Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([O:19][C:20](=[O:35])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:15][C:16]([OH:18])=O.ON1C(=O)CCC1=O.FC(F)(F)C(O)=O.[NH2:52][C@H:53]([C:55]([NH:57][C@H:58]([C:61]([OH:63])=[O:62])[CH2:59][OH:60])=[O:56])[CH3:54].Cl>O1CCOCC1.CN(C)C=O.O.C(N(CC)CC)C>[CH3:36][CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([O:19][C:20](=[O:35])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:15][C:16]([NH:52][C@H:53]([C:55]([NH:57][C@H:58]([C:61]([OH:63])=[O:62])[CH2:59][OH:60])=[O:56])[CH3:54])=[O:18]
Reactant: CC(C)CCCCCCCCCCCC(=O)OC(CCCCCCCCCCCC(C)C)CC(=O)O
Reactant: C[C@H](N)C(=O)N[C@@H](CO)C(=O)O
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CCCCCCCCCCCC(=O)OC(CCCCCCCCCCCC(C)C)CC(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)O
Reaction time: 8 h
Yield: 57.3 %

Procedure:
15-Methyl-3-(13-methyltetradecanoyloxy)hexadecanoic acid (80 mg) prepared by the method described in Preparation 1-(3) and N-hydroxysuccinimide (20 mg) were dissolved in dioxane (2 ml). N,N-Dicyclohexylcarbodiimide (37 mg) was added thereto under ice cooling. The mixture was reached to ambient temperature and stirred at the same temperature overnight. The crystallized urea was filtered off and the filtrate was concentrated to give a residue which was dissolved in N,N-dimethylformamide (3 ml). To the solution was added a solution of N-L-alanyl-L-serine trifluoroacetate (94 mg) and triethylamine (90 μl) in water (2 ml) at 0° C. The resulting mixture was reached to ambient temperature and stirred at the same temperature overnight. The reaction mixture was acidified with 1 N hydrochloric acid, extracted with ethyl acetate, washed with water and dried over magnesium sulfate. Ethyl acetate was distilled off to give a residue which was subjected to preparative thin layer chromatography (Merck, 0.25 mm×5) and eluted with a mixture of benzene, dioxane and acetic acid (10:5:1). The band containing the object compound was extracted with a mixture of methanol and chloroform (3:7) and the solvent was evaporated off under reduced pressure to afford a wax of N-[N-[15-methyl-3-(13-methyltetradecanoyloxy)hexadecanoyl]L-alanyl]-L-serine (60 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)=[O:9].[I-:17].[K+].II>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[C:14]([I:17])[CH:15]=1)=[O:9]
Reactant: O=C(c1ccc(O)cc1)c1ccccc1F
Reactant: [I-]
Agent: II
Agent: [K+]
Product: O=C(c1ccc(O)c(I)c1)c1ccccc1F

Procedure:
(2-Fluorophenyl)(4-hydroxyphenyl)methanone, potassium iodide and iodine were processed as described in Example 68A to provide the title compound. MS (DCI) m/z 343 (M+H)+, 360 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][CH:8]=[CH:7][C:6]2=[O:15].C([O-])([O-])=O.[Cs+].[Cs+].[F:22][C:23]1[CH:24]=[C:25]([N+:30]([O-:32])=[O:31])[CH:26]=[CH:27][C:28]=1F.O>CN(C=O)C.CC#N.C(Cl)(Cl)Cl.CCOC(C)=O>[F:22][C:23]1[CH:24]=[C:25]([N+:30]([O-:32])=[O:31])[CH:26]=[CH:27][C:28]=1[O:15][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: COc1cc2[nH]ccc(=O)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
A mixture of 6,7-dimethoxyquinolin-4(1H)-one (7.9 g, 38.5 mmol), Cs2CO3 (15.4 g) in DMF (55 mL) and CH3CN (80 mL) was stirred for 30 min. at rt. To this mixture was added 3,4-difluoronitrobenzene (6.5 g, 40.9 mmol), and the reaction mixture was stirred over the weekend at rt. To the reaction mixture was added H2O (100 mL), stirred for 10 minutes and the precipitate was filtered, washed with a small amount of H2O to obtain the 1st crop of solid. To the filtrate solution was added EtOAc (200 mL), the EtOAc layer was separated, the aqueous layer was washed with EtOAc (200 mL), and the combined EtOAc solution was dried over MgSO4, concentrated in vacuo to obtain the 2nd crop of solid. The solids of first crop and second crop were combined which was a mixture of O- and N-alkylation products. The mixture of solid product was digested in CHCl3 (35 mL) and DMF (5 mL), and the undissolved solid was filtered which was an N-alkylation product. The filtrate solution was passed through a flash column on SiO2 eluting with 5% MeOH in CH2Cl2 to obtain the desired O-alkylation product (6.2 g, 47%) as a light yellow solid. 1H NMR (CDCl3) δ 8.59 (d, 1H, J=5.0 Hz), 8.19 (dd, 1H, J=9.3, 2.8 Hz), 8.14 (dd, 1H, J=8.8, 2.2 Hz), 7.45 (d, 2H, J=9.9 Hz), 7.34 (t, 1H, J=8.3 Hz), 6.55 (d, 1H, J=5.0 Hz), 4.06 (s, 3H), 4.04 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13](C)=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[SH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26]>>[OH:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[S:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[CH:13]=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1
Reactant: CC1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Reactant: Oc1ccccc1S
Product: O=C1NN=C/C1=C1\C=C(Sc2ccccc2O)c2ccccc2N1

Procedure:
The title compound was prepared from (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one and 2-mercaptophenol using a procedure analogous to the one described in Example 6. 1H NMR (400 MHz, DMSO-D6) δ ppm 2.08 (s, 3H) 7.08 (s, 1H) 7.38-7.68 (m, 3H) 7.76-7.88 (m, 3H) 7.92 (d, J=8.14 Hz, 1H) 8.18 (d, J=8.24 Hz, 1H) 10.38 (s, 1H) 13.10 (bs, 1H); ESI-MS: m/z calc'd for C19H15N3O2S 349.09. found 350.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([CH3:17])[CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.C1C=CC=CC=1.P(=O)(O)(O)O.[CH3:44][S:45]([CH3:47])=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[C:10](=[S:45]([CH3:47])[CH3:44])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([CH3:17])[CH:3]=1
Reactant: CS(C)=O
Reactant: CCOC(=O)CC(=O)Nc1ccc(Br)cc1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=P(O)(O)O
Solvent: c1ccccc1
Product: CCOC(=O)C(C(=O)Nc1ccc(Br)cc1C)=S(C)C
Temperature: 25 °C

Procedure:
A mixture of 30.0 grams (0.10 mole) of ethyl 3-[(4-bromo-2-methylphenyl)amino]-3-oxopropanoate, 51.58 grams (0.25 mole) of 1,3-dicyclohexylcarbodiimide, 100 milliliters of benzene and 100 milliliters of dimethyl sulfoxide was stirred at ambient temperature and a solution of 4.9 grams (0.05 mole) of anhydrous phosphoric acid in 10 milliliters of dimethyl sulfoxide added dropwise. After a few minutes an exothermic reaction occurred with separation of a white solid and an increase in temperature from 25° C. to 35° C. The reaction mixture was then stirred for an approximate 16-hour period at ambient temperature. The mixture was then diluted with 500 milliliters of ethyl acetate and by-product 1,3-dicyclohexylurea removed by filtration. The filtrate was washed with several portions of water, dried over MgSO4, filtered and freed of solvent under reduced pressure to give a yellow solid. This was crystallized from ethyl acetate-hexane (1:1) to give 15.8 grams (0.04 mole) of ethyl 3 -[(4-bromo-2-methylphenyl)amino]-2-(dimethylsulfuranylidene)-3-oxopropanoate having a melting point of 143° C.-150° C. Recrystallization of a small sample gave a white solid of melting point 146° C.-149° C.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]O)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:20])=O>C(Cl)(Cl)Cl>[CH2:1]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][Cl:20])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCOc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
2.5 g of 4-octyloxybenzyl alcohol were dissolved in 20 ml of chloroform, and the resultant solution was further fed dropwise with 1.48 g of thionyl chloride and then stirred for 1 hour at room temperature. The solution reacted was poured into ice-water and extracted with chloroform. The organic layer resulted was then dried with anhydrous magnesium sulfate, and the solvent used was removed by distillation under reduced pressure, thereby affording 2.2 g of 4-octyloxybenzyl chloride.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[OH:22][C:15]1[C:16]([O:20][CH3:21])=[CH:17][CH:18]=[CH:19][C:14]=1[C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=3[OH:23])[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: COc1cccc(-c2cccc(-c3cccc(Br)n3)n2)c1O
Reactant: Cc1cccc(B(O)O)c1O
Product: COc1cccc(-c2cccc(-c3cccc(-c4cccc(C)c4O)n3)n2)c1O
Yield: 59 %

Procedure:
6-(2-Hydroxy-3-methoxyphenyl)-6′-(2-hydroxy-3-methylphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-3-methoxyphenyl)-2,2′-bipyridine and 2-hydroxy-3-methylphenylboronic acid in 59% yield using method F; δH [2H6]-DMSO 13.28,(1H, s), 8.37,(1H, d), 8.35,(1H, d), 8.29,(2H, t), 8.18,(1H, d), 8.10,(1H, d), 7.97,(1H, d), 7.71,(1H, d), 7.29,(1H, d), 7.10,(1H, d), 6.97-6.87,(2H, m), 3.84,(3H, s), 2.29,(3H, s); MS 385 (MH)+; HPLC retention time (system 1) 4.27 minutes.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([C:11]([O:13][CH3:14])=[O:12])[CH2:6]2.C([Sn](CCCC)(CCCC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)CCC.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[F-].[K+]>CN1CCCC1=O>[C:20]1([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][CH:5]([C:11]([O:13][CH3:14])=[O:12])[CH2:6]3)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: COC(=O)C1Cc2cccc(Br)c2C1
Agent: [F-]
Agent: [K+]
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CN1CCCC1=O
Product: COC(=O)C1Cc2cccc(-c3ccccc3)c2C1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
Methyl 4-bromo-2-indancarboxylate (510 mg), tributylphenyltin (881 mg), a tris(dibenzylideneacetone)dipalladium chloroform complex (41 mg) and tri-2-furylphosphine (19 mg) were dissolved in N-methylpyrrolidone (10 ml), and the mixture was stirred at 70° C. for 3 hours and allowed to cool. To the reaction solution was added a saturated potassium fluoride solution and the solution was stirred at room temperature for 30 minutes followed by filtering through Celite. The filtrate was extracted with ether. The organic layers was washed with saturated aqueous sodium bicarbonate and saturated brine and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled away under a reduced pressure. The resultant residue was purified by column chromatography on silica gel (hexane: ethyl acetate=4:1) to obtain methyl 4-phenyl-2-indancarboxylate. The resultant ester was dissolved in methanol to which 1 N sodium hydroxide was added to hydrolyze. Methanol was distilled away under a reduced pressure. To the resultant residue was added 1 N hydrochloric acid. The product was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled away to obtain the title compound (351 mg) (melting point: 97-102° C.).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:29]([N:30]([O:42][CH3:43])[C:31](=[O:41])[CH2:32][C:33]3[N:34]=[C:35]([NH:38][CH:39]=[O:40])[S:36][CH:37]=3)[C:28](=[O:44])[N:10]2[C:11]=1[C:12]([O:14]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13])(=[O:3])[CH3:2].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:29]([N:30]([O:42][CH3:43])[C:31](=[O:41])[CH2:32][C:33]3[N:34]=[C:35]([NH:38][CH:39]=[O:40])[S:36][CH:37]=3)[C:28](=[O:44])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CON(C(=O)Cc1csc(NC=O)n1)C1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(C)=O)CS[C@H]12
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CON(C(=O)Cc1csc(NC=O)n1)C1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12
Reaction time: 1.5 h
Yield: 98.7 %

Procedure:
In methylene chloride (10 ml) is dissolved diphenylmethyl 3-acetoxymethyl-7-[N-methoxy-2-(2-formylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylate (535 mg). Under ice-cooling, anisole (1 ml) and trifluoroacetic acid (1.5 ml) are added and the mixture is stirred for 1.5 hours. The reaction mixture is concentrated under reduced pressure and the residue is dissolved in ethyl acetate and extracted with a dilute aqueous solution of sodium hydrogen carbonate. The water layer is adjusted to pH 1 with dil HCl and extracted with ethyl acetate. The extract is washed with aqueous sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is washed with isopropyl ether to give a powder of 3-acetoxymethyl-7-[N-methoxy-2-(2-formylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (390 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:2]1=2.CC1C=C(O)C=CC=1C.[CH3:21][CH:22]([CH3:39])[CH2:23][CH2:24][N:25]1[C:33]2[C:28](=[C:29]3[S:36][CH:35]=[N:34][C:30]3=[CH:31][CH:32]=2)[C:27](=[O:37])[C:26]1=[O:38].C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(=O)C2=O)C=CC=CC=1>>[OH:37][C:27]1([C:9]2[C:8]([OH:11])=[CH:7][C:3]3[O:4][CH2:5][CH2:6][O:1][C:2]=3[CH:10]=2)[C:28]2[C:33](=[CH:32][CH:31]=[C:30]3[N:34]=[CH:35][S:36][C:29]3=2)[N:25]([CH2:24][CH2:23][CH:22]([CH3:21])[CH3:39])[C:26]1=[O:38]
Reactant: Oc1ccc2c(c1)OCCO2
Reactant: CC(C)CCN1C(=O)C(=O)c2c1ccc1ncsc21
Agent: Cc1ccc(O)cc1C
Agent: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: CC(C)CCN1C(=O)C(O)(c2cc3c(cc2O)OCCO3)c2c1ccc1ncsc21

Procedure:
Following the procedure as described in PREPARATION 6A, and making non-critical variations using 2,3-dihydrobenzo[b][1,4]dioxin-6-ol to replace 3,4-dimethylphenol, and 6-(3-methylbutyl)-6H-[1,3]thiazolo[5,4-e]indole-7,8-dione to replace 1-(diphenylmethyl)-1H-indole-2,3-dione, 8-hydroxy-8-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-6-(3-methylbutyl)-6,8-dihydro-7H-[1,3]thiazolo[5,4-e]indol-7-one was obtained (46%): 1H NMR (300 MHz, CDCl3) δ9.00 (s, 1H), 8.80 (s, 1H), 7.96 (d, J=8.5 Hz, 1H), 7.27 (s, 1H), 7.20 (d, J=8.5 Hz, 1H), 6.55 (s, 1H), 4.15 (s, 4H), 3.81-3.59 (m, 2H), 1.79-1.55 (m, 1H), 1.56-1.42 (m, 2H), 0.93 (d, J=6.6 Hz, 6H); MS (ES+) m/z 427.0 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:14]([Si](C)(C)C)([F:17])([F:16])[F:15].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOCC>[F:15][C:14]([F:17])([F:16])[C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)([OH:3])[CH3:2]
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86 %

Procedure:
To a mixture of methyl 4-acetylbenzoate (5.0 g, 28.1 mmol) and CF3SiMe3 (12.5 mL, 84.2 mmol) in THF (150 mL) was added TBAF (1.0 M, 78.6 mL, 78.6 mmol) dropwise at 0° C. The mixture was stirred for 2.5 h at room temperature, diluted with Et2O (100 mL). The solution was washed with saturated aqueous NaHCO3 and brine, dried and concentrated. Flash chromatography of the residue, using 2:8 EtOAc-Hexane, gave methyl 4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoate (6.0 g). 1H NMR (CDCl3) δ 8.07(d, J=8.5 Hz, 2 H), δ 7.67(d, J=8.5 Hz, 2 H), 3.93(s, 3 H), 2.70(br, 1 H), 1.80(s, 3H). MS 249.1 (M+H+).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]([C:23](=[O:34])[C@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:25])[NH2:22].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:22][NH:21][C:23](=[O:34])[C@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH3:25])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)NN
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 96.3 %

Procedure:
To a solution of 1 (250 mg, 0.9 mmol) in 20 mL of DCM were added tert-butyl [(2R)-1-hydrazinyl-1-oxopropan-2-yl]carbamate 274 (275 mg, 1.35 mmol), HOBt (183 mg 1.35 mmol), DMAP (162 mg, 1.35 mmol) and EDCI (260 mg, 1.35 mmol). The mixture was stirred at room temperature for 48 h and purified by column to afford compound 275 as foam (400 mg, 95%).
Reaction SMILES: [CH2:1]([C:3]([N+:24]#[C-:25])([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([C:3]([NH:24][CH3:25])([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([O:17][CH3:18])[C:10]([O:15][CH3:16])=[C:11]([O:13][CH3:14])[CH:12]=1)[CH3:2]
Reactant: [C-]#[N+]C(CC)(CCCc1cc(OC)c(OC)c(OC)c1)c1cccs1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CCCc1cc(OC)c(OC)c(OC)c1)(NC)c1cccs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
A solution of 2.8 g of 1-ethyl-4-(3,4,5-trimethoxyphenyl)-1-(2-thienyl)butyl isocyanide in 10 ml of tetrahydrofuran is added dropwise to a suspension of 0.6 g of lithium aluminum hydride in 5 ml of tetrahydrofuran under ice-cooling and the mixture is stirred at room temperature for 16 hours. To the reaction mixture are added successively, 0.6 ml of water, 0.6 ml of an aqueous 15% sodium hydroxide solution and 1.8 ml of water, and the insoluble materials are removed by filtration. The filtrate is concentrated under reduced pressure and the residue is purified by silica gel column chromatography (solvent; chloroform:ethanol=20:1) to give 1.7 g of 1-ethyl-4-(3,4,5-trimethoxyphenyl)-1-(2-thienyl)-N-methylbutylamine as a colorless oil. yield:60%
Reaction SMILES: [NH2:1][C:2]1[C:18]2[C:17](=[O:19])[C:16]([C:20]([OH:22])=[O:21])=[CH:15][N:7]3[C:8]4([CH2:14][CH2:13][O:12][CH2:11]4)[CH2:9][O:10][C:5]([C:6]=23)=[C:4](F)[C:3]=1[F:24].[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][CH2:32][CH2:33][NH2:34].C(N(CC)CC)C.[NH4+].[Cl-]>CS(C)=O.O>[NH2:1][C:2]1[C:18]2[C:17](=[O:19])[C:16]([C:20]([OH:22])=[O:21])=[CH:15][N:7]3[C:8]4([CH2:14][CH2:13][O:12][CH2:11]4)[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:34][CH2:33][CH2:32][CH2:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=2)[C:3]=1[F:24]
Reactant: NCCCc1ccccn1
Reactant: Nc1c(F)c(F)c2c3c1c(=O)c(C(=O)O)cn3C1(CCOC1)CO2
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1c(F)c(NCCCc2ccccn2)c2c3c1c(=O)c(C(=O)O)cn3C1(CCOC1)CO2
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
A solution of 8′-amino-9′,10′-difluoro-7′-oxospiro[oxolane-3,3′(2′H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-6′-carboxylic acid (300 mg, 0.887 mmol), 3-(2-pyridyl)propylamine (181 mg, 1.33 mmol) and triethylamine (0.185 mL, 1.33 mmol) in DMSO (4 mL) was stirred at 100° C. for 6 h. To the reaction mixture, water and saturated NH4Cl solution were added to pH <4 and stirred for 30 min. The resulting precipitate was collected by filtration, washed with water and EtOH, and dried to yield 8′-amino-9′-fluoro-7′-oxo-10′-[3-(2-pyridyl)propylamino]spiro[oxolane-3,3′(2′H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-6′-carboxylic acid (373 mg, 93%) as a pale yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ1.90-1.98 (2H, m), 2.26-2.39 (2H, m), 2.77 (2H, t, J=7.3 Hz), 3.42-3.51 (2H, m), 3.73 (1H, d, J=10.4 Hz), 3.91-3.97 (1H, m), 4.07-4.13 (1H, m), 4.16 (1H, d, J=10.4 Hz), 4.24 (1H, d, J=11.0 Hz), 4.35 (1H, d, J=11.0 Hz), 6.01-6.10 (1H, m), 6.92 (2H, brs), 7.18 (1H, dd, J=6.7, 5.5 Hz), 7.24 (1H, d, J=7.9 Hz), 7.67 (1H, td, J=7.3, 1.8 Hz), 8.42 (1H, s), 8.45 (1H, d, J=4.3 Hz), 15.27 (1H, s). HRESIMS (+) 455.17350 (Calcd for C23H23FN4O5, 455.17307).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:29]=[CH:28][C:20]3[N:21]=[C:22]([NH:24][C:25](=[O:27])[CH3:26])[S:23][C:19]=3[CH:18]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[Cl:1][C:2]1[CH:7]=[C:6]([C:17]2[CH:29]=[CH:28][C:20]3[N:21]=[C:22]([NH:24][C:25](=[O:27])[CH3:26])[S:23][C:19]=3[CH:18]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Reactant: Clc1cc(I)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)Nc1nc2ccc(-c3ccnc(Cl)c3)cc2s1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
2-chloro-4-iodopyridine (0.500 g, 2 mmol) was dissolved in 1,4-dioxane (15 ml), then N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.800 g, 3 mmol), tetrakis(triphenylphosphine)palladium(0) (0.300 g, 0.3 mmol) and 2M sodium carbonate (2 ml, 4 mmol) was added to the mixture. The round-bottom flask was fitted with a reflux condenser and placed into a pre-heated (90° C.) bath. The mixture was allowed to stir under inert atmosphere for 3 hours. The progress of the reaction was monitored by LC/MS, which showed desired product in the mixture. The material was allowed to cool to ambient temperature and diluted with DCM and saturated sodium bicarbonate solution. The organic layer was collected by extracting with DCM (3×20 ml). Combined organics, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was diluted with ethyl ether (50 ml) and allowed to stir 10 minutes. The precipitate was collected by filtration and washed with ethyl ether. This gave N-(6-(2-chloropyridin-4-yl)benzo[d]thiazol-2-yl)acetamide (0.200 g, 32% yield) as a tan crystalline solid. MS (ESI pos. ion) m/z: 304 (MH+). Calc'd exact mass for C14H10ClN3OS: 303. 1H NMR (400 MHz, DMSO-d6): 2.23 (s, 3H), 7.80-7.86 (m, 2H), 7.90-7.95 (m, 2H), 8.47 (d, J=5.09 Hz, 1H), 8.54 (s, 1H), 12.49 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:13])[CH:5]=[C:6]([C:8]([Cl:12])=[C:9]([Cl:11])[Cl:10])[CH:7]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:32]N1C(=O)CCC1=O.[I-].[K+]>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:8]([Cl:12])=[C:9]([Cl:10])[Cl:11])[CH:7]=1)[CH2:13][Br:32]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(F)cc(C(Cl)=C(Cl)Cl)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: c1ccccc1
Product: Fc1cc(CBr)cc(C(Cl)=C(Cl)Cl)c1

Procedure:
To a solution of 3-fluoro-5-(trichlorovinyl)toluene (2.39 g) and dibenzoyl peroxide (0.2 g) in 60 ml of benzene at reflux, N-bromosuccinimide (2.21 g) is added in portions. The mixture is heated at reflux until the solution gives a negative reaction with potassium iodide. The reaction mixture is concentrated and the residue triturated with 100 ml of hexane. The precipitated succinimide is collected by filtration and the filtrate concentrated and then chromatographed on silica gel (hexane) to give the desired benzyl bromide.