Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.Br[C:7]1[S:11][C:10]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[N:9][CH:8]=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:29])(=O)=O)=CC=1.O>C1COCC1>[F:29][C:7]1[S:11][C:10]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[N:9][CH:8]=1
Reactant: O=C(Nc1ncc(Br)s1)C(F)(F)F
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ncc(F)s1)C(F)(F)F
Temperature: -30 °C
Reaction time: 1.5 h

Procedure:
NEt3 (63.4 mL, 455 mmol) was added to a stirred suspension of 5-bromothiazol-2-ylamine hydrobromide (102.7 g, 379 mmol) in CH2Cl2 (1.5 L). After 1 h, TFAA (64.2 mL, 455 mmol) was added dropwise at 0° C. over 15 min. The mixture was allowed to warm to 20° C. over 1 h, before being stirred for an additional 2 h. H2O (600 mL) was added and the resulting precipitate was collected. The aqueous layer of the filtrate was separated and extracted with CHCl3 (3×300 mL). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The collected precipitate and residual solid were combined and triturated with EtOAc-n-C6H14 to give N-(5-bromothiazol-2-yl)-2,2,2-trifluoroacetamide: δH (CDCl3): 7.45 (1H, s), 13.05 (1H, br). n-BuLi (253 mL of a 1.58M solution in hexanes, 403 mmol) was added dropwise over 50 min to a stirred solution of the above amide (50.0 g, 183 mmol) in anhydrous THF (1.3 L) at −78° C. After 1.5 h, a solution of N-fluorobenzenesulphonimide (86.0 g, 275 mmol) in anhydrous THF (250 mL) was added dropwise over 30 min. The mixture was stirred for 3 h, before being warmed up to −30° C. H2O (300 mL) was added and the mixture was filtered through a Celite pad. The solid collected and Celite were washed with Et2O (400 mL) and H2O (400 mL). The organic layer of the filtrate was separated and extracted with water (2×400 mL). The combined aqueous layers were washed with Et2O (400 mL), before being acidified to pH 6.5 with 2M HCl and extracted with EtOAc (2×400 mL). The combined organic extracts were washed with H2O (2×400 mL) and brine, before being dried (MgSO4), filtered and concentrated. Column chromatography (EtOAc-n-C6H14, 1:3 to 1:2) gave N-(5-fluorothiazol-2-yl)-2,2,2-trifluoroacetamide: δH (CDCl3): 7.13 (1H, d). AcCl (12.6 mL, 175 mmol) was added dropwise to a stirred solution of this amide (15.7 g, 73 mmol) in MeOH (300 mL) at 0° C. The mixture was stirred at 20° C. for 30 min, heated under reflux for 1 h, and finally concentrated in vacuo. The residual solid was triturated with THF to give the title compound: δH (D2O): 7.00 (1H, d).
Reaction SMILES: O.[OH-].[Li+].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26](=[O:36])[NH:27][CH2:28][C@H:29]([CH3:35])[CH2:30][C:31]([F:34])([F:33])[F:32])[CH:24]=2)[N:19]([CH3:37])[CH:18]=1)[C:9]([O:11]C)=[O:10]>O.CO>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26](=[O:36])[NH:27][CH2:28][C@H:29]([CH3:35])[CH2:30][C:31]([F:33])([F:32])[F:34])[CH:24]=2)[N:19]([CH3:37])[CH:18]=1)[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(C(=O)NC[C@H](C)CC(F)(F)F)cc23)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Cc1cn(C)c2ccc(C(=O)NC[C@H](C)CC(F)(F)F)cc12
Yield: 102.3 %

Procedure:
A solution of lithium hydroxide monohydrate (7.68 g) in water (50 mL) was added to a stirred solution of methyl (R)-3-methoxy-4-[1-methyl-5-(2-methyl-4,4,4-trifluorobutylcarbamoyl)indol-3-ylmethyl]benzoate (14.38 g) in methanol (120 mL) and distilled tetrahydrofuran (120 mL) under an inert atmosphere. After 18 h the solvent was evaporated, the residue was dissolved in water (250 mL) and distilled tetrahydrofuran (23 mL), acidified to pH 1 by addition of concentrated hydrochloric acid, and diluted with water (150 mL). The precipitate was collected and washed with water to give (R)-3-methoxy-4-[1-methyl-5-(2-methyl-4,4,4-trifluorobutylcarbamoyl)indol-3-ylmethyl]benzoic acid (14.28 g, 100%); mp 218°-223° C.; partial NMR (300 MHz, DMSO-d6): 1.00 (d, 3H, CH3), 2.04-2.28 (m, 2H, CF3CH2), 2.32-2.44 (m, 1H, CHCH3), 3.21 (br t, 2H, CH2N), 3.76 (s, 3H, NCH3), 3.90 (s, 3H, OCH3), 4.07 (s, 2H, ArCH2Ar'), 8.43 (br t, 1H, NHCO).
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].C(=O)([O-])[O-].[Na+].[Na+].[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[NH:33][C:32](=O)[CH2:31][S:30][CH2:29]2)=[CH:24][CH:23]=1>C1COCC1>[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[NH:33][C:32](=[S:2])[CH2:31][S:30][CH2:29]2)=[CH:24][CH:23]=1
Reactant: O=C1CSCC(c2ccc(F)cc2)N1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccc(C2CSCC(=S)N2)cc1
Temperature: 25 °C
Yield: 63 %

Procedure:
A mixture of phosphorus pentasulfide (5.12 g, 11.5 mmol) and sodium carbonate (1.22 g, 11.5 mmol) in THF (30 mL) was stirred at room temperature. A solution of 5-(4-fluoro-phenyl)-thiomorpholin-3-one (2.0 g, 9.5 mmol) in THF (25 mL) was slowly added, and the mixture was stirred at room temperature for 90 minutes. The mixture was diluted with 10% aqueous Na3PO4 solution (40 mL), and stirred at room temperature for five minutes. The mixture was extracted with a 1:4 mixture of ethyl acetate and diethyl ether, and the organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. Elution of the residue through silica (15-20% ethyl acetate/hexanes) gave 1.36 g of 5-(4-fluoro-phenyl)-thiomorpholine-3-thione, MP=107-108° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]([C:22]2[C:23](=[O:35])[N:24]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[N:25]=[CH:26][CH:27]=2)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](I)[S:17][C:10]=12.[CH3:36][N:37]1[CH:41]=[CH:40][N:39]=[C:38]1[Sn](CCCC)(CCCC)CCCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]([C:22]2[C:23](=[O:35])[N:24]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[N:25]=[CH:26][CH:27]=2)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:38]3[N:37]([CH3:36])[CH:41]=[CH:40][N:39]=3)[S:17][C:10]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1C
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cn1ccnc1-c1cc2nccc(Oc3ccc(NC(=O)c4ccnn(-c5ccc(F)cc5)c4=O)cc3F)c2s1
Temperature: 100 °C
Yield: 75.2 %

Procedure:
A round-bottomed flask was charged with N-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (230 mg, 0.382 mmol), 1-methyl-2-(tributylstannyl)-1H-imidazole (850.3 mg, 2.29 mmol), tetrakis(triphenylphosphine)palladium (88.25 mg, 0.0764 mmol) and toluene (25 mL). The reaction mixture was stirred at 100° C. until LC-MS showed that the starting material had been consumed (4 hours). Then the reaction was cooled to room temperature and partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to afford product (159.8 mg, 75.2%). LRMS (APCI pos): >99% purity, 254 nm, m/e 557 (M+1). 1H NMR (400 MHz, CDCl3) δ 11.82 (s, 1H), 8.50 (m, 1H), 8.41 (m, 1H), 8.22 (m, 1H), 7.98 (m, 1H), 7.46-7.42 (m, 4H), 7.40 (m, 2H), 7.24 (m, 2H), 6.98 (d, 1H), 6.54 (m, 1H), 3.84 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[OH-].[Na+].[CH:13]1[C:18](=[O:19])[C:17]([OH:20])=[CH:16][O:15][C:14]=1[CH2:21]Cl>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:21][C:14]1[O:15][CH:16]=[C:17]([OH:20])[C:18](=[O:19])[CH:13]=1)=[O:6]
Reactant: O=c1cc(CCl)occ1O
Reactant: O=C(O)c1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(OCc1cc(=O)c(O)co1)c1cccc(O)c1
Yield: 54.9 %

Procedure:
By following the procedure of Example 1 by employing 1.39 g(10.1 mmole) of 3-hydroxybenzoic acid, 0.4 g (10.1 mmole) of sodium hydroxide and 1.46 g(9.1 mmole) of chlorokojic acid, there was obtained 1.31 g(55.1%) of 2-(3-hydroxybenzoyl) oxymethyl-5-hydroxy-4H-pyran-4-one as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][N:11]([C:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])[CH2:10][CH:9]2[N:21]([CH3:36])[C:22](=[O:35])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=2)=[CH:4][CH:3]=1.[CH:37](=O)[CH3:38]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][N:11]([C:13]([CH:15]3[CH2:20][CH2:19][N:18]([CH2:37][CH3:38])[CH2:17][CH2:16]3)=[O:14])[CH2:10][CH:9]2[N:21]([CH3:36])[C:22](=[O:35])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([C:31]([F:33])([F:32])[F:34])[CH:24]=2)=[CH:6][CH:7]=1
Reactant: CC=O
Reactant: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCNCC3)CC2c2ccc(Cl)cc2)cc1C(F)(F)F
Product: CCN1CCC(C(=O)N2CC(c3ccc(Cl)cc3)C(N(C)C(=O)c3ccc(OC)c(C(F)(F)F)c3)C2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 104, the title compound N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(1-ethyl-piperidine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide was prepared from N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using acetaldehyde instead of acetone and was obtained as a light brown oil. MS m/e: 552.2 [M]+.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[CH:22]=[CH:23][C:24]2[N:25]([C:27]([CH:30]([F:32])[F:31])=[N:28][N:29]=2)[N:26]=1>>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:27]([CH:30]([F:31])[F:32])=[N:28][N:29]=3)[N:26]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: FC(F)c1nnc2ccc(Cl)nn12
Product: FC(F)c1nnc2ccc(N3CCN(C(c4ccccc4)c4ccccc4)CC3)nn12

Procedure:
A mixture of 1-benzhydrylpiperazine and 6-chloro-3-difluoromethyl-1,2,4-triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 1 to give 6-(4-benzhydrylpiperazin-1-yl)-3-(difluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][CH:7]=1>O.CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:11](=[O:13])[CH2:10][C:9]([CH3:15])([CH3:14])[S:8][C:4]=2[CH:3]=1
Reactant: CC(C)(CC(=O)O)Sc1cccc(Cl)c1
Solvent: O
Solvent: CCOCC
Product: CC1(C)CC(=O)c2ccc(Cl)cc2S1
Temperature: 70 °C
Yield: 87.3 %

Procedure:
To 270 g of polyphosphoric acid heated to 70° C. was added, portionwise, 31.9 g of the product from Step A over 15 min with mechanical stirring under a nitrogen atmosphere. After heating at 70° C. for an additional 45 min, the reaction mixture was cooled to 0° C. and 150 ml of water was carefully added followed by 100 ml of ether. The resulting mixture was further diluted with 170 ml of water and 110 ml of ether. The layers were separated and the aqueous layer was extracted with ether (2×200 ml). The combined ether layers were washed with 100 ml of 1N NaOH and were then dried (MgSO4) and concentrated under reduced pressure to give 25.8 g of a yellow solid. The 1H NMR was consistent with a 68:32 mixture of the structure for Step B and its 5-chloro isomer, respectively.
Reaction SMILES: [CH:1](NC1CCCCC1)(C)C.C([Li])CCC.[CH2:16]([CH:19]1[N:22]([C:23]([C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:44])=[P:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21](=[O:53])[CH2:20]1)[CH:17]=[CH2:18]>O1CCCC1.CCCCCC>[CH2:16]([CH:19]1[N:22]([C:23]([C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:44])=[P:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:21](=[O:53])[CH:20]1[CH3:1])[CH:17]=[CH2:18]
Reactant: CC(C)NC1CCCCC1
Reactant: C=CCC1CC(=O)N1C(C(=O)OCc1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCC1C(C)C(=O)N1C(C(=O)OCc1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.17 h

Procedure:
A solution of N-isopropylcyclohexylamine (0.30 g) in dry tetrahydrofuran (5 ml) was stirred under argon and cooled to -78°. This was treated with a 2.5 M solution of n-butyl lithium in hexane (0.85 ml) and stirred for 10 minutes. A solution of 4-allyl-1-(1-benzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)azetidine-2-one (9) (0.50 g) in tetrahydrofuran (5 ml) was added and after 5 minutes the anion was quenched by addition of methyl iodide (0.12 ml). After a period of 10 minutes the reaction vessel was transferred to an ice bath and a further 10 minutes later the reaction was neutralized by addition of acetic acid (0.16 ml). The solvent was then stripped off and the residue partitioned between ethyl acetate and brine. The ethyl acetate solution was separated, washed with brine and dried over sodium sulphate. The product was subjected to careful column chromatography on silica gel 60 eluting with cyclohexane/ethyl acetate mixtures grading from 1:1 to 3:7. This gave 4-allyl-3-methyl-1-(1-benzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)azetidine-2-one (38) (0.10 g, 19%); νmax (CHCl3) 3000, 1735 and 1610 cm-1. Running closely behind this was recovered starting phosphorane (9) (0.17 g. 33%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C(N(CC)CC)C.[Br:19][C:20]([CH3:25])([CH3:24])[C:21](Br)=[O:22]>C1(C)C=CC=CC=1>[Br:19][C:20]([CH3:25])([CH3:24])[C:21]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8])=[O:22]
Reactant: CC(C)(Br)C(=O)Br
Reactant: Nc1ccc(O)c(C(=O)O)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(Br)C(=O)Nc1ccc(O)c(C(=O)O)c1

Procedure:
To a suspension of 5-amino-2-hydroxybenzoic acid (3.0 g, 19.6 mmol) in a solution of freshly distilled triethylamine (4.1 mL, 29.4 mmol, 1.5 eq.) in 100 mL of anhydrous toluene was added dropwise 2-bromoisobutyryl bromide (6.8 mL, 53.8 mmol). Addition was performed at 0° C. under inert atmosphere. The mixture was then refluxed for 15 hours. Volatiles were removed under vacuum leaving oily crude materials. The product initiator C was extracted with ethanol concentrated and crystallized at −30° C. Yield: 30%. Analysis: 1H NMR (CDCl3, 300 MHz, 298 K): δ 9.81 (s broad, 3H, NHCO and OH), 8.24 (s, 1H, Hortho), 7.76 (d, 1J=10.5 Hz, 1H, Hmeta), 6.82 (d, 1J=9.8 Hz, 1H, Hpara), 2.10 (s, 6H, Me). 13C NMR (CDCl3, 125 MHz, 298 K): δ 170.6 (CO—N), 167.2 (CO—O), 160.0 (C(aromatic)-OH), 130.8 (C(aromatic)-NH), 124.1 (C(aromatic)-H), 122.2 (C(aromatic)-H), 118.6 (C(aromatic)-H), 114.2 (C(aromatic)-CO2H), 58.9 (C—Br), 33.6 (CH3), confirming the product to be 5-(2-bromo-2-methylpropanamido)-2-hydroxybenzoic acid initiator (initiator C).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[OH:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:24][C:25]1[CH:30]=[CH:29][C:28]([S:31][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)=[CH:4][C:3]=2[N+:21]([O-:23])=[O:22])=[CH:27][CH:26]=1
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1cccc(C(F)(F)F)c1
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of the product of Example 114A (2.00 g, 5.80 mmol), 4-hydroxythiophenol (0.732 g, 5.80 mmol) and potassium carbonate (1.604 g, 11.6 mmol) in N,N-dimethylformamide (40 mL) was heated to 80° C. for 2 hours. After cooling to room temperature the mixture was poured into ice water (100 mL). The solution was then extracted with ethyl acetate (3×150 mL), the combined extracts dried over magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (2.52 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12](=[O:13])[C:9]3([CH2:11][CH2:10]3)[O:8][C:7]=2[CH:14]=1.C(OC(=O)C)(=O)C.[N+:22]([O-])([OH:24])=[O:23]>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:4]([N+:22]([O-:24])=[O:23])=[CH:5][C:6]2[C:12](=[O:13])[C:9]3([CH2:10][CH2:11]3)[O:8][C:7]=2[CH:14]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc2c(c1)OC1(CC1)C2=O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COc1cc2c(cc1[N+](=O)[O-])C(=O)C1(CC1)O2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5.4 g. of 6-Methoxyspiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one was dissolved in a mixture of 25 ml. of acetic anhydride and 7 ml. of glacial acetic acid. While keeping the reaction temperature at 10°-15° C., 3 ml. of fuming nitric acid (d=1.52) was added dropwise to the mixture. After stirring for 30 minutes, the reaction mixture was poured into ice-water. The resulting precipitates were collected by filtration, washed with water and recrystallized from ethanol. By the above procedure, there was obtained 6-methoxy-5-nitrospiro[benzo[b]furan-2(3H), 1'-cyclopropane]-3-one as pale yellow prisms melting at 160°-163° C. Yield: 4.5 g.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[Br:6][C:7]1[CH:12]=[CH:11][C:10](F)=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=1.Cl>CS(C)=O>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=1
Reactant: CCCCN
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: Cl
Solvent: CS(C)=O
Product: CCCCNc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 70 °C

Procedure:
A solution of butylamine (1.25 g, 17.1 mmol) in DMSO (14 mL) was treated with 4-bromo-1-fluoro-2-nitrobenzene (1.50 g, 6.82 mmol), heated to 70° C. for 1 hour, added to 1M HCl (60 mL), and extracted with diethyl ether (3×75 mL). The combined extracts were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated to provide the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[CH:24]=[O:25]>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:24]=[O:25])([O-:3])=[O:2]
Reactant: CN(C)C=O
Reactant: O=[N+]([O-])c1ccccc1-n1cccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cccn1-c1ccccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3.76 g of 1-(2-nitrophenyl)pyrrole in 20 ml of N,N-dimethylformamide at 0° C. is added dropwise with stirring 3 ml of phosphorus oxychloride. Stirring is continued for 30 minutes and the reaction mixture is heated at 90° C. for 1 hour. After cooling to room temperature the mixture is treated with crushed ice and the pH adjusted to 12 with 2N sodium hydroxide. The resulting suspension is filtered, washed with water and dried to give 5.81 g of the desired product as a light yellow solid, m.p. 119°-122° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18]([OH:20])=O)[C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:8][N:9]=2.[CH3:21][NH2:22]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18]([NH:22][CH3:21])=[O:20])[C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:8][N:9]=2
Reactant: O=C(O)Cc1cc(Cl)cc2c(-c3ccccc3)onc12
Reactant: CN
Product: CNC(=O)Cc1cc(Cl)cc2c(-c3ccccc3)onc12

Procedure:
The title compound is prepared by reacting the acid chloride of 5-chloro-3-phenyl-2,1-benzisoxazole-7-acetic acid and excess monomethylamine in a closed container in an aprotic solvent. The unused methylamine is allowed to escape and the solution is washed with hydrochloric acid followed by aqueous base and evaporated. The title compound is obtained by conventional crystallization from alkanolic solution or by chromatography.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:13][CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25]CC)=[O:24])=[CH:19][N:18]=2)[C:9]([O:28][CH3:29])=[C:8]2[C:3]=1[C:4](=[O:33])[CH:5]=[CH:6][N:7]2[CH:30]1[CH2:32][CH2:31]1.Cl>CCO.[OH-].[Na+].O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:13][CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][N:18]=2)[C:9]([O:28][CH3:29])=[C:8]2[C:3]=1[C:4](=[O:33])[CH:5]=[CH:6][N:7]2[CH:30]1[CH2:32][CH2:31]1
Reactant: CCOC(=O)c1ccc(NCCNc2c(F)c(N)c3c(=O)ccn(C4CC4)c3c2OC)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1c(NCCNc2ccc(C(=O)O)cn2)c(F)c(N)c2c(=O)ccn(C3CC3)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 38.3 %

Procedure:
To a solution of ethyl 2-[2-[(5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinolin-7-yl)amino]ethylamino]pyridine-5-carboxylate (320 mg, 0.703 mmol) in EtOH (8 mL), 1M aq. NaOH was added. The mixture was stirred at room temperature for 5 h and then stirred at 50° C. for 3 h. After cooling, the reaction mixture was diluted with water (30 mL) and neutralized with 1M HCl. The product was extracted with CH2Cl2-MeOH (5:1, 2×50 mL). The extaction mixture was dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in a mixture of MeOH (50 mL) and water (50 mL), and the solution was concentrated in vacuo until ca. 30 mL. The resulting precipitate was collected by filtration, washed with water and dried to give 2-[2-[(5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinolin-7-yl)amino]ethylamino]pyridine-5-carboxylic acid (115 mg, 38%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1.[CH3:19][N:20]([CH3:40])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:29]([CH:37]=O)[NH:28][C:27]=1[CH3:39])=[O:25]>>[CH3:19][N:20]([CH3:40])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:29]([CH:37]=[C:13]2[C:12]3[C:16](=[CH:17][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[CH:10][CH:11]=3)[NH:15][C:14]2=[O:18])[NH:28][C:27]=1[CH3:39])=[O:25]
Reactant: COc1ccccc1-c1ccc2c(c1)NC(=O)C2
Reactant: Cc1[nH]c(C=O)c(-c2ccccc2)c1C(=O)NCCN(C)C
Product: COc1ccccc1-c1ccc2c(c1)NC(=O)C2=Cc1[nH]c(C)c(C(=O)NCCN(C)C)c1-c1ccccc1
Yield: 44.2 %

Procedure:
6-(2-Methoxyphenyl)-1,3-dihydroindol-2-one (53 mg, 0.22 mmol) was condensed with 5-formyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid (2-dimethylaminoethyl)amide (65 mg) to give 0.05 g (44%) of the title compound as an orange gum.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]=[CH:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:14](#[N:16])[CH3:15]>CC([O-])=O.CC([O-])=O.[Cu+2].CC(OC)(C)C.CCOC(C)=O>[CH3:1][O:2][C:3]([C:4]1[C:14]([CH3:15])=[N:16][N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=1)=[O:13]
Reactant: CC#N
Reactant: COC(=O)C=CNc1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: COC(C)(C)C
Product: COC(=O)c1cn(-c2ccccc2)nc1C

Procedure:
According to AVV A, 3-phenylamino acrylic acid methylester (197) (177.2 mg, 1.0 mmol, 1.0 equiv.) was stirred with Cu(OAc)2 (544.9 mg, 3.0 mmol, 3.0 equiv.) into acetonitrile (3.0 ml, 57.1 mmol, 57.1 equiv.) for 22 hours at 110° C. The greenish solid obtained as raw product (242.4 mg) was purified by means of column chromatography (silica gel (50 g), pentane/MTBE 95:5→0:100, then MTBE/EtOAc 100:0→0:100), whereby the desired product was obtained in the form of a yellowish solid (35.1 mg, 0.16 mmol, 16%).