Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([NH:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[CH2:11]([N:18]([CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24])[C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[Cl:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: CC(C)(C)[Si](C)(C)OCCNCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCN(Cc1ccccc1)C(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 58.3 %

Procedure:
To a solution of 2-chloronicotinic acid (7.88 g), N-benzyl-2-{[tert-butyl(dimethyl)silyl]oxy}ethanamine (13.3 g) synthesized by known method (e.g., the method described in WO99/31085) and HOBt.H2O (11.5 g) in DMF (50 mL) was added WSC.HCl (14.4 g), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient; 10→33% ethyl acetate/hexane) to give N-benzyl-N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-chloronicotinamide (11.8 g, 58%) as a colorless oil.
Reaction SMILES: [SH:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:14])[N:3]=1.[O-]Cl.[Na+].[OH-].[NH4+:19]>[OH-].[Na+].O>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[N:3]=[C:2]([S:1][NH2:19])[S:6][N:5]=1
Reactant: COc1ccccc1-c1nsc(S)n1
Reactant: [NH4+]
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: O
Product: COc1ccccc1-c1nsc(SN)n1
Reaction time: 0.17 h

Procedure:
A solution of 4.6 g of 5-mercapto-3-(2-methoxyphenyl)-1,2,4-thiadiazole in 70 ml of 5% sodium hydroxide and a solution prepared by diluting 44 ml of 5.25% NaOCl to 70 ml with water were added dropwise simultaneously to 190 ml of ammonium hydroxide solution while maintaining the mixture at 0° with an ice/methanol bath. The resulting mixture was stirred for 10 minutes and the solids were collected, washed with water and dried under high vacuum (with P2O5) to give 3.0 g of solid, m.p. 136°-138° C. dec.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Cl:12][C:13]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:14]=1[CH:15]=[CH:16][N+]([O-])=O.[N+:25]([CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])#[C-:26]>C1COCC1>[Cl:12][C:13]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:14]=1[C:15]1[CH:16]=[CH:26][NH:25][C:27]=1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]
Reactant: [C-]#[N+]CC(=O)OCc1ccccc1
Reactant: O=[N+]([O-])C=Cc1ccc(Cl)cc1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1[nH]ccc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 15 %

Procedure:
DBU (1 eq) was added to a stirred solution of 2,4-Dichloronitrostyrene (1) (1 eq) and benzyl 2-isocyanoacetate (0.9 eq) in THF at −78° C. under N2. The reaction was allowed to warm to room temperature over 2 h. The reaction could be followed by TLC eluting with CHCl3 (Rf=0.3). After stirring for an additional 12 h, the reaction was diluted with CH2Cl2 and EtOAc. The organic mixture was washed with 0.1 N HCl, water, sat. aq. NaHCO3, brine, dried (Na2SO4), filtered and concentrated under reduced pressure to an oil. The crude product was purified using silica column chromatography eluting with CHCl3 to obtain pure phenylmethyl 3-(2,4-dichlorophenyl)pyrrole-2-carboxylate (2) (15% yield).
Reaction SMILES: [CH:1]1[C:6]2[C:7](=O)[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[N:17]1([C:7]2[C:6]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: O=C1Nc2ccccc2Sc2ccccc21
Reactant: C1CNCCN1
Product: c1ccc2c(c1)N=C(N1CCNCC1)c1ccccc1S2
Yield: 10.5 %

Procedure:
10H-Dibenzo[b,f][1,4]thiazepin-11-one (23 mg, 0.1 mmol) and piperazine (43 mg, 0.5 mmol) were reacted according to GP4 to give 3.1 mg of the title compound (160FE17A). MS (ESI) 296 (MH+). Purity for MH+ (UV/MS) 97/90.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH:15]([CH2:33][CH3:34])[CH2:16][O:17][CH2:18][CH2:19][CH:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl>>[NH:23]1[CH2:24][CH2:25][CH:20]([CH2:19][CH2:18][O:17][CH2:16][CH:15]([N:14]2[C:10]3[C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[N:3]=[C:2]([NH2:1])[C:11]=3[N:12]=[CH:13]2)[CH2:33][CH3:34])[CH2:21][CH2:22]1
Reactant: CCC(COCCC1CCN(C(=O)OC(C)(C)C)CC1)n1cnc2c(N)nc3ccccc3c21
Agent: Cl
Product: CCC(COCCC1CCNCC1)n1cnc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 14 h
Yield: 64.8 %

Procedure:
Under a nitrogen atmosphere, tert-butyl 4-{2-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butoxy]ethyl}piperidine-1-carboxylate (1.00 g, 2.1 mmol) and 2N ethanolic hydrochloric acid (10 ml, 20 mmol) were combined and the solution was stirred at ambient temperature for 14 hours. The solvent was removed in vacuo and the resulting tan solid was dissolved in water. Saturated aqueous sodium carbonate was added until the pH reached 10. After extraction with dichloromethane (3×), the organic fractions were combined, washed with brine, dried (Na2SO4), filtered, and the majority of the solvent was removed in vacuo. Hexane was added to form a precipitate. Vacuum filtration yielded 0.5 g of 1-{1-[(2-piperidin-4-ylethoxy)methyl]propyl}-1H-imidazo[4,5-c]quinolin-4-amine as a tan powder. 1H-NMR (300 MHz, DMSO-d6): δ8.34 (bs, 1H), 8.19 (d, J=8.49 Hz, 1H), 7.61 (dd, J=8.31, 1.13 Hz, 1H), 7.45-7.39 (m, 1H), 7.25-7.19 (m, 1H), 6.55 (s, 2H), 5.25-5.15 (m, 1H), 4.00-3.80 (m, 2H), 3.5-3.3 (m, 2H), 2.8-2.64 (m, 2H), 2.22-2.11 (m, 2H), 2.09-1.99 (m, 2H), 1.8-1.63 (bs, 1H), 1.37-1.0 (m, 5H), 0.95-0.7 (m, 5H); 13C-NMR (75 MHz, DMSO-d6): δ152.8, 145.8, 140.6, 133.0, 127.8, 127.0, 126.9, 121.3, 121.0, 115.5, 71.8, 68.1, 58.4, 46.1, 36.3, 33.1, 32.7, 24.5, 9.9; MS (CI) m/e 368.2459 (368.2450 calcd for C21H30N5O).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH2:11][NH:12][CH3:13])[C:3]=1[OH:14].CCN(C(C)C)C(C)C.[CH2:24]([O:31][C:32]([O:34]N1C(=O)CCC1=O)=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[F:1][C:2]1[C:3]([OH:14])=[C:4]([CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1)[CH2:11][N:12]([CH3:13])[C:32](=[O:34])[O:31][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CNCc1cc([N+](=O)[O-])cc(F)c1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(Cc1cc([N+](=O)[O-])cc(F)c1O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.3 %

Procedure:
To a flask containing 27A (1.6 g, 7.99 mmol), DIEA (2.088 ml, 11.99 mmol) in DMF (10 ml), was added N-(benzyloxycarbonyloxy) succinimide (2.19 g, 8.79 mmol). The mixture was stirred at rt for 1 h. The reaction was quenched with H2O and then extracted with EtOAc (3×). The organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude was purified by flash column chromatography (0-60% EtOAc/hexanes) to give 27B (1.8 g, 5.38 mmol, 67.4% yield). MS (ESI) m/z: 335.2 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11].[OH:13][C:14]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:13][C:14]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:19][CH2:18][N:17]([C:2]2[N:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=2[N+:10]([O-:12])=[O:11])[CH2:16][CH2:15]1
Reactant: Cc1nc(Br)c([N+](=O)[O-])c(=O)[nH]1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(N2CCC(O)(c3ccccc3)CC2)c([N+](=O)[O-])c(=O)[nH]1

Procedure:
In analogy to the procedure described in example 1, the 6-bromo-2-methyl-5-nitro-3H-pyrimidin-4-one (as prepared in Eur. Pat. Appl. EP 1 074 549 A2) was treated with the 4-hydroxy-4-phenylpiperidine in N,N-dimethylformamide in the presence of potassium carbonate at room temperature to yield the 6-(4-hydroxy-4-phenyl-piperidin-1-yl)-2-methyl-5-nitro-3H-pyrimidin-4-one as yellow solid; m.p.>250° C. (decomposition); MS: [M+H]+=331.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([C@@:7]([CH3:14])([CH2:11][CH2:12][CH3:13])[C:8](O)=[O:9])[CH3:6]>>[CH2:5]([C@@:7]([CH3:14])([CH2:11][CH2:12][CH3:13])[C:8]([Cl:3])=[O:9])[CH3:6]
Reactant: CCC[C@](C)(CC)C(=O)O
Reactant: O=S(Cl)Cl
Product: CCC[C@](C)(CC)C(=O)Cl
Temperature: 100 °C

Procedure:
121 μl (1.66 mmol) of thionyl chloride were added to 60 mg (0.42 mmol) of (-)-(2S)-2-ethyl-2-methylpentanoic acid [prepared as described in Preparation 16], and the resulting mixture was heated at 100° C. for one hour. At the end of this time, the mixture was concentrated by evaporation under reduced pressure. The whole of the (-)-(2S)-2-ethyl-2-methylvaleryl chloride obtained in this manner was added, directly and without purification, to a solution of 458 mg (0.83 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], 203 mg (1.66 mmol) of 4-(N,N-dimethylamino)pyridine, a catalytic amount (20 mg) of 4-dimethylaminopyridine and 232 μl of triethylamine in 2.5 ml of toluene, and the resulting mixture was heated under reflux for 24 hours. At the end of this time, the reaction mixture was cooled to room temperature and then mixed with 10 ml of a 10% w/v aqueous solution of hydrogen chloride. The aqueous mixture was extracted three times, each time with 20 ml of ethyl acetate. The combined extracts were then washed with a saturated aqueous solution of sodium chloride, after which the washed solution was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting pale-yellow oily residue was purified by flash column chromatography through silica gel, using a 5:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 88 mg (31% yield) of the title compound as a foam-like substance.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[C:25]([O:29][C:30]([NH:32][C@H:33]([C:44](O)=[O:45])[C@@H:34]([CH3:43])[O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([N:5]([C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:44]([C@@H:33]([NH:32][C:30]([O:29][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:31])[C@H:34]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH3:43])=[O:45])[CH2:1][CH:2]([CH3:3])[CH3:4])(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCN)C(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)OCc2ccccc2)C(=O)O)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-L-lysine (100 mg, 0.29 mmol, example 1, step E) as described in general procedure Bc using commercially available Nα-tert-butoxycarbonyl-O-benzyl-L-threonine (93 mg, 0.3 mmol). The final product was triturated with ether to yield 195 mg (98%) of the desired material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:13])[C:11]=1F)[N:8]([CH:14]1[CH2:16][CH2:15]1)[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20].[CH3:21][CH:22]1[CH2:27][NH:26][CH2:25][CH2:24][NH:23]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:13])[C:11]=1[N:26]1[CH2:25][CH2:24][NH:23][CH:22]([CH3:21])[CH2:27]1)[N:8]([CH:14]1[CH2:16][CH2:15]1)[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20]
Reactant: CC1CNCCN1
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(Cl)cc2c1=O
Product: CC1CN(c2c(Cl)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)CCN1

Procedure:
The product from Example C is reacted with 2-methyl-piperazine analogously to Example B1 to give 6,8-dichloro-1cyclopropyl-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid of melting point 288°-291° C. (with decomposition).
Reaction SMILES: [C:1]1([C:7]([OH:11])([C:9]#[CH:10])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1/[C:15](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:16](=[O:22])[NH:17]2>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:11][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:8])[C:9]#[C:10][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1/[C:15](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:16](=[O:22])[NH:17]2
Reactant: C#CC(C)(O)c1ccccc1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(C)(O)c3ccccc3)c21

Procedure:
Using Method C above, 2-phenyl-3-butyn-2-ol (70 mg, 0.48 mmol) (Aldrich) was coupled to (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (146 mg, 0.4 mmol) (Starting Material 2) using (Ph3P)2PdCl2 (20 mg) (Aldrich) and CuI (10 mg) (Aldrich) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 15 h, yielding rac-(Z)-1,3-dihydro-4-[3-hydroxy-3-phenyl-1-butynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 85 mg, 55%).
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([OH:14])[CH:5]=1)([CH3:3])[CH3:2].O[CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(Cl)Cl>[C:26]([O:25][C:23]([N:19]1[CH2:20][CH2:21][CH2:22][CH:17]([CH2:16][O:14][C:6]2[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:13]=[CH:12][C:7]=2[C:8]([O:10][CH3:11])=[O:9])[CH2:18]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: COC(=O)c1ccc(C(C)C)cc1O
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)C)cc1OCC1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.6 %

Procedure:
The methyl 4-isopropyl-2-hydroxybenzoate (4.4 g, 22.7 mmol) was dissolved in THF (100 mL). Then 3-(hydroxy-methyl)-1-tert-butoxycarbonylpiperidine (4.88 g, 22.7 mmol) and triphenylphosphine (7.14 g, 27.24 mmol) were added. The mixture was placed in an ice bath, and then diisopropyl azodicarboxylate (4.59 g, 22.7 mmol) in methylene chloride (15 mL) was added dropwise. The reaction mixture was allowed to warm gradually to room temperature. After 16 h, the solvent was removed under vacuum. The solid residue was subjected directly to flash chromatography on silica (0 to 30% EtOAc in hexane gradient), giving the title compound (3.34 g, 43% yield) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([SH:16])=[N:12][CH:11]=2)=[CH:4][CH:3]=1.Br[CH2:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[Br:28].[OH-].[Na+].O>C(O)C>[Br:28][C:21]1[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:20]=1[CH2:19][S:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:17])=[CH:11][N:12]=1
Reactant: O=C(Nc1ccc(F)cc1)c1ccc(S)nc1
Reactant: COc1ccc(Br)c(CBr)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(Br)c(CSc2ccc(C(=O)Nc3ccc(F)cc3)cn2)c1
Yield: 99 %

Procedure:
As described in Method A, N-(4-fluoro-phenyl)-6-mercapto-nicotinamide IIa (745 mg, 3 mmol, 1 eq.) and 2-bromomethyl-4-methoxyphenyl bromide (0.84 g, 3 mmol, 1 eq.) were suspended in ethanol (36 ml). To the suspension, 1 N sodium hydroxide (5.1 ml, 6 mmol, 2 eq.) was added, and the reaction mixture heated to gentle reflux for 2 hours, then water (200 ml) was added to the reaction mixture while still hot. Upon cooling, a white precipitate formed, and this was filtered, washed with 50% aqueous ethanol, then water and dried in the oven to afford 1.33 g (99% yield, >95% purity by LC-MS) of 6-(2-bromo-5-methoxy-benzylsulfanyl)-N-(4-fluoro-phenyl)-nicotinamide, intermediate VII, as an off-white solid. ESI-MS m/z=448.9 [M+H]+.
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1(C)C=CC=CC=1>[C:28]([NH:1][C:2]1[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Reactant: O=C(Cl)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In toluene (10 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (0.7 g) and triethylamine (1 ml), and benzoyl chloride (0.3 g) was gradually added thereto and the mixture was stirred at room temperature for 3 hours.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[SH:19][C:20]1[CH:25]=[C:24]([CH3:26])[N:23]2[N:27]=[CH:28][C:29]([C:30]([OH:32])=[O:31])=[C:22]2[N:21]=1.B(F)(F)F.O>C(#N)C>[NH2:13][C@@H:10]1[C:11](=[O:12])[N:8]2[C@@H:9]1[S:14][CH2:15][C:6]([CH2:5][S:19][C:20]1[CH:25]=[C:24]([CH3:26])[N:23]3[N:27]=[CH:28][C:29]([C:30]([OH:32])=[O:31])=[C:22]3[N:21]=1)=[C:7]2[C:16]([OH:18])=[O:17]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Cc1cc(S)nc2c(C(=O)O)cnn12
Agent: FB(F)F
Solvent: CC#N
Solvent: O
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](N)[C@H]3SC2)nc2c(C(=O)O)cnn12
Reaction time: 1.5 h

Procedure:
A suspension of 4.00 g of (7R)-7-aminocephalosporanic acid and 3.34 g of 5-mercapto-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid in 20 ml of acetonitrile was treated with 25 ml of a 20 percent solution of boron trifluoride in acetonitrile and the mixture was stirred at 20° for 1.5 hours. 150 ml of cold water were added and the mixture was stirred at 0° for 1.5 hours. The precipitate was filtered off under suction and dried. There was obtained (6R,7R)-7-amino-3-[[(3-carboxy-7-methylpyrazolo[1,5-a]pyri-midine-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid as an almost colorless powder.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:13]([O:17][CH3:18])(=[O:16])[CH:14]=[CH2:15].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CC([O-])=O.CC([O-])=O.[Pd+2].C(#N)C>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:2]=1/[CH:15]=[CH:14]/[C:13]([O:17][CH3:18])=[O:16]
Reactant: Nc1ccc(C(F)(F)F)cc1Br
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)/C=C/c1cc(C(F)(F)F)ccc1N
Temperature: 90 °C
Yield: 36.5 %

Procedure:
A 100 ml 3-neck flask with magnetic stirrer was charged with 2-bromo-4-(trifluoromethyl)aniline (500 mg, 2.08 mmol), methyl acrylate (538 mg, 6.25 mmol), Pd(OAc)2 (23.3 mg, 0.104 mmol), P(o-tolyl)3 (64 mg, 0.21 mmol), triethylamine (422 mg, 4.7 mmol) and acetonitrile (20 ml). The flask was purged with N2 and heated to 90° C. overnight. Saturated aqueous NH4Cl (40 ml) was added, and the mixture was extracted with ethyl acetate (10 ml*3). The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by silica gel chromatography to give (E)-methyl 3-(2-amino-5-(trifluoromethyl)phenyl)acrylate (185.9 mg, 36.5%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J=16 Hz, 1H), 7.53 (s, 1H), 7.32 (d, J=8.8 Hz, 1H), 6.67 (d, J=8.8 Hz, 1H), 6.34 (d, J=16 Hz, 1H), 4.20 (s, 2H), 3.74 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[C:11]([C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1)(=O)[CH3:12].CC([O-])(C)C.[K+]>C1COCC1>[Cl:10][C:6]1[CH:7]=[CH:8][N:9]=[C:2]2[C:3]=1[CH:4]=[CH:12][C:11]([C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1)=[N:1]2
Reactant: CC(=O)c1ncccc1C
Reactant: Nc1nccc(Cl)c1C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cccnc1-c1ccc2c(Cl)ccnc2n1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
Dissolve 2-amino-4-chloronicotinaldehyde (156 mg, 1.0 mmol) and 2-acetyl-3-methylpyridine (136 mg, 1.0 mmol) in anhydrous THF (5.0 mL) and cool it to −20° C. under N2 atmosphere. Add in portion t-BuOK (224 mg, 2.0 mmol) to the reaction mixture and stir the mixture at 110° C. for 2 hours. Concentrate the reaction mixture under vacuum, dilute the residue with water (10 mL), filter the solid, wash the solid with water and dry under high vacuum to afford the title product as a yellow colored solid.
Reaction SMILES: C[O-].[Na+].Cl.[C:5]([NH2:8])(=[NH:7])[CH3:6].[CH3:9][O:10][CH:11]([O:20][CH3:21])[CH:12]([CH:15](OC)OC)[C:13]#[N:14]>CO>[CH3:6][C:5]1[N:8]=[C:13]([NH2:14])[C:12]([CH:11]([O:20][CH3:21])[O:10][CH3:9])=[CH:15][N:7]=1
Reactant: COC(OC)C(C#N)C(OC)OC
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1cnc(C)nc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
In the same reaction apparatus as in Example 9, there was placed 11.6 g (60 mmoles) of a 28 wt. % solution of sodium methylate in methanol. Thereto was added with stirring 5.67 g (60 mmoles) of acetamidine hydrochloride, and the mixture was stirred at room temperature for one hour. Subsequently, 9.45 g (50 mmoles) of 2-dimethoxymethyl-3,3-dimethoxypropanenitrile was added thereto and the mixture was heated and refluxed for 5 hours. After completion of the reaction, the reaction mixture was cooled and the insoluble sodium chloride was removed by filtration. The filtrate was analyzed by gas chromatography according to the internal standard method. As the result, it was confirmed that 8.51 g (yield: 93%) of 2-methyl-4-amino-5-dimethoxymethylpyrimidine had been formed.
Reaction SMILES: [NH2:1][CH:2]([CH2:13][CH2:14][CH:15]([OH:28])[CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C:3]([N:5]1[CH2:12][CH2:11][CH2:10][C@H:6]1[C:7]([OH:9])=[O:8])=[O:4].[C:29]1([CH2:35][CH2:36][C:37](=O)[C:38]([OH:40])=[O:39])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[OH-].[Na+].C([BH3-])#N.[Na+]>C(O)C.O>[CH2:21]([O:20][C:18]([NH:17][CH2:16][CH:15]([OH:28])[CH2:14][CH2:13][CH:2]([NH:1][CH:37]([C:38]([OH:40])=[O:39])[CH2:36][CH2:35][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:3]([N:5]1[CH2:12][CH2:11][CH2:10][C@H:6]1[C:7]([OH:9])=[O:8])=[O:4])=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NC(CCC(O)CNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(O)C(=O)CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(NCC(O)CCC(NC(CCc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O)OCc1ccccc1
Reaction time: 1 h

Procedure:
Compound VI and 4-phenyl-2-oxobutanoic acid (5 eq) were mixed with water (10 ml) and concentrated NaOH was added to raise the pH to 7.5. Ethanol was added (10 ml) and a solution of sodium cyanoborohydride (3 eq) in ethanol (4 ml) was added dropwise over 15 hours. Dowex 50W-2X (H+) (25 cc) was added with stirring. After 1 hour, the slurry was added to a column of Dowex (50 cc), the column was washed with ethanol and water and the product was eluted with 3% pyridine in water. After concentration and purfication over an LH-20 column, freeze drying gave V.