Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([S:12][CH2:13][CH3:14])[C:8](C(O)=O)=[C:7]2[OH:18]>C1(OC2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([S:12][CH2:13][CH3:14])[CH:8]=[C:7]2[OH:18]
Reactant: CCSc1nc2c(Cl)cccc2c(O)c1C(=O)O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCSc1cc(O)c2cccc(Cl)c2n1
Temperature: 250 °C
Yield: 85.2 %

Procedure:
8-Chloro-2-ethylsulfanyl-4-hydroxy-quinoline-3-carboxylic acid (17.17 g, 60.52 mmol) was suspended in diphenyl ether (250 mL) and heated to 250° C. for 30 minutes and the mixture was then cooled down to room temperature. The mixture was directly transferred onto a load cartridge and purified by column chromatography to afford 8-chloro-2-ethylsulfanyl-quinolin-4-ol (12.36 g, 85% yield). 1H NMR (CDCl3, 300 MHz) δ 8.25 (d, 1H), 7.70 (d, 1H), 7.32 (t, 1H), 6.52 (s, 1H), 3.18-3.11 (m, 2H), 1.54-1.44 (m, 3H). LCMS found 240.17 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:4][C:3]=1[O:17][CH2:18][C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1[F:26].[N:27]1([CH2:32][C@@H:33]2[CH2:37][CH2:36][CH2:35][NH:34]2)[CH2:31][CH2:30][CH2:29][CH2:28]1>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:34]3[CH2:35][CH2:36][CH2:37][C@H:33]3[CH2:32][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:14])=[CH:15][CH:16]=2)=[CH:4][C:3]=1[O:17][CH2:18][C:19]1[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=1[F:25]
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1OCc1c(F)cccc1F
Product: Nc1ncc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cc1OCc1c(F)cccc1F

Procedure:
{4-[6-Amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone was prepared from 4-[6-amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoic acid and (2S)-2-pyrrolidin-1-ylmethyl-pyrrolidine following procedure 4.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH:9]([NH2:12])([CH3:11])[CH3:10].CCN(CC)CC>C1COCC1>[Cl:8][C:4]1[N:3]=[C:2]([NH:12][CH:9]([CH3:11])[CH3:10])[CH:7]=[N:6][CH:5]=1
Reactant: CC(C)N
Reactant: Clc1cncc(Cl)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)Nc1cncc(Cl)n1
Temperature: 60 °C
Reaction time: 12 h
Yield: 52.1 %

Procedure:
To a mixture of 2,6-dichloropyrazine (5 g, 33.78 mmolm, Aldrich) and isopropyl amine (2.4 g, 50.67 mmol, Aldrich) in dry THF (5 mL) was added Et3N (2.5 mL) and the reaction was stirred at 60° C. for 12 h. The reaction was cooled to RT, treated with ice cold water (˜25 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was triturated with n-pentane to give 6-chloro-N-isopropylpyrazin-2-amine (3 g, 52.5%) as a white solid. MS (ESI, pos. ion) m/z: 172.0 (M+1); 1H-NMR (400 MHz, DMSO-d6): δ 7.81 (s, 1H), 7.64 (s, 1H), 7.46 (d, J=7.2 Hz, 1H), 3.93-3.88 (m, 1H), 1.15 (d, J=5.6 Hz, 6H).
Reaction SMILES: [Li+].[OH-].[CH3:3][C:4]1[CH:9]=[C:8]([C:10](=[O:13])[NH:11][CH3:12])[CH:7]=[C:6]([CH3:14])[C:5]=1[C:15]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]2[C:16]=1[CH2:17][CH2:18][C@H:19]2[O:25][C:26]1[CH:39]=[CH:38][C:29]2[C@H:30]([CH2:33][C:34]([O:36]C)=[O:35])[CH2:31][O:32][C:28]=2[CH:27]=1>C(O)C.O>[CH3:3][C:4]1[CH:9]=[C:8]([C:10](=[O:13])[NH:11][CH3:12])[CH:7]=[C:6]([CH3:14])[C:5]=1[C:15]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]2[C:16]=1[CH2:17][CH2:18][C@H:19]2[O:25][C:26]1[CH:39]=[CH:38][C:29]2[C@H:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:31][O:32][C:28]=2[CH:27]=1
Reactant: CNC(=O)c1cc(C)c(-c2ccc(F)c3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)OC)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CNC(=O)c1cc(C)c(-c2ccc(F)c3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
LiOH×H2O (3 mg) is added to a solution of methyl 2-((S)-6-((R)-4-(2,6-dimethyl-4-(methylcarbamoyl)phenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (20 mg) in ethanol (0.77 mL) and water (0.5 mL) and the mixture is stirred for 24 hours at room temperature. After concentration the mixture is diluted with water, acidified with aqueous citric acid solution and extracted with dichloromethane. The organic phase is dried (MgSO4) and the residue chromatographed on silica gel (cyclohexane/ethyl acetate 100:0→60:40) to give the title compound. Yield 11 mg, LC (method 20): tR=5.54 min; Mass spectrum (ESI+): m/z=490 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[CH:19][C:18]=2[CH3:30])=[C:13]([F:31])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].[OH-].[Na+]>C1COCC1>[F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[CH:19][C:18]=2[CH3:30])=[C:13]([F:31])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2C)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cccc(F)c2)cc1CNc1c(F)ccc(OCC(=O)O)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
To a stirred solution of ethyl 2-[2,4-difluoro-3-[[5-(3-fluorophenyl)-2-methyl-phenyl]methylamino]phenoxy]acetate (100 mg, 0.23 mmol, 1.0 eq) in THF (8 mL) was added NaOH (1M aqueous solution, 3 mL, 3 mmol, 13.0 eq) at room temperature. The reaction was stirred at room temperature for 2 h. The THF was evaporated in vacuo and the aqueous layer acidified to pH 3 by addition of 1M HCl. The resultant precipitate was collected by filtration and dried in vacuo to give the title compound (I(c)) as a white solid (85 mg, 91%).
Reaction SMILES: C([N:8]1[C:20]2[C:19]([O:21][CH2:22][CH2:23][CH2:24]Br)=[C:18]3[N:26](C(OC(C)(C)C)=O)[C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][C:32]=4[C:17]3=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([F:41])[CH:13]=2)(OC(C)(C)C)=O.[OH:42][C:43]1[CH2:47][CH2:46][NH:45][CH:44]=1>>[F:41][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:20]1[C:19]([O:21][CH2:22][CH2:23][CH2:24][N:45]3[CH2:46][CH2:47][CH:43]([OH:42])[CH2:44]3)=[C:18]3[NH:26][C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][C:32]=4[C:17]3=[CH:16][C:15]2=1
Reactant: CC(C)(C)OC(=O)n1c2ccc(F)cc2c2cc3c4cc(F)ccc4n(C(=O)OC(C)(C)C)c3c(OCCCBr)c21
Reactant: OC1=CNCC1
Product: OC1CCN(CCCOc2c3[nH]c4ccc(F)cc4c3cc3c2[nH]c2ccc(F)cc23)C1
Reaction time: 8 h
Yield: 90 %

Procedure:
The title compound was prepared in a manner analogous to Example 70 except the staring material is 5,7-diBOC-2,10-difluoro-6-(3-bromopropoxy)indolo[2,3-b]carbazole and the reagent is 3-hydroxypyrroline. The reaction can be completed at room temperature overnight. 1H-NMR (400 MHz, CDCl3) δ ppm 9.57 (br s, 2 H), 8.27 (s, 1 H), 7.71 (dd, J=9.2, 2.4 Hz, 2 H), 7.33 (dd, J=8.8, 4.0 Hz, 2H), 7.03 (td, J=8.8, 2.4 Hz, 2 H), 4.67-4.59 (m, 1 H), 4.40-4.26 (m, 2 H), 3.80 (t, J=5.6 Hz, 1 H), 3.15-3.00 (m, 2 H), 2.96-2.80 (m, 3 H), 2.73-2.61 (m, 1 H), 2.38-2.26 (m, 1 H), 2.12-1.93 (m, 2 H), 1.79-1.70 (m, 1 H); MS (ESI) m/z 434.2 (M−H)−; MS (ESI) m/z 436.1 (M+H)+
Reaction SMILES: C[Al](C)C.[CH2:5]([NH2:8])[CH2:6][NH2:7].C(O[C:12]([CH:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=O)C>C1(C)C=CC=CC=1>[NH:7]1[CH2:6][CH2:5][N:8]=[C:12]1[CH:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)C1Cc2ccccc2N1c1ccccc1
Reactant: NCCN
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: c1ccc(N2c3ccccc3CC2C2=NCCN2)cc1
Temperature: 25 °C

Procedure:
To a stirring solution of 2 molar trimethylaluminum in toluene (13.1 ml) at 10° C. under argon is added ethylenediamine (1.75 ml) dropwise under cooling to maintain a temperature of +10° C. It is allowed to warm to room temperature and then ethyl-2,3-dihydro-1-phenylindole-2-carboxylate (3.5 g) in toluene (15 ml) is added under argon. The whole is heated gradually to reflux and maintained at this temperature under argon for 18 hours. This cooled mixture is quenched in water (40 ml) and treated with methanol (40 ml) and methylene chloride (40 ml). The aqueous layer is separated and extracted further with methylene chloride (3×100 ml). The combined organic extracts are dried over sodium sulfate and concentrated to dryness at reduced pressure. The residue is dissolved in boiling ethyl acetate (150 ml), filtered through sodiumsulfate and concentrated to reduced pressure to a small volume from which yellow solid precipitates. The pure dl-2,3-dihydro-2-(4,5-dihydroimidazol-2-yl)-1-phenylindole, mp. 141°- 144°, is thus obtained.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:21]=[C:20]2[C:13]([NH:14][CH:15]=[C:16]2[CH2:17][CH2:18][NH2:19])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37])(OCC)=O>C(N(CC)CC)C>[CH2:2]([O:9][C:10]1[CH:21]=[C:20]2[C:13](=[CH:12][CH:11]=1)[NH:14][CH:15]=[C:16]2[CH2:17][CH2:18][N:19]1[C:31](=[O:32])[C:30]2[C:29](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:28]1=[O:37])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NCCc1c[nH]c2ccc(OCc3ccccc3)cc12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Yield: 99.3 %

Procedure:
To a stirred suspension of 5-benzyloxytryptamine hydrochloride (1.0 g in 10 mL of dry tetrahydrofuran) was added triethylamine (0.50 mL) followed by N-carbethoxyphthalimide (750 mg) and the mixture heated to reflux on an oil bath. After 48 hours the reaction was cooled to room temperature, filtered and the filtrate concentrated in vacuo. The resulting solid was suspended in a mixture of hexane/methylene chloride (2.5:1, 50 mL) and filtered to give the title compound (1.3 g).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C@@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1/[CH:14]=[CH:15]/[C:16]([O:18][CH3:19])=[O:17])[CH3:7].[F:20][C:21]1[CH:22]=[C:23]([CH:30]=[CH:31][C:32]=1[CH3:33])[CH2:24][C@@H:25]1[CH2:29][CH2:28][CH2:27][NH:26]1.Cl([O-])(=O)(=O)=O.[Li+].O>C1(C)C=CC=CC=1>[F:20][C:21]1[CH:22]=[C:23]([CH:30]=[CH:31][C:32]=1[CH3:33])[CH2:24][C@@H:25]1[CH2:29][CH2:28][CH2:27][N:26]1[CH2:3][C@@H:2]([OH:1])[CH2:4][O:5][C@@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1/[CH:14]=[CH:15]/[C:16]([O:18][CH3:19])=[O:17])[CH3:7]
Reactant: Cc1ccc(C[C@@H]2CCCN2)cc1F
Reactant: COC(=O)/C=C/c1ccccc1[C@@H](C)OC[C@H]1CO1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1ccccc1[C@@H](C)OC[C@H](O)CN1CCC[C@H]1Cc1ccc(C)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
A mixture of methyl (2E)-3-(2-{(1R)-1-[(2R)-oxiran-2-yl methoxy]ethyl}phenyl)prop-2-enoate (237 mg, 0.90 mmol) described in WO 2004/106280, (2S)-2-(3-fluoro-4-methylbenzyl)pyrrolidine (167 mg, 0.86 mmol), which had been obtained in Example 1 (1e), and lithium perchlorate (55 mg, 0.52 mmol) in toluene (9 mL) was stirred at room temperature for 16 hours. Water (10 mL) was added to the reaction solution, which was then extracted with ethyl acetate (10 mL×3). After that, the organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound as a yellow oily substance (238 mg, yield 61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][NH:5][C:4]=1/[CH:8]=[C:9]1\[C:10](=[O:27])[NH:11][C:12]2[C:17]\1=[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15]([N+:24]([O-])=O)=[CH:14][CH:13]=2.[Cl-].[NH4+]>O.CO.[Zn]>[NH2:24][C:15]1[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:27])/[C:9]/2=[CH:8]\[C:4]1[NH:5][CH:6]=[CH:7][C:3]=1[O:2][CH3:1]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(-c3ccccc3)c21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(-c3ccccc3)c21
Yield: 100 %

Procedure:
Using Method L above, (Z)-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-4-phenyl-2H-indol-2-one (30 mg, 0.08 mmol) (from Example 38 supra) was reduced with zinc (48.9 mg, 0.75 mmol) and ammonium chloride (9.4 mg, 0.18 mmol) in 10% water in methanol (10 mL) at reflux for 1 day to give (Z)-5-amino-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-4-phenyl-2H-indol-2-one (yield: 26.5 mg, 100%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([S:7]([C:10]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C(#N)C>[NH2:14][C:13]1[CH:15]=[CH:16][C:10]([S:7]([CH:4]2[CH2:3][CH2:2][N:1]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([OH:34])([C:26]([F:27])([F:28])[F:29])[C:30]([F:31])([F:32])[F:33])=[CH:23][CH:24]=3)[CH2:6][CH2:5]2)(=[O:9])=[O:8])=[CH:11][CH:12]=1
Reactant: Nc1ccc(S(=O)(=O)C2CCNCC2)cc1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CS(C)=O
Product: Nc1ccc(S(=O)(=O)C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.7 %

Procedure:
4-(Piperidin-4-ylsulfonyl)aniline (1.748 mmol, 420 mg), 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (1.748 mmol, 589 mg) and potassium carbonate (3.50 mmol, 483 mg) were combined in acetonitrile (5 mL). Dimethylsulfoxide (0.5 mL) was added and the reaction stirred at room temperature for 1.5 hours. The reaction mixture was filtered and filtrate was concentrated under vacuum. The residue was purified by SCX chromatography to give the title compound (700 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)=O.[NH3:14]>>[C:11]([C:9]1[CH:8]=[N:7][CH:6]=[C:5]([C:3](=[O:2])[NH2:14])[CH:10]=1)(=[O:13])[CH3:12]
Reactant: N
Reactant: COC(=O)c1cncc(C(C)=O)c1
Product: CC(=O)c1cncc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 5-acetyl-3-pyridinecarboxylic acid methyl ester (5.0 g) in 28% ammonia solution (30 ml) was stirred at room temperature for 2 hours. The resulting precipitate was collected by filtration to afford 3-acetyl-5-carbamoylpyridine (3.38 g).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]1[C:8]([CH3:14])=[N+:9]([O-:13])[CH:10]=[CH:11][CH:12]=1.[OH-].[Na+]>C(O)(=O)C>[CH3:5][O:6][C:7]1[C:8]([CH3:14])=[N+:9]([O-:13])[CH:10]=[CH:11][C:12]=1[N+:1]([O-:4])=[O:2]
Reactant: COc1ccc[n+]([O-])c1C
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1c([N+](=O)[O-])cc[n+]([O-])c1C
Reaction time: 8 h

Procedure:
8 ml of concentrated nitric acid are added in four portions of 2 ml each to 5.4 g of 3-methoxy-2-methylpyridine 1-oxide in 12 ml of glacial acetic acid at 80° C. in the course of 6 hours, the mixture is stirred at the same temperature overnight, a further 8 ml of nitric acid are added in three portions in the course of 6 hours and the mixture is stirred for a further 15 hours. After cooling, the mixture is poured onto ice (40 g) and brought to pH 6 with 10N sodium hydroxide solution, the by-product (3-methoxy-2-methyl-4-nitropyridine) which has precipitated out is filtered off and the filtrate is extracted four times with 50 ml of methylene chloride. After drying, the combined organic phases are concentrated completely and the residue is recrystallised from a little methylene chloride/petroleum ether. 4.2 g (57% of theory) of the title compound are obtained in the form of yellow crystals of m.p. 103°-104° C.
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([CH3:20])=[N:11][C:12]([CH3:19])=[CH:13][C:14]=1[C:15]([F:18])([F:17])[F:16])=O)(C)(C)C.[ClH:21]>CO>[ClH:21].[ClH:21].[NH2:8][C:9]1[C:10]([CH3:20])=[N:11][C:12]([CH3:19])=[CH:13][C:14]=1[C:15]([F:18])([F:16])[F:17]
Reactant: Cc1cc(C(F)(F)F)c(NC(=O)OC(C)(C)C)c(C)n1
Agent: Cl
Solvent: CO
Product: Cc1cc(C(F)(F)F)c(N)c(C)n1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
3-tert-Butoxycarbonylamino-2,6-dimethyl-4-trifluoromethylpyridine(21.12 g, 72.8 mmol) was dissolved in methanol (70 mL). 10% hydrochloric acid in methanol (140 mL) was added to the solution, followed by stirring for 12 hours at 60° C. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in a solvent mixture of ethyl acetate-ether, followed by collection through filtration and washing with ether, to thereby yield 3-amino-2,6-dimethyl-4-trifluoromethylpyridine dihydrochloride as a colorless powder (15.64 g, 82%).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:25][S:24][C@@H:9]2[C@H:10]([NH:13][C:14]([C@H:16]([NH2:23])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:15])[C:11](=[O:12])[N:8]2[C:7]=1[C:26]([OH:28])=[O:27])=O.[CH2:29]([N:31]1[C:36](=[O:37])[C:35](=[O:38])[NH:34][N:33]=[C:32]1[SH:39])[CH3:30]>>[NH2:23][C@H:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:14]([NH:13][C@@H:10]1[C:11](=[O:12])[N:8]2[C:7]([C:26]([OH:28])=[O:27])=[C:6]([CH2:5][S:39][C:32]3[N:31]([CH2:29][CH3:30])[C:36](=[O:37])[C:35](=[O:38])[NH:34][N:33]=3)[CH2:25][S:24][C@H:9]12)=[O:15]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)[C@H](N)c3ccccc3)[C@H]2SC1
Reactant: CCn1c(S)n[nH]c(=O)c1=O
Product: CCn1c(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)[C@H](N)c4ccccc4)[C@H]3SC2)n[nH]c(=O)c1=O

Procedure:
In a manner analogous to that described in Example 1 8.1 g of cephaloglycine and 3.78 g of 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine were reacted to yield 4.19 g (40.5%); of (7R)-7-[(R)-2-amino-2-phenylacetamido]-3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-3-cephem-4-carboxylic acid which was isolated as a Zwitter ion; yield 4.19g (40.5% melting point >180° (decomposition); [α]D20 = -86.3) (c = 0.276 in dimethylformamide).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[CH:14][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:17]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCC(=O)c1ccc(Br)cc1
Reactant: OB(O)c1cccc(F)c1
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: Cc1ccccc1
Product: COC(=O)CCC(=O)c1ccc(-c2cccc(F)c2)cc1

Procedure:
In a manner similar to Example 12, Step (b), (3-fluoro-phenyl)boronic acid (0.7698 g, 0.005502 mol) was allowed to react with 4-(4-bromo-phenyl)-4-oxo-butyric acid, methyl ester (1.356 g, 0.00500 mol) in the presence of tetrakis(triphenylphosphine)palladium(0) (0.173 g, 0.000150 mol) and 2.0 M aqueous sodium carbonate (5.0 mL, 0.010 mol) in toluene (10 mL) to give, after chromatography on silica gel (270 g, 230-400 mesh), eluting with chloroform (18×125 mL), 1.221 g of 4-(3′-fluoro-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester as a white solid; mp 99-101° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:22])[CH:9]([NH2:21])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[CH3:23][N:24]([CH3:38])[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[CH3:23][N:24]([CH3:38])[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35]([NH:21][CH:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[OH:22])=[O:36])=[CH:27][CH:26]=1
Reactant: CN(C)c1ccc(C(=O)O)c2ccccc12
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: CN(C)c1ccc(C(=O)NC(Cc2ccc(C(F)(F)F)cc2)C(O)c2ccc(F)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
To a solution of (1RS,2RS)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine (150 mg, 0.42 mmol) in acetonitrile (10 ml) were added 4-dimethylaminonaphthalenecarboxylic acid (89 mg, 0.42 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (119 mg, 0.62 mmol) and 1-hydroxy-1H-benzotriazole (63.6 mg, 0.42 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from ethyl acetate-hexane to give the title compound (149 mg, 70%).
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][C:15]=2[F:31])[CH2:10][CH2:9]1)=O)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[O:30]=[C:21]1[N:20]([C:17]2[CH:18]=[CH:19][C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)=[C:15]([F:31])[CH:16]=2)[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)C(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCNCC3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of (S)-(-)-4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-3,6-dihydro-1(2H)-pyridinecarboxylic acid 1,1-dimethylethyl ester (EXAMPLE 38, Step 1, 1.00 g) in dry methylene chloride (9.2 mL) at 0° C. under N2 is treated with trifluoroacetic acid (2.3 mL) over one minute, and the resulting mixture is stirred at 0° C. for three hours and added slowly to saturated aqueous potassium carbonate (30 mL) to neutralize excess trifluoroacetic acid. The resultant slurry is filtered and the precipitate is chromatographed on silica gel (70-230 mesh, 60 g), eluting with ammonium hydroxide/methanol/methylene chloride (0.25/19.75/80). Those fractions with an Rf =0.08 by TLC (methanol/chloroform, 20/80) are pooled and concentrated under reduced pressure to give the title compound, 1H NMR (MeOH-d4, 400 MHz) 7.47, 7.33, 7.25, 6.02, 4.80, 4.15, 3.83, 3.58, 3.47, 3.04, 2.46, 1.98 δ.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH2:35][CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: ClCCCN1CCCCC1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)cc2c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CCCN2CCCCC2)c2ccc(C#CCO)cc2c1=O
Temperature: 90 °C
Reaction time: 38 h

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 5 (0.367 g) is dissolved in DMF (10 mL), and K2CO3 (0.55 g) and N-(3chloropropyl)piperidine hydrochloride (0.408 g) are added. The reaction mixture is heated to 90° C. for 10 h, and then allowed to stir at room temperature for 38 h. Water is added and a precipitate formed. The precipitate is filtered and allowed to dry at room temperature and then under reduced pressure to give 0.187 g of a solid. The solid is dissolved in CHCl3 and filtered to remove 0.045 g of a precipitate. The filtrate is concentrated in vacuo and crystallized from ethyl acetate to give 0.065 g of the title compound as a solid.