Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH3:10].[CH2:11](CN)[OH:12]>>[OH:12][CH2:11][CH2:9][N:4]1[CH:5]=[CH:6][C:7](=[O:8])[C:2]([OH:1])=[C:3]1[CH3:10]
Reactant: NCCO
Reactant: Cc1c(O)c(=O)ccn1C
Product: Cc1c(O)c(=O)ccn1CCO

Procedure:
A reaction analogous to that used for the synthesis of 3-hydroxy-1,2-dimethyl-4- pyridinone was employed, starting with ethanolamine (0.44 g). No precipitate was observed after concentration. Recrystallization from ethanol and diethyl ether resulted in a white powder (0.53 g). Proton NMR (D20): 7.82 (d, 1H), 6.89 (d, 1H), 4.27 (t, 2H), 3.74 (t, 2H), 2.36 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][NH2:5].O=[C:7]([CH2:13][C:14](=O)[CH3:15])[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(N1C(CC)=CC(C(O)=O)=N1)C>C(Cl)Cl>[OH:1][CH2:2][CH2:3][N:4]1[C:14]([CH3:15])=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:5]1
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: NNCCO
Agent: CCc1cc(C(=O)O)nn1CC
Solvent: ClCCl
Product: CCOC(=O)c1cc(C)n(CCO)n1

Procedure:
The title compound was prepared from hydroxyethyl hydrazine (3.64 g, 50 mM) and ethyl 2,4-dioxovalerate (8.5 g, 50 mM) as described in Example 1 Preparation 1 as a colourless oil (9.39 g, 95%); νmax (CH2Cl2) 1700 cm-1 ; δH (CDCl3) 1.39 (3H, t, J7 Hz), 2.40 (3H, s), 2.98 (2H, t, J7 Hz), 4.33-4.48 (4H,m), and 6.39 (1H, s); E.I m/e 198 (95%).
Reaction SMILES: O.[NH2:2][NH2:3].[NH2:4][C:5]1[C:12]([I:13])=[CH:11][C:8]([C:9]#[N:10])=[C:7](S(C)=O)[N:6]=1.O>CC(O)C>[I:13][C:12]1[CH:11]=[C:8]2[C:9]([NH2:10])=[N:3][NH:2][C:7]2=[N:6][C:5]=1[NH2:4]
Reactant: NN
Reactant: CS(=O)c1nc(N)c(I)cc1C#N
Solvent: O
Solvent: CC(C)O
Product: Nc1nc2[nH]nc(N)c2cc1I
Temperature: 80 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
275 μl (2 eq) of hydrazine monohydrate is added to a solution of 872 mg (2.84 mmol) of 6-amino-5-iodo-2-(methylsulfinyl)nicotinonitrile in 11 ml of 2-propanol. The reaction medium is stirred at 80° C. for 3 hours. Water is added and the product is extracted with ethyl acetate. The organic phase is dried on magnesium sulfate, filtered and evaporated. The residue is triturated in a minimum of diisopropyl ether. The solid is filtered to yield 523 mg (67%) of 5-iodo-1H-pyrazolo[3,4-b]pyridin-3,6-diamine in the form of a brown powder.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19]([N:24]2[CH2:28][CH:27]([CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:26][C:25]2=[O:37])[CH:20]=[CH:21][C:22]=1[OH:23]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:23][C:22]1[CH:21]=[CH:20][C:19]([N:24]2[CH2:28][CH:27]([CH2:29][O:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:26][C:25]2=[O:37])=[CH:18][C:17]=1[F:16]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C1CC(COc2ccccc2)CN1c1ccc(O)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(N4CC(COc5ccccc5)CC4=O)cc3F)c2cc1OC
Temperature: 180 °C

Procedure:
A mixture of 4-chloro-6,7-dimethoxyquinoline (0.185 g, 0.83 mmol), 1-(3-fluoro-4-hydroxyphenyl)-4-(phenoxymethyl)pyrrolidin-2-one (Step 4, 250 mg, 0.83 mmol) and DMAP (101 mg, 0.83 mmol) in 8 mL of toluene (in a microwave tube) was heated in a microwave (Personal Chemistry, Emrys Optimizer) at 180° C. for 1.5 h. The mixture was cooled to RT and diluted with 50 mL of EtOAc. The solution was washed with 20 mL of satd. NaHCO3 followed by 20 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (50% to 100% EtOAc/hexane) to provide the product as white solid. MS (ESI pos. ion) m/z: 489.3 (M+H). Calc'd Exact Mass for C28H25FN2O5: 488.51.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[C:4]=1[CH:5]=[CH:6][S:7]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:18][CH3:19])=[C:15]([OH:17])[CH:16]=1)(=[O:9])=[O:8].C(Br)(Br)(Br)Br.C(N(CC)CC)C.[P:40]([O-:57])([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(#N)C>[P:40]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)([O:17][C:15]1[CH:16]=[C:11]([CH2:10][S:7](/[CH:6]=[CH:5]/[C:4]2[C:20]([O:26][CH3:27])=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:3]=2[O:2][CH3:1])(=[O:9])=[O:8])[CH:12]=[CH:13][C:14]=1[O:18][CH3:19])=[O:57]
Reactant: COc1cc(OC)c(C=CS(=O)(=O)Cc2ccc(OC)c(O)c2)c(OC)c1
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Agent: BrC(Br)(Br)Br
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2ccc(OC)c(OP(=O)(OCc3ccccc3)OCc3ccccc3)c2)c(OC)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxy-phenol (1.9 g, 4.8 mmol) in acetonitrile (24 mL) at room temperature, was added carbon tetrabromide (1.94 g, 1.22 eq) and triethylamine (0.728 g, 1.5 eq). The resulting mixture was stirred for 10 minutes and than cooled to 0° C. in an ice-water bath. Dibenzyl phosphite (1.51 g, 1.2 eq) dissolved in acetonitrile (16 mL) was added dropwise to the cooled reaction mixture. The reaction mixture was stirred for 2 h and monitored by TLC. The reaction was terminated by dropwise addition of aqueous potassium dihydrogen phosphate (10 mL, 0.5 M). The resulting mixture was extracted with ethyl acetate (3×30 mL). The combined organic extract was dried (Na2SO4) and concentrated in vacuo to yield the desired product.
Reaction SMILES: C(O[C:4]1([O:14]CC)[NH:8][C:7](=[O:9])[C:6]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:5]12)C.Cl.[O:18]1CC[CH2:20][CH2:19]1>>[O:14]=[C:4]1[C:5]2[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7](=[O:9])[N:8]1[CH2:20][CH:19]=[O:18]
Reactant: CCOC1(OCC)NC(=O)c2ccccc21
Reactant: C1CCOC1
Agent: Cl
Product: O=CCN1C(=O)c2ccccc2C1=O
Temperature: 75 °C

Procedure:
To a solution of phthalimide diethylacetal (15 g) in tetrahydrofuran (THF) (30 mL) was added 10% aqueous HCl (18 mL). After heating at 75° C. for 5 hrs, the solution was allowed to cool to room temperature, and ethyl acetate was separated and dried over magnesium sulfate (MgSO4). The solution was filtered and evaporated to provide 11.2 g of the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:24][CH2:25][CH2:26]OS(C1C=CC(C)=CC=1)(=O)=O>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:26][CH2:25][F:24])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Reactant: Oc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: FCCOc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 44.5 h
Yield: 66.5 %

Procedure:
578 mg (corresponding to 2.0 mmol) of 6-bromo-2-(4′-hydroxyphenyl)imidazo[1,2-a]pyridine that was sufficiently dried to remove moisture was dissolved in 20 mL of N,N-dimethylformamide, and 830 mg (corresponding to 6.0 mmol) of potassium carbonate was added thereto. The mixture was supplemented with 510 μL (corresponding to 3.0 mmol) of 2-fluoroethyl-p-toluenesulfonate, and then the solution was stirred at room temperature for 44.5 hours. After the completion of the reaction, the reaction solution was poured into water and extracted three times with chloroform. The combined chloroform layer was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was purified by flash silica gel column chromatography (elution solvent: chloroform/methanol=100/1), by recycle preparative HPLC (HPLC apparatus: LC-908 (under trade name; manufactured by Japan Analytical Industry Co., Ltd.); column: two JAIGEL 2H (under trade name; manufactured by Japan Analytical Industry Co., Ltd.) connected together; mobile phase: chloroform), and further by preparative TLC (elution solvent: chloroform/methanol=50:1) to obtain 446 mg (corresponding to 1.33 mmol) of 6-bromo-2-[4′-(2″-fluoroethoxy)phenyl]imidazo[1,2-a]pyridine (FIG. 1-6, Step 3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[C:7]([NH2:9])[CH:8]=1.N1C=CC=CC=1.[CH2:17]([S:20](Cl)(=[O:22])=[O:21])[CH2:18][CH3:19]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[C:7]([NH:9][S:20]([CH2:17][CH2:18][CH3:19])(=[O:22])=[O:21])[CH:8]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: COc1ccc(C)c(N)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1cc(OC)ccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
To the solution of 5-methoxy-2-methyl-phenylamine (0.118 g, 0.86 mmol) and pyridine (0.1 mL) and CH2Cl2 (3 mL) at 0° C. was added dropwise propane-1-sulfonyl choride (0.135 g, 0.95 mmol) and the reaction mixture was stirred at RT overnight. The mixture was then concentrated and purified via silica gel chromatography to give the product as an oil (0.145 g, 69%): MS(ES) m/e 244.2 [M+H]+.
Reaction SMILES: N(OC(C)(C)C)=O.I[CH2:9][I:10].NC1[S:13][CH:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:16]=1>C(#N)C.[Cl-].[Na+].O>[CH2:20]([O:19][C:17]([C:15]1[N:16]=[C:9]([I:10])[S:13][CH:14]=1)=[O:18])[CH3:21]
Reactant: CCOC(=O)c1csc(N)n1
Reactant: ICI
Agent: CC(C)(C)ON=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1csc(I)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
A solution of 6.0 ml of t-butyl nitrite in 120 ml of acetonitrile was cooled in ice under an argon atmosphere, and 9.64 g of diiodomethane and 5.16 g of 2-amino-4-ethoxycarbonylthiazole were added to the cooled solution. The mixture was stirred at room temperature for one hr, brine was added thereto, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, were washed twice with brine, were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1 to 3:1) to give 5.58 g of 4-ethoxycarbonyl-2-iodothiazole.
Reaction SMILES: [OH:1][C:2]1[O:6][N:5]([CH3:7])[C:4](=[O:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1.[C:24]1(C)C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C>CO.CCCCCC>[CH3:24][O:1][C:2]1[O:6][N:5]([CH3:7])[C:4](=[O:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1
Reactant: COc1cccc(Oc2ccccc2-c2c(O)on(C)c2=O)c1
Reactant: Cc1ccccc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: CO
Product: COc1cccc(Oc2ccccc2-c2c(OC)on(C)c2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
5-Hydroxy-4-[2-(3-methoxyphenoxy)phenyl]-2-methyl-3(2H)-isoxazolone (2.5 g) was dissolved in 3 mL of methanol and 15 mL of toluene and cooled in an icebath. Trimethylsilyldiazomethane (5 mL of a 2.0M solution in hexane) was added dropwise. Gas evolution was observed. The resulting yellow solution was stirred at room temperature overnight. The solvents were removed under reduced pressure and the residue was purified by flash chromatography (1:1 hexane:ethyl acetate as eluant). The second eluting component was collected to yield 950 mg (36%) of the title compound of Step D. 1H NMR (CDCl3): δ7.51 (dd,J=1.7, 7.5Hz,1H), 7.27 (dt,J=1.7, 7.5Hz,1H), 7.17 (m,2H), 6.97 (dd,J=1, 8Hz,1H), 6.5 (m,3H), 3.92 (s,3H), 3.74 (s,3H), 3.33(s,3H).
Reaction SMILES: [SH:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:13]([C:15]1[N:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:18]=[CH:17][CH:16]=1)#[N:14]>N1C=CC=CC=1>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:3]2[C:4](=[O:6])[N:14]=[C:13]([C:15]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:18]=[CH:17][CH:16]=3)[S:1][C:2]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)CCc1cccc(C#N)n1
Reactant: COc1ccc(C(=O)O)c(S)c1
Solvent: c1ccncc1
Product: COc1ccc2c(=O)nc(-c3cccc(CCC(=O)OC(C)(C)C)n3)sc2c1
Yield: 46.3 %

Procedure:
2-Mercapto-4-methoxybenzoic acid (1.26 g, 6.8 mmol) and tert-butyl 3-(6-cyano-2-pyridyl)propanoate (1.21 g, 5.2 mmol) were dissolved in pyridine (10 ml), and the reaction mixture was refluxed for 24 hrs. The reaction mixture was concentrated under reduced pressure, subjected to a silica gel column chromatography, eluted with hexane-ethyl acetate (1:1, v/v) and recrystallized from ethyl acetate-hexane to give the titled compound (0.96 g, 46%)
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[C@H:12]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11](=[O:24])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].[C:25]1([CH:31](N)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N(OC(C)C)=O>C(#N)C>[CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[C@H:12]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11](=[O:24])[N:6]2[C:7]=1[C:8]([O:10][CH:31]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:9]
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Agent: CC(C)ON=O
Solvent: CC#N
Product: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1

Procedure:
3-Methyl-7β-phenoxyacetamido ceph-3-em-4-carboxylic acid (3.48 g., 10 m. moles), diphenylmethylamine (3.20 g., 17.5 m. moles) and isopropyl nitrite (3.12 g., 35 m. moles) were heated at 35° over 2 hours in acetonitrile (50 ml). The solvent was removed in vacuo, replaced by ethyl acetate (50 ml) and washed as described in example 7. The organic residue was crystallised from hot isopropanol (30 ml) to yield the title ester (4.25 g., 82.6% based on the input acid) m.pt. 155°, pure by t.l.c.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[C:47]1(/[CH:53]=[CH:54]/[C:55](Cl)=[O:56])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(N(CC)CC)C>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH:46][C:55](=[O:56])/[CH:54]=[CH:53]/[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH:43]=[CH:44][CH:45]=2)=[N:8]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: O=C(Cl)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccccc1)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol) in 2.5 mL of tetrahydrofuran was added (2E)-3-phenylprop-2-enoyl chloride (0.062 g, 0.372 mmol) followed by triethyl amine (0.173 mL, 1.24 mmol). The reaction was stirred at room temperature for 2 hours. The reaction mixture was partitioned between water and ethyl acetate. The residue was not purified (yield not calculated). ES-MS (m/z) 733 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[N:13]=1.Br[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: Oc1ccc(C2COC(c3c(F)cccc3F)=N2)cc1
Reactant: BrCc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cccc(F)c1C1=NC(c2ccc(OCc3ccc4ccccc4c3)cc2)CO1
Yield: 50 %

Procedure:
The compound of Example 6 (0.36 g, 1.3 mmol) and 2-bromomethyl naphthalene (0.4 g, 1.7 mmol) were stirred at 23° C. for 18 h with potassium carbonate (0.6 g, 4 mmol) in dimethylformamide (10 mL). The mixture was poured into water (50 mL) and extracted with diethylether (50 mL). The diethylether was washed with water (50 mL) twice, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel chromatography using hexanes/ethyl acetate (6:1) as eluent to give the title compound as a solid (0.27 g): m.p. 148°-150° C. 1H NMR (CDCl3, 200 MHz) δ 7.8-7.0 (m,14H), 5.4 (m,1H), 5.2 (m,2H), 4.8 (m,1H), 4.3 (m,1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[CH:19]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][C:32]1[S:33][C:34](B2OC(C)(C)C(C)(C)O2)=[C:35]([CH3:37])[N:36]=1.[F-].[Cs+]>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:34]2[S:33][C:32]([CH3:31])=[N:36][C:35]=2[CH3:37])=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[CH:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCS(=O)(=O)c1cccc(C#Cc2cc(Br)ccc2OCC(=O)OC(C)(C)C)c1
Reactant: Cc1nc(C)c(B2OC(C)(C)C(C)(C)O2)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)c1cccc(C#Cc2cc(-c3sc(C)nc3C)ccc2OCC(=O)OC(C)(C)C)c1

Procedure:
A solution of tert-butyl(4-bromo-2-{[3-(propylsulfonyl)phenyl]ethynyl}phenoxy)acetate (Intermediate 191; 100 mg; 0.20 mmol), 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (73 mg; 0.30 mmol) was placed in a microwave vial and treated with caesium fluoride (93 mg; 0.61 mmol) and bis(triphenylphosphine)palladium(II) chloride (14 mg; 0.02 mmol). The tube was sealed and degased with N2 before adding dioxane (2 ml) and water (1 ml). The resulting reaction mixture was irradiated in a microwave reactor at 120° C. for 10 minutes. The reaction mixture was taken up in EtOAc and washed with water and brine. The organic phase was dried over MgSO4, filtered, concentrated and purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc affording the title compound as a brown sticky solid (78 mg, 73%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][NH2:8].[C:9]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>CO>[C:9]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17][CH2:7][NH2:8])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(CCN)cc1
Temperature: 25 °C
Reaction time: 41 h
Yield: 53.7 %

Procedure:
p-tert-butyltoluene (14.8 g; 0.10 mol) was dissolved in carbon tetrachloride, and N-bromosuccinimide (17.8 g; 0.10 mol) and benzoyl peroxide (200 mg) were added thereto. The mixture was refluxed for 2 hours, and then cooled. Insoluble matter was filtered off, followed by washing with carbon tetrachloride. The filtrate was concentrated under reduced pressure, and the residue was dissolved in n-hexane, followed by drying over magnesium sulfate. The solvent was evaporated under reduced pressure, to thereby yield 22.7 g of p-tert-butylbenzyl bromide (yield: 100%). The thus-obtained product was analyzed by 1H-NMR, and was found to be a mixture of the target compound, starting compounds, and a dibromo compound (10:1:1). Sodium carbonate (10.6 g; 0.10 mol) was added to 40% solution of methylamine in methanol (200 ml). While the mixture was cooled in an ice bath, p-tert-butyl benzyl bromide (22.7 g; 0.10 mol) in methanol (20 ml) was added dropwise thereto. The mixture was removed from the ice bath, and stirred for 41 hours at room temperature. Methanol was removed under reduced pressure, and the residue was taken up in water, followed by extraction with ether (400 ml). The ether layer was extracted with 1N hydrochloric acid twice (200 ml and 100 ml), and the aqueous layer was extracted with ethyl acetate. The aqueous layer was alkalinized with aqueous 2N sodium hydroxide solution, and extracted with ether (400 ml), followed by drying over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=200:1→100:1→20:1), to thereby yield 9.51 g of the target compound (yield: 53.7%).
Reaction SMILES: CS(C)=O.[NH2:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]([C:21]([OH:23])=[O:22])=[CH:16][N:11]3[C@@H:12]([CH3:15])[CH2:13][O:14][C:9]([C:10]=23)=[C:8](F)[C:7]=1[F:25].C(OC([NH:33][C:34]12[CH2:39][CH:38]1[CH2:37][NH:36][CH2:35]2)=O)(C)(C)C>C(N(CC)CC)C>[NH2:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]([C:21]([OH:23])=[O:22])=[CH:16][N:11]3[C@@H:12]([CH3:15])[CH2:13][O:14][C:9]([C:10]=23)=[C:8]([N:36]2[CH2:37][CH:38]3[C:34]([NH2:33])([CH2:39]3)[CH2:35]2)[C:7]=1[F:25]
Reactant: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Reactant: CC(C)(C)OC(=O)NC12CNCC1C2
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C[C@H]1COc2c(N3CC4CC4(N)C3)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 62.9 %

Procedure:
To a dimethyl sulfoxide (5 ml) solution of 8-amino-9,10-difluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid (200 mg, 0.68 mmol) were added 1-tert-butoxycarbonylamino-3-azabicyclo[3.1.0]hexane (Fr. 1; 270 mg, 1.36 mmol) and triethylamine (1 ml), and the mixture was heated at 100° C. for 24 hours. After evaporation of the solvent under a reduced pressure, the thus obtained residue was mixed with chloroform (50 ml), the resulting solution was washed with 10% citric acid (20 ml×2) and dried over sodium sulfate, and then the solvent was evaporated under a reduced pressure. The thus obtained residue was mixed with concentrated hydrochloric acid (5 ml) and stirred at room temperature for 5 minutes, and the mixture was washed with chloroform (30 ml×3), alkalified by adding 20% sodium hydroxide aqueous solution, then, adjusted to pH 7.2 with concentrated hydrochloric acid and extracted with chloroform (50 ml×3). The extract was dried over sodium sulfate, and the solvent was evaporated under a reduced pressure to yield 201 mg of the crude title compound. By recrystallizing this from 28% ammonia aqueous solution-ethanol, 160 mg (63%) of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16][NH2:17])[CH3:13].CCN=C=NCCCN(C)C>C(Cl)Cl>[Br:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH:17][CH2:16][CH:15]([O:18][CH2:19][CH3:20])[O:14][CH2:12][CH3:13])=[O:6])=[C:2]([Cl:1])[CH:10]=1
Reactant: CCOC(CN)OCC
Reactant: O=C(O)c1ccc(Br)cc1Cl
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CCOC(CNC(=O)c1ccc(Br)cc1Cl)OCC
Reaction time: 4 h
Yield: 99.9 %

Procedure:
To a suspension of 2-chloro-4-bromobenzoic acid (10.0 g, 42.47 mmol) in CH2Cl2 (1000 mL) was added aminoacetaldehyde diethyl acetal (5.1 mL, 46.72 mmol) and WSC (9.77 g, 50.96 mmol) at room temperature, and stirred for 4 hours. The mixture was washed with water (100 mL), dried over MgSO4. Removal of the solvent, gave title compound (14.88 g, 100% yield).