Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:21]([O-:23])=[O:22])=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH:6]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].COC1C([N+]([O-])=O)=C(C=CC=1)C=O.CO[CH2:39][N:40]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH2:41][Si](C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:46]([N:40]1[CH2:41][CH:6]([C:5]2[CH:18]=[CH:19][CH:20]=[C:3]([O:2][CH3:1])[C:4]=2[N+:21]([O-:23])=[O:22])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:39]1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCOC(=O)C(=Cc1cccc(OC)c1[N+](=O)[O-])C(=O)OCC
Agent: COc1cccc(C=O)c1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(C(=O)OCC)CN(Cc2ccccc2)CC1c1cccc(OC)c1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
To a solution of diethyl 2-(3-methoxy-2-nitrobenzylidene)malonate, which was prepared from 3-methoxy-2-nitrobenzaldehyde following the procedure described in Example 1, Part C (162 mg, 0.5 mmol) in 10 mL of methylene chloride was added added N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (237 mg, 1.0 mmol) and trifluoroacetic acid (0.010 mL, 0.125 mmol). The solution was allowed to stir at 40° C. for 18 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography (elution with 4:1 hexane/EtOAc) to afford 201 mg (88%) of the title compound. 1H NMR (CDCl3): δ 7.40-7.25 (m, 7H), 6.93-6.85 (m, 1H), 4.36-4.30 (m, 1H), 4.32-4.15 (m, 2H), 3.87 (s, 3H), 3.77 (q, 2H), 3.69 (s, 2H), 3.60-3.50 (m, 1H), 3.05-2.97 (m, 1H), 2.85-2.78 (m, 1H), 2.75-2.68 (m, 1H), 1.23 (t, 3H, J=7.2 Hz), 0.83 (t, 3H, J=7.2 Hz). LRMS (ESI): 457.4 (M+H)+.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[C:8]1([SH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:15][C:16]1[CH:21]=[C:20](Cl)[CH:19]=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24]>O>[NH2:15][C:16]1[CH:21]=[C:20]([S:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:19]=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24]
Reactant: Sc1ccccc1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Sc2ccccc2)ccc1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
2.53 G. 57% sodium hydride in oil suspension in 20 ml. dimethylformamide is treated with 6.2 ml. thiophenol under nitrogen. 5.0 G. 2-amino-4-chloro-1-nitrobenzene is added and the mixture stirred for three hours. Water is added and the product filtered off and washed with water and hexane. Recrystallization from methanol gives pure 2-amino-4-phenylthio-1-nitrobenzene.
Reaction SMILES: Cl[CH2:2][CH:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1.[CH3:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]3[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=3)[CH:19]=2)[N:14]=[C:13]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[N:12]=1.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC>CN1C(=O)CCC1.CO>[CH3:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]3[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=3)[O:27][CH2:2][CH:3]3[O:7][C:6](=[O:8])[NH:5][CH2:4]3)[CH:19]=2)[N:14]=[C:13]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[N:12]=1
Reactant: CNc1nc(-c2cccnc2)nc2ccc(-c3cccc(O)c3)cc12
Reactant: O=C1NCC(CCl)O1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN1CCCC1=O
Solvent: CO
Product: CNc1nc(-c2cccnc2)nc2ccc(-c3cccc(OCC4CNC(=O)O4)c3)cc12
Temperature: 90 °C

Procedure:
To 5-(chloromethyl)oxazolidin-2-one (45 μmol) was added the solution of 3-(4-(methylamino)-2-(pyridin-3-yl)quinazolin-6-yl)phenol (30 μmol) in NMP (200 μL). PS-BEMP (90 μmol) was added to the vials by resin dispenser. After the reaction mixture was heated at 90° C. for 12 h, the residue was diluted with methanol and purified by PREP-HPLC Condition D. The target fraction was lyophilized to afford the titled compound whose structure was finally confirmed by LCMS using LCMS Method E.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][C:19]([F:24])([F:23])[CH:20]([F:22])[F:21])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[C:25]([N:10]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[C:9]1[S:18][C:19]([F:23])([F:24])[CH:20]([F:22])[F:21])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: FC(F)C(F)(F)Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Product: CC(=O)n1c(SC(F)(F)C(F)F)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 1.8 g (0.005 mole) of 4,5-diphenyl-2-(1,1,2,2-tetrafluoroethylthio)imidazole and 25 ml acetic anhydride was heated at reflux seven hours, then cooled and stirred at room temperature for four days. Most of the acetic anhydride and acetic acid were removed at reduced pressure (~0.5 mm). The white solid residue was chromatographed on silica gel, eluting with toluene, to give 0.8 g of white product, mp 143°-4° (from hexane).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:14][C:15](N)=[O:16]>>[C:15](=[O:16])([O:13][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1)[NH2:14]
Reactant: NC(N)=O
Reactant: Oc1ccc(-c2ccccc2)cc1
Product: NC(=O)Oc1ccc(-c2ccccc2)cc1
Yield: 90 %

Procedure:
6298 g of 4-phenyl phenol and 444 g of urea were charged into an autoclave (Toyo Koatsu Inc., Japan) equipped with a thermometer, stirrer, reflux condenser and gas feed tube and having an internal volume of 12 L followed by stirring at normal pressure while bubbling nitrogen gas with a capillary tube at the rate of 100 L/hr and carrying out the reaction at 140° C. When a portion of the reaction liquid was removed 10 hours later and analyzed by liquid chromatography, the formation of (4-phenylphenyl) carbamate was confirmed. The yield was about 90% based on the charged amount of urea.
Reaction SMILES: [CH2:1]([C@H:3]1[C:20](=O)[CH2:19][CH2:18][C@@:17]2([CH3:22])[CH:4]1[C:5](=[O:24])[CH2:6][C@@H:7]1[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]1[CH2:9][CH2:10][C:11]2=[O:23])[CH3:2].[ClH:25].Cl.[NH2:27][CH2:28][CH2:29][O:30][NH2:31]>C1COCC1.O>[ClH:25].[NH2:27][CH2:28][CH2:29][O:30]/[N:31]=[C:20]1/[C@H:3]([CH2:1][CH3:2])[CH:4]2[C@:17]([CH3:22])([CH2:18][CH2:19]/1)[C@@H:16]1[C@H:7]([C@H:8]3[C@@:12]([CH2:14][CH2:15]1)([CH3:13])[C:11](=[O:23])[CH2:10][CH2:9]3)[CH2:6][C:5]2=[O:24]
Reactant: NCCON
Reactant: CC[C@H]1C(=O)CC[C@@]2(C)C1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC[C@H]1/C(=N/OCCN)CC[C@@]2(C)C1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 3.5 h

Procedure:
To a stirred solution of 4β-ethylandrostan-3,6,17-trione (Preparation 11, 67 mg) in THF (1.1 ml), a solution of 2-aminoethoxyamine dihydrochloride (31 mg) and Na2HPO4.12H2O (15 mg) in H2O (0.55 ml) was added in portions over 45 minutes. After 3.5 h, the solution was evaporated, water was added and the aqueous phase was extracted with THF. The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated to dryness. The crude product was triturated with Et2O and the precipitate was filtered to give the title compound I-bd (34 mg, 42%).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][N:3]=1.[C:15]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[F:1][C:2]1[C:7]([C:8]([O:10][CH3:15])=[O:9])=[C:6]([C:11]([F:12])([F:13])[F:14])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1c(C(F)(F)F)ccnc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1c(C(F)(F)F)ccnc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a mixture of 2-fluoro-4-(trifluoromethyl)pyridine-3-carboxylic acid (1.06 g) and K2CO3 (0.701 g) in DMF (dry) (10 mL) was added MeI (0.317 mL). The mixture was stirred at room temperature for 3 h. The mixture was directly purified by column chromatography (silica gel, EtOAc/hexane) to give the title compound (1.13 g, containing EtOAc and hexane, ca. 75% purity).
Reaction SMILES: [Cl:1][C:2]([C:12]([F:15])([F:14])[F:13])=[CH:3][C@@H:4]1[C@H:6]([C:7]([OH:9])=[O:8])[C:5]1([CH3:11])[CH3:10].Br[CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([F:24])[CH:19]=1.N12CCCN=C1CCCCC2>C(#N)C>[Cl:1][C:2]([C:12]([F:13])([F:14])[F:15])=[CH:3][C@@H:4]1[C@H:6]([C:7]([O:9][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([F:24])[CH:19]=2)=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: Fc1cc(CBr)ccn1
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)OCc1ccnc(F)c1
Yield: 77.5 %

Procedure:
By the method of Example 21, 0.970 g (0.004 mole) of cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylic acid and 0.75 g (0.004 mole) of 4-bromomethyl-2-fluoropyridine (Example 22) were reacted in the presence of 0.609 g (0.004 mole) of 1,8-diazabicyclo[5.4.0]undec-7-ene in 20 ml of acetonitrile to produce 1.09 g of (2-fluoropyridin-4-yl)methyl cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylate, compound 28 in the Tables below. The ir, proton nmr, and 19c nmr spectra were all consistent with the proposed structure.
Reaction SMILES: OO.[C:3]([O:22][CH:23]1[CH2:28][C:27]([CH3:30])([CH3:29])[N:26]([OH:31])[C:25]([CH3:33])([CH3:32])[CH2:24]1)(=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].S([O-])([O-])=O.[Na+].[Na+].[C:40]([OH:44])([CH3:43])([CH3:42])[CH3:41]>>[C:3]([O:22][CH:23]1[CH2:28][C:27]([CH3:30])([CH3:29])[N:26]([O:31][CH2:41][C:40]([CH3:43])([OH:44])[CH2:42][O:31][N:26]2[C:27]([CH3:29])([CH3:30])[CH2:28][CH:23]([O:22][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:24][C:25]2([CH3:32])[CH3:33])[C:25]([CH3:32])([CH3:33])[CH2:24]1)(=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC1CC(C)(C)N(O)C(C)(C)C1
Reactant: CC(C)(C)O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Product: CCCCCCCCCCCCCCCCCC(=O)OC1CC(C)(C)N(OCC(C)(O)CON2C(C)(C)CC(OC(=O)CCCCCCCCCCCCCCCCC)CC2(C)C)C(C)(C)C1

Procedure:
Aqueous hydrogen peroxide is added to a mixture of 4-octadecanoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine and ferrous chloride tetrahydrate in tert-butyl alcohol at 30-50° C. Excess peroxide is decomposed with aqueous sodium sulfite solution. The organic layer is concentrated to obtain a mixture which includes 1-(2-hydroxy-2-methylpropoxy)-4-octa-decanoyloxy-2,2,6,6-tetramethylpiperidine and the title compound. The title compound is separated from the mixture by high pressure liquid chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:7]=1.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][NH:27]2.C1(C)C=CC=CC=1>C(O)(=O)C>[F:14][C:13]([F:15])([F:16])[C:10]([CH:11]=[N:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][NH:27]2)([OH:17])[CH2:9][C:8]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:20][CH3:21])([CH3:18])[CH3:19]
Reactant: Nc1cccc2[nH]ncc12
Reactant: COc1ccc(Br)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc(Br)cc1C(C)(C)CC(O)(C=Nc1cccc2[nH]ncc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 96 h
Yield: 89.5 %

Procedure:
300 mg (0.813 mmol) of 4-(5-bromo-2-methoxyphenyl)-2hydroxy-4-methyl-2-(trifluoromethyl)pentanal is mixed in 1.19 ml of glacial acetic acid with 108.2 mg (0.813 mmol) of 4-aminoindazole, and it is stirred for four days at room temperature. The batch is spun in until a dry state is reached, and the residue is drawn off three times with toluene. Chromatography on silica gel (mobile solvent:ethyl acetate/hexane) yields 352.5 mg (89.5%) of the desired imine (together with the imine of the Desbrom compound).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=O.[CH3:16]N1C=CN=C1.O>C(OC(=O)C)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13](=[O:15])[CH3:16]
Reactant: Cn1ccnc1
Reactant: O=C(O)Cc1cc([N+](=O)[O-])c(F)cc1Br
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Cc1cc([N+](=O)[O-])c(F)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
Treat a solution of 2-(2-bromo-4-fluoro-5-nitrophenyl)acetic acid (30.0 g, 0.11 mol) in acetic anhydride (30 mL) with 1-methylimidazole (4.5 g, 55 mmol), stir at RT for 2 h, treat with water, stir for 5 min, and extract with EtOAc. Wash the combined organics with water, saturated. Na2CO3, then brine, dry over Na2SO4, concentrate and purify via silica gel chromatography (EtOAc/petroleum ether) to afford the title compound (12 g, 40% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.19 (d, J=8.0 Hz, 1H), 8.02 (d, J=10.8 Hz, 1H), 4.09 (s, 2H), 2.23 (s, 3H).
Reaction SMILES: [Mg].Br[C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[P:13]([Cl:16])(Cl)Cl>CCOCC>[C:3]12([P:13]([C:3]34[CH2:12][CH:7]5[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]5)[CH2:4]3)[CH2:10]4)[Cl:16])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2
Reactant: BrC12CC3CC(CC(C3)C1)C2
Reactant: ClP(Cl)Cl
Agent: [Mg]
Solvent: CCOCC
Product: ClP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Temperature: -45 °C
Reaction time: 0.5 h

Procedure:
An oven-dried, round-bottom flask was charged with magnesium turnings (15.3 g, 0.63 mol) and 1-bromoadamantane (9.0 g, 0.041 mol). The flask was evacuated and backfilled with argon two times. To the reaction vessel 45 mL ether was added and the mixture was gently refluxed for 15 hours, without mechanical stirring. The resulting solution of Grignard reagent was taken up in a syringe, and added very slowly dropwise to a separate flame-dried, two-necked, round-bottom flask equipped with a reflux condenser which had been charged with PCl3 (0.9 mL, 10 mmol) and 15 mL ether which had been coooled to −40° C. During the addition the temperature was monitored and kept below −25° C. The resulting mixture was stirred for 30 minutes at −45° C., then the cooling bath was removed and the reaction mixture was allowed to warm slowly to room temperature. After stirring for an additional 30 minutes at room temperature, the reaction vessel was placed into a heated oilbath (37° C.) and was gently refluxed for 22 hours. The mixture was cooled to room temperature, and the solution was filtered through a cannula filter. The solvent as well as some of the adamantane byproduct was removed in vacuo, without exposing the product to air to afford crude di-1-adamantylchlorophosphine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([I:18])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]2[OH:17].[C:19]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([I:18])[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:19])[CH:9]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]2=[O:17]
Reactant: CCOC(=O)c1cnc2c(F)cc(I)cc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cn(C)c2c(F)cc(I)cc2c1=O
Temperature: 95 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
Ethyl 8-fluoro4-hydroxy-6-iodo-3-quinolinecarboxylate (18.1 g) prepared as an intermediate in Preparation No. 1 is dissolved in DMF (430 mL), and K2CO3 (36.1 g, 261 mmol) and methyl iodide (3.25 mL, 52.3 mmol) are added. The reaction mixture is heated to 95° C. for 6 h, then allowed to stir at room temperature overnight. The mixture is split into two parts. The first part is poured into H2O and extracted with five 100-mL portions of CH2Cl2. The combined organic layers are washed with five 200-mL H2O, dried over MgSO4, filtered, and concentrated in vacuo. The work-up is then repeated on the second portion of the reaction mixture to give a total of 15.8 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([OH:16])=[O:15].C(N(CC)CC)C.[C:27]([CH:29]([N:31]1[C:35](=[O:36])[CH2:34][N:33]([CH2:37][C:38]#[CH:39])[C:32]1=[O:40])O)#[N:28]>CCOCC>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([O:16][CH:29]([C:27]#[N:28])[N:31]1[C:35](=[O:36])[CH2:34][N:33]([CH2:37][C:38]#[CH:39])[C:32]1=[O:40])=[O:15]
Reactant: CC(C)C(Nc1ccc(C(F)(F)F)cc1F)C(=O)O
Reactant: C#CCN1CC(=O)N(C(O)C#N)C1=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C#CCN1CC(=O)N(C(C#N)OC(=O)C(Nc2ccc(C(F)(F)F)cc2F)C(C)C)C1=O
Reaction time: 18 h

Procedure:
To the acid chloride of 2-(2-fluoro-4-trifluoromethylphenylamino)-3-methylbutanoic acid (2.5 mmol) in ether is added 1.3 ml of triethylamine followed by the cyano(2,4-dioxo-1-propargyl-3-imidazolidinyl)methanol in 5 ml of ether, from part A above, over about 2 minutes. The reaction mixture is stirred for about 18 hours and then quenched with saturated aqueous sodium bicarbonate. The organic phase is washed with aqueous sodium bicarbonate, water and brine, dried over calcium sulfate and solvent evaporated. The crude product is chromatographed on a circular chromatograph eluting with 20% ether/hexane to give cyano(2,4-dioxo-1-propargyl-3-imidazolidinyl)methyl 2-(2-fluoro-4-trifluoromethylphenylamino)-3-methylbutanoate. (A', R is carbonyl, R' is methylene, R1 =R4 is hydrogen, R2 is 2-fluoro-4-trifluoromethylphenyl, R3 is isopropyl, R5 is cyano, R6 is 2-propynyl).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2.[H-].[Na+].Cl.Cl[CH2:15][C:16]1[C:21]([CH3:22])=[C:20]([O:23][CH3:24])[C:19]([CH3:25])=[CH:18][N:17]=1.O>CN(C)C=O>[CH3:22][C:21]1[C:16]([CH2:15][S:1][C:2]2[NH:3][C:4]3[C:5]([N:10]=2)=[N:6][CH:7]=[CH:8][CH:9]=3)=[N:17][CH:18]=[C:19]([CH3:25])[C:20]=1[O:23][CH3:24]
Reactant: COc1c(C)cnc(CCl)c1C
Reactant: Sc1nc2ncccc2[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C)cnc(CSc2nc3ncccc3[nH]2)c1C
Reaction time: 0.5 h

Procedure:
1.5 Grams of 2-mercaptoimidazo[4,5-b]pyridine was dissolved in 50 ml of dimethylformamide, to this solution was added, under ice-cooled condition, 0.88 g of 60% sodium hydride (in oil), and the mixture was stirred at the same temperature for 30 minutes. Then, to this reaction mixture was added 2.2 g of 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride and the whole mixture was heated at 70° to 80° C. under stirring condition for 3 hours. After the reaction was completed, dimethylformamide was removed by evaporation, and to the residue thus obtained was added water, and then extracted with chloroform. The chloroform extract was washed with water, and dried with anhydrous magnesium sulfate. Chloroform was removed by evaporation, then the residue thus obtained was recrystallized from ethanol to obtain 1.3 g of 2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylthio]-imidazo[4,5-b]pyridine in the form of white powdery crystals. Melting point: 186°-188° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:13][N:14]=[C:7]1[CH:6]=[CH:5]2.[CH2:21]([CH:23]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:24][O:25][C:26](=[O:30])[CH2:27][CH2:28][SH:29])[CH3:22].CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>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]>[CH2:21]([CH:23]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:24][O:25][C:26](=[O:30])[CH2:27][CH2:28][S:29][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:13][N:14]=[C:7]1[CH:6]=[CH:5]2)[CH3:22]
Reactant: CCCCC(CC)COC(=O)CCS
Reactant: Ic1ccc2c(ccc3nnc(-c4ccccn4)n32)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC(CC)COC(=O)CCSc1ccc2c(ccc3nnc(-c4ccccn4)n32)c1
Temperature: 90 °C

Procedure:
5k (890 mg, 2.4 mmol) and 3-mercaptopropionic acid 2-ethylhexyl ester (630 mg, 2.9 mmol) were dissolved in 1,4-dioxane (20 mL) and degassed with N2 for 10 minutes. iPr2NEt (0.86 mL, 4.8 mmol), Pd2dba3 (54 mg, 0.06 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (69 mg, 0.12 mmol) were added, and the mixture was degassed with N2 for an additional 10 minutes. The reaction was heated to 90° C. until no starting material was seen by tlc analysis, and then the mixture was concentrated and purified by silica gel chromatography to give the desired product, 5m.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH:24][CH3:25])[C:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[NH2:17][C:9]1[C:8]2[N:18]=[C:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][N:24]([CH3:25])[C:33]([NH:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:34])[C:7]=2[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[N:10]=1
Reactant: CNCCOCCn1c(CCOC)nc2c(N)nc3c(c21)CCCC3
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: COCCc1nc2c(N)nc3c(c2n1CCOCCN(C)C(=O)Nc1ccccc1)CCCC3
Reaction time: 8 h
Yield: 16.9 %

Procedure:
2-(2-Methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline-4-amine (750 mg, 2.16 mmol) was dissolved in 30 mL of anhydrous CH2Cl2 and treated with phenyl isocyanate (239 μL, 2.20 mmol). After stirring under N2 overnight, the reaction mixture was concentrated under reduced pressure. Crystallization from EtOAc and CH2Cl2 gave 170 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy} ethyl)-N-methyl-N′-phenylurea as fluffy white crystals. m.p. 167.7-170.0° C.;
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4](=[O:35])[CH:5]([CH:24](O)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:6]([CH:8]=[CH:9][CH:10]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1.CN(C1C=CC=CN=1)C.CS(Cl)(=O)=O.C(OCC)(=O)C>ClCCl>[CH3:1][S:2][C:3]1[C:4](=[O:35])[C:5](=[CH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:6]([CH:8]=[CH:9][CH:10]([O:16][Si:17]([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1
Reactant: CCCCCC(C=CC1C=C(SC)C(=O)C1C(O)CCCCCC(=O)OC)O[Si](C)(C)C(C)(C)C
Agent: CN(C)c1ccccn1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCCC(C=CC1C=C(SC)C(=O)C1=CCCCCCC(=O)OC)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 15 h
Yield: 64.2 %

Procedure:
To a solution of 3.47 g of 2-methylthio-5-(1-hydroxy-6-methoxycarbonylhexyl)-4-(3-t-butyldimethylsilyloxy-1-octenyl)-2-cyclopentenone obtained in Example 6 in dichloromethane (30 ml) was added dimethylaminopyridine (1.54 g) and the mixture was cooled to 0° C. To the solution was dropwise added 0.59 ml of methanesulfonyl chloride, and the mixture was stirred at room temperature for 15 hours. To the reaction mixture were added ethyl acetate and an aqueous potassium hydrogensulfate, and the product was extracted into an organic layer. The extract was washed with saturated aqueous sodium hydrogencarbonate and saturated sodium chloride, dried over anhydrous magnesium sulfate, and filtered, followed by concentration. The concentrate was subjected to silica gel chromatography to give 2.15 g (yield 64%) of 2-methylthio-5-(6-methoxycarbonylhexylidene)-4-(3-t-butyldimethylsilyloxy-1-octenyl)-2-cyclopentenone.