Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH2:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7][CH:6]=2>CO.C1COCC1.[Pd]>[CH3:1][N:2]([CH3:15])[CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[CH:9]=2)[CH2:4]1
Reactant: CN(C)C1=Cc2cc([N+](=O)[O-])ccc2C1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)C1Cc2ccc([N+](=O)[O-])cc2C1
Yield: 82.1 %

Procedure:
To a solution of 5-nitro-2-indanone (885 mg, 5 mmol) in THF (15 mL) was added dimethylamine (2N in THF, 5 mL, 10 mmol) dropwise. The reaction mixture was stirred at r.t. for 5 h. Water was added and the reaction mixture was extracted with EtOAc. Combined organic layers were washed with water and brine and dried over Na2SO4. The concentrated crude product was filtered through a short pad of silica gel (EtOAc:hexane=1:1) and the filtrate was concentrated to give dimethyl-(5-nitro-1H-inden-2-yl)-amine as a dark red solid (1.0 g, 98%). Dimethyl-(5-nitro-1H-inden-2-yl)-amine (1.0 g, 4.9 mmol) was hydrogenated using Pd/C (10% dry, ca. 300 mg) and H2 in MeOH:THF (1:1, 30 mL) at 1 atm at r.t. for 5 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated. The concentrated filtrate was further purified via short silica gel column chromatography (EtOAc: MeOH=6:4) to give the title compound as a yellow solid (830 mg, 82%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:16][C:15]3[CH:17]=[C:18]([C:21]4[CH:22]=[C:23]([NH2:28])[C:24]([NH2:27])=[N:25][CH:26]=4)[CH:19]=[CH:20][C:14]=3[O:13][CH2:12][CH2:11]2)=[O:9])[CH2:4][CH2:3]1.[CH3:29][O:30][C:31]([NH:33][C:34](=NC(OC)=O)SC)=[O:32]>C(O)(=O)C.C(OCC)C>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:16][C:15]3[CH:17]=[C:18]([C:21]4[CH:22]=[C:23]5[NH:28][C:34]([NH:33][C:31](=[O:32])[O:30][CH3:29])=[N:27][C:24]5=[N:25][CH:26]=4)[CH:19]=[CH:20][C:14]=3[O:13][CH2:12][CH2:11]2)=[O:9])[CH2:4][CH2:3]1
Reactant: COC(=O)N=C(NC(=O)OC)SC
Reactant: CC1CCN(C(=O)N2CCOc3ccc(-c4cnc(N)c(N)c4)cc3C2)CC1
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)Nc1nc2ncc(-c3ccc4c(c3)CN(C(=O)N3CCC(C)CC3)CCO4)cc2[nH]1
Temperature: 80 °C
Yield: 11.7 %

Procedure:
To a solution of 5-{4-[(4-methylpiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}pyridine-2,3-diamine (0.21 g, 0.55 mmol) in acetic acid (5 mL) was added 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (0.17 g, 0.82 mmol) and the resulting mixture was heated at 80° C. After 12 h the reaction mixture was diluted with ethyl ether (5 mL) and the resulting precipitate was collected by filtration. The resulting brown filter cake was dissolved in methanol and purified by preparative reverse phase HPLC to afford methyl (6-{4-[(4-methylpiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}-1H-imidazo[4,5-b]pyridin-2-yl)carbamate (0.030 g, 12% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): 12.02 (bs, 1H), 8.44 (s, 1H), 7.85 (s, 1H), 7.38-7.55 (m, 2H), 6.96-7.06 (m, 1H), 4.36-4.44 (m, 2H), 4.06-4.22 (m, 2H), 3.76 (s, 3H), 3.44-3.60 (m, 4H), 2.68 (t, 2H) 1.43-1.61 (m, 3H), 1.20 (q, 2H), 0.90 (d, 3H); MS (EI) for C24H28N6O4: 465 (MH+).
Reaction SMILES: [Li]CCCC.[NH:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.N#N.Cl[Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16]>C1COCC1.O>[CH:15]([Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[N:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1)([CH3:17])[CH3:16]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: c1cc[nH]c1
Agent: N#N
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 110.1 %

Procedure:
A solution n-BuLi in THF (2.5 M, 19.6 mL, 49 mmol) was added to a stirred solution of pyrrole (3 g, 44.7 mmol) in anhydrous THF (20 mL) at −78° C. in an N2 atmosphere. Then the mixture was warmed to room temperature and stirred at this temperature for 10 min. The mixture was cooled again to −78° C., and chlorotriisopropylsilane (10.5 g, 44.7 mmol) was added dropwisely with stirring. Then the mixture was warmed to room temperature and stirred for additional 30 min., diluted with water (200 mL), extracted with ether (200 mL). The organic layer was washed with water (2×100 mL) and brine (100 mL), dried over Na2SO4, concentrated to give crude 1-(triisopropylsilyl)-1H-pyrrole (11 g, 100%) as a oil. LCMS: 224 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 0.98 (m, 18H), 1.40 (m 3H), 6.20 (m, 2H), 6.80 (m, 2H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P(OCCCC)(OCCCC)OCCCC>O>[C:13]1([NH:12][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: Nc1ccccc1
Agent: CCCCOP(OCCCC)OCCCC
Solvent: O
Product: c1ccc(Nc2ccc3ccccc3c2)cc1
Reaction time: 5 h
Yield: 94 %

Procedure:
288 parts of β-naphthol, 250 parts of aniline and 9 parts of tributyl phosphite are mixed and fused at 130° C. At 190° C internal temperature, the reaction commences, with elimination of water. After 5 hours, the internal temperature has reached 235° C and 34 parts of water have distilled off. Thereafter, 412 parts of N-phenyl-β-naphthylamine, of melting point 100° - 102° C, distil, passing over at 230° C/15 mm Hg. This corresponds to a yield of 94% of theory.
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[CH:3]=[C:4]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][N:5]12.[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:14][CH:11]2[CH2:10][N:5]3[C:6]4[C:2]([CH:3]=[C:4]3[CH2:13][CH2:12]2)=[CH:1][CH:9]=[CH:8][CH:7]=4)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: NC1CCc2cc3ccccc3n2C1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NC1CCc2cc3ccccc3n2C1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a stirred solution of (+/−) 6,7,8,9-tetrahydropyrido[1,2-α]indol-7-amine from Step 9 in CH2Cl2 (0.14 M) at rt were added 4-fluorobenzenesulfonyl chloride (1.2 equiv.), triethylamine (5 equiv.) and DMAP (0.03 equiv). The reaction mixture was stirred at rt for 2 h. It was poured into aqueous NaHCO3 and extracted with dichloromethane (2×). The combined organic layers were washed with brine, dried with MgSO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel using using a CombiFlashRF (Teledyne ISCO) eluting with EtOAc/Hex (0:100 to 50:50 for 15 min, then at 50:50 for 5 min) to give the title compound (78%) as a light yellow foam.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[C:7](=[O:14])[C:8]([CH:12]=[O:13])=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH2:3][CH3:4].[C:30]1([Mg]Br)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)[C:7](=[O:14])[C:8]([CH:12]([OH:13])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)c(C=O)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)c(C(O)c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 0 °C
Yield: 46 %

Procedure:
To a solution of 4′-[(2-butyl-5-formyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.66 g) in tetrahydrofuran (10 mL) was added phenylmagnesium bromide (1.0 mL, 1 M tetrahydrofuran solution) at −78° C., and the mixture was allowed to warm to 0° C. over 3 hr. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow oil (0.36 g, 46%).
Reaction SMILES: N1C=CC=C2C(N)CCC=12.[CH2:11]([CH:13]1[CH2:14][C:15]2[C:16](/[C:21]/1=[N:22]\O)=[N:17][CH:18]=[CH:19][CH:20]=2)[CH3:12]>>[CH2:11]([CH:13]1[CH:21]([NH2:22])[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH2:14]1)[CH3:12]
Reactant: CCC1Cc2cccnc2/C1=N\O
Agent: NC1CCc2ncccc21
Product: CCC1Cc2cccnc2C1N

Procedure:
Following the procedure for the preparation of 6,7-dihydro-5H-cyclopenta[b]pyridin-5-amine but substituting (7Z)-6-ethyl-5,6-dihydro-7H-cyclopenta[b]pyridin-7-one oxime and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 8.40, 7.51, 7.10, 4.30, 3.95, 3.07, 2.95, 2.74, 2.50, 2.38, 2.03–1.93, 1.75, 1.57, 1.40, 1.09–0.97; HRMS (FAB) calcd for C10H14N2+H 163.1235, found 163.1229.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1.Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([NH:36][C@@H:37]([CH3:40])[CH2:38][OH:39])(=[O:35])=[O:34]>>[F:1][C:2]1[CH:7]=[C:6]([C:27]2[C:28]([S:33]([NH:36][C@@H:37]([CH3:40])[CH2:38][OH:39])(=[O:35])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1
Reactant: C[C@@H](CO)NS(=O)(=O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc4[nH]ccc4c3)c(F)c2)OC1(C)C
Product: C[C@@H](CO)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc3[nH]ccc3c2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Example 376 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine and (S)-2-bromo-N-(1-hydroxypropan-2-yl)benzene-sulfonamide. MS (ESI): mass calcd. for C22H20FN3O3S, 425.12; m/z found, 426.0 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 9.57 (s, 1H), 8.29-8.22 (m, 2H), 7.95-7.85 (m, 1H), 7.69-7.61 (m, 1H), 7.61-7.53 (m, 1H), 7.42-7.33 (m, 4H), 7.29 (d, J=7.8, 1H), 6.54-6.49 (m, 1H), 5.92 (d, J=6.7, 1H), 3.64-3.51 (m, 1H), 3.47-3.34 (m, 2H), 2.34 (s, 1H), 1.03 (d, J=6.5, 3H).
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)=[CH:16][N:17]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:25]([CH2:27][C:28](O)=[O:29])=[CH2:26].C1(N=C=NC2CCCCC2)CCCCC1>N1(C2C=CN=CC=2)CCCC1.ClCCl>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:19]=[CH:20][C:21]([O:24][C:28]([CH2:27][CH:25]=[CH2:26])=[O:29])=[CH:22][CH:23]=3)=[CH:16][N:17]=2)=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C=CCC(=O)O
Reactant: CCCCCCc1ccc(-c2ncc(-c3ccc(O)cc3)s2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: C=CCC(=O)Oc1ccc(-c2cnc(-c3ccc(CCCCCC)cc3)s2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.3 %

Procedure:
30 ml of dichloromethane was added to 2.0 g (5.93 mM) of 2-(4-hexylphenyl)-5-(4-hydroxyphenyl)-1,3-thiazole and 0.52 g (6.16 mM) of vinylacetic acid, followed by stirring at room temperature to the mixture, 1.21 g (5.86 mM) of N,N'-dicyclohexylcarbodiimide (DCC) and 0.02 g of 4-pyrrolidinopyridine were added, followed by stirring for 5 hours at room temperature. The resultant dicyclohexylurea was recovered by filtration, followed by washing with dichloromethane to be added to the filtrate. The resultant dichloromethane solution was condensed into a solid under reduced pressure, followed by purification by silica gel column chromatography (eluent: toluene) and recrystallization from a mixture solvent of ethanol/ethyl acetate to obtain 1.93 g of 2-(4-hexylphenyl)-5-(4-allylcarbonyloxyphenyl)-1,3-thiazole (Yield: 81.1%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][NH:4][N:3]=1.Br[CH2:11][C:12]#[N:13].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]([CH2:11][C:12]#[N:13])[N:3]=1
Reactant: N#CCBr
Reactant: Cc1n[nH]cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nn(CC#N)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 2 h
Yield: 38.3 %

Procedure:
A mixture of 3-methyl-4-nitro-1H-pyrazole (7 g, 0.055 mol), bromoacetonitrile (13.2 g, 0.11 mol) and K2CO3 (23 g, 0.165 mol) in DMF (120 mL) was stirred at 80° C. for 2 hrs. TLC (petroleum ether:EtOAc=2:1) showed the reaction was complete. The mixture was filtered, concentrated and the residue purified by flash chromatography (petroleum ether:EtOAc=4:1) to give the title compound (3.5 g, 38% yield) as light yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([NH:12][C@H:13]2[C:17](=[O:18])[N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][C@H:14]2[C:25]([O:27]C(C)(C)C)=[O:26])=[O:11])=N1.F[C:33](F)(F)C(O)=O>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([NH:12][C@H:13]2[C:17](=[O:18])[N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][C@H:14]2[C:25]([OH:27])=[O:26])=[O:11])=[CH:33]1
Reactant: CC(C)(C)OC(=O)[C@@H]1CN(c2ccccc2)C(=O)[C@@H]1NC(=O)c1n[nH]c2ccccc12
Reactant: O=C(O)C(F)(F)F
Product: O=C(N[C@H]1C(=O)N(c2ccccc2)C[C@H]1C(=O)O)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79 %

Procedure:
The tert-butyl ester (230 mg, 0.547 mmol) of Example 25 was dissolved in trifluoroacetic acid (3 ml) and stirred for 20 min at room temperature after which time the reaction was concentrated in vacuo. Resuspension of the residue in CH2Cl2 and filtration gave the title compound (206 mg, 79%) as a colorless solid. Anal calcd for C19H16N4O4.8/10CF3CO2H: C,54.41; H,3.55; N,12.32; F,10.03. Found C,54.52; H,3.76; N,12.45; F,10.35. DSC=130.85°-140.96° C. at 97.64 J/g. MS calc. for C19H16N4O4 364, found 364.
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@@H:5]([C@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[CH3:11]O>Cl>[O:1]([CH3:11])[CH:2]1[O:8][C@@H:7]([CH2:9][OH:10])[C@@H:5]([OH:6])[C@@H:3]1[OH:4]
Reactant: O=C[C@@H](O)[C@H](O)[C@@H](O)CO
Reactant: CO
Agent: Cl
Product: COC1O[C@@H](CO)[C@@H](O)[C@@H]1O

Procedure:
This compound is prepared according to the procedure described in J. Med. Chem. 41: 3865 (1998). L-Xylose is stirred in 0.5N HCl in anhydrous MeOH for 5-10 h at room temperature. The reaction mixture is neutralized with Amberlite IRA-400 OH or Dowex—X200 anion exchange resin. The resin is removed by filtration. The combined filtrate and washings are concentrated to an oil which is subjected to column chromatography on silica gel using a mixture of CH2Cl2 and MeOH as the eluent to afford compound 1-1 as an α/β anomeric mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[CH3:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([O:20][CH2:21][CH2:22][NH2:23])=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([O:20][CH2:21][CH2:22][NH:23][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:13])=[CH:18][CH:17]=1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Reactant: COc1ccc(OCCN)cc1
Product: COc1ccc(OCCNC(=O)c2cc3cc(Cl)ncc3[nH]2)cc1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and 2-(4-methoxyphenoxy)ethylamine. The product was purified by chromatography on silica gel eluting with methanol/dichloromethane (3:97) to give the title compound as a yellow solid. δH (CD3OD): 3.71 (3H, s), 3.77 (2H, t), 4.12 (2H, t), 6.81–6.91 (4H, m), 7.09 (1H, s), 7.67 (1H, s), 8.58 (1H, s); m/z (ES+)=346 [M+H]+.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:9](=[O:20])[C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[C:12]([F:18])[C:11]=1F)[C:5]([O:7][CH3:8])=[O:6].[C:22]([O:26][C:27]([N:29]([CH3:31])N)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl>[C:22]([O:26][C:27]([N:29]([N:2]1[C:11]2[C:10](=[CH:15][C:14]([F:16])=[C:13]([F:17])[C:12]=2[F:18])[C:9](=[O:20])[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3]1)[CH3:31])=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: COC(=O)C(=CN(C)C)C(=O)c1cc(F)c(F)c(F)c1F
Reactant: CN(N)C(=O)OC(C)(C)C
Solvent: ClCCl
Product: COC(=O)c1cn(N(C)C(=O)OC(C)(C)C)c2c(F)c(F)c(F)cc2c1=O
Reaction time: 1 h
Yield: 62.8 %

Procedure:
To methylene chloride (120 ml) solution of methyl 3-dimethylamino -2-(2,3,4,5-tetrafluorobenzoyl)acrylate (13.2 g) was added methylene chloride (12 ml) solution of 1-tert-butoxycarbonyl-1-methylhydrazine (7.59 g) with ice-cooling, and the mixture was stirred for one hour at the same temperature and then for 15 hours at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was triturated with diisopropyl ether (132 ml). The solid formed was taken out by filtration and dried with phosphorus pentaoxide under reduced pressure to obtain methyl 1-(N-tert-butoxycarbonyl-N-methylamino)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (10.49 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]([C:11]2[N:12](COCC[Si](C)(C)C)[C:13](Br)=[C:14]([Br:16])[N:15]=2)=[O:10])=[CH:3][CH:2]=1.C(OC([N:33]1[C:41]2[C:36](=[CH:37][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:40]=2)[CH:35]=[C:34]1[C:51]1[O:55][N:54]=[C:53]([CH3:56])[N:52]=1)=O)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:1]1[CH:2]=[CH:3][C:4]([CH2:7][NH:8][C:9]([C:11]2[NH:15][C:14]([Br:16])=[C:13]([C:38]3[CH:37]=[C:36]4[C:41](=[CH:40][CH:39]=3)[NH:33][C:34]([C:51]3[O:55][N:54]=[C:53]([CH3:56])[N:52]=3)=[CH:35]4)[N:12]=2)=[O:10])=[CH:5][CH:6]=1
Reactant: Cc1noc(-c2cc3cc(B4OC(C)(C)C(C)(C)O4)ccc3n2C(=O)OC(C)(C)C)n1
Reactant: C[Si](C)(C)CCOCn1c(C(=O)NCc2ccncc2)nc(Br)c1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1noc(-c2cc3cc(-c4nc(C(=O)NCc5ccncc5)[nH]c4Br)ccc3[nH]2)n1
Temperature: 120 °C

Procedure:
To a solution of 4,5-dibromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid(pyridin-4-ylmethyl)-amide (280 mg, 0.57 mmol) and 2-(3-methyl-1,2,4-oxadiazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-indole-1-carboxylic acid tert-butyl ester (243 mg, 0.57 mmol) in toluene (5.0 ml) is added aqueous Na2CO3 solution (2M, 0.63 ml, 1.26 mmol). The mixture is purged with argon for 10 minutes. (Bis(di-t-butyl(4-dimethylaminutesophenyephosphine)dichloropalladium(II) (81 mg, 0.11 mmol) is added and the reaction mixture is sealed in a sealed tube and heated to 120° C. for 14 hours. The reaction mixture is diluted with ethyl acetate (25 ml), washed with water (15 ml), brine (15 ml), dried over MgSO4, filtered, and concentrated in vacuo. The crude material is purified on reversed phase HPLC. The resulting protected analog is dissolved in 50% trifluoroacetic acid in dichloromethane (10 ml). After 2 hours the solvent is evaporated in vacuo, and the product is purified by reverse phase HPLC, 25 mg, 9%, LC/MS ESI m/z (M+H)+=480.33.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].C([C:20]1[CH:25]=[C:24]([C:26]([CH3:28])=[CH2:27])[CH:23]=[CH:22][N:21]=1)=C>CN1C(=O)CCC1.O>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:27][CH:26]([C:24]3[CH:23]=[CH:22][N:21]=[CH:20][CH:25]=3)[CH3:28])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1cc(C(=C)C)ccn1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(C)c2ccncc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.5 mmol) was dissolved in NMP (3 mL) and KOH (280 mg, 5 mmol) was added with vinyl 4-(prop-1-en-2-yl)pyridine (178 mg, 1.5 mmol). The reaction was stirred at RT for 14 h. After completion, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, concentrated and the residue purified by HPLC. 1HNMR (CD3OD, Oxalate salt) d (ppm): 8.4 (d, 2H), 7.25-7.15 (m, 4H), 7.05 (d, 1H), 4.4-4.2 (m, 3H), 3.80-3.79 (m, 2H), 3.50-3.40 (m, 2H), 3.15 (m, 1H), 3.05 (s, 3H) 2.70 (m, 1H), 2.40 (s, 3H), 1.40 (d, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].CO.[Fe:24]>C(O)(=O)C>[Fe:24].[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6]=1[NH2:19])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)Nc1ccc(OCc2ccccc2)cc1N

Procedure:
1-Acetamido-4-benzyloxy-2-nitrobenzene is treated with 100 ml. methanol with 1.5 g. iron powder and 1 ml. acetic acid at reflux, followed after one hour with a further addition of 1 ml. of acetic acid and 1.0 g. of iron powder to afford 1-acetamido-2-amino-4-benzyloxybenzene. This latter compound is treated in accordance with the third paragraph of Example I to afford 2-acetamido-5-benzyloxy-1-(3-methoxycarbonyl-2-thioureido)benzene.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc5ccc(Cl)cc5s4)cc3CC[C@@H]12
Yield: 52.8 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2,6-dichloro-benzothiazole (155 mg, 0.76 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 86 mg (53%) of the title compound as an amorphous solid. mp 156°-162°. FDMS: m/e =429. α[D]589 =+63.53 (c=0.66, chloroform).
Reaction SMILES: [I:1][C:2]1[C:6]([CH:7]=O)=[CH:5][N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:3]=1.[CH3:15][N:16]([CH2:24][CH2:25][NH:26][CH3:27])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.ClCCl>[I:1][C:2]1[C:6]([CH2:7][N:26]([CH3:27])[CH2:25][CH2:24][N:16]([CH3:15])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[CH:5][N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:3]=1
Reactant: CNCCN(C)C(=O)OC(C)(C)C
Reactant: O=Cc1cn(C2CCCCO2)nc1I
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CN(CCN(C)C(=O)OC(C)(C)C)Cc1cn(C2CCCCO2)nc1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
A mixture of 3-iodo-1-(oxan-2-yl)-1H-pyrazole-4-carbaldehyde (21.5 g, 70.24 mmol, 1.00 equiv), tert-butyl N-methyl-N-(2-(methylamino)ethyl)carbamate (20 g, 106.23 mmol, 1.51 equiv) and NaBH(OAc)3 (29.8 g, 137.98 mmol, 1.96 equiv) in dichloroethane (300 mL) was stirred for 1 h at room temperature. The reaction was diluted with 300 mL of dichloromethane and then washed with 3×300 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-7% methanol in dichloromethane to give 31 g (92%) of tert-butyl (2-(((3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.62 (s, 1H), 5.34-5.30 (m, 1H), 4.06-4.02 (m, 1H), 3.68-3.62 (m, 1H), 3.42-3.38 (m, 4H), 2.85 (s, 4H), 2.62-2.53 (m, 2H), 2.47-2.46 (m, 2H), 2.13-1.97 (m, 3H), 1.74-1.69 (m, 3H), 1.46 (s, 9H) ppm. LCMS (method A, ESI): RT=1.17 min, m/z=479.0 [M+H]+.