Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH2:24]([N:27]([CH2:36][CH2:37][CH3:38])[C:28]([CH2:30][CH2:31][CH2:32][C:33](O)=[O:34])=[O:29])[CH2:25][CH3:26]>>[CH2:36]([N:27]([CH2:24][CH2:25][CH3:26])[C:28](=[O:29])[CH2:30][CH2:31][CH2:32][C:33]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])=[O:34])[CH2:37][CH3:38]
Reactant: CCCN(CCC)C(=O)CCCC(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: CCCN(CCC)C(=O)CCCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 4-dipropylcarbamoyl-butyric acid to yield (3aR,4S,7aR)-methyl 4-(5-(dipropylamino)-5-oxopentanoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [2M+H+NH4]=1039; RT=1.41 min; UPLC Method I
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([C:15]2[C:16]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[CH:17][C:18]3[O:22][C:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[C:20]([C:30]([NH:32][CH3:33])=[O:31])[C:19]=3[CH:34]=2)[CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O>[CH:12]1([C:15]2[C:16]([N:35]([C:6]3[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([F:1])[CH:7]=3)[S:36]([CH3:39])(=[O:38])=[O:37])=[CH:17][C:18]3[O:22][C:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[C:20]([C:30]([NH:32][CH3:33])=[O:31])[C:19]=3[CH:34]=2)[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(F)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 100 °C
Yield: 28.9 %

Procedure:
A suspension of 2,4-difluoro-1-nitrobenzene (261 mg, 1.64 mmol) and 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1-benzofuran-3-carboxamide (600 mg, 1.49 mmol) in dimethoxyethane (0.8 mL) and water (0.2 mL) was treated with potassium carbonate (616.86 mg, 4.47 mmol) and heated to 100° C. for 24 hours. The reaction mixture was concentrated and purified by column chromatography to afford 5-cyclopropyl-6-(N-(3-fluoro-4-nitrophenyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (230 mg, 0.43 mmol, 29% yield) as a yellow powder. LCMS (m/z, ES+)=542 (M+H+)
Reaction SMILES: C1O[C:4]2([C:9]3[CH:10]=[CH:11][C:12]4[C:17]([C:8]=3[S:7](=[O:19])(=[O:18])[N:6]([CH2:20][CH3:21])[CH2:5]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[O:3]C1.Cl>CO>[CH2:20]([N:6]1[CH2:5][C:4](=[O:3])[C:9]2[CH:10]=[CH:11][C:12]3[C:17]([C:8]=2[S:7]1(=[O:19])=[O:18])=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:21]
Reactant: CCN1CC2(OCCO2)c2ccc3ccccc3c2S1(=O)=O
Agent: Cl
Solvent: CO
Product: CCN1CC(=O)c2ccc3ccccc3c2S1(=O)=O
Yield: 8.4 %

Procedure:
A suspension of 10.9 gm (0.34 mol) of 2-ethyl-2H-naphtho[2,1-e]-1,2-thiazine-4(3H)-one-1,1-dioxide-ethylene ketal in 200 ml of methanol and 200 ml of aqueous 10% hydrochloric acid was refluxed for 1 hour. Then, the mixture was evaporated to dryness in vacuo, the residue was taken up in methylene chloride, and the solution was neutralized and again evaporated to dryness. Recrystallization of the residue from ethanol yielded 7.9 gm (84% of theory) of 2-ethyl-2H-naphtho[2,1-e]-1,2-thiazine-4(3H)-one-1,1-dioxide, m.p. 146°-147° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][C:13]2[CH:30]=[CH:29][C:16]([C:17]([NH:19][C@@H:20]3[CH2:24][NH:23][CH2:22][C@@H:21]3[C:25]([O:27][CH3:28])=[O:26])=[O:18])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[CH2:38](Br)[C:39]#[CH:40]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:19][C@@H:20]3[CH2:24][N:23]([CH2:40][C:39]#[CH:38])[CH2:22][C@@H:21]3[C:25]([O:27][CH3:28])=[O:26])=[O:18])=[CH:29][CH:30]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: C#CCBr
Reactant: COC(=O)[C@H]1CNC[C@H]1NC(=O)c1ccc(Cc2cc(C)nc3ccccc23)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C#CCN1C[C@H](C(=O)OC)[C@H](NC(=O)c2ccc(Cc3cc(C)nc4ccccc34)cc2)C1
Temperature: 0 °C
Yield: 54.4 %

Procedure:
The TFA salt (403a) (92 mg, 0.15 mmol) was dissolved in 2 mL of chloroform and the solution was cooled to 0° C. Triethylamine (88 mg, 122 μL, 0.87 mmol) and propargyl bromide (65 mg, 50 μL, 0.44 mmol) were added subsequently. The mixture was stirred until disappearance of compound (403a). The solution was diluted with ethyl acetate and washed with H2O and brine, and dried over MgSO4. After filtration and concentration, the residue was purified on silica gel to provide methyl (3S,4S)-4-({4-[(2-methyl-4-quinolinyl)methyl]benzoyl}amino)-1-(2-propynyl)-3-pyrrolidinecarboxylate (36 mg, 56%). MS (AP+): 442 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([CH3:10])=[CH2:9])[CH:7]=1.[Cl:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([CH2:10][Cl:11])=[CH2:9])[CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: C=C(C)c1cncc(Br)c1
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(CCl)c1cncc(Br)c1
Temperature: 80 °C
Reaction time: 7 h
Yield: 26.7 %

Procedure:
A mixture of 7.12 g of 3-bromo-5-isopropenylpyridine, 6.85 g of N-chlorosuccinimide and 15 ml of carbon tetrachloride was stirred at 80° C. for 7 hours. After the reaction mixture was cooled to room temperature, the insoluble matter was filtered out. The filtrate was concentrated under a reduced pressure and the residue was purified by silica gel column chromatography (eluted with ethyl acetate-n-hexane 1:19) to obtain 2.23 g of the objective compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]1[NH:12][C:13]([CH2:15][CH3:16])=[N:14][C:6]1=[N:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]1[N:12]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:13]([CH2:15][CH3:16])=[N:14][C:6]1=[N:5]2
Reactant: CCOC(=O)CBr
Reactant: CCc1nc2nc3cc(Cl)ccc3nc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(CC)nc2nc3cc(Cl)ccc3nc21

Procedure:
A mixture of 100 parts of 6-chloro-2-ethyl-1H-imidazo[4,5-b]quinoxaline, 70 parts of anhydrous potassium carbonate, 75 parts of ethyl bromoacetate, and 600 parts of anhydrous dimethylformamide was heated at 100° for 2.5 hours. The mixture was filtered and the crude product was precipitated from the filtrate by addition of 1200 parts of water, collected by filtration, washed with water, ethanol, and ether, and airdried. Recrystallization from 95% ethanol afforded 63 parts of 6-chloro-2-ethyl-1-ethoxycarbonylmethyl-1H-imidazo[4,5-b]quinoxaline, m.p. 174°-175°.
Reaction SMILES: [CH3:1][N:2]([C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11])[C:3]1[NH:7][N:6]=[N:5][N:4]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[CH2:34]1[CH2:39][CH:38]([C:40]2([NH:53][C:54](NC3C=CC=C(NC4NN=NN=4)C=3)=[O:55])[N:46]=[CH:45][C:44]3[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=3[N:42]([CH3:51])[C:41]2=[O:52])[CH2:37][CH2:36][CH2:35]1>O1CCCC1>[CH2:36]1[CH2:37][CH:38]([C@@:40]2([NH:53][C:54]([NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:8]([N:2]([CH3:1])[C:3]4[NH:7][N:6]=[N:5][N:4]=4)[CH:9]=3)=[O:55])[N:46]=[CH:45][C:44]3[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=3[N:42]([CH3:51])[C:41]2=[O:52])[CH2:39][CH2:34][CH2:35]1
Reactant: CN(c1cccc(N)c1)c1nnn[nH]1
Reactant: CN1C(=O)C(NC(=O)Nc2cccc(Nc3nnn[nH]3)c2)(C2CCCCC2)N=Cc2ccccc21
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1C(=O)[C@@](NC(=O)Nc2cccc(N(C)c3nnn[nH]3)c2)(C2CCCCC2)N=Cc2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 145 %

Procedure:
To a cooled (0° C.) and stirred milky solution of 3-[N-methyl-N-(tetrazol-5-yl)amino]aniline (230 mg) in anhydrous tetrahydrofuran (30 ml) was added solid triphosgene (120 mg) in one portion, under a nitrogen atmosphere. After 5 minutes of stirring, anhydrous triethylamine (505 μl) was added dropwise and the mixture was allowed to warm to 17° C. over 15 minutes. The reaction mixture was recooled to 0° C. and a solution of Intermediate 3 (225 mg) in anhydrous tetrahydrofuran (5 ml) was added dropwise via cannula over 4 minutes. After being stirred at 0° C. for 15 minutes, the mixture was allowed to warm to room temperature and stirred for a further 2 hours before a white precipitate was removed by filtration and the solvent was evaporated under reduced pressure. The remaining residue was partitioned between ethyl acetate (200 ml) and 10% aqueous citric acid (2×40 ml) and the organic phase was then washed with brine (1×40 ml), dried (Na2SO4) and concentrated to a yellow solid. Flash chromatography (silica gel, dichloromethane-methanol, 90:10) afforded the title compound (336 mg) as a solid; mp 222°-225° C. (methanol; decomposition); [α]D23 +15.9° (c=0.71, dimethylformamide); the spectroscopic properties (1H-NMR and MS spectra) of this material were identical to those described for its racemate (Example 3). (Found: C, 61.92; H, 5.87; N, 25.96. C25 H29N9O2 requires: C, 61.59; H, 6.00; N, 25.86%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([C:13]([F:16])([F:15])[F:14])[CH:5]=1)([O-])=O.[CH3:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[NH2:1][C:4]1[CH:12]=[CH:11][C:7]([C:8]([N:28]2[CH2:29][CH2:30][N:25]([C:19]3[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:18]=3[CH3:17])[CH2:26][CH2:27]2)=[O:10])=[C:6]([C:13]([F:16])([F:15])[F:14])[CH:5]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1C(F)(F)F
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N)cc3C(F)(F)F)CC2)c(C)c1
Yield: 106.3 %

Procedure:
Using 4-nitro-2-trifluoromethylbenzoic acid (500 mg) and 1-(2,4-dimethylphenyl)piperazine (403 mg) and by the reaction and treatment in the same manner as in Preparation Example 148, the title compound (850 mg) was obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:39][CH3:40])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][NH:21][C:22]2[N:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:24][N:23]=2)[CH:9]=1)([CH3:3])[CH3:2].[Cl:41][C:42]1[CH:47]=[C:46]([CH2:48]Cl)[CH:45]=[C:44]([Cl:50])[CH:43]=1.[H-].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[Cl:41][C:42]1[CH:47]=[C:46]([CH:45]=[C:44]([Cl:50])[CH:43]=1)[CH2:48][N:21]([CH2:20][C:11]1[CH:12]=[C:13]([C:16]([F:19])([F:17])[F:18])[CH:14]=[CH:15][C:10]=1[C:8]1[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[CH:6][C:7]=1[O:39][CH3:40])[C:22]1[N:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:26][N:27]=1
Reactant: ClCc1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNc1ncc(OCCCC(=O)OC(C)(C)C)cn1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(Cl)cc(Cl)c1)c1ncc(OCCCC(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.6 %

Procedure:
Tert-butyl 4-{2-[(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (180 mg) is dissolved in N,N-dimethylformamide (1.0 ml), and thereto is added 1,3-dichloro-5-chloromethyl-benzene (252 mg), followed by an addition of sodium hydride (60%) (34 mg) under ice-cooling and the mixture is stirred at room temperature for 3 hours. To the reaction solution are added a saturated brine, and the mixture is extracted with ethyl acetate, and the organic layer is dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→9:1) to give tert-butyl 4-{2-[(3,5-dichloro-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (184 mg). MS (m/z): 720/718 [M+H]+
Reaction SMILES: [C:1]([O:18]N1C(=O)CCC1=O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C(N(CC)CC)C.Cl>CN(C=O)C.O>[NH:26]([C:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:18])[CH2:27][C:28]([OH:30])=[O:29]
Reactant: NCC(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)NCC(=O)O
Yield: 49.4 %

Procedure:
A total amount (260.3 g) of N-palmitoyloxy-succinimide synthesized above was suspended in 750 ml of DMF. To the suspension, a solution of Gly (56.3 g, 0.750 mol) and triethylamine (83.2 ml, 0.598 mol) in 250 ml of water was added dropwise with stirring while cooling with ice. The whole was stirred for 30 minutes while cooled with ice, then allowed to gradually reach room temperature, and stirred for 15 hours. An aqueous solution with pH 3 that was prepared by dissolving 100 ml of 6N hydrochloric acid in 1 L of water was stirred while cooled with ice. The reaction solution containing N-palmitoyloxy-succinimide was added dropwise to the aqueous solution. The precipitated solid was collected by filtration. The precipitated solid was washed with 2 L of water and then 1 L of hexane, and recovered to give 114 g (67%) of a target compound.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]2[CH:24]=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[C:29]([O:42][CH3:43])[CH:28]=3)[S:26][C:19]=12)[NH2:13].C(N(CC)CC)C>ClCCl>[F:9][C:10]1[CH:11]=[C:12]([NH:13][C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:14]=[CH:15][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]2[CH:24]=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)=[C:29]([O:42][CH3:43])[CH:28]=3)[S:26][C:19]=12
Reactant: CCOC(=O)C(=O)Cl
Reactant: COc1cc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)ccc1OCCN1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)Nc1ccc(Oc2ccnc3cc(-c4ccc(OCCN5CCOCC5)c(OC)c4)sc23)c(F)c1
Temperature: 25 °C
Yield: 47.4 %

Procedure:
Ethyl chlorooxoacetate (0.11 mL, 0.95 mmol) was added to a solution of the amine 139 (313 mg, 0.63 mmol) and triethylamine (0.18 mL, 1.26 mmol) in dichloromethane (16 mL). The reaction mixture was stirred at room temperature until completion of the reaction. The mixture was quenched with a saturated aqueous solution of ammonium chloride and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and evaporated. The crude product was purified by flash chromatography (eluent: 5% MeOH/95% DCM to 7% MeOH/93% DCM) to afford title compound 140 as a yellow solid (178 mg, 47% yield). MS (m/z): 596.1 (M+H).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][CH3:8].[Li]CCCC.CN([CH:17]=[O:18])C>C(OCC)C>[CH2:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH:17]=[O:18])[CH3:8]
Reactant: CN(C)C=O
Reactant: CCc1sccc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCc1sccc1C=O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 25 %

Procedure:
A solution of 3-bromo-2-ethylthiophene, A7, (8.9 g, 0.0465 mol) in 50 mL of diethyl ether was cooled to -78° C., and a solution of n-BuLi (29.0 mL, 1.6M) in hexanes was added dropwise. When the addition was complete, the reaction was stirred at -78° C. for 5 min. Then DMF (5.1 g, 0.070 mol) was cannulated into the reaction mixture which was allowed to warm to ambient temperature and was stirred overnight. The reaction was quenched with water and extracted twice with diethyl ether. The organic extracts were combined, washed with twice with water and then brine and dried (MgSO4). The solution was filtered and concentrated to provide an oil which was purified on flash silica gel with 97.5:2.5 hexanes:diethyl ether to give 1.66 g (25%) of 2-ethylthiophene-3-carboxaldehyde, B7. The 1H NMR in CDCl3 supported the desired product structure. ##STR55##
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:21][C:22]([NH2:24])=[S:23].C([O-])(=O)C.[Na+].O>C(O)C.O1CCCC1>[NH2:24][C:22]1[S:23][CH:2]=[C:3]([C:4](=[N:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:21]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(=NOCc1ccc(F)cc1)C(=O)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(=NOCc1ccc(F)cc1)c1csc(N)n1
Yield: 90.1 %

Procedure:
Ethyl 4-chloro-2-(4-fluorobenzyloxyimino)-3-oxobutyrate (syn isomer, 29.0 g.), thiourea (8.8 g.), sodium acetate (7.9 g.), water (72.5 ml.), tetrahydrofuran (60 ml.) and ethanol (72.5 ml.) were treated in a similar manner to that of Example C-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-(4-fluorobenzyloxyimino)acetate (syn isomer, 28.0 g.).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]2[O:14][CH2:15][C:16]3([CH2:18][CH2:17]3)[N:7]3[C:8]=2[C:3]=1[C:4](=[O:21])[C:5]([C:19]#[N:20])=[CH:6]3.[NH:22]1[CH:26]=[CH:25][C:24](CCCN)=[N:23]1>>[N:23]1([CH2:4][CH2:3][CH2:2][NH:1][C:10]2[C:9]3[O:14][CH2:15][C:16]4([CH2:17][CH2:18]4)[N:7]4[C:8]=3[C:3]([C:4](=[O:21])[C:5]([C:19]#[N:20])=[CH:6]4)=[C:2]([NH2:1])[C:11]=2[F:12])[CH:24]=[CH:25][CH:26]=[N:22]1
Reactant: N#Cc1cn2c3c(c(F)c(F)c(N)c3c1=O)OCC21CC1
Reactant: NCCCc1cc[nH]n1
Product: N#Cc1cn2c3c(c(NCCCn4cccn4)c(F)c(N)c3c1=O)OCC21CC1

Procedure:
The title compound was prepared from 8-amino-9,10-difluoro-7-oxo-2,7-dihydrospiro[[1,4]oxazino[2,3,4-ij]quinoline-3,1′-cyclopropane]-6-carbonitrile and pyrazolepropylamine using synthetic procedures similar to those described in the examples above. 1H-NMR (400 MHz, DMSO-d6) δ 1.16 (2H, t), 1.58 (2H, t), 1.99 (2H, m), 3.65 (2H, m), 4.16 (2H, s), 4.26 (2H, m), 6.29 (1H, s), 7.49 (1H, s), 7.63 (1H, s), 8.04 (1H, s). MS (EP) m/z: 395 (M++1). (Calcd for C20H19FN6O2, 394.40).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.C([O-])([O-])=O.[K+].[K+].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:22]1[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2Cl)CC1
Temperature: 100 °C
Yield: 83.4 %

Procedure:
3-Chloro-4-fluoronitrobenzene (2.0 g, 11.4 mmol) was added to a stirred suspension of K2CO3 (1.6 g, 11.4 mmol) and N-methylpiperazine (1.3 mL, 1.17 g, 11.4 mmol) in dry DMSO (8 mL) and was heated at 100° C. for 1 h. The reaction was cooled to about 50° C. and poured into ice water (300 mL). The solid was collected by filtration, washed with water, and dried under vacuum to afford the title compound (2.43 g, 84%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:20][CH2:21][O:22][CH3:23]>CN(C=O)C>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:20][CH2:21][O:22][CH3:23])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1cc(C=O)c(F)cc1O
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCOc1cc(F)c(C=O)cc1OC
Reaction time: 86 h

Procedure:
2-Fluoro-4-hydroxy-5-methoxy-benzaldehyde (0.500 g, 2.94 mmol) was dissolved in DMF (2.6 mL) containing Cs2CO3 (2.88 g, 8.82 mmol). 1-Bromo-2-methoxy-ethane (1.23 g, 828 μL, 8.82 mmol) was added and the reaction mixture was allowed to stir for 86 h. The reaction mixture was filtered and the filtrate was evaporated to dryness to give 2-fluoro-5-methoxy-4-(2-methoxyethoxy)benzaldehyde. ESI-MS m/z calc. 228.1. found 229.0 (M+1)+. Retention time: 1.14 minutes (3 min run).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:17]2=[O:32])=[CH:12][CH:11]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:1][C:16]1([C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:17]1=[O:32]
Reactant: O=C1c2cccc(-c3ccccc3)c2C(=O)C1c1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: O=C1c2cccc(-c3ccccc3)c2C(=O)C1(Br)c1ccc(Cl)cc1
Reaction time: 0.25 h

Procedure:
N-bromosuccinimide (0.3 g ) was added portionwise over 15 minutes to a stirred solution of 2-(p-chlorophenyl)-4-phenylindane-1,3-dione (0.5 g) containing benzoyl peroxide (0.01 g) at ambient temperature and the reaction was allowed to stir for a further 15 minutes. The solvent was removed under reduced pressure and the crude product was chromatographed on silica. The fraction eluted with toluene was recrystallised from diethyl etherhexane to give 2-bromo-2-(p-chlorophenyl)-4-phenylindane-1,3-dione, m.p. 121-123.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[N:14][C:15]([O:22][CH3:23])=[C:16](I)[CH:17]=3)[N:12]([CH3:24])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:56]([OH:58])[CH3:57].C(N(CC)CC)C.CN([CH:69]=[O:70])C>C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[CH:17]=[C:16]([C:69]([O:58][CH2:56][CH3:57])=[O:70])[C:15]([O:22][CH3:23])=[N:14][C:13]=3[N:12]([CH3:24])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: COc1nc2c(cc1I)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2nc1OC
Temperature: 80 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
N-(4-Chlorobenzyl)-6-iodo-7-methoxy-1-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxamide (700 mg), palladium acetate (32 mg), DPPP (60 mg), ethanol (10 mL) and triethylamine (1 mL) are dissolved in DMF (20 mL) in a steel bomb. The bomb is flushed with CO (3×) and then pressured with CO (400 psi) and the resulting reaction is stirred at 80° C. for 24 h, cooled to room temperature and diluted with CH2Cl2. The organic is washed with water, 1N HCl, brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography (CH2Cl2/MeOH 1/0, 45/1) and then triturated with MeOH to afford 472 mg (76%) of ethyl 6-{[(4-chlorobenzyl)amino]carbonyl}-2-methoxy-8-methyl-5-oxo-5,8-dihydro[1,8]naphthyridine-3-carboxylate. Physical characteristics are as follows: 1H NMR (CDCl3) δ 10.26-10.23, 9.18, 8.85, 7.32, 4.65, 4.40, 4.19, 4.00, 1.41; 13C NMR (CDCl3) δ 176.33, 164.24, 163.76, 163.28, 150.17, 148.34, 142.24, 137.17, 132.94, 129.00, 128.73, 116.32, 113.96, 113.29, 61.57, 55.17, 42.86, 39.17, 14.24; IR (diffuse reflectance) 1965, 1727, 1663, 1609, 1568, 1542, 1514, 1493, 1466, 1390, 1297, 1260, 1141, 813, 799, cm−1; MS (EI) m/z 429 (M+), 431, 430, 429, 289, 263, 262, 261, 159, 140, 77; Anal. calcd for C21H20ClN3O5: C, 58.68; H, 4.69; N, 9.77; Cl, 8.25. Found: C, 58.39; H, 4.70; N, 9.71.