Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl(O)(=O)(=O)=O.[C:23]1([CH3:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:10]([O:9][CH:1]1[CH2:2][CH:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:5][CH2:4][CH2:3][CH2:2][CH2:7][CH2:6][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:23][CH3:29])[O:17][C:10](=[O:9])[CH:11]1[CH2:12][CH3:13])(=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(OC(=O)c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1
Agent: [O-][Cl+3]([O-])([O-])O
Product: CCCCCCCCCCCCCCCCCC1CC(OC(=O)c2ccccc2)C(CC)C(=O)O1
Yield: 100 %

Procedure:
138.5 g of benzoic anhydride and subsequently 2.5 ml of perchloric acid 70% were added to a suspension of 191.3 g of the δ-lactone from c) in 1250 ml of toluene. After stirring for 2.5 hours the reaction mixture in toluene was extracted with 1N sodium hydroxide solution in 20% sodium chloride solution and then with saturated sodium chloride solution. The organic phases were combined, dried and evaporated. 243.4 g (100.0%) of rac-(2RS,3RS,5SR)-3-benzoyloxy-2-ethyl-5-heptadecyl-δ-valerolactone, m.p. 64.5°-66°, resulted.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[S:8][C:9]([C:11]#[C:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)=[CH:10][C:6]=2[C:5](=[O:21])[CH2:4][S:3]1(=[O:23])=[O:22].C(N(CC)CC)C.[Cl:31][C:32]1[CH:41]=[CH:40][C:35]([CH2:36][N:37]=[C:38]=[O:39])=[CH:34][CH:33]=1>CS(C)=O.Cl>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:36][NH:37][C:38]([C:4]2[S:3](=[O:22])(=[O:23])[N:2]([CH3:1])[C:7]3[S:8][C:9]([C:11]#[C:12][CH2:13][O:14][CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][O:16]4)=[CH:10][C:6]=3[C:5]=2[OH:21])=[O:39])=[CH:40][CH:41]=1
Reactant: CN1c2sc(C#CCOC3CCCCO3)cc2C(=O)CS1(=O)=O
Reactant: O=C=NCc1ccc(Cl)cc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1c2sc(C#CCOC3CCCCO3)cc2C(O)=C(C(=O)NCc2ccc(Cl)cc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.8 %

Procedure:
To a stirring solution of 1-methyl-6-(3-(tetrahydro-2H-pyran-2-yloxy)prop-1-ynyl)-1H-thieno[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide (Preparation 35, 0.64 g) and triethylamine (0.27 g) in DMSO (15mL) at ambient temperature is added 4-chloro-benzylisocyanate (0.45 g). The resulting red solution is stirred overnight at ambient temperature and diluted with 10% aqueous HCl (20 mL). The aqueous layer is extracted with EtOAc (3×25 ml). The combined organic layers are dried over MgSO4 and concentrated in vacuo. The residue is dissolved in EtOAc (15 mL) and allowed to stand at ambient temperature overnight. The resulting solid is collected by filtration, washed with EtOAc (10 ml) and dried in vacuo at 50° C. to afford 0.29 g (31%) of the title compound as a tan solid. Physical characteristics: 1H NMR (CDCl3) δ 1.58-1.82, 3.49, 3.60, 3.89, 4.50, 4.56, 4.86, 7.30, 7.42, 7.71, 15.62; IR (diffuse reflectance) 3353, 2945, 1615, 1581, 1541, 1493, 1431, 1366, 1345, 1308, 1296, 1276, 1183, 1119, 1031 cm−1; MS (EI) m/z 522 (M+). Anal. Found: C, 53.17; H, 4.49; N, 5.67.
Reaction SMILES: [Si:1]([O:18][C@@H:19]1[C@@H:23]([CH2:24][O:25][N:26]2C(=O)C3=CC=CC=C3C2=O)[O:22][C@@H:21]([N:37]2[CH:45]=[C:43]([CH3:44])[C:41](=[O:42])[NH:40][C:38]2=[O:39])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.CNN>C(Cl)Cl>[NH2:26][O:25][CH2:24][C@H:23]1[O:22][C@@H:21]([N:37]2[CH:45]=[C:43]([CH3:44])[C:41](=[O:42])[NH:40][C:38]2=[O:39])[CH2:20][C@@H:19]1[O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cn([C@H]2C[C@H](O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@@H](CON3C(=O)c4ccccc4C3=O)O2)c(=O)[nH]c1=O
Agent: CNN
Solvent: ClCCl
Product: Cc1cn([C@H]2C[C@H](O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@@H](CON)O2)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 12 h
Yield: 88.6 %

Procedure:
To a stirred solution of 3'-O-(t-butyldiphenylsilyl)-5'-O-phthalimidothymidine (10 g, 16 mmol), in dry CH2Cl2 (100 ml) was added methylhydrazine (1.3 ml, 24 mmol) under argon at room temperature and solution stirred for 12 h. The solution was cooled (0° C.) and filtered. The white residue was washed with CH2Cl2 (2×25 ml) and combined filtrates were evaporated to furnish gummy residue. The residue on purification by silica gel column chromatography (elution with CH2Cl2 :MeOH, 98:2, v/v) furnished 7.03 g (89%) of 5'-O-amino-3'-O-(t-butyldiphenylsilyl)thymidine that crystallized from CH2Cl2 /MeOH mp 141°-143° C. 1H NMR (DMSO-d6) δ 11.29 (s, 1, NH), 7.42-7.62 (m, 11, TBDPhH, C6H), 6.25 (dd, 1H1', J1',2' =8.4 Hz, J1',2" 6.3 Hz), 6.02 (s, 2, NH2), 4.35 (m, 1, H4'), 4.04 (m, 1, H3'), 3.34-3.51 (m, 2, H5',5"), 2.04 (m, 2, H2', 2"), 1.73 (s, 3, CH3), 1.03 (s, 9, C(CH3)3).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:21]([O:28][C:29](=[O:32])[CH2:30]Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl.CCOC(C)=O>[CH2:21]([O:28][C:29](=[O:32])[CH2:30][N:11]1[CH2:12][CH2:13][CH:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(CN1CCC(Cc2ccccc2)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a stirring solution of 4-benzylpiperidine (6) (2.00 g, 11.41 mmol) in dichloromethane (20 mL) at 0° C. was added triethylamine (1.59 mL, 11.41 mmol), followed by benzyl-2-bromoacetate (1.81 mL, 11.41 mmol). After 10 minutes a white precipitate was observed. The reaction mixture was allowed to warm to room temperature. After 45 minutes the reaction mixture was condensed to dryness in vacuo, redissolved in EtOAc (50 mL), the organic phase washed with saturated aqueous sodium hydrogen carbonate (50 mL), and saturated brine (50 mL). The organic phase was dried (MgSO4) and condensed to dryness to give (4-benzylpiperidin-1-yl)acetic acid benzyl ester (3.69 g, 100%) as a pale yellow oil:
Reaction SMILES: [CH3:1][NH:2]C(C1C(=O)C(C2C=CN=C(C(F)(F)F)C=2)=C(C)N(C(C2C=CC(Br)=CN=2)C)C=1)=O.[CH2:32]([NH:34][C:35]([C:37]1[C:42](=[O:43])[C:41]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([F:53])([F:52])[F:51])[CH:45]=2)=[C:40]([CH3:54])[N:39]([CH:55]([C:57]2[CH:62]=[CH:61][C:60](Br)=[CH:59][N:58]=2)[CH3:56])[CH:38]=1)=[O:36])[CH3:33]>>[CH2:32]([NH:34][C:35]([C:37]1[C:42](=[O:43])[C:41]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([F:53])([F:52])[F:51])[CH:45]=2)=[C:40]([CH3:54])[N:39]([CH:55]([C:57]2[CH:62]=[CH:61][C:60]([C:1]#[N:2])=[CH:59][N:58]=2)[CH3:56])[CH:38]=1)=[O:36])[CH3:33]
Reactant: CCNC(=O)c1cn(C(C)c2ccc(Br)cn2)c(C)c(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: CNC(=O)c1cn(C(C)c2ccc(Br)cn2)c(C)c(-c2ccnc(C(F)(F)F)c2)c1=O
Product: CCNC(=O)c1cn(C(C)c2ccc(C#N)cn2)c(C)c(-c2cccc(C(F)(F)F)c2)c1=O

Procedure:
Example 17 is prepared as described for Example 15, substituting preparation 15b with preparation 17b. ESI mass spectrum: [M+H]+=455; Retention time HPLC: 1.03 min (Z018_S04).
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[C:30]([NH2:35])[N:29]=[C:28]2[C:36]([N:38]1[CH2:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39]1)=[O:37])=[O:14])=O)(C)(C)C>O1CCOCC1.ClCCl>[ClH:1].[ClH:1].[NH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[C:30]([NH2:35])[N:29]=[C:28]2[C:36]([N:38]1[CH2:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39]1)=[O:37])=[O:14]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCCCC(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
250 μl of 4N HCl in dioxane are added to 300 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]-4,5-difluorobenzyl 4-tert-butoxycarbonylaminobutyrate in 5 ml of dichloromethane with ice-cooling. The mixture is subsequently stirred at 25° C. for a further 1 h, the precipitate is filtered off with suction and washed with 2 ml of dichloromethane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([C:28](O)=[O:29])[CH:23]=4)[NH:19][C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:31][NH:32][CH3:33]>>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1)[CH2:11][CH2:12][C:13]1[N:14]=[C:15]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]([N:32]([CH3:33])[CH3:31])=[O:29])[CH:23]=3)[NH:19][C:16]2=[N:17][CH:18]=1
Reactant: CNC
Reactant: COc1cc(CCc2cnc3[nH]c(-c4ccnc(C(=O)O)c4)cc3n2)cc(OC)c1
Product: COc1cc(CCc2cnc3[nH]c(-c4ccnc(C(=O)N(C)C)c4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 73, Step 3 starting from 4-{2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazin-6-yl}pyridine-2-carboxylic acid and N,N-dimethyl amine (2.0 M in THF). LCMS calculated for C24H26N5O3 (M+H)+: m/z=432.2. Found 432.2.
Reaction SMILES: [CH3:1][Sn:2](Cl)([CH3:4])[CH3:3].[C:6]1([CH3:14])[CH:11]=[CH:10][C:9]([Mg]Br)=[CH:8][CH:7]=1.[Cl-].[NH4+]>C1COCC1>[CH3:1][Sn:2]([CH3:4])([CH3:3])[C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:14])[CH:11]=1
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: C[Sn](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cccc([Sn](C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 21.5 g (100 mmol) trimethyltin chloride in 500 mL THF at -35° C. was added 113 mL (113 mmol) 1.0M p-tolylmagnesium bromide over 3 minutes. The mixture was allowed to warm to RT and stir for 1 hour after which time was added saturated aqueous ammonium chloride. The mixture was extracted three times with ether. The comined organic material was washed with brine, was dried over MgSO4, was stripped of solvent in vacuo, then was distilled at 0.1 Torr with the title compound distilling between 66°-74° C. The bitolyl remaining in the still pot crystallized upon cooling. The title compound was isolated as a clear, shiny liquid, 25.4 (92% yield).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:14])[C:4](=[O:13])[C@@H:5]([C@H:7]1[CH2:11][O:10][C:9](=[O:12])[NH:8]1)[CH3:6].Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H-].[Na+]>C1COCC1>[CH2:16]([N:8]1[C@@H:7]([C@@H:5]([CH3:6])[C:4]([N:3]([O:2][CH3:1])[CH3:14])=[O:13])[CH2:11][O:10][C:9]1=[O:12])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: CON(C)C(=O)[C@H](C)[C@H]1COC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CON(C)C(=O)[C@H](C)[C@H]1COC(=O)N1Cc1ccccc1
Reaction time: 2 h
Yield: 97.4 %

Procedure:
To a mixture of crude (R)—N-methoxy-N-methyl-2-((S)-2-oxooxazolidin-4-yl)propanamide (1.3 g, 6.43 mmol) and (bromomethyl)benzene (1.30 mL, 11.4 mmol) in THF (25 mL) was added slowly sodium hydride (60% wt.; 0.643 g) at 0° C. [Caution: gas development!]. The ice bath was removed and the mixture was stirred for ˜2 hr. The mixture were diluted carefully with water and ethyl acetate. The reaction was repeated on the same scale and the mixtures were combined. The aqueous layer was separated and extracted with ethyl acetate (1×). The combined organic layers were dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 80 g, EtOAc/heptane=5/95 to 75/25] to provide (R)-2-((S)-3-benzyl-2-oxooxazolidin-4-yl)-N-methoxy-N-methylpropanamide (1.83 g) as a slightly yellow oil, which contained also N-methoxy-N-methylisobutyramide. MS m/z 293.7 (M+H)+; Rt-0.64 min.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:6]=2[S:5][CH2:4][C:3]1=[O:13].[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl.S(Cl)(Cl)(=O)=O>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:6]=2[S:5][CH:4]([C:17]2[CH:18]=[CH:19][C:14]([OH:20])=[CH:15][CH:16]=2)[C:3]1=[O:13]
Reactant: Cc1ccc2c(c1)SCC(=O)N2C
Reactant: Oc1ccccc1
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: Cc1ccc2c(c1)SC(c1ccc(O)cc1)C(=O)N2C
Reaction time: 0.25 h
Yield: 69.6 %

Procedure:
To a stirred solution of 3,4-dihydro-4,7-dimethyl-3-oxo-2H-1,4-benzothiazine (11.0 g) in methylene chloride (50 ml), sulfuryl chloride (4.8 ml) is added under ice-cooling. After the addition, the mixture is stirred for 15 minutes under ice-cooling. Phenol (7.0 g) is added to the mixture, and the mixture is stirred for 45 minutes and concentrated in vacuo. Ether is added to the residue and the separated crystals are collected by filtration to give 11.3 g (69.4%) of the titled compound.
Reaction SMILES: [OH-].[Na+].[CH3:3][SH:4].Br[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[O:8]>CO.O1CCCC1>[CH3:3][S:4][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[O:8]
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: CS
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CSCC(=O)c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To 11.3 g (141 mmole) of 50% aqueous sodium hydroxide dissolved in 50 ml of methanol and cooled to -20° C. was added 7.7 g (160 mmole) of gaseous methyl mercaptan. To this solution was added 30.5 g (130 mmole) of 2-bromo-4'-chloroacetophenone dissolved in 40 g of tetrahydrofuran. After warming to room temperature and stirring for 30 minutes the mixture was concentrated in vacuo, partitioned between hexanes and water, dried over anhydrous magnesium sulfate, filtered, and reconcentrated in vacuo to yield 25.3 g of 2-methylthio-4'-chloroacetophenone, an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][N:12]=[C:13]([C:20](=[O:22])[CH3:21])[CH2:14][C:15](OCC)=[O:16])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:10]=[C:9]([N:11]2[C:15](=[O:16])[CH2:14][C:13]([C:20](=[O:22])[CH3:21])=[N:12]2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)CC(=NNc1ccc(C(=O)O)c(Cl)c1)C(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)C1=NN(c2ccc(C(=O)O)c(Cl)c2)C(=O)C1
Reaction time: 8 h

Procedure:
To a suspension of 1.9 gm. (5.8 mmoles) of 2-chloro-4-[N′-(2-ethoxycarbonyl-1-acetylethylidene)hydrazino]benzoic acid in 20 ml of ethanol was added at room temperature 6 ml. of aqueous 1M sodium carbonate. The mixture was left at room temperature overnight. The resulting mixture was acidifed to pH 3 with 6 M hydrochloric acid and the resulting solid collected by filtration and dried. The 2-chloro-4-(3-acetyl-5-oxo-2-pyrazolin-1-yl)benzoic acid had a melting point of >250° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:50]=[CH:49][C:9]2[N:10]([CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23]3[C:28]([C:29]5[CH:34]=[CH:33][C:32](F)=[CH:31][CH:30]=5)=[CH:27][CH:26]=[C:25]([C:36]([N:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)=[O:37])[CH:24]=3)[CH:17]=[CH:16]4)=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[CH3:51][O:52]C1C=CC(B(O)O)=CC=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:50]=[CH:49][C:9]2[N:10]([CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23]3[C:28]([C:29]5[CH:34]=[CH:33][C:32]([O:52][CH3:51])=[CH:31][CH:30]=5)=[CH:27][CH:26]=[C:25]([C:36]([N:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)=[O:37])[CH:24]=3)[CH:17]=[CH:16]4)=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc(F)cc4)ccc3c1)n2C1CCCCC1
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc(OC)cc4)ccc3c1)n2C1CCCCC1

Procedure:
Prepared as described for Compound 549a using 4-methoxyphenylboronic acid instead of 4-fluorophenylboronic acid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)C=O.[CH:11]([NH:13][C:14]1[S:15][CH:16]=[C:17]([C:19](=[N:23][O:24][CH2:25][C:26](=O)[NH2:27])[C:20]([OH:22])=O)[N:18]=1)=[O:12].[NH2:29][CH:30]1[C:47](=[O:48])[N:32]2[C:33]([C:44]([OH:46])=[O:45])=[C:34]([CH2:37][S:38][C:39]3[S:40][CH:41]=[N:42][N:43]=3)[CH2:35][S:36][C@H:31]12>CC(C)=O.C(N(CC)CC)C.O1CCCC1>[CH:11]([NH:13][C:14]1[S:15][CH:16]=[C:17]([C:19](=[N:23][O:24][CH2:25][C:26]#[N:27])[C:20]([NH:29][CH:30]2[C:47](=[O:48])[N:32]3[C:33]([C:44]([OH:46])=[O:45])=[C:34]([CH2:37][S:38][C:39]4[S:40][CH:41]=[N:42][N:43]=4)[CH2:35][S:36][C@H:31]23)=[O:22])[N:18]=1)=[O:12]
Reactant: NC(=O)CON=C(C(=O)O)c1csc(NC=O)n1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: N#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(NC=O)n1
Reaction time: 0.5 h
Yield: 34.8 %

Procedure:
Phosphoryl chloride (0.96 g.), N,N-dimethylformamide (0.459 g.), tetrahydrofuran (12 ml.) and 2-(2-formamidothiazol-4-yl)-2-carbamoylmethoxyiminoacetic acid (syn isomer, 1.2 g.) were treated in a similar manner to that of Example 1-(1) to give an activated acid solution. After a suspension of 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (1.75 g.) in 50% aqueous acetone (16 ml.) was adjusted to pH 7 to 8.5 with triethylamine, the activated acid solution was added to the stirred solution at -5° to 0° C. while keeping at pH 6.5 to 7.5 and stirred at the same temperature for 30 minutes. After removing the solvent from the resultant solution in vacuo, ethyl acetate was added to the residue. The solution was adjusted to pH 1.5 with 10% hydrochloric acid and the insoluble substance was filtered off. The filtrate was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was pulverized with diethyl ether to give 7-[2-(2-formamidothiazol-4-yl)-2-cyanomethoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 0.87 g.).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[Cl-].[NH4+]>[Fe]>[CH2:6]([O:5][P:4]([CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(C=Cc1ccc([N+](=O)[O-])cc1)OCC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: CCOP(=O)(C=Cc1ccc(N)cc1)OCC

Procedure:
A suspension containing 4-nitrostyrylphosphonic acid diethyl ester (3.0 g, 10.5 mmol), iron powder (5.58 g, 100 mmol) and ammonium chloride (5.58 g, 104 mmol) is heated to reflux for 45 minutes. The reaction medium is filtered through Celite. The filtrate is concentrated under vacuum and is bipartitioned in a water/dichloromethane mixture. The organic phase is washed with water, then dried (MgSO4) and evaporated under vacuum to give the expected product, which crystallizes gradually.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([CH:39]=[CH:40][CH:41]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@:12]([F:15])([CH3:14])[CH2:11][N:10]1[C:16](=[O:38])[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27]CC3C=CC=CC=3)[CH:25]=2)[C:20]([C:35](=[O:37])[CH3:36])=[CH:19]1)=[O:8].C(O)(C(F)(F)F)=O.C1(SC)C=CC=CC=1>>[Cl:1][C:2]1[C:3]([F:42])=[C:4]([CH:39]=[CH:40][CH:41]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@:12]([F:15])([CH3:14])[CH2:11][N:10]1[C:16](=[O:38])[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([OH:27])[CH:25]=2)[C:20]([C:35](=[O:37])[CH3:36])=[CH:19]1)=[O:8]
Reactant: CC(=O)c1cn(CC(=O)N2C[C@](C)(F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(OCc3ccccc3)ccc12
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1cn(CC(=O)N2C[C@](C)(F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(O)ccc12

Procedure:
The title compound was prepared in a similar manner as described above for Example 577 from (2S,4R)-1-[2-(3-acetyl-6-benzyloxy-indol-1-yl)-acetyl]-4-fluoro-4-methyl-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide (96.0 mg, 0.137 mmol), TFA (2 mL) and thioanisole (0.162 mL, 1.374 mmol). Solid. MS (LC/MS): 504 [M+H]+; tR (HPLC, conditions k): 3.26 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[N:6][CH:7]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.CC1C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[CH:11][N:10]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][O:13]3)[N:9]=2)=[N:6][CH:7]=1
Reactant: Brc1ccc(-c2nc[nH]n2)nc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: Brc1ccc(-c2ncn(C3CCCCO3)n2)nc1
Yield: 125 %

Procedure:
A solution of 5-bromo-2-(1H-1,2,4-triazol-3-yl)pyridine (0.342 mg, 1.52 mmol), 3,4-dihydro-2H-pyran (0.256 g, 3.04 mmol) and 4-methylbenzenesulfonic acid (0.058 g, 0.30 mmol) in tetrahydrofuran was heated to 75° C. for 6 h. The reaction was concentrated and purified using Biotage column chromatography (0-20% methanol in dichloromethane) to provide semi-clean product as an oil (0.614 g, 1.9 mmol, >100% yield). This material was used without further purification. MS (ESI) m/z 309.4 [M]+, 311.1 [M+2]+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH:14]2[CH2:16][O:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:17]=[N+:18]=[N-:19].[Na+].CO.C(OC)=O>O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH:14]([OH:15])[CH2:16][N:17]=[N+:18]=[N-:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: c1ccc(CCCCCOCC2CO2)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: COC=O
Product: [N-]=[N+]=NCC(O)COCCCCCc1ccccc1
Yield: 94.1 %

Procedure:
A procedure similar to that described in Preparation 12 was repeated, except that 4.0 g of 5-phenylpentyloxymethyloxirane (prepared as described in Preparation 49), 5.9 g of sodium azide, 160 ml of an 8:1 by volume mixture of methanol and water and 40 ml of methyl formate were used, to give 4.5 g of the title compound as a pale yellow oil having an Rf value of 0.25 (on silica gel thin layer chromatography, using a 1:4 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [CH3:1][N:2]([CH:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([N+:23]([O-])=O)[CH:20]=2)[CH2:15]1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1>C(OCC)(=O)C.CO.[Pd]>[NH2:23][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[CH2:15][CH:14]([N:2]([CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH2:11])=[CH:9][CH:10]=1)[CH3:1])[CH2:22]2
Reactant: CN(CCc1ccc([N+](=O)[O-])cc1)C1Cc2ccc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(CCc1ccc(N)cc1)C1Cc2ccc(N)cc2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2-[N-methyl-N-(4-nitrophenethyl)amino]-5-nitroindane (0.5 g) in ethyl acetate/methanol (40 ml/10 ml) containing 5% Pd/C (0.05 g) was stirred under a hydrogen atmosphere [206.8 kPa (30 psi)] for 4 hours at room temperature. The catalyst was then removed by filtration and the filtrate evaporated in vacuo to give a gum which was triturated with ether. The ether was decanted and evaporated to dryness in vacuo to give the title compound, yield 0.33 g. A small sample was taken and recrystallised from diisopropyl ether, m.p. 112°-114°.