Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([NH:24][CH3:25])=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:26]>C(OCC)C.C(O)C>[ClH:26].[CH3:25][NH:24][C:16]1[S:15][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:18][C:17]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1nc(N2CCN(C(=O)OC(C)(C)C)CC2)sc1NC
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1nc(N2CCNCC2)sc1NC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Ethyl 2-(4-tert-butoxycarbonylpiperazin-1-yl)-5-methylamino-thiazole-4-carboxylate (196 mg, 0.529 mmol) was dissolved in a mixture of diethylether (10 ml) and ethanol (absolute, 15 ml), hydrochloric acid (4N in dioxane, 5 ml) was added and the mixture was stirred at room temperature for two days. The resulting precipitate was collected by filtration, washed with diethylether and dried under reduced pressure to give 130 mg of a white solid (0.424 mmol, yield 80) MS (multi-mode) m/z=271.1 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[CH3:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:24][NH:23][C:20]1[CH:19]=[CH:18][C:17]([S:14]([CH3:13])(=[O:16])=[O:15])=[CH:22][CH:21]=1
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Product: CS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(Br)cc32)cc1
Yield: 72 %

Procedure:
The title compound was prepared in 72% yield from 5-bromo-1H-indole-2,3-dione (Meth-Cohn and Goon, Tetrahedron Letters 1996, 37, 9381-4) and 4-methylsulfonylphenylhydrazine according to Procedure G: 1H NMR (DMSO-d6): δ12.7 (s, 1H), 11.3 (s, 1H), 7.9 (d, 2H), 7.7-7.8 (m, 3H), 7.4 (dd, 1H), 6.9 (d, 1H), 3.2 (s, 3H); ESI−MS m/z 392 (M−H)−.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][C:8](=O)[CH2:9]2)([CH3:4])([CH3:3])[CH3:2].[CH3:15][Mg]Br.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:15][C:8]1[CH2:9][C:10]2[C:6]([CH:7]=1)=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:13]=[CH:12][CH:11]=2
Reactant: C[Mg]Br
Reactant: CC(C)(C)c1cccc2c1CC(=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC1=Cc2c(cccc2C(C)(C)C)C1
Reaction time: 4 h
Yield: 33 %

Procedure:
3.6 g (19 mmol) of indanone c3 were reacted with 3.0 equivalents of methylmagnesium bromide and the mixture was worked up, analogously to instructions I.3. The reaction time was 17 hours at room temperature and a further 4 hours under reflux. The mixture was then refluxed with p-toluenesulfonic acid hydrate for 25 minutes. Chromatography gave 1.2 g (33%) of indene c4 as a yellow oil. Unused starting material could be recovered with hexane/ethyl acetate (9:1).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH2:22][CH3:23])[C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([O:18][C:19](=O)[CH3:20])=[CH:12][CH:11]=3)(=O)[CH3:2].[ClH:24].C([N:27]([CH2:31][CH3:32])[CH2:28][CH2:29][Cl:30])C.C[O-].[Na+]>ClC1C=CC=CC=1>[ClH:30].[ClH:24].[CH2:31]([N:27]([CH2:28][CH3:29])[CH2:2][CH2:1][O:4][C:5]1[CH:17]=[CH:16][C:8]2[N:9]([CH2:22][CH3:23])[C:10]3[C:11]([C:7]=2[CH:6]=1)=[CH:12][C:13]([O:18][CH2:19][CH2:20][N:9]([CH2:10][CH3:11])[CH2:8][CH3:7])=[CH:14][CH:15]=3)[CH3:32]
Reactant: CCN(CC)CCCl
Reactant: CCn1c2ccc(OC(C)=O)cc2c2cc(OC(C)=O)ccc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Clc1ccccc1
Product: CCN(CC)CCOc1ccc2c(c1)c1cc(OCCN(CC)CC)ccc1n2CC

Procedure:
A mixture of 15.5 g (0.05 mole) of N-ethyl-3,6-carbazolediol diacetate, 17.2 g (0.1 mole) of 2-diethylaminoethylchloride hydrochloride, 10.8 g (0.2 mole) of sodium methoxide and 400 ml. of chlorobenzene was refluxed for 24 hours. Upon cooling, the reaction mixture was filtered, and the filtrate was washed with several portions of water, dried over anhydrous magnesium sulfate, diluted with ether and acidified with ethereal HCl. The resulting precipitate was separated and recrystallized from methanol-ethyl acetate to give the desired product. M.P. 208°-210°C, λmaxEtOH 232, E1cm1% 853.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10](Cl)[CH:11]=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:14]=[C:15](/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(Cl)(Cl)Cl>[Si:1]([O:8][CH2:9][C@@H:10]1[C:11](=[O:12])[O:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][C@@H:22]1[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(=O)/C=C/c1ccc(C)cc1
Reactant: CC(C)(C)[Si](C)(C)OCC(Cl)C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1=C[C@H](c2ccc(C)cc2)[C@H](CO[Si](C)(C)C(C)(C)C)C(=O)O1
Yield: 83 %

Procedure:
Prepared according to the general procedure from 3-(tert-butyldimethylsilyloxy)-2-chloropropanal and (E)-ethyl 2-oxo-4-p-tolylbut-3-enoate using 2 mol % 1 as the catalyst in 83% yield as a single diastereomer (white solid). [α]D2 (c 1.27, CHCl3)=+244.6; mp=60-61° C.; 1H NMR (400 MHz, CDCl3) δ 7.32-7.24 (m, 3H), 7.12 (d, 2H, J=8.1 Hz), 6.99 (d, 2H, J=8.1 hz), 6.70 (d, 1H, J=7.5 Hz), 4.32 (q, 1H, J=7.2 Hz), 3.77 (t, 1H, J=6.8 Hz), 2.81 (q, 1H, J=6.8 Hz), 2.33 (s, 3H), 1.72-1.63 (m, 2H), 1.37-1.14 (m, 19H), 0.88 (t, 3H, J=6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 167.3, 160.7, 142.6, 138.2, 132.0, 129.8, 128.5, 118.9, 62.1, 58.7, 45.8, 38.3, 26.0, 21.3, 18.3, 14.4, −5.3, −5.4; IR (thin film) ν 3027, 2953, 2929, 2857, 1776, 1740, 1658, 1471, 1370, 1317, 1262, 1084 cm−1; HRMS (EI) calcd for C25H36O4 [M-Bu]+ 347.1315, found 347.1305; 95% ee (4S,5R)-isomer as determined by HPLC (AD-H, 100:1 hexanes/i-PrOH), tr (4S,5R)=8.5 min, tr (4R,5S)=10.0 min.
Reaction SMILES: [N:1]([C:4](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([P:18]([O:24][O:25][CH2:26][CH3:27])([O:20][O:21][CH2:22][CH3:23])=[O:19])[OH:17])=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[N+]=[N-].[H][H]>CO.[Pd]>[CH2:22]([O:21][O:20][P:18]([CH:16]([OH:17])[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH:4]([C:5]([O:7][CH3:8])=[O:6])[NH2:1])=[CH:11][CH:12]=1)([O:24][O:25][CH2:26][CH3:27])=[O:19])[CH3:23]
Reactant: [H][H]
Reactant: CCOOP(=O)(OOCC)C(O)c1ccc(C=C(N=[N+]=[N-])C(=O)OC)cc1
Agent: [Pd]
Solvent: CO
Product: CCOOP(=O)(OOCC)C(O)c1ccc(CC(N)C(=O)OC)cc1
Yield: 85.6 %

Procedure:
A total of 3.4 g (9.2 mmol) of 38 in 100 mL MeOH was hydrogenated at 40 psi H2 over 300 mg 10% Pd.C. Hydrogen was replenished at t=15, 60, 135, 210 and 255 minutes and 300 mg additional 10% Pd, C was added at t=135 and 255 minutes and the reaction terminated at t=6 hours. The mixture was filtered through celite and rotovapped (30° C.) to yield 39 as a clear colorless oil (2.97 g, 95%). The oil crystallized from ether yielding white crystals, mp 94°-100° C. (soften 77° C.). 1H NMR (250 MHz, DMSO-d6) δ: 7.34 (d, 2H, J=7.5 Hz, aromatic), 7.15 (d, 2H, J=7.5 Hz, aromatic), 6.16 (br s, 1H, OH) , 4.89 (d,1H, J=13.0 Hz, PCH), 3.93 (m, 4H, OCH2), 3.59 (m, 1H, Hα), 3.57 (s, 3H, CO2CH3), 2.87 (dd, 1H, J=13.4, 6.7 Hz, Hβ), 2.76 (dd, 1H, J=13.4, 7.2 Hz, Hβ) , 1.17 (t, 3H, J=7.0 Hz, CH3), 1.13 (t, 3H, J=7.0 Hz, CH3), mp 94°-100° C.; FABMS m/z 346.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1.O[CH2:14][C:15]([C:17]1[CH:21]=[C:20]([CH3:22])[O:19][N:18]=1)=O.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH3:22][C:20]1[O:19][N:18]=[C:17]([C:15]2[N:3]3[NH:4][C:5](=[O:12])[C:6]4[C:11]([C:2]3=[N:1][CH:14]=2)=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH:21]=1
Reactant: Cc1cc(C(=O)CO)no1
Reactant: Nc1n[nH]c(=O)c2ccccc12
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cnc3c4ccccc4c(=O)[nH]n23)no1
Yield: 42.8 %

Procedure:
4-Amino-1-phthalazinone (2.28 g, 14.2 mmol) [Angew. (1967) 6(2) 173-4] and 2-hydroxy-1-(5-methylisoxazol-3-yl)ethanone (2.0 g, 14.2 mmol) were suspended in toluene (100 ml) and trifluoroacetic acid (5 ml) was added. The suspension was heated at reflux under Dean & Stark conditions, for 24 hours. The solvent was then removed in vacuo and the residue was purified by chromatography on silica gel eluting with 10% methanol:dichloromethane, to provide the title product (1.62 g, 43%), 1H NMR (360 MHz, d6-DMSO) 2.50 (3H, s), 5.96 (2H, br s), 7.79-8.22 (4H, m) 11.48 (1H, s).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:22]([NH:24][CH2:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35](=[O:43])[C:36]1[CH:41]=[C:40]([Br:42])[CH:39]=[CH:38][N:37]=1)=[O:27])=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14]C(OC(C)(C)C)=O)=O)(C)(C)C.[ClH:44].C(OCC)C>O1CCOCC1>[ClH:44].[ClH:44].[ClH:44].[NH2:8][C@H:9]([C:22]([NH:24][CH2:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35](=[O:43])[C:36]1[CH:41]=[C:40]([Br:42])[CH:39]=[CH:38][N:37]=1)=[O:27])=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)Nc1ccccc1C(=O)c1cc(Br)ccn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: NCCCC[C@H](N)C(=O)NCC(=O)Nc1ccccc1C(=O)c1cc(Br)ccn1
Yield: 88 %

Procedure:
1.0 g of (Nα,Nε-ditertbutoxycarbonyl-L-lysyl)-N-(4-bromo-2-picolinoylphenyl)glycinamide was stirred for 1 hour in a solution of hydrogen chloride in dioxan (4-M). Diethyl ether was added and the solid which separated was filtered off, washed with diethyl ether and dried. The solid was dissolved in methanol and precipitated with ethyl acetate. The precipitate was dissolved in 20 ml of water and, after extraction with chloroform, the aqueous solution was lyophilised to yield 0.7 g (88%) of L-lysyl-N-(4-bromo-2-picolinoylphenyl)glycinamide trihydrochloride 1.5 H2O; [α]D20 = +20.1° (c = 1 in water).
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N+:32]([O-:34])=[O:33]>>[C:1]1([CH:7]([C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)[O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N+:32]([O-:34])=[O:33])[CH2:13][CH2:14]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C(OC2CCNCC2)c2ccncc2)cc1
Reactant: O=[N+]([O-])c1ccccc1OCCCCl
Product: O=[N+]([O-])c1ccccc1OCCCN1CCC(OC(c2ccccc2)c2ccncc2)CC1

Procedure:
The procedure of Example 24 (a) was repeated except for using 4-(phenyl-4-pyridylmethoxy)piperidine and 1-chloro-3-(2-nitrophenoxy)propane instead of 4-[(2-chlorophenyl)-phenylmethoxy]piperidine and 1-chloro-3-(2-nitrophenoxy)propane to give oily 4-(phenyl-4-pyridylmethoxy)-1-[3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)=[N:5][NH:6][C:7]=1[N:8]=[CH:9][N:10](C)C)#[N:2].Cl.[Cl:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)N.CN(C=O)C>O>[Cl:24][C:25]1[CH:31]=[C:30]([NH:2][C:1]2[N:10]=[CH:9][N:8]=[C:7]3[NH:6][N:5]=[C:4]([NH:13][C:14]4[CH:15]=[CH:16][C:17]([N:20]([CH3:21])[CH3:22])=[CH:18][CH:19]=4)[C:3]=23)[CH:29]=[CH:27][CH:26]=1
Reactant: CN(C)C=Nc1[nH]nc(Nc2ccc(N(C)C)cc2)c1C#N
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Temperature: 130 °C

Procedure:
A mixture of 5 g (16.8 mmol) of 4-cyano-5-(dimethylamino-methyleneamino)-3-(4-dimethylamino-phenylamino)-pyrazole, 3.3 g (20.1 mmol) of 3-chloro-aniline hydrochloride and 40 ml of DMF is heated for 8 hours, with stirring, at 130° C. The reaction mixture is then cooled to RT, water is added dropwise thereto, and the reaction mixture is then filtered and the filter residue is dissolved in approx. 20 ml of DMF. After precipitation with water, followed by recrystallization from DMF/water, the resulting crystals are suspended in 10 ml of water. 6 ml of 1N hydrochloric acid are added, the mixture is heated briefly to reflux and filtered and 3 ml of 2N sodium hydroxide solution are added to the filtrate. The crystalline precipitate is filtered off, washed with water and dried under a high vacuum at 120° C., yielding the title compound having a water content of 2.32%; m.p. 250-255° C. (decomp.).
Reaction SMILES: [OH:1][N:2]1[C@@H:5]([CH3:6])[C@H:4]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:3]1=[O:15].Br[CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].C(N(CC)CC)C>CN(C)C=O>[C:11]([O:10][C:8]([NH:7][C@H:4]1[C@H:5]([CH3:6])[N:2]([O:1][CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C:3]1=[O:15])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1OCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.8 %

Procedure:
(3S-trans)-1-Hydroxy-3-[(t-butyloxycarbonyl)-amino]-4-methyl-2-azetidinone (21.6g) was dissolved in 300ml of dimethylformamide, 25.2g of bromoacetic acid. phenylmethyl ester was added. 17 ml of triethylamine was added. and the mixture was stirred for 3 hours at room temperature. The resulting precipitate was filtered off. The filtrate evaporated in vacuo, the residue dissolved in ethyl acetate and the solution treated with water, the pH of which was adjusted to 7. The organic phase was washed twice with water, dried (MgSO4) and evaporated to yield 33.4g of the title compound as an oil.
Reaction SMILES: [OH-].[Na+].[CH:3]1[C:13]2[CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]([CH2:18][C:19]3[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=3)[C:22]([O:24]C)=[O:23])[C:7]=2[CH:6]=[CH:5][CH:4]=1>O1CCOCC1.CO>[CH:14]1[C:10]2[CH2:11][CH2:12][C:13]3[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=3[N:8]([CH2:18][C:19]3[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=3)[C:22]([OH:24])=[O:23])[C:9]=2[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cccc(CN2c3ccccc3CCc3ccccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)c1cccc(CN2c3ccccc3CCc3ccccc32)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
1N aqueous solution of sodium hydroxide (9 ml) was added to a solution of methyl 3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-ylmethyl)benzoate (1.06 g) in a mixture of 1,4-dioxane (25 ml) and methanol (15 ml) at 25° C. The mixture was stirred at 25° C. for 3 hours, and then at 50° C. for 30 minutes. After evaporation of the solvent, the residue was partitioned between ethyl acetate and 0.1N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated to give 3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-ylmethyl)benzoic acid (1.01 g) as powder.
Reaction SMILES: S(=O)(=O)(O)O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[C:17]([NH:27][C@H:28]([C:32]([NH:34][CH:35]([C:39]([F:69])([F:68])[CH:40]([OH:67])[CH:41]([NH:49][C:50](=[O:66])[C@H:51]([CH:63]([CH3:65])[CH3:64])[NH:52][C:53]([O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:54])[CH2:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)[CH:36]([CH3:38])[CH3:37])=[O:33])[CH:29]([CH3:31])[CH3:30])([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>C(O)(=O)C>[C:17]([NH:27][C@H:28]([C:32]([NH:34][CH:35]([C:39]([F:68])([F:69])[C:40](=[O:67])[CH:41]([NH:49][C:50](=[O:66])[C@H:51]([CH:63]([CH3:65])[CH3:64])[NH:52][C:53]([O:55][CH2:56][C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1)=[O:54])[CH2:42][CH:43]1[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]1)[CH:36]([CH3:38])[CH3:37])=[O:33])[CH:29]([CH3:31])[CH3:30])([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]
Reactant: CC(C)C(NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(F)(F)C(O)C(CC1CCCCC1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)C(NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(F)(F)C(=O)C(CC1CCCCC1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
A solution of oxidant was prepared as follows: to 392 mg of sulfuric acid was added 5 ml of acetic acid and 298 mg of sodium dichromate. To a solution of 150 mg of the resultant compound of Example 182 in 10 ml of acetic acid was added 2 ml of the oxidant. After stirring at ambient temperature for 1 hr, the acetic acid was removed under vacuum and the residue was dissolved in 50 ml of ethyl acetate and washed with 30 ml of water. The aqueous layer was extracted with ethyl acetate (2×40 ml) and the combined ethyl acetate solution was dried, filtered and concentrated. The crude product was purified by silica gel column chromatography (10% EtOAc/CH2Cl2) to give 120 mg of the desired compound (80%). Mass spectrum: (M+H)+ =743. 1H NMR CDCl3): d 0.85-0.98 (m, 18H), 3.90-4.02 (m, 2H), 460 (m, 1H), 5.35 (br d, 1H), 6.10 (br d, 1H), 6.20 (br d, 1H), 7.35 (m, 10H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([Cl:11])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=[O:14].O.[C:17]1(C)C=CC(S(O)(=O)=O)=C[CH:18]=1>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([Cl:11])=[CH:4][C:3]=1[CH2:12][C:13]([O:15][CH2:17][CH3:18])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)Cc1cc(Cl)c([N+](=O)[O-])cc1Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1cc(Cl)c([N+](=O)[O-])cc1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 690.9 %

Procedure:
(2,5-dichloro-4-nitrophenyl)acetic acid (22) (Valerie K. Chamberlain and R. L. Wain. Ann. appl. Biol. (1971), 69, 65-72.) (500 mg, 2.0 mmol) was dissolved in ethanol (10 ml), and after adding p-toluenesulfonic acid monohydrate (50 mg, 0.26.mmol), the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, and concentrated and exsiccated under reduced pressure. To the resulting residue was added a saturated solution of sodiumbicarbonate (30 ml), and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography using silica gel, and from the eluate of chloroform was obtained the title compound (505 mg, 91%) as a pale yellow crystal powder.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)=[CH:5][C:4]=1F)#[N:2].[C:23]([O-])([O-])=[O:24].[K+].[K+]>CO.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)=[CH:5][C:4]=1[O:24][CH3:23])#[N:2]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc2c(ccn2-c2ccc(C#N)c(F)c2)c1
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc2c(ccn2-c2ccc(C#N)c(OC)c2)c1
Temperature: 75 °C
Yield: 102 %

Procedure:
A solution of 95 mg (0.32 mmol) of compound 9m was combined with 120 mg (0.87 mmol) of K2CO3 in 8 mL of MeOH and heated at 75° C. for 5 h. The mixture was cooled, diluted with water, and extracted with CH2Cl2. The organic solution was concentrated to give 100 mg (100%) of 9n as a white solid.
Reaction SMILES: [C:1]([CH2:3][CH:4]=[C:5]1[CH:10]([CH3:11])[CH:9]2[CH2:12][CH:6]1[CH2:7][CH2:8]2)#[N:2].[H][H]>[Pd]>[C:1]([CH2:3][CH2:4][CH:5]1[CH:10]([CH3:11])[CH:9]2[CH2:12][CH:6]1[CH2:7][CH2:8]2)#[N:2]
Reactant: CC1C(=CCC#N)C2CCC1C2
Reactant: [H][H]
Agent: [Pd]
Product: CC1C2CCC(C2)C1CCC#N
Yield: 89 %

Procedure:
A mixture of 10.0 g (0.062 mol) of 2-(2-cyanoethyl-idene)-3-methylbicyclo[2.2.1]heptane, 10 ml of 2B alcohol and 0.1 g of palladium supported on charcoal (5%) catalyst was hydrogenated under 50 psi of hydrogen until 1 equivalent of hydrogen was absorbed. The mixture was then filter, concentrated under reduced vacuum. The residual oil was distilled under vacuum to give 9.6 g (89% yield) of 2-(2-(2-cyanoethyl)-3-methylbicyclo[2.2.1]heptane: b.p. 55-57° C/0.5 mm; ir 2940, 2870, 2250, 1700, 1460, 1430, 1380; nmr 0.95, 1.1 (3H.5), 1.2-2.5 (14H, m); ms 163.
Reaction SMILES: [NH:1]([S:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[C:13]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:12]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC.[ClH:41]>CO>[ClH:41].[N:17]1([C:14]2[CH:15]=[CH:16][C:11]([S:8]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)(=[O:10])=[O:9])=[CH:12][C:13]=2[NH:31][S:32]([CH3:35])(=[O:33])=[O:34])[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(S(=O)(=O)Nc3ccccc3)cc2NS(C)(=O)=O)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CS(=O)(=O)Nc1cc(S(=O)(=O)Nc2ccccc2)ccc1N1CCCNCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48 %

Procedure:
A mixture of tert-butyl 4-[2-amino-4-(anilinosulfonyl)phenyl]-1,4-diazepane-1-carboxylate (176 mg, 0.39 mmol), methylsulfonyl chloride (0.040 mL, 0.47 mmol) and pyridine (0.285 mL, 3.51 mmol) in CH2CL2 (5 mL) was stirred at room temperature overnight. The reaction mixture was quenched with NaHCO3 aq (3×30 mL). The organic phase was separated, dried (MgSO4) and filtered. The volatiles were evaporated followed by purification of the oily residue by chromatography (SiO2, hexane/EtOAc 4:1) to give 110 mg of tert-butyl 4-{4-(anilinosulfonyl)-2-[(methylsulfonyl)amino]phenyl}-1,4-diazepane-1-carboxylate (yield 58%). 1H NMR (CDCl3) δ 7.90-7.85 (m, 1H), 7.50-7.43 (m, 1H), 7.30-7.24 (m, 2H), 7.20-7.08 (m, 4H), 6.84-6.79 (m, 1H), 3.65-3.51 (m, 4H), 3.12-3.06 (m, 1H), 3.04-2.96 (m, 6H), 2.04-1.91 (m, 2H), 1.49 (s, 3H); MS (posEI-DIP) m/z=524 (M+H+). tert-Butyl 4-{4-(anilinosulfonyl)-2-[(methylsulfonyl)amino]phenyl}-1,4-diazepane-1-carboxylate (0.077 g, 0.147 mmol) was dissolved in MeOH, and ether saturated with HCl gas was added. The mixture was stirred at room temperature for 4 h and then concentrated. The crude solid was dissolved in a small amount of MeOH, and ether was added. The precipitate was collected and dried to give 30 mg of the pure product as the HCl salt (yield 48%): 1H NMR (DMSO-d6) δ 7.72-7.70 (m, 1H), 7.46-7.42 (m, 1H), 7.25-7.20 (m, 3H), 7.14-7.09 (m, 2H), 7.03-6.99 (m, 1H), 3.45-3.15 (m, partly obscured by solvent signal, HDO, 6H), 2.96 (s, 3H), 2.02-1.95 (m, 2H); MS (posES-FIA) m/z=425 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([F:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([F:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1cnc2ccc(F)cc2c1Cl
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1cnc2ccc(F)cc2c1

Procedure:
A solution of 4-chloro-6-fluoro-quinoline-3-carboxylic acid ethyl ester (4.2 g, 16.6 mmol) and diisopropylethylamine (8.7 mL, 50 mmol) in ethanol (50 mL) was hydrogenated over 10% palladium on carbon (0.2 g) at 1 atmosphere of hydrogen for 1 day. Additional catalyst (0.3 g) was added and the hydrogenation was continued at 50 psi of hydrogen for 2 hours. The catalyst was removed by filtration. The solvent was evaporated in vacuo, and the residue was partitioned between water and dichloromethane. The organic layer was dried over sodium sulfate. The product was preabsorbed onto silica gel and purified by flash chromatography, using a gradient of ethyl acetate (0% to 30%) in heptanes as the eluant, to give the product as a yellow solid, 2.2 g (60%). MS: m/z 219.9 (MH+).
Reaction SMILES: [Na].[CH:2]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[N:11]=[CH:12][N:13]4[C:22]5[CH:21]=[CH:20][CH:19]=[C:18](F)[C:17]=5[C:16]5=[N:24][CH2:25][CH2:26][N:15]5[C:14]=34)[N:6]=2)[CH2:4][CH2:3]1.[CH:27]([OH:30])([CH3:29])[CH3:28]>>[CH:2]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[N:11]=[CH:12][N:13]4[C:22]5[CH:21]=[CH:20][CH:19]=[C:18]([O:30][CH:27]([CH3:29])[CH3:28])[C:17]=5[C:16]5=[N:24][CH2:25][CH2:26][N:15]5[C:14]=34)[N:6]=2)[CH2:4][CH2:3]1
Reactant: Fc1cccc2c1C1=NCCN1c1c(-c3noc(C4CC4)n3)ncn1-2
Reactant: CC(C)O
Agent: [Na]
Product: CC(C)Oc1cccc2c1C1=NCCN1c1c(-c3noc(C4CC4)n3)ncn1-2

Procedure:
Sodium (30 mg, 1.3 mmol) was dissolved in 20 ml of dry isopropyl alcohol. 5-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-12-fluoro-2,3-dihydrodiimidazo[1,5-a:1',2'-c]quinazoline (0.2 g, 0.6 mmol) was added and the mixture was heated at reflux for 10 min. Then the solvent was evaporated in vacuo and the residue was triturated with 25 ml of water. The insoluble material was filtered off and dried to give the title compound as pale crystals, m.p. 211°-214° C. Yield 0.17 g (75%). (Compound 43).