Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](Br)(C)C.[CH2:6]([O:13][C@@H:14]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@@H:19]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@@H:18]([CH2:37][O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:17][CH:15]1[OH:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:46][CH2:47][CH2:48]O>[Br-].C([N+](CC)(CC)CC)C.C(Cl)Cl.[Co](Br)Br>[CH2:6]([O:13][C@@H:14]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@@H:19]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C@@H:18]([CH2:37][O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[O:17][C@@H:15]1[O:16][CH2:48][CH2:47][Br:46])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: OCCBr
Reactant: OC1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: Br[Co]Br
Agent: CC[N+](CC)(CC)CC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: BrCCO[C@H]1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
Trimethylsilyl bromide (7.96 g, 6.78 ml. 52 mmol) was added with a syringe to a mixture of 2,3,4,6-tetra-O-benzyl-D-galactopyranose (28 g, 52 mmol), 2-bromoethanol (4.46 ml, 40.0 mmol), cobalt(II)bromide (11.4 g, 52.0 mmol), tetraethylammonium bromide (10.9 g, 52.0 mmol) and molecular sieves (4 Å, 41 g) in 138 ml of methylene chloride under nitrogen with protection from light. (The cobalt(II)chloride had been dried at 180°, 5×10-3 mm Hg over night. ) The reaction mixture was stirred at room temperature over night and filtered. The residue was washed with 100 ml of methylene chloride. The filtrate was evaporated at reduced pressure to give 25.8 g of the crude product, which was chromatographed (SiO2, isooctane:ethyl acetate 3:2) Fraction 1 was the pure title compound (6.0 g) and fraction 2 was a mixture of the anomers (α/β, 10.0 g) Total yield of glycosides 16 g (48 %) (This procedure is a slight modification of that of Koto et al.34.) [α]D23 =+30.5° (c 1.4, CHCl3). 1H-NMR (CDCl3, TMS) δ 7.30 (m, 20H, Ph), 4.97-4.42 (m, 9H), 4.0-3.8 (m, 6H), 3.52 (t, 4H, inter alia CH2Br). 13C-NMR (CDCl, TMS) δ 103.3 (d, Cl, JC--H =168 Hz), 84.2, 81.6, 80.2, 75.0 (C2-C5), 80.0, 78.7, 78.6, 78.5, 74.2, 73.5 (C6, benzylic CH2 and aglycon O--CH2), 35.5 (CH2Br)
Reaction SMILES: [C:1](I)([C:4]([C:7]([C:10]([C:13]([C:16]([F:19])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[C:21](#[N:24])[CH:22]=[CH2:23]>[Zn].C([O-])(=O)C.[Cu+2].C([O-])(=O)C.[Zn].[Cu]>[C:1]([CH2:23][CH2:22][C:21]#[N:24])([C:4]([C:7]([C:10]([C:13]([C:16]([F:19])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Reactant: C=CC#N
Agent: [Cu+2]
Agent: [Cu]
Agent: CC(=O)[O-]
Product: N#CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
A series of tests was carried out according to the operating method of Example 1, but by modifying the nature of the solvent. These tests were made by dispersing 4 g. of coarse zinc powder in a solution of 100 mg of copper acetate in 30 ml of acid, by varying the latter. The dispersion of the zinc/copper metal pair is cooled to ambient temperature, and a mixture of 23 g. of C6F13I (0.05 mole) and 2.7 g. of acrylonitrile are introduced into the above dispersion, with agitation, during a period of one hour. One hour after termination of the addition of the two reactants, the reaction mixture is washed with water and analyzed by nuclear magentic resonance. The results are indicated in Table I in which the indicated percentages are molar percentages.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]3[CH2:12][CH2:13][CH:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]3=[CH:6][C:5]=2[C:4]=1[CH3:21].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]3[CH2:12][CH2:13][CH:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]3=[CH:6][C:5]=2[C:4]=1[CH3:21]
Reactant: CCOC(=O)CC1CCn2c1cc1c(C)c(OC)ccc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CC1CCn2c1cc1c(C)c(O)ccc12
Reaction time: 1 h
Yield: 65.7 %

Procedure:
To a stirred solution of ethyl 2-(7-methoxy-8-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (320 mg, 1.114 mmol) in anhydrous DCM (8 mL) was added a 1M solution of boron tribromide in DCM (3341 μL, 3.34 mmol) at 0° C. under nitrogen protection. The reaction mixture was stirred at this temperature for 1 h, neutralized by addition of saturated NaHCO3 solution. The organic layer was separated and washed with water and dried over anhydrous Na2SO4. The solvent was evaporated, and the residue was purified by column chromatography to give the title compound (200 mg) as a light yellow oil. LCMS m/z=274.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.32 (t, J=7.1 Hz, 3H), 2.25-2.32 (m, 1H), 2.40 (s, 3H), 2.58 (dd, J=16.0, 8.5 Hz, 1H), 2.82-2.90 (m, 2H), 3.73-3.80 (m, 1H), 3.95-4.02 (m, 1H), 4.05-4.13 (m, 1H), 4.20-4.27 (m, 2H), 4.58 (s, 1H), 6.09 (s, 1H), 6.69 (d, J=8.5 Hz, 1H), 6.95 (d, J=8.5 Hz, 1H).
Reaction SMILES: Cl.[C:2]1([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[S:13][CH:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:21]1[N:22]([CH2:30][C:31](O)=[O:32])[CH:23]=[C:24]2[C:29]=1[CH:28]=[CH:27][CH:26]=[CH:25]2>>[N:21]1[N:22]([CH2:30][C:31]([N:18]2[CH2:19][CH2:20][CH:15]([C:12]3[S:13][CH:14]=[C:10]([CH2:9][CH2:8][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[N:11]=3)[CH2:16][CH2:17]2)=[O:32])[CH:23]=[C:24]2[C:29]=1[CH:28]=[CH:27][CH:26]=[CH:25]2
Reactant: O=C(O)Cn1cc2ccccc2n1
Reactant: c1ccc(CCc2csc(C3CCNCC3)n2)cc1
Agent: Cl
Product: O=C(Cn1cc2ccccc2n1)N1CCC(c2nc(CCc3ccccc3)cs2)CC1

Procedure:
4-[4-(2-Phenylethyl)-1,3-thiazol-2-yl]piperidine hydrochloride (II-1, 309 mg), prepared according to Process 1.2, is reacted analogously to Example I-63 with 2H-indazol-2-ylacetic acid (194 mg). After chromatographic purification, this gives 2-(2H-indazol-2-yl)-1-{-4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone (67 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)[CH3:2].[I:15]N1C(=O)CCC1=O.S(=O)(=O)(O)O.S([O-])(O)=O.[Na+]>C(O)(=O)C.O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:13])([CH3:14])[C:10]([OH:12])=[O:11])=[CH:5][C:4]=1[I:15])[CH3:2]
Reactant: CCc1ccc(C(C)(C)C(=O)O)cc1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCc1ccc(C(C)(C)C(=O)O)cc1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(4-Ethylphenyl)-2-methylpropanoic acid (58.1 g, 302.2 mmol) was dissolved in acetic acid (175 ml), added with N-iodosuccinimide (71.4 g, 317.3 mmol, 1.05 eq.) and conc. sulfuric acid (75 ml) at 0° C. Thereafter, the mixture was stirred at room temperature for 2 hrs. After cooling the reaction solution to 0° C., 10% aqueous solution of sodium hydrogen sulfite (100 ml) was added and the mixture was stirred for 1 hr. H2O (450 ml) was added to the mixture and the precipitated solid was filtered to obtain the title compound as a crude product. Ethanol (150 ml) and 10% aqueous solution of sodium hydrogen sulfite (50 ml) were added to the crude product, and the mixture was dissolved under heating at 50° C. After confirming the dissolution, the solution was cooled to room temperature, added with H2O (300 ml), and then stirred at 0° C. for 1 hr. The precipitated solid was filtered to obtain the title compound (95.8 g, 99%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:14])([CH3:13])[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][C:3]=1[NH:15][C:16](=O)[CH2:17][CH2:18][C:19]1[CH:27]=[CH:26][C:22]2[O:23][CH2:24][O:25][C:21]=2[CH:20]=1>C(O)(=O)C>[O:23]1[C:22]2[CH:26]=[CH:27][C:19]([CH2:18][CH2:17][C:16]3[NH:15][C:3]4=[CH:4][C:5]5[C:6]([CH3:14])([CH3:13])[C:7](=[O:12])[N:8]([CH3:11])[C:9]=5[CH:10]=[C:2]4[N:1]=3)=[CH:20][C:21]=2[O:25][CH2:24]1
Reactant: CN1C(=O)C(C)(C)c2cc(NC(=O)CCc3ccc4c(c3)OCO4)c(N)cc21
Solvent: CC(=O)O
Product: CN1C(=O)C(C)(C)c2cc3[nH]c(CCc4ccc5c(c4)OCO5)nc3cc21
Yield: 99.7 %

Procedure:
A solution of N-(6-amino-1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-3-benzo[1,3]dioxol-5-yl-propionamide (60 mg) in acetic acid (1.6 ml) is heated in a microwave apparatus at 150° C. for 15 min. After dilution with water the mixture is extracted with EtOAc (3×15 ml). The organic layer is washed with brine, dried over MgSO4 and concentrated in vacuo to give the desired compound (57 mg).
Reaction SMILES: CC1N([CH2:7][CH:8]2[C:21](=[O:22])[C:12]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[N:19]([CH3:20])[C:11]=3[CH2:10][CH2:9]2)C=CN=1.CI.CN(C)C>>[CH3:20][N:19]1[C:11]2[CH2:10][CH2:9][C:8](=[CH2:7])[C:21](=[O:22])[C:12]=2[C:13]2[C:18]1=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: Cc1nccn1CC1CCc2c(c3ccccc3n2C)C1=O
Agent: CN(C)C
Solvent: CI
Product: C=C1CCc2c(c3ccccc3n2C)C1=O

Procedure:
Peculiarly, the above-said patent specification indicates this tertiary amine to be known per se and, in addition, ondansetron can be prepared therefrom in an other way, too. After quaternizing the tertiary amine with methyl iodide, trimethylamine is split off from the obtained methoiodide by Hofmann's elimination reaction to give 9-methyl-3-methylene-1,2,3,9-tetrahydro-4H-carbazol-4-one. The thus-obtained electrophilic conjugated enone is subjected to an addition reaction with 2-methylimidazole (see Example 8 of the specification). The surprisingly moderate yield of 43.2% of the reaction shows that the significance of this simple direct addition, starting from the separated enone, should not be overestimated.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1([C:6](O)=[O:7])[CH2:5][CH2:4]1.C(Cl)(=O)C(Cl)=O.[NH4+:17].[OH-]>C(Cl)Cl.CN(C=O)C.C1COCC1>[F:1][C:2]([F:10])([F:9])[C:3]1([C:6]([NH2:17])=[O:7])[CH2:5][CH2:4]1
Reactant: [NH4+]
Reactant: O=C(O)C1(C(F)(F)F)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: NC(=O)C1(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
A solution of 1-(trifluoromethyl)cyclopropane-1-carboxylic acid (0.5 g, 3.24 mmol) in DCM (5 mL) was treated with oxalyl chloride (0.355 mL, 4.06 mmol) and 1 drop of DMF, stirred for 1 h at RT, added drop-wise to a solution of NH4OH (˜15M, 5 mL, ˜75 mmol) in THF (5 mL) and stirred at RT overnight. The solids were removed via filtration through diatomaceous earth and rinsed well with 4:1 DCM/THF. The filtrate was saturated with solid NaCl, extracted with 4:1 DCM/THF (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness to afford 1-(trifluoromethyl)cyclopropanecarboxamide (440 mg, 89%). 1H NMR (400 MHz, DMSO-d6): δ 7.31 (s, 1H), 7.15 (s, 1H), 1.29-1.24 (m, 2H), 1.19-1.15 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:20](OCC)=[O:21])[C:15](OCC)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].C1(C)C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([CH2:15][OH:16])[CH2:20][OH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(CO)CO)CC1

Procedure:
A mixture of 1-tert-butoxycarbonylpiperidin-4-ol, triethylamine, benzenesulfonyl chloride, and methylene chloride was stirred at ambient temperature for 2 days to yield 1-tert-butoxycarbonylpiperidin-4-yl benzenesulfonate. A mixture of 1-tert-butoxycarbonylpiperidin-4-yl benzenesulfonate obtained, diethyl malonate, 20% NaOEt-EtOH, and EtOH was heated under reflux with stirring for 22 hours to yield diethyl[1-(tert-butoxycarbonyl)piperidin-4-yl]malonate. A mixture of diethyl [1-(tert-butoxycarbonyl)piperidin-4-yl]malonate obtained, lithium borohydride, toluene, and THF was stirred at 60° C. for 18 hours to yield 2-(1-tert-butoxycarbonylpiperidin-4-yl)propane-1,3-diol, which was stirred together with 4M HCl-dioxane solution in MeOH at ambient temperature for 1 hour to yield 2-piperidin-4-ylpropane-1,3-diol hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[I:8].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[NH2:50][CH2:51][C:52]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:53].C(N(CC)C(C)C)(C)C>C(=O)(O)[O-].[Na+].CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[I:8])[CH2:9][C@H:10]([NH:14][C:15](=[O:16])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11](=[O:13])[NH:50][CH2:51][C:52](=[O:53])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)c(Br)c1)C(=O)O
Reactant: NCC(=O)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)c(Br)c1)C(=O)NCC(=O)c1ccccc1
Reaction time: 0.17 h
Yield: 33.5 %

Procedure:
A solution of (2S)-3-(3-bromo-4-iodophenyl)-2-[(tert-butoxycarbonyl)amino]propanoic acid (4.10 g, 6.10 mmol), N,N-dimethylformamide (49 mL) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (4.24 g, 9.59 mmol) was stirred at 25° C. After stirring for 10 min, added 2-amino-1-phenylethanone hydrochloride (2.24 g, 13.1 mmol) and N,N-diisopropylethylamine (7.60 mL). The reaction was stirred at 25° C. for 2 h. The reaction was diluted with saturated sodium bicarbonate and extracted with ethyl acetate three times, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (1.2 g, 33%). MF=C22H24BrIN2O4; LCMS found for C22H25BrIN2O4 (M+H−Boc)+: m/z=487.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([Cl:16])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.Cl[C:23]([O:25][CH2:26][CH2:27][Cl:28])=[O:24]>ClCCl>[Cl:28][CH2:27][CH2:26][O:25][C:23]([NH:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([Cl:16])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1)=[O:24]
Reactant: O=C(Cl)OCCCl
Reactant: Cc1cccc(N)c1CNc1cccn2c(Cl)c(C)nc12
Solvent: ClCCl
Product: Cc1cccc(NC(=O)OCCCl)c1CNc1cccn2c(Cl)c(C)nc12

Procedure:
According to the procedure indicated in Example 1a, 8-(2-amino-6-methylbenzylamino)-3-chloro-2-methylimidazo[1,2-a]pyridine (0.27 g) and 2-chloroethyl chloroformate (0.18 g) in dichloromethane (30 ml) give the title compound as a brown oil, which is used directly for further reaction in 2b.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:36])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31](O)=[O:32])=[CH:27][CH:26]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:66][CH2:67][C:68]([NH:70][C@@H:71]([C:79]([OH:81])=[O:80])[CH2:72][CH:73]1[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]1)=[O:69]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:36])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)[C@@H:14]3[C:25]3[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31]([NH:66][CH2:67][C:68]([NH:70][C@@H:71]([C:79]([OH:81])=[O:80])[CH2:72][CH:73]4[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]4)=[O:69])=[O:32])=[CH:27][CH:26]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc4c(c3)CCO4)C(=O)N2c2ccc(F)cc2)cc1
Reactant: NCC(=O)N[C@H](CC1CCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc4c(c3)CCO4)C(=O)N2c2ccc(F)cc2)cc1)NCC(=O)N[C@H](CC1CCCCC1)C(=O)O
Temperature: 30 °C
Reaction time: 0.42 h

Procedure:
To a stirred solution of {4-[(2R,3R)-3-{[2-(2,3-dihydro-1-benzofuran-5-yl)-2-oxoethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetic acid (Method 2) (15.7 mg, 0.031 mmol) in DMF (2 ml, dry) was added N-methylmorpholine (10 μl, 0.091 mmol). TBTU (13.1 mg, 0.041 mmol) and additional DMF (2 ml) were added and the reaction mixture was stirred under at 30° C. for 25 minutes. Glycyl-3-cyclohexyl-D-alanine (7.1 mg, 0.031 mmol) (Method 7) was added and the reaction mixture was stirred for 2 hours. The formation of the ketone of the title compound was confirmed. M/z: 716.57 (M−1). Without further purification, methanol (6 ml) and sodium borohydride (16.1 mg, 0.043 mmol) were added and the reaction mixture was stirred for 20 minutes. Ammonium acetate (85.5 mg) was added. The methanol was removed under reduced pressure and the remaining DMF-solution was purified with preparative HPLC on a C8 column. A gradient from 20 to 55% MeCN in 0.1M NH4OAc was used as eluent. The pure fractions were collected and the MeCN was removed under reduced pressure. The residue was extracted between EtOAc and water, the water phase was acidified to pH 2 with KHSO4 (2M). The phases were separated and the organic phase was passed through a phase separator. The solvent was removed under reduced pressure. The residue was dissolved in ACN and water. After lyophilisation, the title compound was obtained. H-NMR (400 MHz, DMSO-d6): 0.69-1.67 (m, 13H), 2.76-2.91 (m, 2H), 2.98-311 (m, 2H), 3.75 (d, 2H), 4.15-4.25 (m, 2H), 4.40-4.47 (m, 2H), 4.49 (s, 2H), 4.55-4.64 (m, 1H), 5.00 (b, 1H), 5.54 (b, 1H), 6.61 (dd, 1H), 6.96 (d, 3H), 7.08-7.16 (m, 3H), 7.18-7.24 (m, 2H), 7.34 (d, 2H), 8.07 (d, 1H), 8.19 (t, 1H), 12.51 (b, 1H). M/z: 718.57 (M−1).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]([NH2:16])=[CH:11][C:12]([Br:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:19](OC)(OC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH2:1]([N:8]1[C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=2[N:16]=[C:19]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(Br)ccc1NCc1ccccc1
Reactant: COC(OC)(OC)c1ccccc1
Solvent: ClCCl
Product: Brc1ccc2c(c1)nc(-c1ccccc1)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
p-TsOH-H2O (311.7 mg, 1.606 mmol) was added to a DCM (50 ml) solution of N1-benzyl-4-bromobenzene-1,2-diamine (4451 mg, 16.06 mmol) and trimethyl orthobenzoate (3096 μl, 17.66 mmol) and the resulting mixture was stirred at rt under an atmosphere of Nitrogen for 40 h. The reaction mixture was then concentrated in vacuo to give a yellow solid which was triturated with 40% MeOH/water (375 mL), filtered, washed with saturated NaHCO3 (20 ml)+H2O (80 ml) twice and 40% MeOH/H2O (2×50 ml), and dried to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm =5.44 (s, 2 H), 7.05-7.08 (m, 3 H), 7.30-7.36 (m, 4 H), 7.44-7.50 (m, 3 H), 7.66-7.68 (m, 2 H) and 7.99 (dd, 1 H, J=0.4 & 1.6 Hz). MS(ES+): m/z 363.20 and 365.26[MH+].
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:13]([CH3:22])[N:12]=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[Br:34]Br.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:1]([O:8][CH2:9][N:10]1[C:14]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:13]([CH3:22])[N:12]=[C:11]1[Br:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: Cc1ncn(COCc2ccccc2)c1Sc1ccccc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1nc(Br)n(COCc2ccccc2)c1Sc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 92.5 %

Procedure:
In 5 ml of dry tetrahydrofuran is dissolved 300 mg of 1-benzyloxymethyl-4-methyl-5-phenylthioimidazole (I-3) (1 mmol) obtained in Example 3, and the resulting solution is chilled at -78° C. To the solution is added dropwise 1.64M solution of n-butyl lithium in 0.71 ml of hexane (1.16 mmol) and the mixture allowed to stand for 10 minutes, when 185 mg of bromine (1.16 mmol) is added thereto. Fifteen minutes later, the mixture is poured onto ice water. The mixture is neutralized with sodium bicarbonate and extracted with ethyl ether. The extract is washed with water, dried over sodium sulfate, filtered and the filtrate is concentrated. The crude product is chromatographed on a column of silica gel, eluting with ethyl acetate/n-hexane (1:2) to give 360 mg of the product (I-20; mp. 55° C.). Yield, 96%.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][C:13](=[O:21])[CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([NH:36][S:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)(=[O:39])=[O:38])[CH:33]=[N:34][CH:35]=2)O1.O>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.[Cl-].[Na+].O>[C:15]1([CH2:14][C:13]([NH:12][C:8]2[CH:7]=[N:6][C:5]3[C:10](=[CH:11][C:2]([C:30]4[CH:35]=[N:34][CH:33]=[C:32]([NH:36][S:37]([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)(=[O:39])=[O:38])[CH:31]=4)=[CH:3][CH:4]=3)[N:9]=2)=[O:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cc1ccccc1)Nc1cnc2ccc(Br)cc2n1
Reactant: CC1(C)OB(c2cncc(NS(=O)(=O)c3ccccc3)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Cc1ccccc1)Nc1cnc2ccc(-c3cncc(NS(=O)(=O)c4ccccc4)c3)cc2n1
Temperature: 100 °C
Yield: 33.4 %

Procedure:
A mixture of N-(7-bromo-2-quinoxalinyl)-2-phenylacetamide (0.254 mmol), N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (0.508 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (0.007 mmol) in 2M aqueous sodium carbonate (0.5 mL) and 1,4-dioxane (2 mL) was heated at 100° C. for 5 h. The reaction mixture was cooled, poured into water (60 mL) and brine (15 mL), and extracted with ethyl acetate (50 mL). The aqueous layer was acidified with 1N aqueous HCl until the pH was approximately 6-7 and then further extracted with (3×50 mL) ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by silica gel chromatography eluting with 50-70% ethyl acetate/hexanes followed by reverse phase HPLC (30-75% acetonitrile/water with 0.1% TFA) afforded the title product as a tan solid (42 mg, 33%). MS(ES)+ m/e 496 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:40]=[CH:39][C:15]([CH2:16][N:17]2[C:25]3[C:20](=[CH:21][C:22]([OH:26])=[CH:23][CH:24]=3)[C:19]([S:27][CH2:28][CH2:29][OH:30])=[C:18]2[CH2:31][C:32]([CH3:38])([CH3:37])[C:33]([O:35][CH3:36])=[O:34])=[CH:14][CH:13]=1.CCN(CC)CC>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][N:17]2[C:25]3[C:20](=[CH:21][C:22]([OH:26])=[CH:23][CH:24]=3)[C:19]([S:27][CH2:28][CH:29]=[O:30])=[C:18]2[CH2:31][C:32]([CH3:38])([CH3:37])[C:33]([O:35][CH3:36])=[O:34])=[CH:39][CH:40]=1
Reactant: COC(=O)C(C)(C)Cc1c(SCCO)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(C)(C)Cc1c(SCC=O)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
To a solution of oxalyl chloride (579 mg, 4.56 mmol) in CH2Cl2 (15 mL) at -70° C. there was slowly added DMSO (711 mg, 9.12 mmol). The mixture was stirred for 3 minutes, then at -70° C. there was slowly added a solution of the alcohol from Step 5 (1.7 g, 3.8 mmol) in CH2Cl2 (15 mL). The resulting mixture was stirred at -70° C. for 20 minutes, then there was slowly added Et3N (1.92 g, 19 mmol). The mixture was stirred in the cold for a further 5 minutes, then it was allowed to warm up to room temperature. After dilution with Et2O (200 mL) the mixture was washed twice with 1N HCl, then with H2O (3×), dried and evaporated to a residue which was chromatographed on silica gel, eluting with a 1:1 mixture of hexane and EtOAc, to afford the title compound as a thick oil.