Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][NH:11][CH2:10][CH2:9][N:8]2[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>C1C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]1([CH:7]2[CH2:12][N:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:10][CH2:9][N:8]2[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1c1ccccc1
Reactant: Brc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: O=C(OCc1ccccc1)N1CCN(c2ccccc2)CC1c1ccccc1
Yield: 78.7 %

Procedure:
A solution of benzyl 2-phenylpiperazine-1-carboxylate (0.17 g, 0.58 mmol), bromobenzene (0.37 g, 2.37 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.06 g, 0.06 mmol), sodium tert-butoxide (0.20 g, 2.0 mmol) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.25 g, 0.64 mmol) in benzene (20 mL) was heated to 80° C. for 4.5 hours. After cooling, the reaction was diluted with ethyl acetate (60 mL), and washed with water (2×30 mL), then dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes, 1:4) to give benzyl 2,4-diphenylpiperazine-1-carboxylate (0.17 g, 79% yield) as an oil. MS (EI) for C24H24N2O2: 373 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[N:7]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:16]=1I)[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>CCCCCCC.CCOC(C)=O>[C:1]([O:5][C:6](=[O:18])[N:7]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:16]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[Cl:19])[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)N(C(=O)OC(C)(C)C)c1cnccc1I
Reactant: OB(O)c1ccccc1Cl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(C)N(C(=O)OC(C)(C)C)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-isopropyl-carbamic acid tert-butyl ester and 2-chlorophenylboronic acid (CAS RN 1679-18-1) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Colorless oil (85%). MS (ESI): m/z=347.15 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:20]=[CH:19][C:14]([O:15][CH2:16][C:17]#[N:18])=[CH:13][CH:12]=3)=[CH:8][CH:9]=2)[C:4]([CH3:21])=[C:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[N-:28]=[N+:29]=[N-:30].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:20]=[CH:19][C:14]([O:15][CH2:16][C:17]4[NH:30][N:29]=[N:28][N:18]=4)=[CH:13][CH:12]=3)=[CH:8][CH:9]=2)[C:4]([CH3:21])=[C:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1c(-c2ccccc2)n(C)c2ccc(-c3ccc(OCC#N)cc3)cc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2)n(C)c2ccc(-c3ccc(OCc4nnn[nH]4)cc3)cc12
Yield: 75.9 %

Procedure:
The desired product was prepared using a procedure similar to step 6 of example 3. Thus, [4-(1,3-dimethyl-2-phenyl-1H-indol-5-yl)-phenoxy]-acetonitrile (0.355 g, 1.007 mmol) was reacted with NaN3 (0.327 g, 5.036 mmol) and NH4Cl (0.269 g, 5.036 mmol) in DMF (5 ml) to give the desired product (0.302 g, 0.764 mmol, 76%) as a white solid, dec. 261-262° C. 1H NMR (DMSO-d6) δ 2.25 (s, 3H), 3.61 (s, 3H), 5.52 (s, 2H), 7.14 (d, J=8.6 Hz, 2H), 7.45-7.51 (m, 5H), 7.55 (t, J=7.6 Hz, 2H), 7.67 (d, J=8.6 Hz, 2H), 7.75 (s, 1H), 16.80 (broad s, 1H); IR (solid) 3040, 2860, 2620, 1580, 1520, 1480, and 1230 cm−1; [ESI(+)], m/z 396 (M+H)+; Anal. Calcd. for C24H21N5O: C, 72.89; H, 5.35; N, 17.71; Found: C, 72.84; H, 5.33; N, 17.80.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl.Cl[CH2:12][C:13]1[N:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]2=[N:15][C:14]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(N(CC)CC)C>CN(C=O)C.O>[O:7]([CH2:12][C:13]1[N:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]2=[N:15][C:14]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1nc2ccccn2c1CCl
Reactant: Oc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nc2ccccn2c1COc1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 39.8 %

Procedure:
A solution of a mixture of phenol (2.20 g) and sodium hydride (95 wt %, 500 mg) in DMF (40 ml) was added dropwise to a solution of ethyl 3-(chloromethyl)imidazo[1,2-a]pyridine-2-carboxylate hydrochloride (3.5 g) in DMF (50 ml) at 0° C. Triethylamine (2.7 ml) was added at the same temperature over 30 min. The reaction mixture was stirred at 50° C. for 3 hr, and the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (6:1) was concentrated under reduced pressure to give the object product (1.5 g).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][N:15]=[C:16]([NH:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[C:26]([O:30][C:31](=[O:43])[NH:32][CH2:33][CH:34]([NH2:42])[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=1)([CH3:29])([CH3:28])[CH3:27].CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:26]([O:30][C:31](=[O:43])[NH:32][CH2:33][CH:34]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=1)[NH:42][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][N:15]=[C:16]([NH:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:11]3=[N:10][CH:9]=2)[N:7]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: Brc1cccc(-c2cnc3c(NCCN4CCOCC4)nccn23)n1
Reactant: CC(C)(C)OC(=O)NCC(N)c1cccc(Cl)c1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCC(Nc1cccc(-c2cnc3c(NCCN4CCOCC4)nccn23)n1)c1cccc(Cl)c1
Temperature: 130 °C

Procedure:
A mixture of [3-(6-bromo-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 41 supra) (0.403 g, 1.0 mmol), [2-amino-2-(3-chloro-phenyl)-ethyl]-carbamic acid tert-butyl ester (from Example 78 supra) (0.406 g, 1.5 mmol), Pd2(dba)3(60 mg), Davephos (80 mg), K2CO3 (207 mg, 1.5 mmol) in dioxane (25 mL) in a sealed tube was bubbled with N2 for several minutes and then heated under N2 at 130° C. overnight. The solution was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography (CH2Cl2:MeOH, 50:1 to 20:1) to give crude (2-(3-chloro-phenyl)-2-{6-[8-(2-morpholin-4-yl-ethylamino)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-ylamino}-ethyl)-carbamic acid tert-butyl ester. (Yield 210 mg). LC-MS: [M+H]+ 593.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[C@H:7]([CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[NH:8][S:9]([C:12]1[CH:21]=[C:20]2[C:15]([C:16]([Cl:23])=[CH:17][N:18]=[C:19]2[Cl:22])=[CH:14][CH:13]=1)(=[O:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].Cl[C:38]1C2C(=CC=C(S(Cl)(=O)=O)C=2)C(Cl)=CN=1.Cl.C(OC(=O)[C@H](CCCCN)NC(OC(C)(C)C)=O)(C)(C)C.C(N(CC)CC)C>C(Cl)Cl>[O:5]([CH:1]([CH3:3])[CH3:4])[CH:6]([CH3:7])[CH3:38].[C:1]([O:5][C:6](=[O:36])[C@H:7]([CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[NH:8][S:9]([C:12]1[CH:21]=[C:20]2[C:15]([C:16]([Cl:23])=[CH:17][N:18]=[C:19]2[Cl:22])=[CH:14][CH:13]=1)(=[O:11])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)cnc(Cl)c2c1
Agent: CC(C)(C)OC(=O)NCCCC[C@H](NS(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(C)C

Procedure:
Nα-[(1,4-Dichloro-7-isoquinolinyl)sulphonyl]-Nε-tert-butyloxycarbonyl-L-lysine tert-butyl ester ##STR190## A solution of 1,4-dichloro-7-isoquinolinylsulphonyl chloride (250 mg, 0.84 mmol), Ne-tert-butyloxycarbonyl-L-lysine tert-butyl ester hydrochloride (286 mg, 0.84 mmol) and triethylamine (235 μl, 1.69 mmol) in CH2Cl2 (25 ml) was stirred at 23° C. for 3h. The reaction mixture was washed with water (2×20 ml), dried (MgSO4) and concentrated in vacuo to a residue which upon trituration with hexane and then i-Pr2O gave Nα-[(1,4-dichloro-7-isoquinolinyl)sulphonyl]-Nε-tert-butyloxycarbonyl-L-lysine tert-butyl ester as a white powder (270 mg, 0.48 mmol).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl>C1COCC1.O>[C:17]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:18]=[CH:19][C:14]([C:11]2[NH:10][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=3[N:12]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)c1cccc2[nH]c(-c3ccc(-c4ccccc4)cc3)nc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc2[nH]c(-c3ccc(-c4ccccc4)cc3)nc12
Temperature: 25 °C

Procedure:
2-Biphenyl-4-yl-1H-benzoimidazole-4-carboxylic acid methyl ester (180 mg, 0.54 mmol) was taken in THF (20 mL) and was refluxed with 5N NaOH (5 mL) solution for 14 h. It was then cooled to room temperature; THF was removed under reduced pressure to obtain a thick mass. This residue was diluted with water (10 mL) and adjusted pH to 2 with conc. hydrochloric acid. The precipitated solid was filtered, washed with water and dried in a vacuum oven to obtain compound the required compound as a pale yellow solid.
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([O:23][CH3:24])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17](Br)=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Li]CCCC.[CH3:32][N:33]1[C:37]([C:38]([C:40]2[N:44]([CH3:45])[N:43]=[N:42][CH:41]=2)=[O:39])=[CH:36][N:35]=[N:34]1.C(=O)=O.CC(C)=O>C1COCC1>[N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([O:23][CH3:24])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:38]([C:37]3[N:33]([CH3:32])[N:34]=[N:35][CH:36]=3)([C:40]3[N:44]([CH3:45])[N:43]=[N:42][CH:41]=3)[OH:39])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cn1nncc1C(=O)c1cnnn1C
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COc1nc2ccc(C(O)(c3cnnn3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reaction time: 0.03 h

Procedure:
A solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (0.271 g, 0.632 mmol; Intermediate 16) in THF (6 mL) was stirred under argon at ˜−70° C. while n-BuLi (1.63 M in hexanes, 0.368 mL, 0.6 mmol) was added dropwise by syringe over 1 minute. After another 2 minutes, a solution of bis(1-methyl-1H-1,2,3-triazol-5-yl)methanone (0.128 g, 0.664 mmol; Intermediate 43) in THF (6 mL) was added dropwise over 2 minutes, and the reaction was allowed to warm to room temperature overnight as the dry ice/acetone bath slowly warmed (11 hours). The resulting yellow mixture was quenched in one portion at 0° C. with 5 M aqueous NH4Cl (1 mL), and the organic layer was dried (Na2SO4), filtered, and concentrated. The residue was dry load flash chromatographed with a DCM to 100% EtOAc gradient to yield the impure title compound. This was then triturated from ˜0.5 mL DMSO+˜2 mL MeOH at 70° C., and the opaque milky mixture was allowed to cool to room temperature, filtered, and the white filter cake washed with MeOH (2×2 mL). The filter cake was air dried at 110° C. to provide the title compound as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.41 (d, J=2.53 Hz, 1H), 8.16 (d, J=2.02 Hz, 1H), 7.96 (s, 1H), 7.90 (d, J=8.59 Hz, 1H), 7.74 (s, 1H), 7.71 (d, J=4.55 Hz, 2H), 7.46 (dd, J=2.27, 8.84 Hz, 1H), 7.36 (d, J=8.59 Hz, 2H), 7.19 (s, 2H), 6.51 (s, 1H), 4.30 (s, 2H), 4.06 (s, 3H), 3.84 (s, 6H); MS m/e 542.3 [M+H]+.
Reaction SMILES: [CH3:1][Si:2]([CH3:12])([CH3:11])[O:3][C:4]1([C:9]#N)[CH2:8][CH2:7][CH2:6][CH2:5]1.[H-].C([Al+]CC(C)C)C(C)C.CCCCCC.[Cl-].[NH4+].S(=O)(=O)(O)[OH:32]>C1(C)C=CC=CC=1.C(OCC)C>[CH3:1][Si:2]([CH3:12])([CH3:11])[O:3][C:4]1([CH:9]=[O:32])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: O=S(=O)(O)O
Reactant: C[Si](C)(C)OC1(C#N)CCCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C[Si](C)(C)OC1(C=O)CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
The reaction was carried out in a procedure similar to that described in Tetrahedron, 50(9), 2821-30; 1994: To a solution of 1-[(trimethylsilyl)oxy]cyclopentanecarbonitrile (2.25 g, 12.3 mmol, prepared as described in Organometallics, 3(11), 1660-5; 1984) in toluene (18 mL) at −45° C. was added dropwise 1.0 M of diisobutylaluminum hydride in hexane (17.2 mL, 17.2 mmol). The solution was then allowed to warm to 0° C. and stir for 1 h at this temperature. The reaction mixture was poured into a mixture of diethyl ether (25 mL) and ammonium chloride (25 mL, saturated). To the resulting mixture, at 15° C., was added a dilute solution of sulfuric acid (prepared by diluting 1.53 mL of concentrated H2SO4 with 50 mL water). The solution was then stirred at a temperature of 5° C. overnight. The mixture was extracted with three portions of diethyl ether, the combined extracts were washed with brine, dried over sodium sulfate, decanted and concentrated to afford product (0.84 g, 36%), which was used without further purification in Step 2. 1H NMR (300 MHz, CDCl3): δ 9.47 (s, 1H), 1.88-1.46 (m, 8H), 0.00 (s, 9H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:12](=[O:23])[N:13]([CH3:22])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:9]([CH3:11])[CH3:10])(C)(C)C.C(=O)(O)[O-].[Na+]>Cl.C(O)(C)C.C(OCC)(=O)C>[NH2:7][CH:8]([CH:9]([CH3:11])[CH3:10])[C:12]([N:13]([CH3:22])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:23]
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)N(C)CCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC(C)C(N)C(=O)N(C)CCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
[2-Methyl-1-(methyl-phenethyl-carbamoyl)-propyl]-carbamic acid tert-butyl ester (3.79 g, 11.3 mmol) was added slowly in hydrochloric acid in isopropyl alcohol ([5M], 25 mL). The resulting mixture was stirred for 5 hours at room temperature, then the solvent was evaporated under reduced pressure to yield an oil. The oil was dissolved in ethyl acetate and treated with sodium bicarbonate solution. The organic layer was dried with MgSO4, filtered and the solvent evaporated under reduced pressure to yield an oil, which was purified by column chromatgraphy (10-50% EtOAc/heptane) to yield a residue.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:22])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS([Li])(=O)=O.[CH3:28][S:29]([CH3:32])(=[O:31])=[O:30]>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([OH:22])([CH2:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(C)(=O)=O
Reactant: O=C(NC1CC(=O)c2ccccc2C1)OCc1ccccc1
Agent: [Li]S(C)(=O)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)CC1(O)CC(NC(=O)OCc2ccccc2)Cc2ccccc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl sulfone (64 mg) in tetrahydrofuran (4 mL) stirring at −78° C. under nitrogen was slowly added lithium hexamethyldisilazide (1.0 M tetrahydrofuran solution, 0.67 mL). The resulting mixture was stirred for 1 h to form lithio methyl sulfone, and then a solution of 3-benzyloxycarbonylamino-1-oxo-1,2,3,4-tetrahydronaphthalene (40 mg) in tetrahydrofuran (0.4 mL) was added. Upon completion of addition, the resulting mixture was stirred for 30 min at −78° C. After this time, the reaction mixture was allowed to warm to room temperature at which it was stirred for 16 h. At the conclusion of this period, the reaction mixture was analyzed by HPLC, which indicated that starting material was still present. The reaction mixture was again cooled to −78° C. and additional lithio methyl sulfone mixture (prepared from methyl sulfone, 64 mg, in the manner set forth above) was added. The resulting mixture was stirred for 30 minutes and then analyzed by HPLC, which indicated that the starting material had been consumed. The reaction mixture was quenched at −78° C. with saturated aqueous ammonium chloride solution, warmed to room temperature, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated under vacuum to yield a residue. The residue was purified by reverse phase preparative HPLC (trifluoroacetic acid containing solvents were used) to obtain the title compound (23 mg) as a racemic diastereomeric mixture, predominantly the diastereomer leading to Example 12 that results from nucleophilic addition of lithio methyl sulfone to the carbonyl of 3-benzyloxycarbonylamino-1-oxo-1,2,3,4-tetrahydronaphthalene anti to the benzyloxycarbonylamino group.
Reaction SMILES: [NH2:1][C:2]([CH3:24])([CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[C:25]([N:29]=[C:30]=[O:31])([CH3:28])([CH3:27])[CH3:26]>ClCCl>[CH3:26][C:25]([NH:29][C:30]([NH:1][C:2]([CH3:24])([CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4])=[O:31])([CH3:28])[CH3:27]
Reactant: CC(C)(C)N=C=O
Reactant: CC(N)(Cc1c[nH]c2ccccc12)C(=O)NCCc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)NC(=O)NC(C)(Cc1c[nH]c2ccccc12)C(=O)NCCc1ccccc1

Procedure:
The product of Example 12 (0.25 g, 0.78 mmol) was dissolved in 1.5 ml of dichloromethane and treated with 90 μl (0.78 mmol) of tert-butylisocyanate, and then heated under reflux overnight. The crystalline product, (±)-α-[[[(1,1-dimethylethyl)amino]carbonyl]-amino ]-α-methyl-N-(2-phenylethyl)-1H-indole-3-propanamide, separated and was collected by filtration and dried.
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[CH2:22]([NH2:25])[CH2:23][CH3:24].C(N(CC)CC)C.O>C(O)C>[CH2:22]([NH:25][C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19])[CH2:23][CH3:24]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c2[nH]c(C(F)(F)F)nc12
Reactant: CCCN
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCNc1c(C(F)(F)F)cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c12

Procedure:
4-Chloro-7-nitro-2,5-bis(trifluoromethyl)benzimidazole (2.2 grams), propylamine (0.39 gram), and excess triethylamine were mixed in about 50 milliliters of ethanol. The reaction mixture was heated to reflux and refluxed over a weekend (about 60 hours). The reaction mixture was then poured into water and acidified. The desired 4-propylamino-7-nitro-2,5-bis(trifluoromethyl)benzimidazole product precipitated and was separated by filtration. After recrystallization from a mixture of ethanol and water, the compound melted at 129°-31°C. Analysis, Calc.: C, 40.4; H, 2.81; N, 15.73 Found: C, 40.5; H, 2.78; N, 15.51
Reaction SMILES: [As](C)(C)(=O)[O-].C(S)[C@@H](O)[C@H](O)CS.[P:14]([O:26][CH2:27][C@H:28]1[O:32][C@@H:31]([N:33]2[CH:40]=[CH:39][C:37]([NH2:38])=[N:36][C:34]2=[O:35])[CH2:30][C@@H:29]1[OH:41])([O:17]P(OP(O)(O)=O)(O)=O)(=[O:16])[OH:15].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>O>[CH2:30]1[C@H:31]([N:33]2[C:34](=[O:35])[N:36]=[C:37]([NH2:38])[CH:39]=[CH:40]2)[O:32][C@H:28]([CH2:27][O:26][P:14]([OH:16])([OH:17])=[O:15])[C@H:29]1[OH:41]
Reactant: Nc1ccn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)n1
Agent: C[As](C)(=O)[O-]
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: O[C@H](CS)[C@H](O)CS
Solvent: O
Product: Nc1ccn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Reaction time: 0.03 h

Procedure:
Double-stranded cDNA was homopolymer tailed essentially by the method of R. Roychoudhury and R. Wu, Meth. Enz., 65, pp. 43-62 (1980). The following were added together, in order: 3 μl dCTP32 (>800 Ci/mmol), 20 μl 10 X cacodylate buffer (1.4 mM potassium cacodylate, 0.3M Tris-hydrochloride, pH 7.6), 4 μl 5 mM DTT, 3 μl 10 mM dCTP, 2 μl 100 mM CoCl2, 12 units terminal deoxynucleotide transferase (PL Biochemicals; at least 8 units/pmol 3' end) in 1.5 μl, H2O to 200 μl final volume. The reaction was carried out at 12° for 1.5 min then stopped by adding 10 μl 0.5M EDTA This reaction resulted in an average of 15 dCMP residues added per 3' end of dsDNA, the optimal number for annealing and transformation (Peacock et al., Bioch. Biophys. Acta, 655, pp. 243-50 (1981)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:28][C@@H:29]([N:36]=[C:37]=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:37]([NH:36][C@@H:29]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH3:28])=[O:38])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: C[C@@H](N=C=O)c1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)N[C@H](C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and (R)-(+)-α-methylbenzyl isocyanate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:11])[CH3:10].C([OH:14])C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([CH:10]=[O:14])=[O:11]
Reactant: CCO
Reactant: COc1ccccc1C(C)=O
Product: COc1ccccc1C(=O)C=O

Procedure:
SeO2 (12.4 g., 0.112 mol) was dissolved in 75 ml. of 95% ethanol by warming to 55°. o-Methoxyacetophenone (15.3 g., 0.102 mol) was added in one portion and the mixture refluxed 21 hours. The reaction mixture was treated with activated carbon, filtered over diatomaceous earth, and the filtrate stripped to yield to an oil, 23.2 g. The latter was distilled to yield purified title product, 8.4 g., bp 94°-96°/0.5 mm, which solidified on cooling.