Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=O)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2([OH:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[N:15][C:14]([O:17][CH2:18][C:19]([N:32]3[CH2:31][CH2:30][C:29]([C:26]4[CH:27]=[CH:28][C:23]([Br:22])=[CH:24][CH:25]=4)([OH:35])[CH2:34][CH2:33]3)=[O:21])=[N:13][CH:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: OC1(c2ccc(Br)cc2)CCNCC1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Product: O=C(Nc1ccc(F)cc1)c1cnc(OCC(=O)N2CCC(O)(c3ccc(Br)cc3)CC2)nc1
Yield: 84 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 4-(4-bromophenyl)-piperidin-4-ol (56 mg, 0.22 mmol) as the coupling partner. Concentration (no chromatography) yielded 76 mg (84%) of the titled compound. ESI-MS m/z 530, 532 (MH+), 527, 529 (M−H−).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.NC(N)=[S:17]>C(O)C>[N+:8]([C:7]1[C:2]([SH:17])=[N:3][CH:4]=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Reactant: NC(N)=S
Solvent: CCO
Product: O=[N+]([O-])c1cc(C(F)(F)F)cnc1S
Temperature: 50 °C
Reaction time: 5.5 h
Yield: 79.5 %

Procedure:
A mixture of 4.88 g of 2-chloro3-nitro-5-(trifluoromethyl)pyridine, 1.81 g of thiourea and 40 ml of ethanol was stirred at 50° C. for 5.5 hours. The reaction mixture was cooled down to room temperature, then, concentrated under reduced pressure. To the residue was added 24 ml of water and a mixture of 2.8 g of sodium hydroxide and 6 ml of water, and this was stirred at room temperature for 1.5 hours. The reaction mixture was washed with diethyl ether, then, acetic acid was added. This was cooled with ice, and the deposited solid was collected by filtration. This solid was dried under reduced pressure, to obtain 3.84 g of 3-nitro-5-(trifluoromethyl)pyridine-2-thiol.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:22][CH2:23][CH3:24])[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:9]2[O:12]COC)=[CH:4][C:3]=1[O:25][CH3:26].Cl>O1CCOCC1>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:22][CH2:23][CH3:24])[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:9]2[OH:12])=[CH:4][C:3]=1[O:25][CH3:26]
Reactant: CCCc1cc2cc(OC)c(F)cc2c(OCOC)c1-c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCc1cc2cc(OC)c(F)cc2c(O)c1-c1ccccc1
Yield: 101 %

Procedure:
7-Fluoro-6-(methyloxy)-1-{[(methyloxy)methyl]oxy}-2-phenyl-3-propyl naphthalene (136) (0.48 g, 1.34 mmol) was treated with 4 M HCl in dioxane at room temperature to give 0.42 g (˜100%) of the title compound (137) as a light yellow viscous oil. 1H NMR (400 MHz, CDCl3): δ 0.79 (t, J=7.4 Hz, 3H), 1.40-1.60 (m, 2H), 2.44 (t, J=7.8 Hz, 2H), 4.00 (s, 3H), 5.13 (s, 1H), 7.13 (d, J=8.2 Hz, 1H), 7.21 (s, 1H), 7.30-7.36 (m, 2H), 7.42-7.49 (m, 1H), 7.50-7.56 (m, 2H), 7.79 (d, J=12.5 Hz, 1H). LCMS (ESI): m/z 311 (M+H)+, m/z 309 (M−H)−.
Reaction SMILES: [H-].[Na+].C(O)(CC)(C)C.[Cl:9][C:10]1[CH:34]=[CH:33][C:13]([O:14][C:15]2[CH:32]=[CH:31][C:18]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)=O)=[CH:17][CH:16]=2)=[CH:12][CH:11]=1.[C:35]([N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)(=[O:37])[CH3:36]>C1(C)C=CC=CC=1>[Cl:9][C:10]1[CH:34]=[CH:33][C:13]([O:14][C:15]2[CH:32]=[CH:31][C:18]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)=[CH:36][C:35]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[O:37])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1
Reactant: CC(=O)N1CCOCC1
Reactant: COc1ccc(C(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCC(C)(C)O
Product: COc1ccc(C(=CC(=O)N2CCOCC2)c2ccc(Oc3ccc(Cl)cc3)cc2)cc1OC
Temperature: 100 °C

Procedure:
Sodium hydride (with 20% of paraffin oil; 2.25 g, 75 mmol) was stirred under reflux with absolute toluene (50 ml) and tert.-amyl alcohol (7.25 g, 82.5 mmol) was added dropwise within 30 minutes. When the solution had cooled to 100° C., 4-(4-chlorophenoxy)-3',4'-dimethoxy benzophenone (9.22 g, 25 mmol) and acetyl morpholine (16.17 g, 125 mmol) were added and the mixture was stirred under reflux for 8 hours.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)=O.[C:14]1([CH:21]=[CH:20][CH:19]=[C:17]([OH:18])[CH:16]=1)[OH:15].C(N1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([OH:34])[CH:32]=2)C(C)=CC1(C)C)C>CO>[OH:15][C:14]1[CH:21]=[CH:20][C:19]2[C:1]([C:3]3[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=3)=[C:28]3[C:33]([O:18][C:17]=2[CH:16]=1)=[CH:32][C:31](=[O:34])[CH:30]=[CH:29]3
Reactant: O=Cc1ccc(OCC(=O)O)cc1
Reactant: CCN1c2cc(O)ccc2C(C)=CC1(C)C
Reactant: Oc1cccc(O)c1
Solvent: CO
Product: O=C(O)COc1ccc(-c2c3ccc(=O)cc-3oc3cc(O)ccc23)cc1
Yield: 34 %

Procedure:
Dye 3 (shown below) was prepared using the procedure described in Example 4 except that 2-(4-formylphenoxy)acetic acid and resorcinol substituted for 1-ethyl-2,2,4-trimethyl-1,2-dihydroquinolin-7-ol and 2-(4-formylphenoxy)acetic acid. Yield: 34%. λabs=485 nm (in methanol), λem=511 nm (in methanol).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[C:9]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:10](=[O:12])[CH3:11].[OH:19]O.[OH-].[Na+]>CO.O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[O:19][C:9]1([C:13]1[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=1)[C:10](=[O:12])[CH3:11]
Reactant: OO
Reactant: CC(=O)C(=Cc1ccccc1C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)C1(c2ccncc2)OC1c1ccccc1C
Temperature: 25 °C
Reaction time: 70 h

Procedure:
To a solution of 4-(2-methylphenyl)-3-(4pyridyl)-3-butene-2-one (step 1) (1.0 g, 4.2 mmol) in methyl alcohol (18 ml), a solution of H2O2 (30% by wt.) (0.95 g, 8.4 mmol) and sodium hydroxide (0.18 g, 4.6 mmol) in water (4 ml) was-added. The reaction was stirred at room temperature for 70 hours. After methyl alcohol was removed, water (25 ml) and ethyl acetate (100 ml) were added and the two phase mixture was stirred for 30 minutes. The layers were separated, and the aqueous layer was washed with ethyl acetate (100 ml). The combined organic layer was dried with Na2SO4, filtered and concentrated to give an oil. 4-(2-Methylphenyl)-3-(4-pyridyl)-3,4-epoxy-2-butanone was isolated from the oil residue by chromatography.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc2ccccc12
Product: Clc1ccnc2ccccc12

Procedure:
In this scheme, the ethyl ester (A1) is condensed with the appropriate aniline (A2), in the presence of acid, to form an imine. The imine is then cyclized by heating at about 260-280° C. to give the corresponding 4-hydroxyquinoline (A3). The 4-hydroxyquinoline (A3) is subsequently refluxed with phosphorous oxychloride to form a 4-chloroquinoline (A4).
Reaction SMILES: [C:1]1(C)C(C)=CC=CC=1.[CH3:9][C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[O:11]>>[CH3:1][CH2:16][O:15][CH2:14][CH2:13][O:12][C:10]([CH3:9])=[O:11]
Reactant: Cc1ccccc1C
Reactant: COCCOC(C)=O
Product: CCOCCOC(C)=O

Procedure:
When the polyamide-imide resin obtained in this invention is made into a varnish, there may be used as auxiliary solvents xylene, NISSEKI HISOL-100, 150 (trade names, mfd. by Nippon Petrochemicals Co., Ltd., aromatic hydrocarbons obtained from petroleum, b.p. 80°-300° C.), methyl Cellosolve acetate, ethyl Cellosolve acetate, γ-butyrolacetone and the like in combination with the basic organic solvents described above.
Reaction SMILES: [K+].[Cl:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[C:8]2[C:12](=[O:16])[C:13]([O-:15])=O.[C:17]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:17]([N:25]1[CH2:30][CH2:29][N:28]([C:13](=[O:15])[C:12]([C:8]2[C:7]3[C:11](=[C:3]([Cl:2])[N:4]=[CH:5][CH:6]=3)[NH:10][CH:9]=2)=[O:16])[CH2:27][CH2:26]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(c1ccccc1)N1CCNCC1
Reactant: O=C([O-])C(=O)c1c[nH]c2c(Cl)nccc12
Agent: [K+]
Product: O=C(C(=O)N1CCN(C(=O)c2ccccc2)CC1)c1c[nH]c2c(Cl)nccc12

Procedure:
Precursor 5k, 1-benzoyl-4-[(7-chloro-6-azaindol-3-yl)-oxoacetyl]piperazine was prepared by the same method as Precursor 5a, starting from (7-chloro-6-azaindol-3-yl)-oxoacetic acid potassium salt, Precursor 4a, and 1-benzoylpiperazine. MS m/z: (M+H)+ calcd for C20H18ClN4O3: 397.11; found 396.97. HPLC retention time: 2.37 minutes (column F, gradient time=3 min, flow rate=4 ml/min).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.CN(C=O)C.[CH3:35][NH:36][CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][C:42]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=2)([OH:45])[CH2:41][CH2:40]1>O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:36]([CH2:37][CH2:38][N:39]2[CH2:40][CH2:41][C:42]([OH:45])([CH2:46][C:47]3[CH:48]=[CH:49][C:50]([CH3:53])=[CH:51][CH:52]=3)[CH2:43][CH2:44]2)[CH3:35])=[O:15])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNCCN1CCC(O)(Cc2ccc(C)cc2)CC1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(CC2(O)CCN(CCN(C)C(=O)c3ccc(OCc4ccccc4)cc3)CC2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 41.2 %

Procedure:
A mixture of 4-benzyloxy benzoic acid (265 mg, 1.16 mmol), 1,1 '-carbonyl-diimidazole (197 mg, 1.21 mmol) and DMF (7 ml) was stirred at 50° C. for 1 h. After cooling to r.t., 1-(2-methylamino-ethyl)-4-(4-methyl-benzyl)-piperidin-4-ol (335 mg, 1.27 mmol) was added and stirring was continued for 1 h. After the addition of water, the mixture was extracted with ether. The organic layer was dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (silica gel, dichloromethane-methanol 95:5) to give 4-benzyloxy-N-[2-[4-hydroxy-4-(4-methyl-benzyl)-piperidin-1-yl]-ethyl]-N-methyl-benzamide (226 mg) as a pale yellow oil. MS: me/e=473 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:17][C:18]#[N:19].Cl>CN(C)C=O.O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][N:8]2[CH2:17][C:18]#[N:19])=[CH:4][CH:3]=1
Reactant: O=C(O)c1c[nH]c2cc(Br)ccc12
Reactant: N#CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCn1cc(C(=O)O)c2ccc(Br)cc21
Temperature: 0 °C
Yield: 68 %

Procedure:
6-Bromo-1H-indole-3-carboxylic acid (0.24 g, 1 mmole) was dissolved in anhydrous dimethylformamide (2 ml) and cooled to 0° C. in a nitrogen atmosphere. With stirring, sodium hydride (60% in oil, 0.088 g, 2.2 mmole) was added all at once and the mixture was stirred at this temperature until no more bubbles evolved (ca. 20-30 minutes). Bromoacetonitrile (0.132 g, 1.1 mmole) was added to the reaction mixture which was then allowed to warm to room temperature over the next hour. The reaction mixture was poured into water, acidified with HCl and a precipitate formed. When dried the product weighed 0.190 g (68% yield) and was sufficiently pure to be used directly in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([C:19](O)=[O:20])[O:16][C:15]2=[O:22])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.Cl.[CH3:24][O:25][NH2:26].Cl.CN(C)CCCN=C=NCC>O1CCCC1.O.O>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([C:19]([NH:26][O:25][CH3:24])=[O:20])[O:16][C:15]2=[O:22])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: O=C(O)[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Reactant: CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CONC(=O)[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (5R)-(−)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxylic acid (EXAMPLE 1, Step 1, 150 mg, 0.483 mmol) and O-methylhydroxylamine hydrochloride (61 mg, 0.724 mmol) in tetrahydrofuran/water (1/1, 4.8 mL) is treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (278 mg, 1.45 mmol), and the resulting mixture is stirred at ambient temperature for 30 minutes and is then diluted with water (10 mL) and extracted with ethyl acetate (2×20 mL). The combined organic phase is washed with water (10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the crude product is chromatographed on a Flash 40S silica gel (40 g, 32-63 μm) cartridge, eluting with methanol/methylene chloride (2.5/97.5). Pooling and concentration of those fractions with an Rf=0.53 by TLC (methanol/chloroform, 10/90) gives the title compound, mp 206-208° C. (decomp.); MS (ESI+) for C15H18FN3O5 m/z 340 (M+H)+; [α]25D=−56° (c 0.92, DMSO).
Reaction SMILES: [C:1]([CH:4]([CH2:14][CH2:15][CH2:16][CH:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[NH2:2].[CH:24](O)=[O:25]>>[C:1]([CH:4]([CH2:14][CH2:15][CH2:16][CH:17]([O:23][CH:24]=[O:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[NH2:2]
Reactant: O=CO
Reactant: CCCCCC(O)CCCC(CCCCCCC(=O)O)C(N)=O
Product: CCCCCC(CCCC(CCCCCCC(=O)O)C(N)=O)OC=O
Temperature: 60 °C

Procedure:
A mixture of 8-carbamoyl-12-hydroxyheptadecanoic acid (8.2 g., 0.025 mole) (Example 1, Step F) and 97% formic acid (10 ml.) is heated at 60° C. for 24 hours. The mixture is cooled, dissolved in 100 ml. ether, washed with 3 portions of water and dried over sodium sulfate. Evaporation of the ether leaves the product 8-carbamoyl-12-formyloxyheptadecanoic acid as a slightly yellowish viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:4].[CH3:20][S:21]([NH:24][C:25]1[CH:40]=[CH:39][C:28]2[NH:29][C:30]([CH2:35][C:36](O)=[O:37])=[N:31][S:32](=[O:34])(=[O:33])[C:27]=2[CH:26]=1)(=[O:23])=[O:22].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>CN(C)C=O>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[N:11]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:36](=[O:37])[CH2:35][C:30]1[NH:29][C:28]2[CH:39]=[CH:40][C:25]([NH:24][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:26][C:27]=2[S:32](=[O:33])(=[O:34])[N:31]=1)=[O:4]
Reactant: COC(=O)[C@H]1CCCC[C@H]1NCc1ccc(F)cc1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CCCC[C@H]1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The crude (1S,2R)-2-(4-fluoro-benzylamino)-cyclohexanecarboxylic acid methyl ester (4.97 mmol) was dissolved in N,N-dimethylformamide (40 mL) at 25° C. and (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 1.47 g, 4.41 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.887, 4.63 mmol), and N-methylmorpholine (1.01 mL, 9.19 mmol) were added sequentially. The reaction mixture was stirred at 25° C. for 2 h, and then was concentrated in vacuo. The residue was partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate, decanted, and were concentrated in vacuo to afford the crude product, (1S,2R)-2-{(4-fluoro-benzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclohexanecarboxylic acid methyl ester as a yellow oil, which was used directly in the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]#[C:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]#[C:22][CH2:23][N:24]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]2=[O:34])=[N:19][CH:20]=1.C(O)(=O)C.[H][H]>CN(C=O)C.[Pd]>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][N:24]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]2=[O:34])=[N:19][CH:20]=1
Reactant: [H][H]
Reactant: O=C1c2ccccc2C(=O)N1CC#Cc1ccc(C#CCN2C(=O)c3ccccc3C2=O)nc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1CCCc1ccc(CCCN2C(=O)c3ccccc3C2=O)nc1
Yield: 63.8 %

Procedure:
A mixture of 2-(3-{5-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl-prop-1-ynyl]pyridin-2-yl}prop-2-ynyl)-1H-isoindole-1,3(2H)-dione (5-1) (200 mg), 10% Pd/C (50 wt %; 60 mg), and acetic acid (1 mL) in DMF (1 mL) was stirred at ambient temperature under 1 atmospheric pressure of hydrogen for 2 days. The catalyst was removed by filtration through Solka-floc and washed with ethanol. The filtrate and wash were combined and concentrated under reduced pressure to give 11-1 (130 mg) as colorless crystals.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][S:5][CH2:4][CH2:3]1.C(N(CC)CC)C.I.[NH2:16][C:17]1[C:18]([C:25]([NH:27][C:28](=[NH:31])SC)=[O:26])=[N:19][C:20]([Cl:24])=[C:21]([NH2:23])[N:22]=1>O1CCCC1>[NH2:16][C:17]1[C:18]([C:25]([N:27]=[CH:28][NH:31][N:2]2[CH2:7][CH2:6][S:5][CH2:4][CH2:3]2)=[O:26])=[N:19][C:20]([Cl:24])=[C:21]([NH2:23])[N:22]=1
Reactant: C1CSCCN1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: Cl
Agent: I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1nc(N)c(C(=O)N=CNN2CCSCC2)nc1Cl
Temperature: 0 °C

Procedure:
Thiomorpholine hydrochloride (2.10 g., 0.015 mole), triethylamine (2.1 ml., 0.015 mole), and 1-(3,5-diamino-6-chloropyrazinoyl)-2-methyl-2-thiopseudourea hydroiodide (1.94 g., 0.005 mole) are heated in tetrahydrofuran (50 ml.) at reflux for 4 hrs. The reaction mixture is added to ice-water to precipitate 590 mg. of 3,5-diamino-6-chloro-N-[(4-thiomorpholinyl)aminomethylene]-2-pyrazinecarboxamide which melts at 234°-6° C. after reprecipitation from dilute hydrochloric acid with sodium hydroxide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[CH2:23](I)[CH:24]=[CH2:25]>CN(C)C=O>[CH2:25]([N:10]1[C:11]2[C@@:12]3([CH3:22])[C:19]([CH3:21])([CH3:20])[C@H:15]([CH2:14][CH2:13]3)[C:16]=2[C:17](=[O:18])[N:9]1[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[CH:24]=[CH2:23]
Reactant: C=CCI
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Solvent: CN(C)C=O
Product: C=CCn1c2c(c(=O)n1-c1ccc(F)cc1F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 65.9 %

Procedure:
A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 420 mg, 1.38 mmol) and allyl iodide (600 μL, 5.5 mmol) in dimethylformamide (5 mL) was heated in an oil-bath at 100° C. for 8 h. The solvent was evaporated and the residue was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (2×100 mL) and the combined organic layers were washed with water (5×100 mL) and aqueous sodium thiosulfate (100 mL). The solvent was evaporated and the residue was purified using an ISCO 40 g column, eluting with 90-100% ethyl acetate/hexanes to give (4S,7R)-1-allyl-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (313 mg, 66%) as a white solid. APCI(+)-MS (M+H) 345.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:21])=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]=2[N:3]=1.Br[CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][CH2:36][P:37](=[O:44])([O:41][CH2:42][CH3:43])[O:38][CH2:39][CH3:40]>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][CH2:36][P:37](=[O:44])([O:41][CH2:42][CH3:43])[O:38][CH2:39][CH3:40])=[CH:16][C:15]=3[CH3:21])=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]=2[N:3]=1
Reactant: CCOP(=O)(CCCOCCOCCBr)OCC
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3C)cc12
Product: CCOP(=O)(CCCOCCOCCOc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1)OCC

Procedure:
Diethyl 3-(2-(2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)ethoxy)propylphosphonate was prepared from following the procedure described for Example 139, but using 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenol (from Example148) and diethyl 3-(2-(2-bromoethoxy)ethoxy)propylphosphonate. 1H NMR (Acetone-d6): δ 8.75 (s, 1H), 8.70 (s, 1H), 8.26 (d, 1H), 7.42 (s, 1H), 7.16 (d, 1H), 7.09 (d, 1H), 6.77 (s, 1H), 6.71 (d, 1H), 6.58 (br, 2H), 3.95-4.11 (m, 6H), 3.76-3.80 (m, 2H), 3.63-3.67 (m, 2H), 3.55-3.58 (m, 2H), 3.57-3.51 (m, 2H), 3.14-3.18 (m, 2H), 3.04-3.05 (m, 2H), 2.46 (s, 3H), 2.29 (s, 3H), 1.71-1.87 (m, 4H), 1.22-1.29 (m, 8H). LRMS [M+H]=610.3.
Reaction SMILES: Cl[C:2]([O:4][C:5]([CH2:8][CH3:9])([CH3:7])[CH3:6])=[O:3].[OH:10][N:11]=[C:12]([C:18]#[N:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(CC)CC)C.O>C1C=CC=CC=1>[C:5]([O:4][C:2]([O:10][N:11]=[C:12]([C:18]#[N:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:3])([CH2:8][CH3:9])([CH3:7])[CH3:6]
Reactant: CCOC(=O)C(C#N)=NO
Reactant: CCC(C)(C)OC(=O)Cl
Solvent: O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C#N)=NOC(=O)OC(C)(C)CC
Yield: 39.8 %

Procedure:
A solution of t-amyl chloroformate (0.05 mol) in an ether-toluene mixture (30 ml) is cooled to -10°C, and a solution of ethyl 2-hydroxyimino-2-cyanoacetate (7.2 g) and triethylamine (7.0 ml) in dry benzene (50 ml) is dropwise added thereto. The resulting mixture is allowed to stand at room temperature over night. The reaction mixture is admixed with water and filtered. The organic layer is separated, washed with water, dried and concentrated to give ethyl 2-t-amyloxycarbonyloxyimino-2-cyanoacetate (5.1 g) as an oil.
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=CC=C[CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29]C(C)=CC=O.Cl.CCN(C(C)C)C(C)C>C(OC(=O)C)C>[CH3:28][C:23]([CH3:24])=[CH:22][CH2:21][N:7]([C@H:1]1[CH2:2][CH2:3][C@H:4]([CH3:29])[CH2:5][CH2:6]1)[C:8](=[O:20])[NH:9][C:10]1[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=1
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Reactant: CC(C)=CC=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)=CCN(C(=O)Nc1ncc(SCC(=O)O)s1)[C@H]1CC[C@H](C)CC1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid, from 4-trans-methyl-cyclohexylamine hydrochloride, 3-methyl-but-2-enal and 2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. The hydrochloride was added one equivalent DIPEA prior to the reaction.