Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]3[C:36]4[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=4[CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[CH:29]4)=[CH:19][C:18]=2[CH3:39])(=[O:15])=[O:14])=[CH:9][C:8]=1[OH:40])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[Cl:48][C:49]1[CH:57]=[CH:56][C:52]([C:53](Cl)=[O:54])=[CH:51][CH:50]=1>>[C:1]([O:5][C:6](=[O:41])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]3[C:36]4[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=4[CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[CH:29]4)=[CH:19][C:18]=2[CH3:39])(=[O:14])=[O:15])=[CH:9][C:8]=1[O:40][C:53](=[O:54])[C:52]1[CH:56]=[CH:57][C:49]([Cl:48])=[CH:50][CH:51]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Cc1cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)OC(C)(C)C)c(O)c1
Solvent: c1ccncc1
Product: Cc1cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)OC(C)(C)C)c(OC(=O)c2ccc(Cl)cc2)c1

Procedure:
The title compound was prepared according to the procedure in Example 17, step 1, using 4-[4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxysulfonyl]-2-hydroxy-benzoic acid tert-butyl ester (0.362 g, 0.615 mmol), pyridine (0.298 mL, 3.69 mmol) and 4-chlorobenzoyl chloride (0.156 mL, 1.23 mmol) to give the title compound. 1H NMR (DMSO-d6) δ 1.35 (s, 9 H), 1.57 (s, 3 H), 2.17 (s, 6 H), 2.33 (s, 3 H), 7.17 (s, 2 H), 7.35-7.40 (m, 2 H), 7.43 -7.48 (m, 1 H), 7.72 (d, 2 H), 7.98 (d, 1 H), 8.13-8.24 (m, 5 H), 8.50 (s, 1 H).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)(=O)=O.[NH:13]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:22]=[O:23])[C:16]=2[CH:15]=[CH:14]1>>[N:8]1([CH2:7][CH2:6][N:13]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([CH:22]=[O:23])[C:16]=3[CH:15]=[CH:14]2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CS(=O)(=O)OCCN1CCCC1
Reactant: O=Cc1cccc2[nH]ccc12
Product: O=Cc1cccc2c1ccn2CCN1CCCC1
Yield: 32.3 %

Procedure:
The same procedures used in Example 154 were repeated except for using 5.32 g of N-(2-methanesulfonyloxyethyl)pyrrolidine and 2.00 g of indole-4-carbaldehyde as a starting material to give 1.08 g of 1-[2-(pyrrolidin-1-yl)ethyl]indole-4-carbaldehyde as a yellow oily substance. The yield thereof was found to be 33%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.CCN(S(F)(F)[F:19])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([F:19])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(Br)cc2)COC1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FC1(c2ccc(Br)cc2)COC1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
3-(4-Bromophenyl)oxetan-3-ol (1.55 g, 6.77 mmol) was taken up in DCM (100 mL) and cooled to −78° C. DAST (1.073 mL, 8.12 mmol) was added and the mixture was stirred at −78° C. for 90 minutes followed by 0° C. for 20 minutes. Saturated NaHCO3 was added and the products extracted into DCM (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by flash silica gel column chromatography (0-10% EtOAc-hexanes) gave the title compound as a yellow oil.
Reaction SMILES: [I:1]Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[C:13]3[CH2:14][CH2:15][CH2:16][CH2:17][N:12]3[N:11]=2)=[CH:6][CH:5]=1.O>ClCCl>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:18]([I:1])=[C:13]3[CH2:14][CH2:15][CH2:16][CH2:17][N:12]3[N:11]=2)=[CH:8][CH:9]=1
Reactant: ClI
Reactant: Fc1ccc(-c2cc3n(n2)CCCC3)cc1
Solvent: O
Solvent: ClCCl
Product: Fc1ccc(-c2nn3c(c2I)CCCC3)cc1
Reaction time: 12 h

Procedure:
A solution of 2.20 g (13.5 mmol) of iodine monochloride in 5 ml of dichloromethane is added dropwise to a solution of 2.66 g (12.3 mmol) of 2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine in 50 ml of dichloromethane, and the mixture is stirred for 12 h. 100 ml of water are added, and the reaction mixture is extracted with 3×50 ml of dichloromethane. The combined organic phases are dried over MgSO4 and freed from the solvent under reduced pressure. This gives 4.40 g (98%) of the desired product; log P(HCOOH): 3.79; 1H-NMR (MeCN-d3): 7.82 (dd, 2H), 7.18 (dd, 2H), 4.11 (dd, 2H), 2.67 (dd, 2H), 2.06 (m, 2H), 1.94 (m, 2H).
Reaction SMILES: C(OC([NH:11][C@@H:12]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]([OH:15])=O)=O)C1C=CC=CC=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.[Pd]>[NH2:11][C@@H:12]([C:16]([CH3:17])([CH3:18])[CH3:19])[C:13]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:15]
Reactant: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: C1COCCN1
Agent: [Pd]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)[C@H](N)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To a solution of (S)-2-(benzyloxycarbonylamino)-3,3-dimethylbutanoic acid (2.0 g, 7.54 mmol) in DMF (10 mL) were added morpholine (1.31 g, 15.1 mmol) and DIEA (3.95 mL, 22.62 mmol). TBTU (3.63 g, 11.31 mmol) was added in three portions 15 minutes apart. The reaction stirred at room temperature for 2 hours. DMF was removed under vacuum and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude material (2.11 g, 7.54 mmol) was combined with palladium on carbon, 10% dry basis, (0.29 g, 2.69 mmol) in MeOH (15 mL) and placed on a Parr Shaker under H2 atmosphere, 20 psi, for 3 hours. The reaction was filtered through a celite plug and concentrated under reduced pressure to provide 1.46 g (7.31 mmol) of intermediate 77D. LCMS (+ESI) m/z 201.1 [M+H]+.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[NH2:2].[CH3:9][C:10]([CH3:17])([CH3:16])[C:11](=O)[CH2:12][C:13]#[N:14]>C1(C)C=CC=CC=1>[C:10]([C:11]1[CH:12]=[C:13]([NH2:14])[N:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[N:2]=1)([CH3:17])([CH3:16])[CH3:9]
Reactant: NNc1ccncc1
Reactant: CC(C)(C)C(=O)CC#N
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(N)n(-c2ccncc2)n1
Temperature: 25 °C
Yield: 51.6 %

Procedure:
4-hydrazinopyridine hydrochloride (400 mg, 2.74 mmol) was dissolved in MeOH and passed through a column filled with the ion-exchange resin Ambersep 900-OH (Fluka). MeOH was eluted until no product remains in the column (checked by TLC). Concentration of the resulting methanolic solution afforded 4-hydrazinopyridine (285 mg, 95%) as a red oil. 1H-NMR (δ, ppm, DMSO-d6): 4.14 (s, 2H, NH2), 6.62 (d, 2H, Harom,Py, J=6.2 Hz), 7.51 (s, 1H, NH), 8.00 (d, 2H, Harom,Py, J=6.2 Hz). A mixture of 4-hydrazinopyridine (285 mg, 2.61 mmol) and 4,4-dimethyl-3-oxopentanenitrile (327 mg, 2.61 mmol) in toluene (1 mL) was heated under reflux during 16 h. After cooling to room temperature, evaporation of the solvent in vacuo afforded a brown residue which was purified by chromatography on silica gel (cyclohexane-EtOAc, 6:4 until 3:7). The title compound (291 mg, 51%) was obtained as a pale yellow solid (Rf 0.27, cyclohexane-EtOAc, 3:7). 1H-NMR (δ, ppm, DMSO-d6): 1.22 (s, 9H, t-Bu), 5.46 (s, 1H, HPyz,4), 5.56 (s, 2H, NH2), 7.70 (s, 2H, Harom,Py), 8.56 (s, 2H, Harom,Py). 13C-NMR (δ, ppm, DMSO-d6): 29.8 ((CH3)3), 31.9 (C(CH3)3), 88.7 (CPyz,4), 114.6 (CPy,3+5), 146.0 and 148.5 (CPyz,5 and CPyz,3), 150.4 (CPy,2+6), 162.5 (CPyz,4). LC-MS (m/z): 217 (M+H, 100).
Reaction SMILES: [C:1]1([CH2:7][NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[O:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][CH2:22][CH2:23][C:24]#[N:25].CN(C)C=O>C(N(CC)CC)C>[O:11]1[C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[CH2:14][CH2:15][CH:10]1[CH2:9][N:8]([CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:21][CH2:22][CH2:23][C:24]#[N:25]
Reactant: N#CCCCBr
Reactant: c1ccc(CNCC2CCc3ccccc3O2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCCCN(Cc1ccccc1)CC1CCc2ccccc2O1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.6 %

Procedure:
A mixture of 12.5 g of 3,4-dihydro-N-(phenylmethyl)-2H-1-benzopyran-2-methanamine, 9 g of 4-bromobutanenitrile, 200 ml of N,N-dimethylformamide and 10 ml of N,N-diethylethanamine was stirred for 72 hour at room temperature. The reaction mixture was evaporated and the residue was partitioned between 1,1'-oxybisethane and water. The organic layer was separated, dried, filtered and evaporated, yielding 11 g (68.7%) of (±)-4-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl](phenylmethyl) amino]-butanenitrile (interm. 53).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[C:12](=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].O1CCCC1.C([O-])(=O)C.[Na+].Cl.[NH2:30][OH:31]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[C:12](=[N:30][OH:31])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NO
Reactant: O=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccsc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: ON=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccsc21
Temperature: 25 °C
Yield: 93.7 %

Procedure:
A 100 mL round bottomed flask charged with 4-(3,4-dichlorophenyl)-5,6-dihydro-1-benzothiophen-7(4H)-one (1.29 g, 4.34 mmol), tetrahydrofuran (11.0 mL) and ethanol (12.5 mL). The mixture was stirred and sodium acetate (1.117 g, 13.62 mmol) and hydroxylamine hydrochloride (0.9242 g, 13.30 mmol) were added. The mixture was stirred for 16 h at 50° C. under an atmosphere of Nitrogen. The reaction was then cooled to rt, giving a pale yellow solution with much white ppt. The reaction was quenched into ˜75 ml saline solution w/stirring and the resulting mixture was transferred to a separatory funnel and extracted with ethyl acetate (2×). the extracts were combined, washed with saline, dried over sodium sulfate, filtered, and evaporated to leave 1.27 g (94% yield) product as pale yellow powder. LCMS: (FA) ES+ 312, 314. 1H NMR indicated that the product was an ˜3:1 mixture of geometric oxime isomers.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C[Al](C)C.[CH3:14][N:15]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18](=O)[O:17]C1=O.Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([Cl:9])=[C:4]([NH:5][C:18](=[O:17])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH:15][CH3:14])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1Cl
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: CNc1ccccc1C(=O)Nc1cccc(Br)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28 %

Procedure:
A mixture of 3-bromo-2-chloroaniline [prepared according to the procedure described in U.S. Pat. No. 8,242,260] (240 mg, 1.162 mmol) and toluene (10 mL) at 0° C. was slowly treated with 2 M trimethylaluminum in toluene (0.99 mL, 1.98 mmol). The mixture was allowed to warm to room temperature and stirred for 15 min. A partial suspension of 1-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (300 mg, 1.52 mmol) in toluene (4 mL) was added slowly. The resulting mixture was heated at 50° C. for 4 h, cooled to 0° C., and treated dropwise with 1M aqueous HCl until no more gas evolution was observed. The mixture was stirred for 2 h while warming to room temperature, then was extracted with EtOAc. The organic phase was washed sequentially with NaHCO3 and brine, dried and concentrated. The residue was purified by column chromatography on silica gel (80 g), eluting with EtOAc-hexanes (gradient from 0-30%), to provide N-(3-bromo-2-chlorophenyl)-2-(methylamino)benzamide as a yellow solid (110 mg, 28% yield). Mass spectrum m/z 339, 341 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 7.78 (dd, J=7.9, 1.5 Hz, 1H), 7.67 (dd, J=8.1, 1.5 Hz, 1H), 7.57 (dd, J=8.0, 1.4 Hz, 1H), 7.53 (d, J=1.3 Hz, 1H), 7.38 (ddd, J=8.4, 7.1, 1.4 Hz, 1H), 7.32 (t, J=8.0 Hz, 1H), 6.70 (d, J=8.4 Hz, 1H), 6.68-6.61 (m, 1H), 2.79 (d, J=5.1 Hz, 3H).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[N+](C1C=C(S(O[CH2:26][C@:27]2([CH3:30])[CH2:29][O:28]2)(=O)=O)C=CC=1)([O-])=O.C(N(CC)CC)C>ClCCl>[CH3:26][C@@:27]1([CH2:30][O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH2:29][O:28]1
Reactant: C[C@@]1(COS(=O)(=O)c2cccc([N+](=O)[O-])c2)CO1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@]1(CON2C(=O)c3ccccc3C2=O)CO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.6 %

Procedure:
A mixture of N-hydroxypthalimide (5.3 g), [(2S)-2-methyloxiran-2-yl]methyl 3-nitrobenzenesulfonate (5.9 g) and triethylamine (10.6 ml) in dichloromethane (15 ml) was stirred under nitrogen at ambient temperature for 24 hours. The reaction mixture was poured onto a silica column and eluted with dichloromethane to give the sub-title compound as a colourless solid (3.1 g).
Reaction SMILES: Cl[CH2:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[N:15][C:16](=[O:19])[NH:17][CH:18]=1.C(N(CC)CC)C>ClCCl>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:2][N:17]2[CH:18]=[C:13]([C:12]([F:20])([F:21])[F:11])[CH:14]=[N:15][C:16]2=[O:19])=[CH:5][CH:6]=1
Reactant: ClCOc1ccc(Cl)cc1
Reactant: O=c1ncc(C(F)(F)F)c[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1ncc(C(F)(F)F)cn1COc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A solution of 1-chloromethoxy-4-chloro-benzene [see Preparation 11](0.35 mmol) in dichloromethane (1 ml) was added with stirring at room temperature to a solution prepared from 5-trifluoromethyl-pyrimidin-2-one (0.33 mmol) and triethylamine (0.33 mmol) in dichloromethane (5 ml). The mixture was stirred at room temperature for 24 h and then it was stirred at 70° C. for 30 min, the solvent was then distilled off, the residue triturated with water, the residual material extracted with chloroform and the dried (MgSO4) chloroform solution evaporated to yield the product, 60 mg (62%), as a mixture of the N- and O-isomers in the ratio 5:1. The isomers were separated by their different solubilities in ether, the O-isomer being the more soluble. The title compound, the N-isomer had m.p. 98° C. (Found C46.78; H2.88. Calc. for C12H8ClF3N2O3 : C47.30; H2.65) 1H NMR (CDCl3); δ 5.85 (CH2), 6.8-7.4 (Ph), 8.15 (H-4, J4.6 3 Hz) 8.76 (H-6) MS [70 eV; m/z (% rel. int.)]; 177 (100), 150(10), 75(5), IR (KBr); 1690 cm-1 (CO).
Reaction SMILES: [CH:1]([OH:14])([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.O[CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:1]([O:14][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCNCC1
Reactant: OC(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a round bottom flask, benzhydrol (1.84 g, 10 mmol, 1.0 eq.), 4-hydroxypiperidine (1.01 g, 10 mmol, 1.0 eq.), and p-toluenesulfonic acid monohydrate (2.09 g, 1.1 eq.) were suspended in toluene (400 ml). The mixture was refluxed with a Dean-Stark condenser for 3-4 hours. After cooling to room temperature, the solution was washed with 5% NaOH solution (2×20 ml), then with water (2×20 ml). The solution was then dried over anhydrous Na2SO4. The solvent was then removed under vacuum. The crude product, 4-benzhydryloxy-piperidine was obtained (2.46 g, 92.0% yield). 1H-NMR (CDCl3, ppm): 7.10-7.25 (m, 10H), 5.41 (s, 1H), 3.48 (m, 1H), 3.13 (m, 2H), 2.78 (m, 2), 1.86 (m, 2H), 1.66 (m, 2H). ESMS 268.1 (M+1), 290.1 (M+23).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.O[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1>CO.ClCCl>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([O:20][C:19](=[O:21])[CH2:18][O:17][C:14]2[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:16][N:15]=2)[CH:24]=1
Reactant: Oc1cccnc1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Solvent: CO
Solvent: ClCCl
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)Oc1cccnc1
Yield: 14 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 3-hydroxypyridine (12 mg, 0.13 mmol) as the source alcohol. Chromatography (5% methanol/dichloromethane) through SiO2 yielded 9 mg (14%) of the titled compound. ESI-MS m/z 391 (M+Na+), 367 (M−H−).
Reaction SMILES: [CH2:1]([SH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][SH:7].C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:32])[C:23]([CH3:31])([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH3:24])=[CH:18][CH:17]=1>CC(N(C)C)=O.C(OCC)(=O)C>[SH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][S:8][C:16]1[CH:17]=[CH:18][C:19]([C:22](=[O:32])[C:23]([CH3:24])([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[CH3:31])=[CH:20][CH:21]=1
Reactant: CC(C)(C(=O)c1ccc(Cl)cc1)N1CCOCC1
Reactant: SCCCCCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C(=O)c1ccc(SCCCCCCS)cc1)N1CCOCC1
Temperature: 85 °C
Reaction time: 18 h

Procedure:
10.0 g (0.066 mol) of 1,6-hexanedithiol are added to a suspension of 3.6 g (0.026 mol) of potassium carbonate in 15 ml of dimethylacetamide. The suspension is heated to 85° C., and a solution of 3.6 g (0.013 mol) of 1-(4-chlorophenyl)-2-methyl-2-morpholin-4-yl-propan-1-one in 20 ml of dimethylacetamide is added dropwise over 20 min. After stirring for 18 h, the reaction mixture is cooled, diluted with ethyl acetate (60 ml), and filtered. The filtrate is washed with water (3×50 ml), dried over MgSO4, and concentrated i.v. (85° C./5 mm Hg). The resulting oil is purified by flash chromatography on silica gel (hexane/ethyl acetate 85:15) to a pale yellow oil which crystallizes to a colorless solid upon standing. m.p. 61-64° C. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm] 1.31 (s, 6H), 1.35 (t, SH), 1.4-1.8 (m, 8H), 2.53 (q, 2H), 2.57 (t, 4H), 3.00 (t, 2H), 3.69 (t, 4H), 7.24 (d, 2H), 8.50 (d, 2H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([CH2:18][N:19]3[C:27]4[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=4)[CH:21]=[CH:20]3)[CH2:16][CH2:17][C@H:10]2[CH2:9]1)(OC(C)(C)C)=O.O>FC(F)(F)C(O)=O>[F:28][C:24]1[CH:23]=[C:22]2[C:27](=[CH:26][CH:25]=1)[N:19]([CH2:18][C@H:15]1[CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]3[CH2:17][CH2:16]1)[CH:20]=[CH:21]2
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@H](Cn3ccc4cc(F)ccc43)CC[C@H]2C1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc2c(ccn2C[C@@H]2CC[C@H]3CNCCN3C2)c1
Yield: 89.8 %

Procedure:
A solution of 3.0 g (7.75 mmol) of (7R,9aS)-2-BOC-7-(5-fluoroindol-1-yl)methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine in 200 mL of 70:30 trifluoroacetic acid:water was stirred at room temperature for 1 h. The mixture was concentrated in vacuo, basified with 15% sodium hydroxide and extracted with ethyl acetate (2×). The combined organics were dried (magnesium sulfate), filtered and evaporated to give 2.0 g (90%) of (7R,9aS)-7-(5-fluoroindol-1-yl)methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:49])[C:19]([C:24]3[N:25]=[C:26]([NH:29]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:27][CH:28]=3)=[N:20][O:21][CH:22]=[CH2:23])[C:15](=[O:50])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=[O:3])[CH3:2].[Na+].C(O)=O>O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:49])[C:19]([C:24]3[N:25]=[C:26]([NH2:29])[S:27][CH:28]=3)=[N:20][O:21][CH:22]=[CH2:23])[C:15](=[O:50])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: C=CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(COC(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: C=CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
1.612 g of the sodium salt of Example 35 was added to 4 ml of 98% formic acid and immediately after, 4 ml of distilled water were added thereto and the mixture was stirred for 15 minutes at 40° C. The heterogenous mixture was triturated for 30 minutes at room temperature and was vacuum filtered at 20° C. The filter was rinsed twice with 1.6 ml of 50% formic acid and the filtrate was evaporated to dryness. The residue was taken up in 5 ml of distilled w ater and the mixture was vacuum filtered at room temperature. The recovered product was rinsed with distilled water and then with ether and dried to obtain 300 mg of the syn isomer of 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-vinyloxyimino-acetamido]-ceph-3-eme-4-carboxylic acid. Reextraction of insolubles with 50% formic acid recovered another 0.214 g of the said product.
Reaction SMILES: [CH2:1]1[O:18][C:17]2[CH:16]=[CH:15][C:5]([O:6][C:7]3[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=3)=[CH:4][C:3]=2[O:2]1.Cl.[NH2:20][NH:21][C:22]([NH2:24])=[O:23].C([O-])(=O)C.[Na+]>C(O)C.O>[CH2:1]1[O:18][C:17]2[CH:16]=[CH:15][C:5]([O:6][C:7]3[CH:14]=[CH:13][C:10]([CH:11]=[N:20][NH:21][C:22]([NH2:24])=[O:23])=[CH:9][CH:8]=3)=[CH:4][C:3]=2[O:2]1
Reactant: O=Cc1ccc(Oc2ccc3c(c2)OCO3)cc1
Reactant: NNC(N)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=O)NN=Cc1ccc(Oc2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
To a solution of 4-(3,4-methylenedioxyphenoxy)benzaldehyde (1.7 g, 7.0 mmol) in ethanol (40 mL) was added a solution of semicarbazide hydrochloride (0.82 g, 7.1 mmol) and sodium acetate (0.55 g, 6.7 mmol) in water (10 mL). The mixture was stirred at room temperature for 30 min. The resulting white solid was collected by filtration, washed with water and dried in vacuo to yield the title compound (1.2 g, 4.0 mmol, 57%), mp: 225-226° C. 1H NMR (DMSO-d6): δ 10.17 (s, 1H), 7.80 (s, 1H), 7.70 (d, J=8.7, 2H), 6.93 (d, J=8.3, 1H), 6.92 (d, J=8.7, 2H), 6.77 (d, J=2.4, 1H), 6.53 (dd, J=2.4, 8.3, 1H), 6.44 (s, 2H), 6.06 (s, 2H).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[CH2:20]([NH:22][CH2:23][CH2:24][CH:25]1[O:30][CH2:29][CH2:28][NH:27][CH2:26]1)[CH3:21]>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:27]3[CH2:28][CH2:29][O:30][CH:25]([CH2:24][CH2:23][NH:22][CH2:20][CH3:21])[CH2:26]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: CCNCCC1CNCCO1
Product: CCNCCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(CC)c3c2F)CCO1

Procedure:
By the use of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2-(2-ethylaminoethyl)morpholine, the reaction is similarly carried out as Example 1 to give 1-ethyl-7-[2-(2-ethylaminoethyl)morpholino]-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.