added 85.8 mg (0.6217 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated for 41 hours at room temperature, for a further 5 hours at 70° C. and for 8 hours at 100° C. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and aqueous sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 20 g of WAKO-gel C-200, eluent: toluene and toluene/ethyl acetate of 1000/1 and 500/1) and further purified by silica-gel column chromatography (with 15 g of WAKO-gel C-200, eluent: hexane and hexane/ethyl acetate 50/1, 30/1, 15/1 and 12/1) to obtain 28.3 mg (0.0605 mmol, 12%) of 2-cyclohexyloxy-2'-hydroxy-5,5'-bis (2-ethoxycarbonylethyl) biphenyl as an oily product.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[CH:11]=[C:12]([F:18])[C:13]([C:16]#[N:17])=[N:14][CH:15]=1.[I:19]I>C1COCC1>[Cl:9][C:10]1[C:11]([I:19])=[C:12]([F:18])[C:13]([C:16]#[N:17])=[N:14][CH:15]=1
Reactant: N#Cc1ncc(Cl)cc1F
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ncc(Cl)c(I)c1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 82.1 %

Procedure:
To a cooled (−78° C.) solution of LDA (34.9 mmol, 1.1 equiv) in dry THF (200 mL) was added dropwise 5-chloro-3-fluoropicolinonitrile (5 g, 31.9 mmol) in dry THF (100 mL) over 15 min. The resulting mixture was stirred at −78° C. for an additional 15 min. A cooled (−78° C.) solution of iodine (12 g, 47 mmol, 1.5 equiv) in dry THF (72 mL) was poured rapidly into the reaction, and the resulting mixture was removed from the cold bath and stirred for 20 s. The reaction was then quenched by the addition of saturated aq. NaS2O3. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (5% EtOAc, 95% hexanes) provided the title compound as a yellow solid (7.4 g, 82%) which was characterized by 1HNMR.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)[CH:10]=[CH:9][C:8]=1[CH3:19])[CH3:2].[F:21][C:22]([F:39])([F:38])[C:23]1[CH:37]=[CH:36][C:26]([CH2:27][O:28][C:29](N2C=CN=C2)=[O:30])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[F:21][C:22]([F:38])([F:39])[C:23]1[CH:37]=[CH:36][C:26]([CH2:27][O:28][C:29]([N:15]2[CH2:16][CH2:17][CH2:18][CH:13]([C:11]3[CH:10]=[CH:9][C:8]([CH3:19])=[C:7]([NH:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:20])[CH:12]=3)[CH2:14]2)=[O:30])=[CH:25][CH:24]=1
Reactant: CCOC(=O)CNc1cc(C2CCCNC2)ccc1C
Reactant: O=C(OCc1ccc(C(F)(F)F)cc1)n1ccnc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CNc1cc(C2CCCN(C(=O)OCc3ccc(C(F)(F)F)cc3)C2)ccc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.3 %

Procedure:
(2-Methyl-5-piperidin-3-yl-phenylamino)-acetic acid ethyl ester (63 mg, 0.23 mmol) was dissolved in 3 mL toluene and imidazole-1-carboxylic acid 4-trifluoromethyl-benzyl ester (93 mg, 0.34 mmol) was added. The reaction was stirred for 18 h at room temperature under nitrogen. The reaction was flash chromatographed with 15% ethyl acetate/hexanes to yield 40 mg (37%) of the desired 3-[3-(ethoxycarbonylmethyl-amino)-4-methyl-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11][C:12]1[NH:13][C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=2.Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:35])([F:34])[F:33])[CH:26]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11][C:12]1[N:13]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:33])([F:34])[F:35])[CH:26]=2)[C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=2
Reactant: FC(F)(F)Oc1cccc(CCBr)c1
Reactant: COc1ccc(OC)c(Sc2nc3c(N)ncnc3[nH]2)c1
Product: COc1ccc(OC)c(Sc2nc3c(N)ncnc3n2CCc2cccc(OC(F)(F)F)c2)c1
Yield: 17 %

Procedure:
The title compound was prepared from 8-(2,5-dimethoxy-phenylsulfanyl)-9H-purin-6-ylamine and. 1-(2-bromo-ethyl)-3-trifluoromethoxy-benzene by a procedure similar to examples 1 and 2. The compound was purified by preparative HPLC. 8-(2,5-Dimethoxy-phenylsulfanyl)-9-[2-(3-trifluoromethoxy-phenyl)-ethyl]-9H-purin-6-ylamine: Yield 17%, 1H NMR (CD3OD) δ 8.18 (s, 1H), 7.33 (t, J=8.0 Hz, 1H), 7.12-7.10 (m, 2H), 7.04-7.01 (m, 3H), 6.95 (bs, 1H), 4.57 (t, J=7.2 Hz, 2H), 3.75 (s, 3H), 3.74 (s, 3H), 3.24 (t, J=7.2 Hz, 2H); LC-MS [M+H]+ 492.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([O:14][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:12][CH2:13]1)=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of (trans-4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester (7.0 g, 33 mmol) in CH2Cl2 (165 mL) was charged with pyridine (13 mL, 79 mmol) and methanesulfonylchloride (6.4 mL, 82 mmol). The reaction was stirred at RT for 14 h and concentrated in vacuo. The residue was dissolved in EtOAc and the resulting solution was washed successively with water (2×) and brine (1×) before being dried (MgSO4), filtered, and concentrated in vacuo to afford methanesulfonic acid trans-4-tert-butoxycarbonylamino-cyclohexyl ester (9.3 g, 96% yield). MS found: (M+H)+=294.2.
Reaction SMILES: Cl.C([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)C1C=CC=CC=1.[C@@H:17]1([C:26]([OH:28])=O)[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]1[C:23]([OH:25])=O>CCOC(C)=O>[C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:23]([C@H:18]1[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]1[C:26]([N:12]1[CH2:13][CH2:14][CH2:15][CH:11]1[C:10]([OH:9])=[O:16])=[O:28])=[O:25])([OH:16])=[O:9]
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Reactant: O=C(O)[C@@H]1CCCC[C@H]1C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)C1CCCN1C(=O)[C@H]1CCCC[C@@H]1C(=O)N1CCC[C@@H]1C(=O)O
Yield: 90.5 %

Procedure:
Using General Procedure A with 2.0 g (8.2 mmol) D-Proline benzyl ester hydrochloride and 700 mg (4.1 mmol) trans-cyclohexane-1,2-dicarboxylic acid afforded, after flash chromatography (EtOAc), 1.36 g (62%) of the title compound as a colorless oil. MS m/e (%): 547 (M+H+, 100).
Reaction SMILES: [CH2:1]([C:3]([CH:5]([CH3:13])[CH2:6][CH:7]([CH3:12])[CH:8]([OH:11])[CH2:9][CH3:10])=C)[CH3:2].I([O-])(=O)(=O)=[O:15].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH3:10][CH2:9][CH:8]([OH:11])[CH:7]([CH2:6][CH:5]([C:3]([CH2:1][CH3:2])=[O:15])[CH3:13])[CH3:12]
Reactant: C=C(CC)C(C)CC(C)C(O)CC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCC(=O)C(C)CC(C)C(O)CC
Reaction time: 0.25 h
Yield: 90.7 %

Procedure:
Osmium tetraoxide (80 mg, 0.3 mmol) was added to a solution of [S-(3R*,5R*,6R*)-2-ethyl-3,5-dimethyl-1-octen-6-ol (15a) (0.552 g, 3 mmol) in 36 mL of 1,4-dioxane and 12 mL of water at 20°-25° C. After 15 min, finely powdered sodium periodate (10.0 g, 46.8 mmol) was added in several portions over a period of 1 h, in accord with the literature procedure [Pappo, R. et al., J. Org. Chem., 1956, 21:478-479]. The mixture was stirred for 16 h, then extracted with ether (2∞50 mL). The ether solution was washed with sodium sulfite solution, dried over anhydrous magnesium sulfate (0.5 g), filtered, and concentrated at 50 torr to yield a residue of serricornin (1 and 2) (0.507 g, 91%). The NMR data are consistent with those previously reported [Mori, K. and Watanabe, H., Tetrahedron, 1985, 41:3423-3428]:300 MHz 1H-NMR (C6 D6) (literature data in parentheses) δ0.8-2.4 (m, 23), 3.2 (lit 3.17) (m, 0.75, CH--O of 2), 3.75 (lit 3.82) (ddd, 0.25, CH--O of 1); 75 MHz 13C-NMR (C6D6), assigned to 1:δ8.0, 10.7, 14.0, 16.5, 27.0, 33.9, 36.1, 36.8, 43.6, 76.4, 213.4 (8.0, 10.8, 13.7, 16.4, 27.5, 33.9, 35.8, 36.8, 43.8, 76.4, 213.6); assigned to 2:7.4, 10.7, 11.7, 16.8, 26.2, 30.2, 31.3, 33.1, 36.1, 72.6, 98.5 (7.4, 10.7, 11.7, 16.7, 26.2, 30.2, 31.3, 33.1, 36.2, 72.7, 98.6), HRMS: calcd for C11 H20O [(M-18)+] 168.1514; found, 168.1506.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:21][C:20](=[O:22])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[S:18]2(=[O:30])=[O:29])=[C:13]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:12]=1)(C)(C)C.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>C(Cl)Cl>[OH:44][C:42]([C:41]([F:46])([F:45])[F:40])=[O:43].[NH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[S:18](=[O:30])(=[O:29])[N:19]([CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])[C:20](=[O:22])[CH2:21]2)=[C:13]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:12]=1
Reactant: CC(C)(C)OC(=O)NCCCc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CCCN)cc2OCc2ccccc2)S1(=O)=O
Reaction time: 1 h

Procedure:
To a solution of (3-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-propyl)-carbamic acid tert-butyl ester (6.0 g, 10.4 mmol) (from Example 57, step B) in 20 mL of CH2Cl2 is added trifluoroacetic acid (5.0 mL). The mixture stirred for 1 h and then the solvent is removed under reduced pressure to afford the title compound as an orange oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][O:11][C:10](=[O:13])[N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:33]=[CH:32][N:31](COCC[Si](C)(C)C)[N:30]=5)=[CH:25][CH:24]=4)=[C:16]3[N:15]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:31]1[CH:32]=[CH:33][C:29]([C:26]2[CH:25]=[CH:24][C:23]([C:22]3[CH:21]=[N:20][N:17]4[CH:18]=[CH:19][C:14]([N:9]5[C@@H:8]([C:5]6[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=6)[CH2:12][O:11][C:10]5=[O:13])=[N:15][C:16]=34)=[CH:28][CH:27]=2)=[N:30]1
Reactant: C[Si](C)(C)CCOCn1ccc(-c2ccc(-c3cnn4ccc(N5C(=O)OC[C@@H]5c5ccc(F)cc5)nc34)cc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1OC[C@H](c2ccc(F)cc2)N1c1ccn2ncc(-c3ccc(-c4cc[nH]n4)cc3)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.8 %

Procedure:
To (S)-4-(4-fluorophenyl)-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one (80 mg, 0.14 mmol) in DCM (4 mL) was added TFA (1 mL) and the reaction was stirred for 4 hours at ambient temperature. The reaction was concentrated to dryness, and 7N ammonia in methanol was added to the residue. After concentration to dryness, the residue was purified by reverse phase chromatography (SP4, 12M, water/CH3CN 100:0 to 0:100, 20 column volumes) to yield (S)-3-(3-(4-(1H-pyrazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-(4-fluorophenyl)oxazolidin-2-one (35 mg, 57% yield) as a white solid. LCMS (APCI+) m/z 441.2 [M+H]+.
Reaction SMILES: O[C:2]1[C:11]2[N:10]=[C:9]([NH:12][C:13]3[CH:14]=[C:15]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=3)[N:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH:3]=1.BrBr.[C:25]([NH2:28])(=[S:27])[CH3:26]>C(Cl)(Cl)Cl.C(O)C>[CH3:26][C:25]1[S:27][C:3]2[CH2:4][CH2:5][C:6]3[C:11](=[N:10][C:9]([NH:12][C:13]4[CH:14]=[C:15]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=4)=[N:8][CH:7]=3)[C:2]=2[N:28]=1
Reactant: NS(=O)(=O)c1cccc(Nc2ncc3c(n2)C(O)=CCC3)c1
Reactant: CC(N)=S
Agent: BrBr
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: Cc1nc2c(s1)CCc1cnc(Nc3cccc(S(N)(=O)=O)c3)nc1-2
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
A solution of 3-(8-hydroxy-5,6-dihydro-quinazolin-2-ylamino)benzenesulfonamide (100 mg, 0.314 mmol) in chloroform (1 mL) was treated with a solution of bromine (32 μl, 0.628 mmol) in chloroform (1 mL) and the mixture stirred at room temperature for 2 hours giving an insoluble black residue. The solvent was decanted and the residue treated with thioacetamide (47 mg, 0.6 mmol) in ethanol (3 mL). The mixture was stirred at 80° C. for 3 hours and filtered to give a black solid (75 mg). The solid was dissolved in DMSO and purified by reverse phase preparative HPLC [Waters Delta-Pak C18, 15 uM, 100 A column, gradient 10%-100% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 10 minutes at 25 mL/min] to give a yellow solid (6.9 mg) which was further purified by flash chromatography on silica gel eluting with ethyl acetate to afford the title compound (1.9 mg) as a pale yellow solid. MS (ES+) 374, (ES−) 372. δH (CD3OD) 2.78 (3H, s), 3.01-3.07 (2H, m), 3.10-3.16 (2H, m), 7.46 (1H, t), 7.53 (1H, d), 7.65 (2H, s, partially exchanged), 7.83 (1H, d), 8.27 (1H, s), 8.48 (1H, s).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([O:16][C:17](=[O:27])[N:18]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[CH3:19])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17](=[O:27])[N:18]([C@H:20]1[CH2:21][CH2:22][C@H:23]([O:26][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:24][CH2:25]1)[CH3:19])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](O)CC1
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])CC1

Procedure:
Prepared analogously to example III.1 from 1.11 ml 2,4-difluoronitrobenzene and 1.56 g trans-(4-hydroxy-cyclohexyl)-methyl-carbamic acid tert-butyl ester.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([Cl:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([F:9])=[CH:7][CH:8]=1.[Cl:21][C:22]1[N:23]=[C:24]([CH3:30])[NH:25][C:26]=1[C:27](O)=[O:28].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:21][C:22]1[N:23]=[C:24]([CH3:30])[NH:25][C:26]=1[C:27]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:4]=1[Cl:20])=[O:28]
Reactant: Cc1nc(Cl)c(C(=O)O)[nH]1
Reactant: N#Cc1cc(Cl)cc(Oc2c(F)ccc(CN)c2Cl)c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1nc(Cl)c(C(=O)NCc2ccc(F)c(Oc3cc(Cl)cc(C#N)c3)c2Cl)[nH]1
Yield: 68.3 %

Procedure:
The title compound was prepared as described herein using 3-{[3-(aminomethyl)-2-chloro-6-fluorophenyl]oxy}-5-chlorobenzonitrile (40 mg, 0.129 mmol), 4-chloro-2-methyl-1H-imidazole-5-carboxylic acid (20.64 mg, 0.129 mmol), EDC (27.4 mg, 0.143 mmol) and HOBT (27.3 mg, 0.178 mmol) in DMF (3.0 ml) to give the title compound as a white solid (40 mg, 69%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.42 (1H, br. s.) 7.46-7.54 (0H, m) 7.31-7.41 (2H, m) 7.16-7.23 (2H, m) 7.14 (1H, d, J=2.1 Hz) 7.00 (1H, s) 4.72 (2H, d, J=6.2 Hz) 2.41 (3H, s). LCMS: m/z 453 (M+1).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:27])([F:26])[F:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH3:37]>>[CH3:37][O:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:27])([F:25])[F:26])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5]
Reactant: COc1ccccc1Br
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1
Product: COc1ccccc1C(=O)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1

Procedure:
This compound is prepared by method C using compound 12f and 2-bromoanisole
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(Cl)(=O)C([Cl:16])=O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([Cl:16])=[O:12])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(C)cc(CC(=O)O)c1
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(CC(=O)Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3,5-dimethylphenyl)acetic acid (2.32 g in 25 mL dry methylene chloride) at 0° C. was added 0.055 mL N,N-dimethylformamide followed by the dropwise addition of 1.3 mL of oxalyl chloride. After 15 minutes the mixture was warmed to room temperature and stirred for an additional 2 hours. Removal of the solvents in vacuo provided the title compound which was used without purification.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][N:6]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=3)[CH2:5]2)[CH2:3][O:2]1.CS(O[CH:21]1[CH2:24][N:23]([C:25]([C:27]2[O:28][C:29]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)=[N:30][N:31]=2)=[O:26])[CH2:22]1)(=O)=O>>[CH2:3]1[C:4]2([CH2:7][N:6]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH:21]4[CH2:24][N:23]([C:25]([C:27]5[O:28][C:29]([C:32]6[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=6)=[N:30][N:31]=5)=[O:26])[CH2:22]4)=[CH:11][CH:10]=3)[CH2:5]2)[CH2:1][O:2]1
Reactant: Oc1ccc(CN2CC3(COC3)C2)cc1
Reactant: CS(=O)(=O)OC1CN(C(=O)c2nnc(-c3ccc(Cl)cc3)o2)C1
Product: O=C(c1nnc(-c2ccc(Cl)cc2)o1)N1CC(Oc2ccc(CN3CC4(COC4)C3)cc2)C1
Yield: 12 %

Procedure:
The title compound was prepared using a similar protocol as described in Example 1 employing 2A and 2C as starting materials. There was obtained 70 mg (12%) of 2 as an oil. The oil gradually solidified on standing in room temperature. 1H NMR (500 MHz, CDCl3): δ 3.41 (s, 4H), 3.53 (s, 2H), 4.34 (d, 1H), 4.65 (m, 1H), 4.74 (s, 5H), 5.09 (m, 1H), 5.14 (m, 1H), 6.73 (d, 2H), 7.21 (d, 2H), 7.52 (d, 2H), 8.10 (d, 2H), MS (APCI+) m/z 467 [M+H]−, LC purity: 92%.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:14][Li]>O1CCCC1>[OH:1][C:2]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](=[O:6])[CH3:14]
Reactant: CC(C)c1cccc(C(=O)O)c1O
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(=O)c1cccc(C(C)C)c1O
Temperature: -75 °C
Reaction time: 8 h

Procedure:
2-Hydroxy-3-isopropylbenzoic acid (Aldrich, 4.0 g, 22.2 mmol) was dissolved in tetrahydrofuran (20 mL), chilled to −75° C., and methyllithium (1.6M in diethyl ether, 42 mL, 66.6 mmol) was added. The mixture stirred overnight at ambient temperature. The mixture was quenched with methanol (50 mL), concentrate under reduced pressure, and ethyl acetate (200 mL) was added. The mixture was washed with 1N hydrochloric acid (200 mL), water (200 mL), and brine and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrate under reduced pressure. The residue was chromatographed on silica gel eluting with 0-to-30% ethyl acetate in hexane to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.23 (d, 6H), 2.64 (s, 3H), 3.39 (m, 1H), 6.87 (t, 1H), 7.41 (dd, 1H), 7.59 (dd, 1H), 12.69 (s, 1H). MS (DCI) m/z 179.07 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[S:34]([N:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]([CH:46]=O)=[CH:38]1)(=[O:36])=[O:35].N1CCCCC1>CO>[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[S:34]([N:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39](/[CH:46]=[C:7]2\[O:8][C:4]3[C:3]([CH2:12][N:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[CH:38]1)(=[O:36])=[O:35]
Reactant: O=Cc1cn(S(=O)(=O)c2ccc(Cl)cc2Cl)c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2cn(S(=O)(=O)c4ccc(Cl)cc4Cl)c4ccccc24)C3=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.287 mmol) obtained in Example A16, Step 1 in methanol (1.2 mL) was added with 1-(2,4-dichlorophenylsulfonyl)-1H-indole-3-carboxaldehyde (0.102 g, 0.287 mmol) and piperidine (0.00244 g, 0.0287 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with methanol (2 mL), and the solid was suspended in methanol and thereby washed to obtain tert-butyl (Z)-4-[(2-{[1-(2,4-dichlorophenylsulfonyl)-1H-indol-3-yl]methylene}-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.147 g, 74%).