Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([C:5]([CH:7]([N:15]2[CH2:20][CH2:19][CH:18]([SH:21])[CH2:17][CH2:16]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[O:6])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:29](Cl)(=[O:33])[CH2:30][CH2:31][CH3:32].O>ClCCl>[C:29]([S:21][CH:18]1[CH2:17][CH2:16][N:15]([CH:7]([C:5]([CH:2]2[CH2:4][CH2:3]2)=[O:6])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[CH2:20][CH2:19]1)(=[O:33])[CH2:30][CH2:31][CH3:32]
Reactant: CCCC(=O)Cl
Reactant: O=C(C1CC1)C(c1ccccc1F)N1CCC(S)CC1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
In 5 ml of dichloromethane, 0.50 g (1.5 mmol) of 1-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4-mercaptopiperidine hydrochloride were dissolved, followed by the addition of 0.3 g (3 mmol) of triethylamine. To the resulting mixture, a solution of 0.16 g (1.5 mmol) of butyryl chloride in 1 ml of dichloromethane was added dropwise under ice cooling and the resulting mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with dichloromethane. The extract was dried over anhydrous sodium sulfate. The solvent was concentrated by evaporation under reduced pressure and the residue was subjected to chromatography on a silica gel column (eluting solvent: toluene/ethyl acetate=30/1), whereby 0.32 g (yield: 58%) of the title compound was obtained as white crystals.
Reaction SMILES: [CH2:1]1[C@@H:5]2[C@@H:6]3[C:11](=[O:12])[O:10][C:8](=[O:9])[C@@H:7]3[C@H:2]1[CH:3]=[CH:4]2.C1(C)C=CC=CC=1.COC1C=CC2N=CC=C([C@@H](O)[C@H]3N4C[C@H](C=C)[C@@H](CC4)C3)C=2C=1.[CH3:44][OH:45]>C(Cl)(Cl)(Cl)Cl>[CH3:44][O:45][C:11]([C@@H:6]1[C@@H:5]2[CH2:1][C@@H:2]([CH:3]=[CH:4]2)[C@@H:7]1[C:8]([OH:10])=[O:9])=[O:12]
Reactant: CO
Reactant: O=C1OC(=O)[C@H]2[C@@H]1[C@@H]1C=C[C@H]2C1
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)[C@H]1[C@@H](C(=O)O)[C@@H]2C=C[C@H]1C2
Temperature: -55 °C
Reaction time: 0.17 h
Yield: 99.5 %

Procedure:
The starting material (a) was prepared as described in J. Org. Chem. 2000, 65, 6984-6991. cis-5-Norbornene-exo-2,3-dicarboxylic anhydride (5 g, 30.45 mmol) was suspended in a 1:1 mixture of toluene and carbon tetrachloride (610 mL). The mixture was stirred for 10 min. Quinine (10.87 g, 33.5 mmol) was added and the flask was degassed and backfilled with nitrogen. The solution was cooled to −55° C. While stirring, methanol (3.7 mL, 91.35 mmol) was added. The mixture was stirred at −55° C. for 16 h. Upon warming to 25° C., the mixture was concentrated in vacuo to a foam. The foam was dissolved in a mixture of ethyl acetate (400 mL) and 1.0M aqueous hydrochloric acid solution (400 mL). The layers were separated and the organic layer was further washed with 1.0M aqueous hydrochloric acid solution (2×200 mL), saturated aqueous brine solution (100 mL) and dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the desired product, (1S,2S,3R,4R)-3-(methoxycarbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (5.95 g, 30.3 mmol, 99%), as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ: 1.31 (1H, d, J=8.5 Hz), 1.98 (1H, d, J=8.6 Hz), 2.51 (2H, d, J=1.6 Hz), 2.95 (2H, bs), 3.52 (3H, s), 6.17-6.21 (2H, m), 12.16 (1H, s).
Reaction SMILES: [CH3:1][C:2]([CH3:58])([CH3:57])[C@H:3]([N:43]1[CH2:47][CH2:46][N:45]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([CH3:55])[N:50]=2)[C:44]1=[O:56])[C:4]([NH:6][C@@H:7]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@@H:8]([OH:35])[CH2:9][C@@H:10]([NH:24]C(=O)OCC1C=CC=CC=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:14][CH:13]=1)=[O:5].Cl>CO.O1CCOCC1.[Pd]>[NH2:24][C@@H:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:14][CH:13]=1)[CH2:9][C@H:8]([OH:35])[C@@H:7]([NH:6][C:4](=[O:5])[C@@H:3]([N:43]1[CH2:47][CH2:46][N:45]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([CH3:55])[N:50]=2)[C:44]1=[O:56])[C:2]([CH3:57])([CH3:1])[CH3:58])[CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: Cc1cccc(CN2CCN([C@H](C(=O)N[C@@H](Cc3ccccc3)[C@@H](O)C[C@H](Cc3ccc(-c4ccccn4)cc3)NC(=O)OCc3ccccc3)C(C)(C)C)C2=O)n1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cccc(CN2CCN([C@H](C(=O)N[C@@H](Cc3ccccc3)[C@@H](O)C[C@@H](N)Cc3ccc(-c4ccccn4)cc3)C(C)(C)C)C2=O)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution containing the product from Example 130B (0.067 g, 0.086 mmol) in methanol (3 mL) was treated with a solution of HCl in dioxane (0.025 mL, 4 M) and Pd on carbon (0.007 g, 10% Pd by wt.), stirred under a hydrogen atmosphere (balloon pressure) at 25° C. for 16 hours, filtered through a bed of celite® and rinsed with methanol. The solvent was concentrated to give the title compound as the hydrochloride salt (0.053 g), which was used without further purification.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[C:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11](=O)[CH2:12]Br)=[CH:9][CH:8]=1)#[N:6].[OH-].[Na+].O>C(O)C>[NH2:1][C:2]1[S:3][CH:12]=[C:11]([C:10]2[CH:15]=[CH:16][C:7]([C:5]#[N:6])=[CH:8][CH:9]=2)[N:4]=1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: NC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(-c2csc(N)n2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 89.3 %

Procedure:
Thiourea (0.76 g, 10 mmol) was added to 4-cyanophenacyl bromide (2.0 g, 8.9 mmol) in ethanol (20 mL), and the reaction heated under reflux. After 45 min, the mixture was cooled to room temperature, and poured into 2N NaOH (10 mL)/water (40 mL). The precipitate was collected and air-dried to give 4-(2-amino-thiazol-4-yl)benzonitrile (1.6 g, 90%), which was used without further characterization.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
To a 1000 mL RB flask fitted with magnetic stirrer was charged 250 mL of DMF, 3-(4-Hydroxy-phenyl)-propanoic acid (25.0 g, 150.43 mmol) and K2CO3 (41.58 g, 300.87 mmol). The resulting mixture was stirred at RT for 30 minutes. Methyl Iodide (25.627 g, 180.51 mmol) was added to the resulting mixture which was precooled to 0° C. The resulting mixture was stirred at RT for 3 h. After completion of the reaction (reaction monitored by TLC), the solvent was removed under reduced pressure and the crude mass was dissolved in ethyl acetate (250 mL). The organic layer was washed with water (250 mL), saturated sodium bicarbonate solution (250 mL×2), and saturated brine solution (250 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as yellow color oil (26 g, Yield: 95.9%): MS (ESI, 120 eV): m/z=178.9 (M−H)+; 1H NMR (300 MHz, CDCl3): δ 6.97-7.00 (d, 2H), 6.66-6.69 (d, 2H), 4.94 (s, 1H), 3.59 (s, 3H), 2.78-2.83 (t, 2H), 2.50-2.55 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]([CH3:31])[C:26](=[O:32])[CH:25]=[C:24]3[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([OH:20])[C:9]2[N:10]=[CH:11][N:12](S(N(C)C)(=O)=[O:15])[CH:13]=2)=[CH:4][CH:3]=1.N>Cl.O.CO>[OH2:15].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:20])([C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)[C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]([CH3:31])[C:26](=[O:32])[CH:25]=[C:24]3[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:4][CH:3]=1
Reactant: CN(C)S(=O)(=O)n1cnc(C(O)(c2ccc(Cl)cc2)c2ccc3c(c2)c(-c2ccccc2)cc(=O)n3C)c1
Agent: Cl
Agent: N
Solvent: O
Solvent: CO
Product: Cn1c(=O)cc(-c2ccccc2)c2cc(C(O)(c3ccc(Cl)cc3)c3c[nH]cn3)ccc21
Temperature: 110 °C
Yield: 49.7 %

Procedure:
A mixture of (±)-4-[(4-chlorophenyl)(1,2-dihydro-1-methyl-2-oxo-4-phenyl-6-quinolinyl)hydroxymethyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide (2.4 g) in hydrochloric acid (10 ml), water (30 ml) and methanol (15 ml) was stirred and heated at 110° C. for 14 hours. The mixture was cooled, basified with NH3 (aq.) and extracted with DCM. The organic layer was dried (MgSO4), filtered off and evaporated till dryness. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH/NH4OH 95/5/0.2). The pure fractions were collected and evaporated. The residue (1.25 g) was crystallized from 2-propanone/DIPE, yielding 1 g (48.3%) of (±)-6-[(4-chlorophenyl)hydroxy(1H-imidazol-4-yl)methyl]-1-methyl-4-phenyl-2(1H)-quinolinone monohydrate (comp. 43).
Reaction SMILES: [CH3:1][C:2]1[N:10]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[C:19]([O:21]C)=[O:20].[OH-].[Li+]>O1CCCC1.CO.O>[CH3:1][C:2]1[N:10]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[C:19]([OH:21])=[O:20]
Reactant: COC(=O)c1c(C)n(C(C)c2ccccc2)c2ncccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)c2cccnc2n1C(C)c1ccccc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 83.9 %

Procedure:
To a solution of methyl 2-methyl-1-(1-phenylethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (500 mg, 1.70 mmol) in tetrahydrofuran (10 mL), methanol (20 mL) and water (4 mL) was added lithium hydroxide (163 mg, 6.80 mmol). The resultant reaction mixture was stirred at 60° C. for 48 hours. The mixture was concentrated in vacuo. Then the residue was diluted with water (40 mL) and slowly acidified with 1N hydrogen chloride to pH=4-5. The mixture was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to give 2-methyl-1-(1-phenylethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid as a white solid (400 mg, 84.0%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13]>CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:11][Si:12]([CH3:14])([CH3:13])[C:15]#[C:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccccc1[N+](=O)[O-]
Reaction time: 18 h
Yield: 75.8 %

Procedure:
A mixture of 2-iodonitrobenzene (2.0 g, 8.0 mmol), bis(triphenylphosphine)palladium(II) chloride (0.30 g, 0.40 mmol) and copper(I) iodide (0.080 g, 0.40 mmol) in 25 mL of Et3N was degassed by freeze/pump/thaw technique (three times). Trimethylsilylacetylene (1.0 g, 10 mmol) was added and the mixture was stirred for 18 hours. The reaction mixture was filtered through a celite pad and the pad was rinsed with CH2Cl2. The filtrate was washed with sat. NH4Cl (aq.) and brine and the organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (Hexane, then EtOAc;Hexane=1:60, 1:30) to afford trimethyl((2-nitrophenyl)ethynyl)silane (1.33 g, 76%): 1H-NMR (300 MHz, CDCl3) δ 8.02 (dd, J=8.1, 1,2 Hz, 1H), 7.66 (dd, J=7.5, 1.5 Hz, 1H), 7.56 (ddd, J=7.2, 7.2, 1.2 Hz, 1H), 7.45 (ddd, J=8.1, 8.1, 1.5 Hz, 1H) , 0.28 (s, 9H).
Reaction SMILES: C([O-])C.[Na+].[CH3:5][C:6]1[S:10][C:9]([C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][CH:7]=1.Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].O>C(O)C>[CH3:5][C:6]1[S:10][C:9]([C:11]([CH:12]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:18])=[CH:8][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)CC(=O)c1ccc(C)s1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(C(=O)OCC)C(=O)c1ccc(C)s1
Reaction time: 8 h

Procedure:
1.54 g of sodium ethanolate (22.6 mmol), 4.00 g ethyl 3-(5-methylthiophen-2-yl)-3-oxopropanoate (2) and 6.67 g of ethyl bromoacetate are suspended under argon in absolute ethanol at 0° C. The mixture is stirred overnight. Water is added, ethanol is evaporated and the aqueous solution is extracted with diethyl ether. The organic phase is washed with water containing few drops of concentrated HCl, dried and evaporated to provide diethyl 2-(5-methylthiophene-2-carbonyl)succinate (3) which is used without further purification. A mixture of compound 3 and 11.64 g of ammonium acetate in glacial acetic acid is stirred at 120° C. under argon for 4 hours. After cooling to room temperature, the mixture is poured into water. The precipitate formed is isolated by filtration, washed with water and diethyl ether to provide compound 4. 1H NMR (300 MHz, CDCl3) δ 9.57 1H s, 7.61 1H d, 6.81 1H m, 4.24 2H q, 3.53 2H s, 2.54 3H large s, 1.31 3H t.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:23][C@H:24]([C:29]([NH2:31])=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27].FC(F)(F)C(O)=O>>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([NH:23][C@H:24]([C:29]([NH2:31])=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(N)=O

Procedure:
30 mg (0.1 mole) Z-Phe-OH and 13 mg (0.1 mmole) Leu-NH2 are placed into an unsealed glass container having a 12 mm inner diameter and stirred with a spatula. Then, a mixture of 161 mg (0.5 mole) Na2 SO4.10H2O and 5 mg thermolysine is added, the glass container is closed and subjected to ultrasonic waves in an ultrasound bath at 40° C. After 20 minutes the reaction is stopped with 0.4 ml 5% (v/v) aqueous trifluoroacetic acid. The analytical evaluation is carried out by means of HPLC and comparison with an authentic specimen.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:13])=[C:9](/[CH3:12])\[CH2:10][OH:11])=[CH:4][CH:3]=1.[CH2:14]([O:16][C@@H:17]([CH2:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:15]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[CH3:13])=[C:9](/[CH3:12])\[CH2:10][O:11][C:27]2[CH:26]=[CH:25][C:24]([CH2:23][C@H:17]([O:16][CH2:14][CH3:15])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:29][CH:28]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: C/C(CO)=C(\C)c1ccc(Br)cc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C(C)=C(/C)c2ccc(Br)cc2)cc1)OCC
Yield: 95.3 %

Procedure:
The title compound (0.91 g, 95% yield) was prepared from (Z)-3-(4-bromophenyl)-2-methyl-but-2-en-1-ol (0.50 g, 2.07 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.519 g, 2.18 mmol) by a procedure analogous to that described in example 52 c.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:25])[C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]([OH:20])=[C:12]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:11]=1.C(NC(C)C)(C)C.Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:35]>ClCCl>[C:21]([C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([C:16]([CH3:18])([CH3:19])[CH3:17])[C:13]=1[OH:20])[C:9]([NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:34](=[O:35])[O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:25])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)c1cc(C(=O)Nc2ccccc2N)cc(C(C)(C)C)c1O
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CC(C)(C)c1cc(C(=O)Nc2ccccc2NC(=O)Oc2ccccc2)cc(C(C)(C)C)c1O
Reaction time: 8 h
Yield: 1095.8 %

Procedure:
N-(2-aminophenyl)-3,5-di-t-butyl-4-hydroxybenzamide (0.85 g) and diisopropylamine (0.39 ml) were suspended in dichloromethane (20 ml) and a solution of phenyl chloroformate (16.8 g) in dichloromethane (30 ml) was added dropwise under ice-cooling. After stirring the mixture overnight, the reaction solution was washed with water, saturated saline, dried over anhydrous MgSO4 and the solvent was distilled off. Purification of the residue by a silica gel column chromatography (chloroform:ethyl acetate=10:1) followed by crystallization from hexane/ethyl acetate afforded phenyl N-[2-(3,5-di-t-butyl-4-hydroxybenzoylamino)phenyl]carbamate (12.6 g, 49%).
Reaction SMILES: [CH3:1][C:2]([O:41][CH2:42][C@H:43]1[CH2:45][O:44]1)([CH3:40])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:13]2)=[O:11])=[N:5]1.C(N(C(C)C)CC)(C)C.[NH2:55][CH2:56][CH2:57][CH2:58][OH:59]>C(O)(C)C>[OH:44][C@H:43]([CH2:45][NH:55][CH2:56][CH2:57][CH2:58][OH:59])[CH2:42][O:41][C:2]([CH3:1])([CH3:40])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:38])([CH3:37])[CH3:39])[NH:13]2)=[O:11])=[N:5]1
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@H]3CO3)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: NCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@H](O)CNCCCO)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 20.8 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {1-[2-methyl-2-((R)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3-yl}-amide (43.6 mg, 0.066 mmol), isopropyl alcohol (2 mL), diisopropylethyl amine (0.1 mL, 0.56 mmol) and 3-amino-1-propanol (0.1 mL, 1.3 mmol) was microwaved at 130° C. for 15 min. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-{2-[(R)-2-hydroxy-3-(3-hydroxy-propylamino)-propoxy]-2-methyl-propyl}-1H-pyrazol-3-yl)-amide (10.1 mg, 20.8%) as an off-white powder. HRMS (ES+) m/z Calcd for C36H46Cl2F2N6O4S+H [(M+H)+]: 735.2999. found: 735.2998.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([F:24])[CH:23]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[N:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[N:27][CH:26]=1>>[F:24][C:22]1[CH:23]=[C:18]([C:8]2([C:16]3[CH:11]=[CH:12][CH:13]=[C:14]([C:29]4[CH:30]=[N:25][CH:26]=[N:27][CH:28]=4)[CH:15]=3)[C:4]3[C:3](=[CH:2][CH:7]=[CH:6][CH:5]=3)[C:10]([NH2:17])=[N:9]2)[CH:19]=[N:20][CH:21]=1
Reactant: NC1=NC(c2cncc(F)c2)(c2cccc(Br)c2)c2ccccc21
Reactant: OB(O)c1cncnc1
Product: NC1=NC(c2cncc(F)c2)(c2cccc(-c3cncnc3)c2)c2ccccc21
Yield: 41 %

Procedure:
The title compound was synthesized from 1-(3-bromophenyl)-1-(5-fluoropyridin-3-yl)-1H-isoindol-3-amine (Example 123) as described in Example 67 Scheme #10, D in 41% yield using pyrimidine-5-boronic acid. 1H NMR (DMSO-d6) δ 9.18 (s, 1 H), 9.04 (s, 2 H), 8.49 (t, J=1.77 Hz, 1 H), 8.45 (d, J=2.53 Hz, 1 H), 8.08-8.02 (m, 1 H), 7.90-7.80 (m, 1 H), 7.74-7.64 (m, 2 H), 7.62-7.43 (m, 5 H), 6.98 (br s, 2 H); MS (ESI) m/z 382 [M+1]+.
Reaction SMILES: I[CH2:2][C:3]12[CH2:10][CH2:9][C:6]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][O:19]4)[CH:12]=3)([CH2:7][CH2:8]1)[O:5][CH2:4]2.[C-:24]#[N:25].[Na+]>CN(C=O)C.CCOC(C)=O>[O:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH:18]1[O:17][C:13]1[CH:12]=[C:11]([C:6]23[CH2:9][CH2:10][C:3]([CH2:2][C:24]#[N:25])([CH2:8][CH2:7]2)[CH2:4][O:5]3)[CH:16]=[CH:15][CH:14]=1
Reactant: [C-]#N
Reactant: ICC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Temperature: 80 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A mixture of 4-(iodomethyl)-1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octane (1.5 g, 3.50 mmol) and NaCN (0.687 g, 14.01 mmol) in DMF (8 mL) was stirred at 80° C. for 18 h. The reaction was diluted with EtOAc (10 mL), washed with water (3×10 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give 2-(1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)acetonitrile (1.15 g, 3.50 mmol, 100% yield) as light brown oil. The above nitrile (1.15 g, 3.50 mmol) was taken up in ethylene glycol (20 mL) and treated with 40% KOH (5.00 mL, 35.0 mmol). The reaction was stirred at 165° C. for 18 h and concentrated in vacuo. The residue was dissolved in water (15 mL), acidified to pH 2 with 1 N aqueous HCl, and extracted with EtOAc (5×5 mL). The combined extracts were washed with brine, dried with MgSO4, filtered, and concentrated in vacuo to afford the title compound (0.91 g, 99% yield) as a light brown solid. LCMS, [M−H]+=261.3.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:37](=[O:38])[N:12]2[CH:13]([C:21]([O:23][CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[C:14]([C:17](=[O:20])[CH2:18][CH3:19])=[CH:15][S:16][C@H:11]12)=[O:8].C(Cl)(Cl)Cl.ClC1C=CC=C(C(OO)=O)C=1>CN(C)C=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:37](=[O:38])[N:12]2[C:13]([C:21]([O:23][CH:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:22])=[C:14]([C:17](=[O:20])[CH2:18][CH3:19])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: CCC(=O)C1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCC(=O)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: 5 °C

Procedure:
To a cooled (5° C.), stirred solution of 0.363 g. of benzhydryl 7-(2-thienylacetamido)-3-propionyl-2-cephem-4-carboxylate in 30 ml. of chloroform was added dropwise a solution of 0.149 g. of 85 percent m-chloroperbenzoic acid in 3 ml. of chloroform. The reaction was allowed to stir with cooling for one hour, after which time it was washed twice with aqueous sodium bicarbonate solution and twice with brine and then dried over anhydrous sodium sulfate. The solution was then evaporated in vacuo to provide a gel which was dissolved in 15 ml. of dimethylformamide. This solution was cooled for five minutes in an ice bath, removed from the ice bath, and subsequently treated with 0.145 ml. of phosphorous trichloride. This mixture was allowed to stir at room temperature for 45 minutes, after which time it was transferred to a separatory funnel with the aid of ethyl acetate and washed successively with aqueous sodium bicarbonate (2X), water (4X), and brine (2X) and then dried over anhydrous sodium sulfate. Evaporation in vacuo to dryness gave a product which when chromatographed on silica gel using a toluene-ethyl acetate gradient provided 0.267 g. (74 percent) of the title product as a white solid which crystallized as white needles from methylene chloride/hexane (m.p. 220°-221° decomp.): nmr (DMSO d-6) δ0.80 (t, 3, J = 7.0 Hz, --CH2CH3), 2.5 (m), 3.84 (s, 2, side chain CH2), 5.22 (d, 1, J = 4.0 Hz, C6 --H), 5.92 (q, 1, J = 4.0 and 8.0 Hz, C7 --H).