Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([C:13](=O)[CH3:14])=[CH:9][C:8]=2[CH3:16])=[CH:4][CH:3]=1.[CH3:19][C:20]([S@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>>[F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([CH:13]([NH:25][S@@:23]([C:20]([CH3:22])([CH3:21])[CH3:19])=[O:24])[CH3:14])=[CH:9][C:8]=2[CH3:16])=[CH:4][CH:3]=1
Reactant: CC(=O)c1cnc(Oc2ccc(F)cc2)c(C)c1
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1Oc1ccc(F)cc1
Yield: 76 %

Procedure:
The title compound is prepared in 76% yield (2.67 g, white solid) from 1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethanone (2.47 g, 10.1 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (1.83 g, 15.1 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([NH2:16])[C:4]=1[C:5]([O:7]CC)=O.[CH3:17][N:18]=[C:19]=[O:20].CC(O)=O>N1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]2[C:4]=1[C:5](=[O:7])[N:18]([CH3:17])[C:19](=[O:20])[NH:16]2
Reactant: CN=C=O
Reactant: CCOC(=O)c1c(N)ccc(OC)c1OC
Solvent: O
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: COc1ccc2[nH]c(=O)n(C)c(=O)c2c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
A cold solution of ethyl 2,3-dimethoxy-6-aminobenzoate (8.0 g, 35.5 mM) in pyridine (15.4 ml) was added to CH3NCO (3.2 g, 55.9 mM) in pyridine (11.5 ml) at 0° C. The solution was stirred at 0° C. for 30 minutes then at room temperature for 1 hour. The reaction mixture was concentrated to dryness. The resulting brown gummy residue was dissolved in 73 ml of 1N NaOH (4:1, MeOH: H2O, 2.9 g of NaOH pellets in 14.7 ml H2O and 58.3 ml MeOH) and refluxed for 2 hours. The solvent was removed in vacuo to give a light brown solid. This was dissolved in H2O (180 ml) and the pH adjusted to 5 with AcOH. The resulting solid was filtered and dried to afford 6.2 g (73%) of the desired product, mp 247°-250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[Cl:23][C:24]1[CH:33]=[CH:32][C:27]2[N:28]=[C:29]([NH2:31])[S:30][C:26]=2[CH:25]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:23][C:24]1[CH:33]=[CH:32][C:27]2[N:28]=[C:29]([NH:31][C:13](=[O:15])/[C:12](/[C:4]3[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=3)=[N:16]/[O:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[S:30][C:26]=2[CH:25]=1
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1Cl
Reactant: Nc1nc2ccc(Cl)cc2s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)Nc2nc3ccc(Cl)cc3s2)cc1Cl
Reaction time: 2 h
Yield: 53.7 %

Procedure:
(E)-(3-chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (prepared as in Example 1, 84 mg, 0.24 mmol), 6-chloro-2-aminobenzothiazole (45 mg, 0.24 mmol) and N,N-diisopropylethylamine (127 μL, 0.73 mmol) were combined in methylene chloride (2 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (92 mg, 0.24 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 33% ethyl acetate/hexanes) to afford (E)-N-(6-chloro-benzothiazol-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-acetamide (66 mg, 53%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C21H19Cl2N3O4S2 [M+] 511.02, found 512 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.68 (m, 4 H, 2×CH2), 1.91 (m, 4 H, 2×CH2), 3.32 (s, 3 H, SO2CH3), 4.97 (m, 1 H, OCH), 7.43 (dd, Jo=8.6, Jm=2.1 Hz, 1 H, Ar), 7.60 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.71 (m, 2 H, Ar), 7.81 (m, 1 H, Ar), 8.23 (d, Jo=8.2 Hz, 1 H, Ar), 10.18 (s, 1 H, NH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:10][CH3:11])=[CH:5][CH:4]=1.[Br:20]Br>ClCCCl>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[C:10]([Br:20])[CH3:11])=[CH:17][CH:16]=1
Reactant: CC=C(c1ccc(OC)cc1)c1ccc(OC)cc1
Reactant: BrBr
Solvent: ClCCCl
Product: COc1ccc(C(=C(C)Br)c2ccc(OC)cc2)cc1
Temperature: -20 °C
Yield: 99.6 %

Procedure:
Into a reactor were introduced 2.50 g (9.82 mmol) of the 1,1-bis(4-methoxyphenyl)propene and 25 mL of 1,2-dichloroethane under a nitrogen atmosphere. The contents were cooled to −20° C. A mixture of 1.57 g (9.82 mmol) of bromine and 13 mL of 1,2-dichloroethane was gradually added dropwise thereto, and the resultant mixture was stirred overnight at room temperature. This reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and then dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure to obtain 3.26 g (100%) of the target compound as a light-yellow oily substance.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:16][CH2:15][C:14]2([CH3:20])[C:17]([CH3:19])([CH3:18])[CH:10]1[CH2:11][C:12]1[CH:24]=[C:23]3[O:25][CH2:26][O:27][C:22]3=[CH:21][C:13]=12)=O)(C)(C)C>ClCCl>[CH2:26]1[O:25][C:23]2[C:22](=[CH:21][C:13]3[C:14]4([CH3:20])[C:17]([CH3:18])([CH3:19])[CH:10]([NH:9][CH2:16][CH2:15]4)[CH2:11][C:12]=3[CH:24]=2)[O:27]1.[ClH:1]
Reactant: CC(C)(C)OC(=O)N1CCC2(C)c3cc4c(cc3CC1C2(C)C)OCO4
Agent: Cl
Solvent: ClCCl
Product: CC12CCNC(Cc3cc4c(cc31)OCO4)C2(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Isopropanolic hydrochloric acid (5 mol/L, 0.55 mL) is added to 8,9-methylenedioxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylic acid tert-butyl ester (0.19 g) dissolved in dichloromethane (2 mL). The resulting solution is stirred for 2 h at room temperature. Then, the solution is concentrated under reduced pressure to give the title product as its hydrochloric acid salt.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[C:19][CH2:20][CH2:21][CH2:22]OS(C)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:30][NH:31][CH3:32]>>[CH3:30][N:31]([CH3:32])[CH2:22][CH2:21][CH2:20][C:19]#[C:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:29])([F:28])[F:1])=[CH:4][CH:5]=3)=[N:10][S:11][C:12]=2[CH:17]=1
Reactant: CNC
Reactant: CS(=O)(=O)OCCCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Product: CN(C)CCCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 17.1, Methanesulfonic acid 5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester and dimethylamine were converted to yield Dimethyl-{5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-amine as off-white solid, MS: 389 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH:6]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([NH:16][NH2:17])=[CH:11][C:10]=2[Cl:18])[C:7]#[N:8])=[CH:4][CH:3]=1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.S([O-])([O-])(=O)=O.[Mg+2]>C(OC(=O)C)C>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH:6]([C:9]2[C:10]([Cl:18])=[CH:11][C:12]([NH:16][N:17]=[CH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:13][C:14]=2[Cl:15])[C:7]#[N:8])=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: N#CC(c1ccc(Cl)cc1)c1c(Cl)cc(NN)cc1Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Product: N#CC(c1ccc(Cl)cc1)c1c(Cl)cc(NN=Cc2ccccc2)cc1Cl
Reaction time: 1 h

Procedure:
In 30 ml of acetic acid ethyl ester was dissolved 3.26 g of 4-(4-chloro-α-cyanobenzyl)-3,5-dichlorophenyl hydrazine. To the solution was added equimolar benzaldehyde and three times as much mol. of anhydrous magnesium sulfate, then the reaction was allowed to proceed for one hour at room temperature. After completion of the reaction, insolubles were removed, and the solution was concentrated, which was recrystallized from acetonitrile to afford 3.3 g of the titled compound as colorless crystals, m.p.162-163° C.
Reaction SMILES: Cl.C(OCC)C.C([Si](C)(C)[O:12][CH2:13][C@H:14]([NH-:25])[C:15]1[CH:16]=[N:17][C:18]([O:21][CH2:22][CH2:23][CH3:24])=[CH:19][CH:20]=1)(C)(C)C>CO>[NH2:25][C@H:14]([C:15]1[CH:16]=[N:17][C:18]([O:21][CH2:22][CH2:23][CH3:24])=[CH:19][CH:20]=1)[CH2:13][OH:12]
Reactant: CCCOc1ccc([C@@H]([NH-])CO[Si](C)(C)C(C)(C)C)cn1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CCCOc1ccc([C@@H](N)CO)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
A 2.00 M solution of hydrogen chloride in diethyl ether (28 mL, 56 mmol) was added to a stirred solution of [(R)-2-(tert-butyl-dimethyl-silanyloxy)-1-(6-propoxy-pyridin-3-yl)-ethyl]-amide (2.33 g, 5.62 mmol) dissolved in MeOH (11 mL) at 0° C. under Ar. After the addition was completed the cooling bath was removed and the solution was stirred at room temperature overnight. The mixture was then evaporated to dryness and the residue was suspended in methylene chloride and transferred to a short silica gel column. After eluding with EtOAc:EtOH:Et3N (90:5:5) (R)-2-Amino-2-(6-propoxy-pyridin-3-yl)-ethanol, IM36, was obtained as an oil (0.813 g, 74%). The overall yield from 5-bromo-2-propoxypyridine IM3 was 36%.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:13](=[O:14])[C@H:12]([CH2:15][CH2:16][C@@H:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[OH:18])[C@H:11]2[C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH2:39][C@H:40]4[O:46][CH:44]([OH:45])[C@H:43]([OH:47])[C@@H:42]([OH:48])[C@@H:41]4[OH:49])[CH:33]=3)=[CH:28][CH:27]=2)=[CH:6][CH:5]=1>C(#N)C.O.C(#N)C>[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:13](=[O:14])[C@H:12]([CH2:15][CH2:16][C@@H:17]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[OH:18])[C@H:11]2[C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH2:39][C@@H:40]([OH:46])[C@@H:41]([OH:49])[C@H:42]([OH:48])[C@@H:43]([OH:47])[CH2:44][OH:45])[CH:33]=3)=[CH:28][CH:27]=2)=[CH:6][CH:5]=1
Reactant: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(-c3cccc(OC[C@H]4OC(O)[C@H](O)[C@@H](O)[C@@H]4O)c3)cc2)N1c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(-c3cccc(OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO)c3)cc2)N1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.6 %

Procedure:
Sodium borohydride (1.6 mg, 0.04 mmol) was added to 6-O-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)-D-glucopyranose (26.3 mg, 0.04 mmol) dissolved in 80:20 acetonitrile-water (1 mL) at room temperature. The reaction was stirred for 10 min at room temperature monitoring by LCMS. Upon completion, the reaction was diluted with 50:50 acetonitrile:water (3 mL) and filtered through a Whatman 0.45 μM glass microfiber filter then purified by preparative HPLC (Polaris C18-A 10 μ 250×21.2 mm column, 30% to 95% acetonitrile-0.1% trifluoroacetic acid in water) affording 6-O-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)-D-glucitol (21.2 mg, 80% yield). 1H NMR (300 MHz, CDCl3/1% CD3OD) δ 7.58 (d, J=8.1 Hz, 2H), 7.39-7.24 (m, 7H), 7.17-7.15 (m, 2H), 7.04-6.92 (m, 5H), 4.71 (d, J=2.1 Hz, 1H), 4.68 (t, J=6.3 Hz, 1H), 4.31-4.27 (m, 1H), 0.19-4.14 (m, 1H), 4.08-4.02 (m, 1H), 3.97-3.95 (m, 1H), 3.86-3.65 (m, 4H), 3.14-3.12 (m, 1H), 2.01-1.88 (m, 4H) ppm; MS [M+HCO2−]− 694.0.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]([CH:11]1[CH2:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[O:12]1)(O)[CH3:9].P(Cl)(Cl)(Cl)=O>CCOCC>[C:8](=[C:11]1[CH2:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[O:12]1)([CH3:9])[CH3:7]
Reactant: CC(C)(O)C1Cc2ccccc2O1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)=C1Cc2ccccc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
Into 40 ml of dried pyridine, was dissolved 6.6 g of 2-(1-methyl-1-hydroxyethyl)-2,3-dihydrobenzofuran. To the solution, with ice-cooling, was added dropwise 11.38 g of phosphorus oxychloride over a period of 10 minutes. After the addition was finished, the mixture was stirred for 2 hours at room temperature and poured into ice water. After ether was added to the mixture, the ether layer was separated and the aqueous layer was extracted twice with 50 ml of ether. The ether layers were combined, washed successively with 5% aqueous hydrochloric acid solution, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain 5.7 g of the crude 2-isopropylidene-2,3-dihydrobenzofuran. This crude product contained 2-isopropylbenzofuran, 2-isopropenyl-2,3-dihydrobenzofuran and small amount of many other unidentifiable impurities, in addition to the intended product. However, because of labileness of the intended product, the crude product was used in the starting material without further purification in the next preparative step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12]C(C)([O-])C.[K+].S(OC)(OC)(=O)=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH:7][CH3:12]
Reactant: CC(C)(C)[O-]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: CNc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution at 0° C. of 5-chloro-2-nitroaniline (100 g) in dimethylformamide (1.0 l) was added potassium t-butoxide (70.3 g) and the mixture was stirred at 0° C. for 1 hour. To the reaction mixture was added dropwise a solution of dimethyl sulfate (62 ml) in dimethylformamide (100 ml) and the resulting mixture was stirred at 25° C. for 1.5 hours to afford a solution of 5-chloro-N-methyl-2-nitroaniline in dimethylformamide. To the resulting mixture was added 24% sodium methoxide in methanol (230 ml) and the mixture was heated at 55° C. for 2 hours with stirring. At the end of this time the reaction mixture was cooled to 25° C. and water (1.5 l) was added. The precipitated crystals were collected by filtration and washed with water and methanol to give the desired compound (94.5 g, yield 90%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH2:20])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)=[CH:6][CH:5]=1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[NH:20][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([F:21])=[CH:23][CH:24]=2)=[CH:6][CH:5]=1
Reactant: COc1ccc(C(N)c2cccc([N+](=O)[O-])c2)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Product: COc1ccc(C(NC(=O)c2ccc(F)cc2)c2cccc([N+](=O)[O-])c2)cc1
Yield: 88.3 %

Procedure:
In a similar manner to that described in Example (46c) α-(4-methoxyphenyl)-3-nitrobenzylamine hydrochloride (1.51 g) [prepared as described in Example 46(b) above] and 4-fluorobenzoyl chloride (813 mg) were reacted, to afford the title compound (1.72 g) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12](=[O:22])[O:13][CH:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:2]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12](=[O:22])[O:13][CH:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(NC1(c2ccc(Br)cc2)CC1)OC1CN2CCC1CC2
Product: O=C(NC1(c2ccc(-c3ccccc3)cc2)CC1)OC1CN2CCC1CC2
Yield: 24.6 %

Procedure:
Using general procedure E, the above carbamate (400 mg, 1.12 mmol), phenylboronic acid (267 mg, 2.22 mmol) and [PdCl2(pddf)]CH2Cl2 the title compound as a viscous oil (100 mg, 25%). 1H NMR (500 MHz, CDCl3) δ 7.47 (d, J=7.5 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 7.33 (t, J=7.5 Hz, 2H), 7.26-7.15 (m, 3H), 5.93 (br s, 0.6H), 5.89 (br s, 0.4H), 4.67 (m, 1H), 3.20-3.06 (m, 1H), 2.88-2.42 (m, 5H), 1.98-1.08 (m, 9H) ppm. 13C NMR (125 MHz, CDCl3) δ 155.0, 141.0, 139.7, 138.2, 127.7, 126.1, 126.0, 124.8, 124.1, 70.0, 54.5, 46.3, 45.4, 34.1, 24.3, 23.2, 18.3, 17.0 ppm. Purity: 100% LCMC (214 nm & 254 nm); retention time 1.52 min; (M+1) 363.
Reaction SMILES: Cl.O.[N+:3]([C:6]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:10][C:7]=1[C:8]#[N:9])([O-])=O>C(O)C.[Fe]>[NH2:3][C:6]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1cc(Oc2ccc(Cl)cc2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: N#Cc1cc(Oc2ccc(Cl)cc2)ccc1N
Temperature: 25 °C
Reaction time: 7 h
Yield: 9.1 %

Procedure:
A mixture of 2.0 grams (0.035 mole) of iron powder, 1.0 mL of concentrated hydrochloric acid, 4.0 mL of water, in 30 mL of ethanol was stirred, and 2.5 grams (0.009 mole) of 2-nitro-5-(4-chlorophenoxy)benzonitrile was added slowly. Upon completion of addition, the reacton mixture was warmed to reflux where it stirred for about seven hours. After this time, the reaction mixture was allowed to cool to ambient temperature where it stirred for about 18 hours. The reaction mixture was then warmed and filtered through a pad of diatomaceous earth. The filtrate was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel, using 1:1 petroleum ether/methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.2 gram of 2-amino-5-(4-chlorophenoxy)benzonitrile, mp 116°-118° C. The NMR spectrum was consistent with the proposed structure. The reaction was repeated.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C[O-].[Na+].CO.[CH3:13][O:14][C:15]1[CH:73]=[CH:72][C:18]([CH2:19][O:20][C:21]([C:23]2[N:28]3[C:29](=[O:69])[C@@H:30]([NH:31][C:32](=[O:68])[C:33]([C:55]4[N:56]=[C:57]([NH:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[S:58][CH:59]=4)=[N:34][O:35][C:36]([C:39]([O:41][CH:42]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[O:40])([CH3:38])[CH3:37])[C@H:27]3[S:26][CH2:25][C:24]=2[CH2:70]Cl)=[O:22])=[CH:17][CH:16]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:13][O:14][C:15]1[CH:73]=[CH:72][C:18]([CH2:19][O:20][C:21]([C:23]2[N:28]3[C:29](=[O:69])[C@@H:30]([NH:31][C:32](=[O:68])[C:33]([C:55]4[N:56]=[C:57]([NH:60][C:61]([O:63][C:64]([CH3:65])([CH3:67])[CH3:66])=[O:62])[S:58][CH:59]=4)=[N:34][O:35][C:36]([C:39]([O:41][CH:42]([C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[O:40])([CH3:37])[CH3:38])[C@H:27]3[S:26][CH2:25][C:24]=2[CH2:70][S:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[O:22])=[CH:17][CH:16]=1
Reactant: Sc1ccncc1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](NC(=O)C(=NOC(C)(C)C(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(=O)OC(C)(C)C)n4)C(=O)N23)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(COC(=O)C2=C(CSc3ccncc3)CS[C@@H]3[C@H](NC(=O)C(=NOC(C)(C)C(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(=O)OC(C)(C)C)n4)C(=O)N23)cc1
Yield: 64.4 %

Procedure:
To a solution of 4-mercaptopyridine (178 mg; 2 Eq.) in N,N-di-methylformamide (10 ml) at 0° C. are added a solution of sodium methoxide in methanol (1.5 Eq.) and then 7β-[2-(2-t-butoxycarbonylamino-4-thiazolyl)-2-(1-diphenylmethoxycarbonyl-1-methylethoxyimino)acetamido]-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester (2) (712 mg; 0.8 mMol.), and the mixture is stirred for 15 minutes. The reaction mixture is diluted with ethyl acetate, washed with water, dried and concentrated under reduced pressure. The residue is purified by silica gel chromatography (toluene: ethyl acetate) to give 7β-[2-(2-t-butoxycarbonylamino-4-thiazolyl)-2-(1-diphenylmethoxycarbonyl-1-methylethoxyimino)acetamido]-3-(4-pyridyl)thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester (3) (497 mg).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[NH:4][N:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][C:23](=[O:25])[NH:22][C:21]([CH3:26])=[C:20]2[C:27](O)=[O:28])=[CH:15][CH:14]=1.C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH2:24][C:23](=[O:25])[NH:22][C:21]([CH3:26])=[C:20]2[C:27]([NH:11][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[CH3:1])=[O:28])=[CH:17][CH:18]=1
Reactant: Cc1n[nH]c2ccc(N)cc12
Reactant: CC1=C(C(=O)O)C(c2ccc(Cl)cc2)CC(=O)N1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(C)c3c2)C(c2ccc(Cl)cc2)CC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.6 %

Procedure:
3-Methyl-1H-indazol-5-amine (166 mg, 1.129 mmol, 1.0 equiv) was combined with the product from Example 4, Step 2 (300 mg, 1.129 mmol, 1.0 equiv), EDC (260 mg, 1.355 mmol, 1.2 equiv) and Et3N (189 μL, 1.355 mmol, 1.2 equiv) in DMF (3 mL) and stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was concentrated en vacuo. The residue was purified by flash chromatography (20-100% EtOAc in Hexanes) to provide 105 mg (24%) of the title compound as an off white solid. MS (ES+) m/e 446 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14](S(C)=O)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[C:20]([O:30][CH3:31])(=[O:29])[C@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[OH:22].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH3:31][O:30][C:20](=[O:29])[C@@H:21]([O:22][C:14]1[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:16][N:15]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CS(=O)c1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: COC(=O)[C@@H](O)c1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)[C@@H](Oc1ncc(C(=O)Nc2ccc(F)cc2)cn1)c1ccccc1
Yield: 10.9 %

Procedure:
A suspension of 2-methanesulfinylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide (100 mg, 0.36 mmol) and (S)-(+)-methyl mandelate (86 mg, 0.52 mmol) in 3.6 mL of THF was treated dropwise with DBU (80 μL, 0.54 mmol) at room temperature. The reaction mixture clarified and turned yellow over the course of 5 min. The reaction was quenched after 24 hours by the addition of 5 mL 1 M HCl, followed by 25 mL of 1:1 (v:v) ethyl acetate:water. The mixture was extracted with 2×25 mL portions of ethyl acetate. The organic extracts were combined, dried using Na2SO4 and concentrated in vacuo. The crude material was dissolved in 30% (v/v)-ethyl acetate/hexanes and chromatographed through 15 g silica gel, followed by a second chromatography through 20 g silica gel. The product fractions were concentrated to yield 15 mg (11%) of the titled compound as a white solid. ESI-MS z/z 382 (MH+), 380 (M−H−).