Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C(O)(=O)[CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19].CC#N.O>[N+]([O-])([O-])=O.[Ag+].C(OCC)(=O)C>[C:18]([CH2:17][CH2:16][CH2:15][C:11]1[C:10](=[O:12])[C:9]2[C:4]([C:3](=[O:13])[C:2]=1[CH3:1])=[CH:5][CH:6]=[CH:7][CH:8]=2)([OH:20])=[O:19]
Reactant: O=C(O)CCCC(=O)O
Reactant: CC1=CC(=O)c2ccccc2C1=O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CC1=C(CCCC(=O)O)C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
The CPVK3 was synthesized referring to a document (Salmon-Chemin L., Buisine E., Yardley V., Kohler S., Debreu M. A., Landry V., Sergheraert C., Croft S. L., Krauth-Siegel R. L., and Davioud-Charvet E., J. Med. Chem., 2001, 44, 548-565). 2-methyl-1,4-naphthoquinone, glutaric acid, and AgNO3 were suspended in a 30% aqueous CH3CN solution, heated, and stirred to dissolve completely. Then, a 30% aqueous CH3CN solution of (NH4)2S2O8 was added dropwise in 60 minutes. After completing the dropwise addition, the mixture was stirred at 65° C. for 5 minutes as it was. Cooling of the reaction mixture to room temperature resulted in precipitation of a yellow brown solid. Water and ethyl acetate were added to the reaction mixture, and an organic layer was washed with water using a separating funnel. Further, the organic layer was washed with water. A 2N-aqueous solution of sodium bicarbonate was added to the organic layer, and a sodium salt of a target compound was extracted to an aqueous layer. Then, the aqueous layer was adjusted to a pH of 2 or less using 37% hydrochloric acid, and a precipitated solid was collected by filtration. The solid was sufficiently washed with cool water, and dried under reduced pressure, to thereby obtain a yellow brown powder 2-(3-carboxypropyl)-3-methyl-1,4-naphthoquinone.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])=[O:5].C1N=CN([C:25](N2C=NC=C2)=[O:26])C=1>CN(C1C=CN=CC=1)C.C(#N)C>[OH:26][C:25]1[N:6]([CH:7]2[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]2=[O:14])[C:4](=[O:5])[C:3]2[C:2](=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:19])[N:1]=1
Reactant: Cc1cccc(N)c1C(=O)NC1CCC(=O)NC1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: Cc1cccc2nc(O)n(C3CCC(=O)NC3=O)c(=O)c12
Yield: 81.5 %

Procedure:
A solution of 2-amino-N-(2,6-dioxo-piperidin-3-yl)-6-methyl-benzamide (1.00 g, 3.8 mmol), CDI (0.62 g, 3.8 mmol) and DMAP (0.10 g, 0.82 mmol) in acetonitrile (12 mL) was heated at 150° C. in a microwave oven for 10 minutes. The suspension was filtered and washed with acetonitrile (2×20 mL), water (2×20 mL), HCl (1N, 25 mL), water (25 mL), methanol (2×20 mL), and ethyl acetate (2×20 mL) to give 3-(2-hydroxy-5-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as an off-white solid (0.89 g, 81% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 25/75 CH3CN/0.1% H3PO4, 5.72 min (99%); mp: 373-375° C.; 1H NMR (DMSO-d6) δ 1.90-1.97 (m, 1H, CHH), 2.49-2.58 (m, 2H, CH2), 2.61 (s, 1.5H, CH3), 2.69 (s, 1.5H, CH3), 2.81-2.92 (m, 1H, CHH), 5.55 (dd, J=5, 11 Hz, 0.5H, NCH), 5.72 (dd, J=5, 11 Hz, 0.5H, NCH), 6.99-7.08 (m, 2H, Ar), 7.50-7.55 (m, 1H, Ar), 10.92 (s, 0.5H, Oh), 11.42 (s, 0.5H, NH), 11.56 (s, 0.5H, NH) (observed at 350K); 13C NMR (DMSO-d6) δ 20.90, 21.38, 22.11, 22.41, 30.72, 30.77, 49.74, 50.99, 111.52, 112.15, 113.38, 125.67, 134.26, 134.34, 140.29, 140.63, 141.09, 141.45, 148.77, 149.99, 161.60, 162.39, 170.00, 170.38, 172.74; LCMS: MH=288; Anal. Calcd. for C14H13N3O4: C, 58.53; H, 4.56; N, 14.63. Found: C, 58.40; H, 4.32; N, 14.59.
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O:32][C:33]1[CH:43]=[CH:42][C:36]([CH2:37][C:38]2([NH2:41])[CH2:40][CH2:39]2)=[CH:35][CH:34]=1)C1C=CC=CC=1.FC(F)(F)C([O-])=O>>[OH:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:24])[CH2:21][NH:41][C:38]2([CH2:37][C:36]3[CH:42]=[CH:43][C:33]([OH:32])=[CH:34][CH:35]=3)[CH2:40][CH2:39]2)=[CH:11][CH:10]=1
Reactant: NC1(Cc2ccc(OCc3ccccc3)cc2)CC1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Agent: O=C([O-])C(F)(F)F
Product: O=C1COc2c(C(O)CNC3(Cc4ccc(O)cc4)CC3)ccc(O)c2N1

Procedure:
Prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 253 mg (1 mmol) 1-(4-benzyloxy-benzyl)-cyclopropylamine. Yield: 20 mg (4%, trifluoroacetate); mass spectroscopy: [M+H]+=371.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][C:3]#[C:4][CH3:5].[C:7]1(=[O:13])[O:12][C:10](=[O:11])[CH:9]=[CH:8]1>C1(C)C=CC=CC=1.CS(O)(=O)=O>[C:10]([O:12][CH2:5][CH2:4][C:3]#[C:2][CH3:1])(=[O:11])/[CH:9]=[CH:8]\[C:7]([O:6][CH2:1][CH2:2][C:3]#[C:4][CH3:5])=[O:13]
Reactant: CC#CCCO
Reactant: O=C1C=CC(=O)O1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC#CCCOC(=O)/C=C\C(=O)OCCC#CC

Procedure:
15 g of 3-pentyn-1-ol was reacted with 8.35 g of maleic anhydride in 25 ml of toluene and in the presence of one drop of methanesulfonic acid. 11.5 g of DPTNM was isolated from the reaction mixture (bp=134-140° C./full vacuum GC purity=98.8 %). 1H NMR data: 1.77 (t, J=3 Hz, CH3), 2.52 (m, CH2CC), 4.22 (t, J=7 Hz, CH2 -O), 6.22 (s, maleate olefin CHs).
Reaction SMILES: [C:1]([C@H:5]1[O:9][C:8](=[O:10])[CH2:7][CH2:6]1)(=[O:4])[CH2:2][CH3:3].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>>[OH:4][CH:1]([C@H:5]1[O:9][C:8](=[O:10])[CH2:7][CH2:6]1)[CH2:2][CH3:3]
Reactant: CCC(=O)[C@@H]1CCC(=O)O1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Product: CCC(O)[C@@H]1CCC(=O)O1
Temperature: -78 °C
Reaction time: 2 h
Yield: 56.3 %

Procedure:
To a solution of (5S)-5-propanoyltetrahydrofuran-2-one (compound 28c, 35 g, 246.5 mmol) was added L-selectride (320 mL, 320 mmol, 1 M in THF) at −78° C. under N2. After addition, the reaction mixture was stirred at −78° C. for 2 hours. The reaction mixture was then quenched with 2N HCl (200 mL) and extracted with EtOAc (400 mL) twice. The combined organic layers were washed with brine (100 mL), concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 1:7 to 1:3 EtOAc in petroleum ether) to afford 20 g of (5S)-5-(1-hydroxypropyl)tetrahydrofuran-2-one (compound 28d) as a yellow oil. (Refer to Eur. J. Med. Chem. 1997, 32, 617-623).
Reaction SMILES: C1(C2[C:8](=O)[C:9]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)=[C:10]([C:37]3[CH:42]=[CH:41][C:40]([C:43]4[CH:55]=[CH:54][C:53]5[C:52]6[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=6)[C:46]([CH2:59][CH2:60][CH3:61])([CH2:56][CH2:57][CH3:58])[C:45]=5[CH:44]=4)=[CH:39][CH:38]=3)[C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:30]=[CH:29][C:28]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[C:21]([CH2:34][CH2:35][CH3:36])([CH2:31][CH2:32][CH3:33])[C:20]=4[CH:19]=3)=[CH:14][CH:13]=2)C=CC=CC=1.[C:69]([C:71]1[CH:76]=[CH:75][C:74]([C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][N:78]=2)=[CH:73][CH:72]=1)#[CH:70]>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:12]1([C:70]2[C:11]([C:12]3[CH:13]=[CH:14][C:15]([C:18]4[CH:30]=[CH:29][C:28]5[C:27]6[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=6)[C:21]([CH2:34][CH2:35][CH3:36])([CH2:31][CH2:32][CH3:33])[C:20]=5[CH:19]=4)=[CH:16][CH:17]=3)=[C:10]([C:37]3[CH:38]=[CH:39][C:40]([C:43]4[CH:55]=[CH:54][C:53]5[C:52]6[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=6)[C:46]([CH2:59][CH2:60][CH3:61])([CH2:56][CH2:57][CH3:58])[C:45]=5[CH:44]=4)=[CH:41][CH:42]=3)[C:9]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)=[CH:8][C:69]=2[C:71]2[CH:76]=[CH:75][C:74]([C:77]3[CH:82]=[CH:81][CH:80]=[CH:79][N:78]=3)=[CH:73][CH:72]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCCC1(CCC)c2ccccc2-c2ccc(-c3ccc(C4=C(c5ccccc5)C(=O)C(c5ccccc5)=C4c4ccc(-c5ccc6c(c5)C(CCC)(CCC)c5ccccc5-6)cc4)cc3)cc21
Reactant: C#Cc1ccc(-c2ccccn2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCC1(CCC)c2ccccc2-c2ccc(-c3ccc(-c4c(-c5ccccc5)cc(-c5ccc(-c6ccccn6)cc5)c(-c5ccccc5)c4-c4ccc(-c5ccc6c(c5)C(CCC)(CCC)c5ccccc5-6)cc4)cc3)cc21
Temperature: 210 °C
Yield: 126.4 %

Procedure:
A solution of (10) (1.48 g, 1.67 mmol) and (3) (200 mg, 1.12 mmol) in diphenyl ether (3 mL) was deoxygenated and heated at 210° C. under argon for 3 hours. The crude product was purified by column chromatography over silica using dichloromethane: light petroleum (1:1) as the eluent. The main band was isolated and the solvent completely removed to give (11) (1.09 g, 95%).
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:7]([CH:9](C(OCC1C=CC=CC=1)=O)[F:10])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C>C(O)C.[Pd]>[NH:1]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[C@H:2]([C:7]([CH2:9][F:10])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)C(F)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)CF
Reaction time: 36 h
Yield: 65.9 %

Procedure:
To a solution of Boc-LeuCHFCOOBzl (3.58 g, 9.39 mmol) in ethanol (50 mL) was added 10% palladium on active charcoal (0.36 g). The mixture was subjected to hydrogenolysis on a Parr shaker for 36 hours. The solution was filtered and the solvent was evaporated. The residue was dissolved in ethyl acetate (100 mL), washed with saturated aqueous NaHCO3 (50 mL), brine (50 mL), dried over MgSO4, filtered, and evaporated to give an almost colorless, viscous oil, Boc-LeuCH2F (1.53 g, 66%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:25]=[CH:24][C:15]([CH:16]=[C:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.C(OC(C1CC(C(OCC)=O)=C(C)NC=1C)=O)C>>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:25]=[CH:24][C:15]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: CSc1ccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)cc1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Product: CSc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)cc1
Temperature: 160 °C
Reaction time: 2 h
Yield: 34.3 %

Procedure:
1 g (2.7 mmole) 5-(4-[2-(4-methylmercaptophenyl)ethoxy]benzylidene)thiazolidine-2,4-dione and 1.36 g (5.4 mmole) diethyl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate were mixed and heated to 160° C. under vacuum (when it melted), after 1 hour at this temperature the heat was removed. Toluene was added, crystals of the starting material was removed by filtration, the filtrate was evaporated and purified by chromatography on silica gel twice using first dichloromethane:methanol (98:2) and then diisopropyl ether as eluents. The reaction was restarted with unreacted material and 0.4 g diethyl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate and kept at 160° C. for 2 hours. The product was boiled in diisopropyl ether, and purified by chromatography on silica gel using diisopropyl ether as eluent. The combined fractions gave 0.346 g (yield 36%) of the desired product.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:31])([F:30])[C:10]([N:12]1[CH2:17][C:16]2([CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[O:15][CH2:14][CH2:13]1)=[O:11].C1(C)C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:31][C:9]([F:8])([F:30])[C:10]([N:12]1[CH2:17][C:16]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:15][CH2:14][CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(C(=O)C(F)(F)F)CCO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(N1CCOC2(CCNCC2)C1)C(F)(F)F
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
Trifluoroacetic acid (15 mL) was added to a stirred solution of tert-butyl 4-(2,2,2-trifluoroacetyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 12, step c) (1 g) in DCM (15 mL) at 20° C. The resulting solution was stirred at 20° C. for 10 minutes. Toluene (50 mL) was added and the solvents were evaporated under reduced pressure to afford the subtitled compound. Yield 1.4 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:27]1[CH:28]=[C:29]([CH3:32])[S:30][CH:31]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:27]3[CH:28]=[C:29]([CH3:32])[S:30][CH:31]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(Br)cs1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Product: Cc1cc(-c2ccc3c(c2)CN(C(=O)OC(C)(C)C)C3)cs1

Procedure:
Prepared in analogy to Example A23(b) from 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and 4-bromo-2-methylthiophene (commercial). Light yellow solid. MS (m/e): 315.2 ([M]+, 100%)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[CH2:17]([O:24][C:25]1[C:30]([CH3:31])=[CH:29][C:28]([C:32]([C:34]2[CH:39]=[C:38](Cl)[N:37]=[CH:36][N:35]=2)=[O:33])=[CH:27][C:26]=1[CH3:41])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:17]([O:24][C:25]1[C:26]([CH3:41])=[CH:27][C:28]([C:32]([C:34]2[N:35]=[CH:36][N:37]=[C:38]([N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[C:15]5[C:10](=[N:11][CH:12]=[CH:13][CH:14]=5)[NH:9][C:8]4=[O:16])[CH2:5][CH2:6]3)[CH:39]=2)=[O:33])=[CH:29][C:30]=1[CH3:31])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc(C)c1OCc1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)cc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
170 mg (0.779 mmol) 1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one, 270 mg (0.727 mmol) (4-benzyloxy-3,5-dimethyl-phenyl)-(6-chloro-pyrimidin-4-yl)-methanone and 0.200 mL (1.42 mmol) TEA were combined in 2.0 mL DMF and stirred overnight at RT. The reaction mixture was stirred into ice water, the precipitate was suction filtered and dried.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([NH2:14])[CH:8]=1)[CH3:6])[CH3:2].C1C=CC(O[C:23](Cl)=[S:24])=CC=1.C1CCN2C(=NCCC2)CC1.O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]2[O:13][C:23](=[S:24])[NH:14][C:9]=2[CH:8]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)c1ccc(O)c(N)c1
Reactant: S=C(Cl)Oc1ccccc1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1ccc2oc(=S)[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-(3-amino-4-hydroxy-phenyl)-propionic acid ethyl ester (370 mg) in DMF (2 mL) was added phenyl chlorothionoformate (380 mg in DMF), and DBU (540 mg, in DMF) at room temperature. The reaction mixture was stirred for 16 h at room temperature and water was added to this mixture. The resulting mixture was extracted with ethyl ether. The combined organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel (n-Hex:EtOAc=4:1) to afford the product as white solid. (130 mg, 29.2%)
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C@@H:14]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22]CC2C=CC=CC=2)=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C@@H:14]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OC[C@H](Cc2ccccc2)N1[C@H](Cc1ccc(OCc2ccccc2)cc1)Oc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1OC[C@H](Cc2ccccc2)N1[C@H](Cc1ccc(O)cc1)Oc1ccccc1

Procedure:
A solution of (S)-4-benzyl-3-[(1S)-2-(4-benzyloxyphenyl)-1-phenoxyethyl]-2-oxazolidinone (1.8 g) in ethyl acetate (50 ml) containing 10% palladium on carbon (1.8 g) was hydrogenated at 40 psi overnight. The catalyst was filtered, the solution concentrated and the product purified by flash-chromatography (hexanes/ethyl acetate, 3:2) as an oil (0.81 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])=[CH:5][CH:4]=1)#[CH:2].C#CCCCCCC.I[C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[CH:31]2.IC1C=C2C(=CC=1)CN(C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C2>>[F:18][C:15]([F:16])([F:17])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[NH:33][CH:32]=[CH:31]3)=[CH:4][CH:5]=1
Reactant: C#Cc1ccc(-c2ccccc2C(F)(F)F)cc1
Reactant: Ic1ccc2[nH]ccc2c1
Agent: C#CCCCCCC
Agent: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Product: FC(F)(F)c1ccccc1-c1ccc(C#Cc2ccc3[nH]ccc3c2)cc1
Yield: 86 %

Procedure:
When the product of Step A was substituted for 1-octyne and 5-iodoindole was substituted for 5-iodo-2-tritylisoindoline in Example 2, Step D, the similar process afforded the title compound in 86% yield, as a colourless paste. 1H-NMR (CDCl3) 7.56 (broad s, 1H); 7.28-7.4 (m, 5H); 7.46 (tr, 1H, J=7.25 Hz); 7.53-7.58 (m, 3H); 7.73 (d, 1H, J=7.85 Hz); 7.87 (s, 1H); 8.23 (broad s, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([NH2:12])=[N:10][C:9]([C:13]([F:16])([F:15])[F:14])=[C:8]([Br:17])[N:7]=1)=O)C.O.[NH2:19][NH2:20].O>CCO>[NH2:12][C:11]1[C:6]([C:4]([NH:19][NH2:20])=[O:3])=[N:7][C:8]([Br:17])=[C:9]([C:13]([F:16])([F:15])[F:14])[N:10]=1
Reactant: CCOC(=O)c1nc(Br)c(C(F)(F)F)nc1N
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1nc(Br)c(C(F)(F)F)nc1N
Temperature: 90 °C

Procedure:
To a solution of 3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid ethyl ester (Int. F1) (1.00 g, 3.18 mmol) in dry EtOH (25 ml) was added hydrazine monohydrate (309 ul, 6.37 mmol) and the mixture was stirred at reflux (ca. 90° C.). After 3 hr 45 min the reaction mixture was cooled in an ice bath and added to water. The resulting yellow ppt was filtered under vacuum and dried in a vacuum oven overnight to give the title compound as a yellow solid 1H NMR (400 MHz, DMSO-d6) 610.10 (1H, s), 8.00 (2H, s), 4.65 (2H, s).
Reaction SMILES: [NH2:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][CH3:22].[CH3:23][C:24]([CH3:26])=O>CO>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][CH3:22])[N:6]([CH2:5][CH2:4][CH2:3][O:2][N:1]=[C:24]([CH3:26])[CH3:23])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1CCCON
Reactant: CC(C)=O
Solvent: CO
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCON=C(C)C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
A mixture of 1-[3-(aminooxy)propyl]-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (prepared as described in Example 1, 0.605 g, 2.02 mmol) in methanol was heated until the starting material dissolved. Acetone (3 mL, 40 mmol) was then added, and the resulting solution was stirred for two hours. The reaction was then concentrated under reduced pressure, and the residue (800 mg) was purified by column chromatography on silica gel (25 g, eluting sequentially with 98:2 dichloromethane:methanol and 95:5 dichloromethane:methanol) to provide 600 mg of acetone O-[3-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]oxime as a beige powder, mp 147-150° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:23]=[CH:24][C:25]3[C:37](=[O:38])[C:36]4[C:35]5[C:30](=[CH:31][C:32]([C:39]#[N:40])=[CH:33][CH:34]=5)[NH:29][C:28]=4[C:27]([CH3:42])([CH3:41])[C:26]=3[CH:43]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>C1COCC1>[CH3:41][C:27]1([CH3:42])[C:28]2[NH:29][C:30]3[C:35](=[CH:34][CH:33]=[C:32]([C:39]#[N:40])[CH:31]=3)[C:36]=2[C:37](=[O:38])[C:25]2[CH:24]=[CH:23][C:22]([O:21][CH:18]3[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]3)=[CH:43][C:26]1=2
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)CC1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)c2cc(OC3CCNCC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 25 °C
Yield: 133.3 %

Procedure:
THF (0.5 mL) and TFA (0.5 mL) were added to 4-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (Compound A7-1, 35 mg, 0.072 mmol), and the mixture was stirred at room temperature until Compound A7-1 disappears. The reaction solution was concentrated under reduced pressure and the residue was desalinated by using anion exchanger PL StratoSpheres (trademark) PL-HCO3 MP to obtain the title compound (37 mg, 76%).
Reaction SMILES: [O:1]1CCO[C:2]21[CH2:21][C:10]1[CH:11]=[C:12]3[C:16](=[CH:17][C:9]=1[CH2:8][CH2:7][CH2:6]2)[N:15]([C:18](=[O:20])[CH3:19])[N:14]=[CH:13]3.[Li+].[OH-]>FC1C=CC(N2C3C(=CC=C(CCCC(O)=O)C=3)C=N2)=CC=1.C1COCC1.O>[C:18]([N:15]1[C:16]2[C:12](=[CH:11][C:10]3[CH2:21][C:2](=[O:1])[CH2:6][CH2:7][CH2:8][C:9]=3[CH:17]=2)[CH:13]=[N:14]1)(=[O:20])[CH3:19]
Reactant: CC(=O)n1ncc2cc3c(cc21)CCCC1(C3)OCCO1
Agent: O=C(O)CCCc1ccc2cnn(-c3ccc(F)cc3)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)n1ncc2cc3c(cc21)CCCC(=O)C3
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 59 %

Procedure:
In a 10 L 3 necked flask, 1-(5,7,8,9-tetrahydro-1H-spiro[cyclohepta[f]indazole-6,2′-[1,3]dioxolan]-1-yl)ethanone (79) (440 g, 1.54 mol) was dissolved in THF (5.2 L). A solution of LiOH (143 g, 5.97 mol) in water (3.5 L) was added. The mixture was stirred at rt for about 50 min. The mixture was extracted with EtOAc (2×15 L). The combined organic layers were washed with water, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was recrystallized from ethanol to give 1-acetyl-5,7,8,9-tetrahydrocyclohepta[f]indazol-6(1H)-one (81) (220 g, 59% yield) as a light yellow solid. 1H NMR (300 MHz, CDCl3): δ 10.05 (s, 1H), 7.96 (s, 1H), 7.47 (s, 1H), 7.20 (s, 1H), 4.03 (m, 4H), 3.16 (s, 2H), 2.91 (m, 2H), 2.04 (m, 2H), 1.88 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[CH:6][CH:7]=1.[CH:9]([C:12]1[CH:13]=[CH:14][C:15]([S:18](Cl)(=[O:20])=[O:19])=[N:16][CH:17]=1)([CH3:11])[CH3:10]>>[C:2]1([CH3:1])[CH:7]=[CH:6][C:5]([NH:8][S:18]([C:15]2[CH:14]=[CH:13][C:12]([CH:9]([CH3:11])[CH3:10])=[CH:17][N:16]=2)(=[O:19])=[O:20])=[CH:4][CH:3]=1
Reactant: Cc1ccc(N)cc1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)nc1
Product: Cc1ccc(NS(=O)(=O)c2ccc(C(C)C)cn2)cc1

Procedure:
prepared by reaction of p-tolylamine with 5-isopropyl-pyridine-2-sulfonyl chloride
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.[N+:24]([O-])([OH:26])=[O:25]>>[N+:24]([C:14]1[CH:15]=[CH:16][C:11]([C:1]2[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:3][CH:2]=2)=[CH:12][CH:13]=1)([O-:26])=[O:25]
Reactant: O=S(=O)(O)c1ccc(-c2ccccc2)cc1
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(-c2ccc(S(=O)(=O)O)cc2)cc1
Temperature: -5 °C
Reaction time: 2 h

Procedure:
Biphenyl-4-sulfonic acid (30 g) was mixed with trifluoroacetic acid and a suspension was formed. The mixture was cooled to −5° C. Fuming nitric acid (12.8 ml) was added dropwise over 30 min. The reaction mixture was stirred at 0° C. for 2 h. The chloroform was removed in vacuo and the residue was recrystallized from acetic acid to provide 15 g of 4′-nitro-biphenyl-4-sulfonic acid, obtained as white crystals.