Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH2:36]([O:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)[CH2:37][CH3:38]>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([C:43]3[CH:44]=[CH:45][C:40]([O:39][CH2:36][CH2:37][CH3:38])=[CH:41][CH:42]=3)=[CH:35][CH:34]=2)[N:8]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH2:27]3)=[CH:22][CH:21]=2)[CH:9]=1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Reactant: CCCOc1ccc(B(O)O)cc1
Product: CCCOc1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(N4CC(=O)NS4(=O)=O)cc3)cc2)cc1

Procedure:
5-{-4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using 4-propoxyphenylboronic acid (36 mg, 0.2 mmol) to give 5-{-4-[4-(2,4-dichloro-phenyl)-2-(4′-propoxy-biphenyl-4-ylmethyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [H-].[Na+].C1COCC1.[CH3:8][O:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[CH2:19](Br)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O.CN(C)C=O>[CH3:8][O:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: BrCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 29.7 %

Procedure:
NaH (60%) (4.400 g, 120.0 mmol) was added to freshly distilled THF chilled to 0° C., followed by 4-hydroxybenzoic acid methyl ester 9 (15.215 g, 100.0 mmol). After H2 evolution ceased, dimethylformamide (DMF) (20 ml) was added clearing the cloudy solution followed by phenethyl bromide 8 (16.39 ml, 120.0 mmol), and the mixture was stirred at 80° C. for 24 hours. Upon cooling, the mixture was poured into H2O and extracted. The organic extracts were combined, washed, dried, and evaporated. The residue was purified by chromatography to give about 7.6 g of 4-phenethyloxybenzoic acid methyl ester 10.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[OH:12].N1C=CC=CC=1.S(Cl)([Cl:21])=O>O1CCCC1.CN(C)C=O>[Cl:21][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[OH:12]
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc(CCCO)c1O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1cccc(CCCCl)c1O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(3-hydroxypropyl)-6-methylphenol (3.0 g) in tetrahydrofuran (30 mL) were added pyridine (730 μL), thionyl chloride (2 mL) and one drop of N,N-dimethylformamide. After stirring at 60° C. for 2 hours, the reaction mixture was evaporated, and then diethyl ether was added to the residue. The resulting solution was washed with distilled water and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo to give the title compound in quantitative yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:11])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:18]([O:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[N+:8]([C:5]1[C:4]([NH2:11])=[CH:3][C:2]([O:32][C:29]2[CH:28]=[CH:27][C:26]([NH:25][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])=[CH:31][CH:30]=2)=[CH:7][N:6]=1)([O-:10])=[O:9]
Reactant: Nc1cc(Br)cnc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2cnc([N+](=O)[O-])c(N)c2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.1 %

Procedure:
To a solution of 5-bromo-2-nitropyridine-3-ylamine (436 mg, 2.0 mmol) in DMF (10 mL) was added Cs2CO3 (977 mg, 3.0 mmol) followed by 4-(t-butoxycarbonyl)aminophenol (459 mg, 2.2 mmol) in DMF (10 mL) at 0° C. then stirred at room temperature for 3 days. The mixture was extracted with ethyl acetate. The organic layer was washed with NaHCO3 (aq) and brine, dried over Na2SO4 then evaporated. Sequence purification on SiO2 column chromatography gave the title compound (624.2 mg, 90%): MS m/e 347 (M+1).
Reaction SMILES: BrC1C=CC(S([O:11][C@@H:12]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:14]([C:24]([O:26][CH3:27])=[O:25])[CH2:13]2)(=O)=O)=CC=1.[Br:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[CH:33][C:32]2=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN1CCCC1>[Br:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[C:34]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH:33]=[C:32]2[O:11][C@H:12]1[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C@H:14]([C:24]([O:26][CH3:27])=[O:25])[CH2:13]1
Reactant: O=c1cc(-c2ccccc2)[nH]c2ccc(Br)cc12
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Agent: CN1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: COC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3ccc(Br)cc23)CN1C(=O)OC(C)(C)C
Temperature: 45 °C
Reaction time: 5 h
Yield: 62.2 %

Procedure:
To a solution of 1-tert-butyl 2-methyl (2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate 23 (14.0 g, 30.2 mmol) and 6-bromo-2-phenylquinolin-4(1H)-one (1, 9.5 g, 31.7 mmol) in N-methylpyrrolidine (100 mL) was added cesium carbonate (14.7 g, 45.2 mmol). The reaction mixture was heated to 45° C. and stirred for 5 h and cooled. The reaction mixture was poured onto EtOAc and water and the white solids were removed by filtration. The layers were separated and the organic was washed with saturated aqueous NaHCO3, water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel (gradient elution 5% to 45% EtOAc in hexanes) to give 1-tert-butyl 2-methyl (2S,4R)-4-[(6-bromo-2-phenylquinolin-4-yl)oxy]pyrrolidine-1,2-dicarboxylate 24 (9.9 g, 62% yield) as a pale yellow solid. LRMS (M+H)+ Calcd.: 527. found 527.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[C:7]([CH3:13])[C:6]([CH3:14])=[C:5]2[OH:15].[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[CH2:18]([O:15][C:5]1[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=[C:2]([Br:1])[CH:3]=2)[N:8]=[C:7]([CH3:13])[C:6]=1[CH3:14])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1nc2c(C)cc(Br)cc2c(O)c1C
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2c(C)cc(Br)cc2c(OCc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
26.6 Grams of 6-bromo-4-hydroxy-2,3,8-trimethylquinoline synthesized in the same way as that described in Example 1 was suspended in 70 ml of dimethylformamide, to which 4.4 g of 60% sodium hydride was added under cooling with ice and then the mixture was stirred at room temperature for 30 minutes. 19 Grams of benzyl bromide was added dropwise to the reaction mixture under cooling with ice and the mixture was allowed to react at room temperature overnight. After 50 ml of water was added, the reaction mixture was extracted with ethyl acetate and the organic layer was washed with a saturated brine and dried over anhydrous sodium sulfate overnight. After the solvent was evaporated under reduced pressure, the resultant crude product was purified by column chromatography on silica gel (WAKOGEL® C-200) eluting with n-hexane/ethyl acetate (6:1) to obtain 24.3 g of 4-benzyloxy-6-bromo-2,3,8-trimethylquinoline.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([Br:22])=[C:16]([O:20][CH3:21])[C:17]=2[Br:19])[NH:12][C:11]=1[Br:23])[NH:5][C:6](=[O:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[C:32]#[CH:33].O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([Br:22])=[C:16]([O:20][CH3:21])[C:17]=2[Br:19])[N:12]([CH2:33][C:32]#[CH:31])[C:11]=1[Br:23])[NH:5][C:6](=[O:8])[CH3:7]
Reactant: C#CCBr
Reactant: COC(=O)[C@H](Cc1c(Br)[nH]c2cc(Br)c(OC)c(Br)c12)NC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCn1c(Br)c(C[C@H](NC(C)=O)C(=O)OC)c2c(Br)c(OC)c(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution containing 23.6 mg (0.04 mmol) of (S)-(+)-N-acetyl-2,4,6-tribromo-5-methoxytryptophan methyl ester (4) dissolved in 2.0 mL of N,N-dimethylformamide was charged with 21.6 mg (0.16 mmol) of potassium carbonate and subsequently with 0.08 mL (d=1.335, 0.9 mmol) of propargyl bromide. The mixture was stirred at room temperature for 30 minutes. The reaction solution was charged with water and subjected to extraction with ethyl acetate. The organic phase was washed with a saturated saline and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to obtain pink oil. Purification by column chromatography using silica gel as a carrier and chloroform as an elution solvent was performed to obtain the substance of interest (7) at a yield of 23.9 mg (94%).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:8].F[B-](F)(F)F.[CH3:14][O+](C)C>C(Cl)Cl>[CH3:14][O:8][C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:1]=1
Reactant: O=C1CCCCCN1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC1=NCCCCC1

Procedure:
A solution of azepan-2-one (5.0 g, 44 mmol) and trimethyloxonium tetrafluoroborate (7.8 g, 53 mmol) in DCM (30 mL) was stirred at room temperature for 12 h. Then the reaction mixture was quenched with saturated sodium carbonate (50 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give the desired product. MS (ESI): 128 (MH+).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH3:20])[C:3]1=[O:21].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1.C(N(CC)CC)C>C1COCC1>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([NH:30][C:31]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=3)[C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=3[N:4]([CH3:20])[C:3]2=[O:21])=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: COc1cccc(N=C=O)c1
Reactant: Cc1ccc(C2=NC(N)C(=O)N(C)c3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(NC(=O)NC2N=C(c3ccc(C)cc3)c3ccccc3N(C)C2=O)c1
Reaction time: 0.33 h

Procedure:
Equimolar amounts of 3-(R,S)-amino-1,3-dihydro-1-methyl-5-(p-tolyl)-2H-1,4-benzodiazepin-2-one, 3-methoxyphenylisocyanate, and triethylamine were mixed in THF at 0° C. and stirred 20 minutes. Removal of THF in vacuo and crystallization from MeOH gave the title compound: m.p. 240°-242° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]=[N+]=[N-])=[CH:13][CH:12]=1)(O)=O.[OH2:24].[OH-].[Na+]>C1COCC1>[OH:24][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])=[CH:13][CH:12]=1
Reactant: [N-]=[N+]=NCCCCc1ccc(CC(=O)O)cc1
Reactant: O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCCCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
Lithium aluminum hydride (35 mL of a 1.0 M solution in THF, 0.035 mol) was added drop wise to a vigorously stirred solution of 4-(4-carboxymethylphenyl)butylazide 8 (2.4 g, 0.010 mol) in dry THF (120 mL) at 0° C. and stirred overnight at room temperature under a nitrogen atmosphere. To break up the complex water (1.5 mL), 15% NaOH (1.5 mL) and water (4.5 mL) were added drop wise to the cold reaction mixture. The white solid precipitate was filtered off and washed with THF. All organics phases were combined and evaporated. The material was purified by column chromatography (silica gel, 2:1:0.05 chloroform/ethanol/concentrated ammonium hydroxide) to provide 67 (1.17 g, 64%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.15 (br s, 2H), 1.54 (br s, 2H) 1.70 (br s, 2H), 2.60 (m, 4H), 3.77 (s, 1H), 4.67 (s, 2H), 7.47 (s, 2H), 7.60 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.O.[CH3:17]O>>[CH3:17][O:9][C:8]([C:3]1[C:2]([Br:1])=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:10]
Reactant: CO
Reactant: O=C(O)c1ncccc1Br
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ncccc1Br
Yield: 42 %

Procedure:
A mixture of 5.45 g of 3-bromo-2-pyridine carboxylic acid (27.0 mmol, 1 eq.), obtained in example 3b), in 100 ml of methanol is reflux heated in the presence of 8 ml of sulfuric acid. The reaction mixture is allowed to return to ambient temperature and poured into water. It is extracted 3 times with ethyl acetate, the organic phase is dried on Na2SO4 and vacuum evaporated. 2.48 g (42%) of esterified product is obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:13]([CH:21]=O)[CH:12]=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(OP([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])(OCC)=O)C>CN(C)C=O>[CH2:3]([N:10]1[C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:13](/[CH:21]=[CH:31]/[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:12]=[N:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cnn(Cc2ccccc2)c1-c1ccccc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cnn(Cc2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 71 %

Procedure:
Sodium hydride (60%, oily, 1.28 g) was added to a mixture of 1-benzyl-5-phenyl-1H-pyrazole-4-carbaldehyde (7.00 g), ethyl diethylphosphonoacetate (6.59 g), and N,N-dimethylformamide (100 ml) at 0° C., and the mixture was stirred at room temperature for 2.5 days. The reaction mixture was poured into ice water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water and then with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and ethyl(E)-3-(1-benzyl-5-phenyl-1H-pyrazol-4-yl)propenoate (6.30 g, yield: 71%) was obtained as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 62–63° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].C([Mg]Cl)(C)C.[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH:21]=[O:22].[NH4+].[Cl-]>C1COCC1>[Cl:17][C:18]1[CH:19]=[C:20]([CH:21]([OH:22])[C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[O:10][CH3:11])[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: COc1cc(C#N)ccc1Br
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(C#N)ccc1C(O)c1ccc(Cl)c(Cl)c1

Procedure:
To a solution of 4-bromo-3-methoxybenzonitrile (606 mg, 2.86 mmol) in dry THF (10 mL) was added iso-propylmagnesium chloride (2 M in diethylether, 1.54 mL, 3.09 mmol) slowly via microsyringe. To the reaction mixture was added 3,4-dichlorobenzaldehyde (270 mg, 1.54 mmol) in dry THF (1 mL) via syringe. After 1 hour at room temperature saturated aqueous NH4Cl (20 mL) was added and the mixture extracted with EtOAc (3×20 mL). The combined organics were concentrated in vacuo and taken through to the next step as crude.
Reaction SMILES: O(N(C)[C:4](=[O:12])[C:5]1[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH2:7])C.Br[C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1N)[O:18][CH3:19].[Li]CCCC.Cl>C1COCC1>[NH2:7][C:6]1[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=1[C:4]([C:15]1[CH:22]=[CH:21][CH:20]=[C:17]([O:18][CH3:19])[CH:16]=1)=[O:12]
Reactant: CON(C)C(=O)c1ccccc1N
Reactant: COc1ccc(N)c(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(C(=O)c2ccccc2N)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 74 %

Procedure:
In a flame-dried round bottom flask, anthranilic acid N-methoxyl-N-methylamide (8.00 g, 44.4 mmol) and m-bromoanisidine (8.31 g, 44.4 g) were dissolved in 250 mL of THF and the resulting solution was cooled to -78° C. With vigorous stirring, 2 equiv of nBuLi in hexanes (55.5 mL, 1.6 M, 88.8 mmol) was added dropwise by a syringe pump at 0.6 mL/min. After 20 min, 80 mL of 1 N hydrochloric acid was carefully added, the mixture was extracted with ethyl acetate (600 mL), and the ethyl acetate was washed with water (300 mL) and brine (300 mL), dried over sodium sulfate and concentrated in vacuo. Flash chromatography with 95:5 hexanes/ethyl acetate afforded 6.92 g (69% yield) of 2-amino-3'-methoxybenzophenone as a yellow oil. 2-Amino-3'-methoxybenzophenone was converted to 2-amino-3'-hydroxybenzophenone (below) prior to characterization.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11].Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])[CH2:25][CH2:24]1.[OH-].[Na+].C1(C)C=CC=CC=1>CC[N+](CC1C=CC=CC=1)(CC)CC.[Cl-].O>[F:1][C:2]([F:18])([F:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:21][CH2:22][N:23]1[CH2:24][CH2:25][N:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])[CH2:27][CH2:28]1
Reactant: O=C(Nc1ccccc1C(F)(F)F)C1CCCCC1
Reactant: COc1ccccc1N1CCN(CCCl)CC1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 33.2 %

Procedure:
A mixture of N-(2-trifluoromethylphenyl)cyclohexanecarboxamide (0.2 g) (Compd 26A), 1-(2-chloroethyl)-4-(2-methoxyphenyl)piperazine (0.37 g),50% (w/w) NaOH (0.5 mL), TEBAC (0.16 g) and toluene (2 mL) was stirred at 80° C. for 3.5 h. An additional amount of compd 26A (0.2 g) was then added and after 6 h stirring at 80° C. the mixture was poured into H2O and extracted with CH2Cl2. The organic phase was dried on anhydrous Na2SO4, evaporated to dryness and the residue purified by flash chromatography (EtOAc-petroleum ether 3:7) giving 0.12 g (17%) of the title compound.
Reaction SMILES: C(O)(=O)C.[NH3:5].[C:6]([OH:25])(=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>O>[CH3:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]/[CH:15]=[CH:14]\[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:25])=[O:24].[NH3:5]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: N
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O

Procedure:
Separately, a 200-ml capacity beaker was charged with 1.44 g of granular acetic acid, 2.08 ml of aqueous ammonia having a concentration of 0.736 mole/l and 50 ml of water, and the mixture was heated at 90° C. under agitation on by a glass rod to completely emulsify stearic acid and form an ammonia soap suspension.
Reaction SMILES: [CH3:1][CH:2]1[C@@H:6]2[CH2:7][C:8](=[O:9])[N:5]2[C:4]([C:10]([O-:12])=[O:11])=[CH:3]1.[CH2:13]([O:16][C:17]([N:19]1[CH2:23][C@@H:22]([S:24]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:21][C@H:20]1[CH2:44][CH:45]1[NH:49][C:48](=[O:50])[NH:47][C:46]1=[O:51])=[O:18])[CH:14]=[CH2:15]>>[CH2:13]([O:16][C:17]([N:19]1[CH2:23][C@@H:22]([S:24][C:3]2[C@H:2]([CH3:1])[C@@H:6]3[C@@H:7]([C@H:8]([OH:9])[CH3:7])[C:8](=[O:9])[N:5]3[C:4]=2[C:10]([O:12][CH2:3][CH:2]=[CH2:1])=[O:11])[CH2:21][C@H:20]1[CH2:44][CH:45]1[NH:49][C:48](=[O:50])[NH:47][C:46]1=[O:51])=[O:18])[CH:14]=[CH2:15]
Reactant: CC1C=C(C(=O)[O-])N2C(=O)C[C@@H]12
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CC1NC(=O)NC1=O
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CC3NC(=O)NC3=O)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 31 %

Procedure:
The same procedure as in Example 8-1 was carried out by using allyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (220 mg, 0.440 mmol) and (2R,4S)-N-allyloxycarbonyl-2-(2,4-dioxoimidazolidin-5-ylmethyl)-4-tritylthiopyrrolidine diastereomer B (220 mg, 0.406 mmol, compound of Reference Example 29) to obtain allyl (1R,5S,6S)-2-[(2R,4S)-N-allyloxycarbonyl-2-(2,4-dioxoimidazolidin-5-ylmethyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate diastereomer B (70 mg, yield: 31%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[C:12]1([CH2:18][CH2:19][CH:20]=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CO.[BH4-].[Na+]>C1C=CC=CC=1>[C:12]1([CH2:18][CH2:19][CH2:20][NH:1][C:2]2[CH:11]=[CH:10][C:5]3[NH:6][C:7](=[O:9])[O:8][C:4]=3[CH:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Reactant: O=CCCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: O=c1[nH]c2ccc(NCCCc3ccccc3)cc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 6-amino-2-benzoxazolone (6.00 g) and molecular sieves 4A (10.0 g) in dry benzene (100 ml) was added 3-phenylpropanal (5.25 ml), and then the mixture was stirred at room temperature for 1 hour. Methanol (150 ml) was combined with this and sodium borohydride (1.50 g) was added in portions at room temperature. The reaction mixture was filtered, the filtrate was concentrated and 5% sodium bicarbonate was added. The organic material was extracted with dichloromethane. The dichloromethane phase was separated, washed with brine. Drying and removal of solvent under reduced pressure gave a crude product which was crystallized from hot ethanol to afford 7.07 g of the title compound: mp 129°-130° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:31])[CH:20]=[CH:21]S(C2C=CC=CC=2)(=O)=O)=[CH:14][CH:13]=1.[OH-].[Na+]>CN(C=O)C>[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:31])[CH:20]=[CH:21][S:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[CH:16][CH:17]=1
Reactant: Cc1cccc(S)c1
Reactant: Cc1ccc(NC(=O)C=CS(=O)(=O)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C=CSc2cccc(C)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.3 %

Procedure:
To a solution of 3-methylthiophenol (0.85 g) in DMF (10 mL) was added 60% sodium hydride (81 mg) under a nitrogen atmosphere under ice-cooling. The mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere, and then was added dropwise to a solution of N-(4-methylphenyl)-3-(phenylsulfonyl)acrylamide (0.85 g) in DMF (10 mL) under ice-cooling. The mixture was stirred at room temperature for 2 hours, alkalinized by addition of a 1N aqueous sodium hydroxide solution, and then extracted with tert-butyl methyl ether (100 mL). The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain N-(4-methylphenyl)-3-(3-methylphenylthio)acrylamide (0.45 g) as a white crystal.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH:6]1([O:12][N:13]2[C:18]([CH3:20])([CH3:19])[CH2:17][CH:16]([OH:21])[CH2:15][C:14]2([CH3:23])[CH3:22])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)CC)C>C(Cl)Cl>[CH:6]1([O:12][N:13]2[C:14]([CH3:23])([CH3:22])[CH2:15][CH:16]([O:21][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:17][C:18]2([CH3:19])[CH3:20])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: C=CC(=O)Cl
Reactant: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)OC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1.6 ml of acryloyl chloride in 20 ml of methylene chloride is added to a stirred solution of 5.11 grams of 1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-ol and 3.10 ml of triethylamine in 20 ml of methylene chloride at 0° C. After stirring at room temperature for 2 hours, the solvent is removed under reduced pressure. The residue is then purified by liquid chromatography to afford the title compound as a white solid with a melting point of 49°-52° C.