Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:21](N1C=CN=C1)([N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)=O.CN(C)CCN>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([NH:25][CH2:26][CH2:27][N:23]([CH3:24])[CH3:21])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Agent: CN(C)CCN
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Yield: 479.8 %

Procedure:
A solution of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (6.7 g, 0.00233 mole), 1,1'-carbonyldiimidazole (4.0 g, 0.0245 mole), and anhydrous tetrahydrofuran (150 ml) was stirred at room temperature with a stream of nitrogen bubbling through for 21/2 hours. The nitrogen flow was stopped and a solution of N,N-dimethylethylenediamine (2.3 g, 0.0257 mole) in dry tetrahydrofuran (50 ml) was stirred at room temperature under nitrogen for 2 hours. The reaction was concentrated in vacuo and partitioned between methylene chloride (75 ml) and water (75 ml). The layers were separated and the aqueous portion washed with methylene chloride (25 ml). The combined organic portions were washed with potassium bicarbonate solution (2×50 ml), water (25 ml), dried over sodium sulfate, and concentrated in vacuo. The solid residue, 5.7 g (68%) was recrystallized from isopropyl alcohol-isopropyl ether to give 4.0 g of off-white granular solid, mp 124°-125° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=[O:8])[CH:4]=[N:3]1.CC(C)=[O:11].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:11])=[O:8])[CH:4]=[N:3]1
Reactant: CC(C)=O
Reactant: Cn1cc(C=O)cn1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: Cn1cc(C(=O)O)cn1
Yield: 52 %

Procedure:
3.9 g of 1-methylpyrazole-4-aldehyde (described in J. Chem. Soc., page 3314, 1957) was dissolved in 20 ml of acetone, and while heating the solution, the Jones reagent was added. After the reaction, the excess of the Jones reagent was treated with a dilute aqueous alkaline solution, and the precipitate was collected by filtration. The filtrate was made weakly acidic and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 2.3 g (yield 52%) of 1-methylpyrazole-4-carboxylic acid. m.p. 205°-206° C.
Reaction SMILES: C(N(CC)CC)C.[N:8]([CH:11]1[CH:14]([CH2:15][CH2:16][O:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[NH:13][C:12]1=[O:24])=[N+:9]=[N-:10].[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>CN(C)C=O>[Si:25]([N:13]1[CH:14]([CH2:15][CH2:16][O:17][C:18](=[O:23])[C:19]([F:20])([F:21])[F:22])[CH:11]([N:8]=[N+:9]=[N-:10])[C:12]1=[O:24])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: [N-]=[N+]=NC1C(=O)NC1CCOC(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)N1C(=O)C(N=[N+]=[N-])C1CCOC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Triethylamine (0.2 mol) is added dropwise to an ice-cold stirred solution of 3-azido-4-(2-trifluoroacetoxyethyl)-azetidin-2-one (0.2 mol) and t-butyldimethylsilyl chloride (0.2 mol) in dimethylformamide (100 ml). The resulting mixture is stirred for 10 min. in the cold and for 10 min at room temperature, and then evaporated under vacuum to remove DMF. The residue is taken up to methylene chloride, washed with water and brine, dried with magnesium sulfate, and evaporated under vacuum to provide N-(t-butyldimethylsilyl)-3-azido 4-(2-trifluoroacetoxyethyl)-azetidin-2-one.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[Br:12][CH2:13][CH2:14]Br>C(O)C>[Br:12][CH2:13][CH2:14][O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: BrCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=Cc1ccc(OCCBr)cc1
Yield: 40.9 %

Procedure:
To a solution of potassium hydroxide (3.70 g, 54.0 mmol) in ethanol (50 ml) is added 4-hydroxybenzaldehyde (6.00 g, 49.1 mmol) and 1,2-dibromoethane (46.15 g, 245.7 mmol). Then the mixture is heated to reflux for 8 hours. After cooled, the reaction mixture is evaporated under vacuum. The residue is dissolved in water and extracted with dichloromethane (3×50 ml). The organic phase is washed with water (3×50 ml), dried over MgSO4 and evaporated to give a crude product, which is crystallized from ethanol to give the title compound (4.60 g, 41%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C:11](=[O:35])[C:10]=2[C:36]2[CH:37]=[N:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl.[OH-].[Na+]>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C:11](=[O:35])[C:10]=2[C:36]2[CH:37]=[N:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCCN4CCN(C(=O)OC(C)(C)C)CC4)cc3C2=O)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCCN4CCNCC4)cc3C2=O)cn1
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 4-(3-(3-(3,5-difluorophenyl)-2-(6-methoxypyridin-3-yl)-1-oxo-1H-inden-6-yloxy)propyl)piperazine-1-carboxylate (115 mg, 0.2 mmol) obtained in Step 1 in CH2Cl2 was added trifluoroacetic acid (20 eq, 3.0 mmol). After being stirred for 1.5 h, the mixture was diluted with CH2Cl2 and basicified to pH 9 with a 3N NaOH solution. The organic layer was washed with H2O and brine, dried over MgSO4, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].[CH3:11][CH:12]([CH3:30])[CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:22][CH:23]=1)=[O:17]>>[CH:12]1([CH2:13][CH2:14][NH:15][C:16]([C:18]2[N:19]=[N:20][C:21]([N:24]3[CH2:29][CH2:28][N:27]([C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])[CH2:26][CH2:25]3)=[CH:22][CH:23]=2)=[O:17])[CH2:30][CH2:11]1
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Product: CC(O)(C(=O)N1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1)C(F)(F)F

Procedure:
Following the procedure of Example 14, making variations only as required to use 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid in place of 4,4,4-trifluoro-2-methylbutyric acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white solid (55% yield). m.p. 181-183° C. 1H NMR (300 MHz, CDCl3) δ8.07, 7.98, 7.01, 4.86, 3.92-3.81, 3.55, 1.74, 1.51, 0.81-0.68, 0.46, 0.09. 13C NMR (75 MHz, CDCl3) δ 167.2, 163.1, 160.0, 145.4, 127.1, 126.3, 122.5, 112.5. 76.8-75.6 (q, J=117 Hz, C-19F), 44.6, 39.7, 35.3, 20.5, 8.5, 4.8. MS (ES+) m/z 416 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].[Al+3].[Cl-].[Cl-].[Cl-].ClC[CH2:20][C:21](Cl)=[O:22].Cl[CH2:25][Cl:26]>>[Cl:26][CH2:25][C:21](=[O:22])[CH2:20][C:8]1[CH:9]=[CH:10][C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:12][CH3:13])[C:2]=2[Cl:1])[CH:7]=1
Reactant: COc1ccc2ccccc2c1Cl
Reactant: O=C(Cl)CCCl
Reactant: ClCCl
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc2cc(CC(=O)CCl)ccc2c1Cl
Yield: 90 %

Procedure:
To the solution of 1-chloro-2-methoxynaphthalene (0.05 mol) dissolved in dichloromethane (30 mL), AlCl3 (0.10 mol) is added batch by batch and 3-chloropropionyl chloride (0.055 mol) is added dropwise, while the internal temperature is maintained below 5° C. Following procedures described in General Method One-Method A, 3-chloro-1-(5-chloro-6-methoxynaphthalen-2-yl)-acetone is obtained as a white solid (12.7 g). The yield is 90.0%. MS(m/z): 283.0 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[CH2:22][NH:21][CH:20]([CH3:28])[CH2:19]2>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH:20]([CH3:28])[CH2:19][C:18]4[C:23](=[CH:24][C:25]([O:26][CH3:27])=[C:16]([O:15][CH3:14])[CH:17]=4)[CH2:22]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: COc1cc2c(cc1OC)CC(C)NC2
Product: COc1cc2c(cc1OC)CN(C(=O)c1cc3ncc(Br)cn3n1)C(C)C2

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-dimethoxy-3-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound as a colorless solid.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][N:16]=1.Cl>CC(OC)(C)C.C(O)C.O>[ClH:14].[Cl:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([N:8]2[CH2:9][CH2:10][CH2:11][N:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)[CH2:6][CH2:7]2)=[O:20])=[CH:22][CH:23]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: C1CC(N2CCCNCC2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: COC(C)(C)C
Product: O=C(c1ccc(Cl)nc1)N1CCCN(C2CCC2)CC1
Temperature: 12.5 °C
Reaction time: 0.62 h

Procedure:
A mixture of 1-cyclobutyl-[1,4]diazepane (prepared e.g. as in Example 13 above, 20.0 g, 129.7 mmol, 1.00 eq), water (95.2 g) and NaOH 30% aq. (34.6 g, 259.5 mmol, 2.00 eq) was cooled to 10-15° C. To the resulting mixture was added a solution of 6-chloronicotinic acid chloride (24.0 g, 136.4 mmol, 1.05 eq) in MTBE (250.0 g) at 10-15° C., over about 30-45 min, while stirring vigorously. The resulting emulsion was maintained at 10-20° C. for 45-60° C., before the layers were allowed to separate. The aqueous layer was removed and the organic layer washed with water (25.0 g). After removal of the aqueous layer, the organic layer was concentrated by distillation (140 g solvent are distilled off), ethanol (120 g) was added and additional solvent was distilled off (170 g solvent). The resulting solution was then heated to about 50-60° C. and HCl (gas, 4.8 g, 130.2 mmol) in ethanol (9.1 g) was added dropwise. The resulting solution was cooled to 43-45° C. and seeded crystals of the title compound. The product crystallized slowly at 43-45° C. when stirred for about 4-6 h. MTBE (60 g over 1.5-2 h, 120 g over 0.5-1 h) was added, the resulting mixture was then cooled to room temperature over 1-2 h and maintained for 1-2 h, before the title compound was isolated by filtration, washed with MTBE (2×40 g) and dried in vacuo at 65-75° C. for 2 days, to yield the title compound as a white solid.
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[C:4]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.Cl[C:27]1[N:32]=[CH:31][C:30]([C:33]2[CH:34]=[C:35]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=3)[C:36]3[S:40][C:39]([NH:41][C:42]([NH:44][CH2:45][CH3:46])=[O:43])=[N:38][C:37]=3[CH:47]=2)=[CH:29][N:28]=1>CC(N(C)C)=O>[CH2:45]([NH:44][C:42](=[O:43])[NH:41][C:39]1[S:40][C:36]2[C:35]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=3)=[CH:34][C:33]([C:30]3[CH:31]=[N:32][C:27]([N:7]4[CH2:6][CH2:5][C:4]([C:3]([F:2])([F:15])[F:16])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8]4)=[N:28][CH:29]=3)=[CH:47][C:37]=2[N:38]=1)[CH3:46]
Reactant: CCOC(=O)C1(C(F)(F)F)CCNCC1
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(Cl)nc3)cc(-c3ccccn3)c2s1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C(=O)OCC)(C(F)(F)F)CC4)nc3)cc(-c3ccccn3)c2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.8 %

Procedure:
To the solution of ethyl 4-(trifluoromethyl)piperidine-4-carboxylate hydrochloride (0.1 g, 0.44 mmol) in DMA (5.0 mL) was added DIPEA (0.25 mL, 1.46 mmol) at rt and the mixture stirred at rt for 10 min followed by addition of 1-(5-(2-chloropyrimidin-5-yl)-7-(pyridin-2-yl)benzothiazol-2-yl)-3-ethylurea (0.12 g, 0.29 mmol). The reaction was heated up to 80° C. for 16 h and after completion (by TLC), the mixture was poured into 50 mL of ice cold water, extracted with EtOAc (3×50 mL) and the combined organics washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified over 100-200 M silica-gel using 1.50% MeOH: DCM to obtain an off white solid (0.09 g, 51%). 1H NMR (DMSO-d6): δ 1.15 (t, J=7.20 Hz, 3H), 1.20 (t, J=6.80 Hz, 3H), 1.45 (m, 2H), 2.06 (m, 2H), 2.54 (m, 2H), 3.21 (q, J=7.20, 2H), 4.15 (q, J=6.80 Hz, 2H), 4.32 (m, 2H), 6.86 (br s, 1H), 7.44 (m, 1H), 7.99 (m, 2H), 8.23 (s, 1H), 8.47 (m, 1H), 8.80 (m, 1H), 8.92 (s, 2H) and 10.56 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C@H:7]2[CH2:13][C@H:12]3[N:14]([CH2:15][CH2:16][C@H:17]([NH:24][C:25]([CH:27]4[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29][CH2:28]4)=[O:26])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C@H:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]([CH:35]([CH3:37])[CH3:36])=[N:4][N:3]=1.P([O-])([O-])([O-])=O.N.CCCCCC>C(Cl)Cl.O>[CH:35]([C:5]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C@H:17]([NH:24][C:25]([CH:27]4[CH2:28][CH2:29][C:30]([F:34])([F:33])[CH2:31][CH2:32]4)=[O:26])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:2]([CH3:1])=[N:3][N:4]=1)([CH3:36])[CH3:37]
Reactant: Cc1nnc(C(C)C)n1[C@@H]1C[C@H]2CC[C@@H](C1)N2CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Agent: N
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: O
Product: Cc1nnc(C(C)C)n1C1CC2CCC(C1)N2CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Reaction time: 0.25 h
Yield: 92.8 %

Procedure:
Maraviroc phosphate (6 gm) was dissolved in methylene chloride (50 ml) and water (40 ml). The pH of the reaction mass was adjusted to 8.0 to 8.5 with ammonia solution (4 ml) and stirred for 15 minutes. The layers were separated and the organic layer was dried with sodium sulfate and treated with carbon. The methylene chloride was distilled off under vacuum at below 45° C. to obtain residual mass. To the residual mass was added hexane (40 ml) and stirred for 30 minutes at room temperature. The solid obtained was collected by filtration and dried to obtain 4.7 gm of maraviroc amorphous form (HPLC Purity: 99.95%).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([N:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](=[O:24])[C:14]([C:25]([OH:27])=O)=[CH:13]1)[CH3:11].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.[NH2:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]2[C:63]([NH2:78])=[N:64][CH:65]=[C:66]([C:68]3[CH:73]=[CH:72][C:71]([O:74][CH3:75])=[C:70]([O:76][CH3:77])[CH:69]=3)[CH:67]=2)=[CH:58][CH:57]=1>CN(C=O)C.O>[NH2:78][C:63]1[C:62]([C:59]2[CH:58]=[CH:57][C:56]([NH:55][C:25]([C:14]3[C:15](=[O:24])[C:16]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:17][N:12]([CH2:10][CH3:11])[CH:13]=3)=[O:27])=[CH:61][CH:60]=2)=[CH:67][C:66]([C:68]2[CH:73]=[CH:72][C:71]([O:74][CH3:75])=[C:70]([O:76][CH3:77])[CH:69]=2)=[CH:65][N:64]=1
Reactant: CCn1cc(C(=O)O)c(=O)c(-c2ccccc2)c1
Reactant: COc1ccc(-c2cnc(N)c(-c3ccc(N)cc3)c2)cc1OC
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1cc(C(=O)Nc2ccc(-c3cc(-c4ccc(OC)c(OC)c4)cnc3N)cc2)c(=O)c(-c2ccccc2)c1
Reaction time: 0.33 h
Yield: 74.2 %

Procedure:
DIPEA (601 μl) was added to a solution of 1-ethyl-4-oxo-5-phenyl-1,4-dihydropyridine-3-carboxylic acid (420 mg) and COMU (961 mg) in DMF (5.0 ml) at room temperature, and the mixture was stirred for 20 minutes. The compound obtained in Step 2 of Example 1 (610 mg) was added at room temperature. The mixture was stirred for 15 hours, followed by the addition of water. The organic layer was extracted with ethyl acetate, and then washed with water and brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform:methanol=300:1->60:1 (v/v)] to give 700 mg of the title compound as a solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:17][C:16]3[C:11](=[N:12][CH:13]=[CH:14][C:15]=3[O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=3[F:28])[CH:10]=2)=[N:7][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:35]1(=[O:41])[NH:39][C:38](=[O:40])[CH2:37][CH2:36]1.O>CN(C=O)C>[F:28][C:20]1[CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:19]=1[O:18][C:15]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:10]=[C:9]([C:6]3[N:7]=[CH:8][C:3]([CH2:2][N:39]4[C:35](=[O:41])[CH2:36][CH2:37][C:38]4=[O:40])=[CH:4][CH:5]=3)[S:17][C:16]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CCl)cn4)sc23)c(F)c1
Reactant: O=C1CCC(=O)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCC(=O)N1Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.5 %

Procedure:
To a solution of 102 (200 mg, 0.481 mmol, scheme 26) in DMF (5 mL) was added Cs2CO3 (313 mg, 0.962 mmol) and succinimide (95 mg, 0.962 mmol) and the reaction mixture was stirred at RT for 4 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated to afford title compound 138 (100 mg, 43% yield) that was triturated with Et2O and used with no additional purification. MS (m/z)=479.50 (M+H)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[CH3:16][NH:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH4-].[Na+].O>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][N:17]([CH3:16])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: CNCCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1noc(-c2ccc(Br)cc2)c1CN(C)CCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (0.150 g, 0.56 mmol) and N-methyl-phenethyl-amine (0.10 mL, 0.67 mmol) were combined in MeOH and stirred at room temperature overnight. Once no starting material was seen by analytical LCMS, sodium borohydride (0.064 g, 1.69 mmol) was added and the reaction was stirred at room temperature for 1 hour. H2O was added and the mixture was extracted with EtOAc. The combined organic layers were dried and concentrated, and the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH2:32][C:33]([NH2:35])=[S:34])[C:27]([OH:29])=O)[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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.N1C=CC=CC=1.[CH3:42][C:43]([O:45][CH2:46][C:47]1[CH2:56][S:55][C@@H:50]2[C@H:51]([NH2:54])[C:52](=[O:53])[N:49]2[C:48]=1[C:57]([OH:59])=[O:58])=[O:44]>C(Cl)Cl>[C:43]([O:45][CH2:46][C:47]1[CH2:56][S:55][C@@H:50]2[CH:51]([NH:54][C:27](=[O:29])[C:26]([C:24]3[N:25]=[C:21]([NH:20][C:1]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[S:22][CH:23]=3)=[N:30][O:31][CH2:32][C:33]([NH2:35])=[S:34])[C:52](=[O:53])[N:49]2[C:48]=1[C:57]([OH:59])=[O:58])(=[O:44])[CH3:42]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: NC(=S)CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(N)=S)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 25 °C

Procedure:
A solution of 0.5 g of dicyclohexyldicarbodiimide in 5 ml of methylene chloride was added to a solution of 1.01 g of the product of Step A, 2 ml of pyridine and 0.656 g of 7-amino-cephalosporanic acid and the mixture was stirred at room temperature to effect precipitation and was vacuum filtered. The product was rinsed with methylene chloride and dried to remove about 0.5 g of dicyclohexylurea. The filtrate was poured into 25 ml of hydrochloric acid and the mixture was stirred for 5 minutes. The decanted organic phase was washed with 25 ml of water and was dried and vacuum filtered. The filtrate was evaporated to dryness and the residue was taken up in isopropyl ether. Efflorescence occured and the mixture was vacuum filtered. The recovered product was rinsed and was dissolved in 4 ml of ethyl acetate 0.18 g of activated carbon were added thereto and the mixture was vacuum filtered. The filter was rinsed with ethyl acetate and the filtrate was stirred while 20 ml of isopropyl ether were added over 5 minutes. The mixture was stirred another 5 minutes and was vacuum filtered. The recovered product was rinsed with isopropyl ether and was dried to obtain the syn isomer of 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(2-amino-2-thioxoethoxyimino)-acetamido]-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[C:7]([CH3:30])=[N:8][C:9]([NH:13][C:14]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26](OC)=[O:27])(=[O:19])=[O:18])=[O:15])=[N:10][C:11]=1[CH3:12].[CH3:31][SH:32]>C1(C)C=CC=CC=1>[Cl:5][C:6]1[C:7]([CH3:30])=[N:8][C:9]([NH:13][C:14]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([S:32][CH3:31])=[O:27])(=[O:19])=[O:18])=[O:15])=[N:10][C:11]=1[CH3:12]
Reactant: CS
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)c(Cl)c(C)n1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CSC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)c(Cl)c(C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trimethylaluminum (6.0 ml, 2 M) is charged via syringe to 15 ml dry toluene under nitrogen atmosphere and 3.8 g N-[(5-chloro-4,6-dimethylpyrimidin-2-yl)aminocarbonyl]-2-methoxycarbonylbenzenesulfonamide is added portionwise. After stirring at room temperature for one hour, methyl mercaptan (gas) is passed through the reaction mixture until the initial temperature rise subsided, whereupon the addition is discontinued. The reaction mixture is allowed to stir at room temperature for 1 hour, and quenched with 25 ml of 10% HCl. The resultant white suspension is filtered to give the desired product.
Reaction SMILES: [Cl-].[Li+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[F:9])=[O:7].N12CCCN=C1CCCCC2.[C:29]([N:36]1[CH2:41][CH2:40][CH:39]([CH:42]=O)[CH2:38][CH2:37]1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>C(#N)C>[F:9]/[C:8](=[CH:42]/[CH:39]1[CH2:40][CH2:41][N:36]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:37][CH2:38]1)/[C:6]([O:5][CH2:4][CH3:3])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)/C(F)=C\C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Compound 9 was prepared using the methods described in Scheme AE. Intermediate AE1 was prepared as follows. Lithium chloride (0.39 g) was added to a solution cooled to 0° C. of triethyl-2-fluoro-2-phophonoacetate (1.84 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.15 mL) in acetonitrile (6 mL). The mixture was stirred until the lithium chloride was dissolved to form a homogeneous solution. N-Boc-piperidine-4-carboxaldehyde (1.61 g) in acetonitrile (2.0 mL) was added to the mixture and stirred for 24 h at room temperature. The reaction was quenched with saturated ammonium chloride (20 mL), diluted with ethyl acetate (150 mL), and washed with saturated sodium chloride (50 mL). The organic layer was dried (magnesium sulfate) and evaporated to yield 2.27 g of (E)-ethyl 2-fluoro-3-(N-Boc-piperdin-4-yl)propenoate (AE1). AE1 was carried forward as shown in Scheme AA to afford 9. Compound 9 was isolated as white flakes: mp 147-150° C.; MS m/e 515 (MH+). Anal. calcd. for C25H31FN6O5•2.3 HCl•1.6 H2O (627.25): C, 47.88; H, 5.87; N, 13.40; Cl, 13.00. Found: C, 48.26; H, 6.02; N, 12.90; Cl, 12.74.