Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][C:14]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37]O)=[C:26]([N+:29]([O-:31])=[O:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:13]([F:39])[CH:12]=1.C(=O)(O)[O-].[Na+]>ClCCl.O>[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][C:14]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][F:7])=[C:26]([N+:29]([O-:31])=[O:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:13]([F:39])[CH:12]=1
Reactant: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCOCCO
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCOCCF
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.4 %

Procedure:
DAST (0.16 gram, 1 mmol) was added slowly to a cooled solution (−78° C.) of Compound 29a (0.047 gram, 0.1 mmol) in dichloromethane (2 ml) and the resulting mixture was allowed to warm to room temperature and was thereafter stirred for 12 hours. The reaction mixture was then poured to a saturated solution of sodium bicarbonate), diluted with water, extracted thrice with dichloromethane, washed with brine, and dried over sodium sulfate. Removal of the solvent under reduced pressure afforded Compound 35a (0.036 gram, 78% yield) having a purity of 94%, as determined by HPLC. The compound was used in the following procedures without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1>CN(C)C=O.C(OCC)C>[F:14][C:13]([F:16])([F:15])[C:10]([CH2:12][N:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1)([OH:11])[CH2:9][C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:19][CH3:20])([CH3:18])[CH3:17]
Reactant: C1CSCCN1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CN1CCSCC1)C(F)(F)F

Procedure:
A solution of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (see Example 1) (130 mg) and thiomorpholine (84.6 μL) in dimethylformamide (1 μL) was heated at 100° C. for 15 hours. The resulting mixture was diluted with diethyl ether, washed with water and brine, dried over sodium sulfate, filtered, and the volatiles removed in vacuo. The residue was purified by silica gel column chromatography using 2% EtOAc-hexanes as the eluent. The product-rich fractions were concentrated in vacuo to provide the title compound as a clear oil (161 mg).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[N:8]=[N:7][C:6]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)=[CH:5][CH:4]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29][C:24]=3[N:25]([CH3:28])[C:26]=2[CH:27]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.[Cu]I>[CH3:28][N:25]1[C:26]2[CH:27]=[C:19]([N:12]3[CH:13]=[CH:14][C:9]([C:6]4[N:7]=[N:8][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:4][CH:5]=4)=[CH:10][C:11]3=[O:15])[CH:20]=[CH:21][C:22]=2[C:23]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29][C:24]1=2
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)CC2
Reactant: O=c1cc(-c2ccc(C(F)(F)F)nn2)cc[nH]1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nn5)cc4=O)cc31)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 135 °C
Reaction time: 8 h
Yield: 31.3 %

Procedure:
A suspension of 4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one (106 mg, 0.438 mmol), tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (183 mg, 0.482 mmol), CuI (100 mg, 0.526 mmol), 8-hydroxyquinoline (13 mg, 0.09 mmol) and Cs2CO3 (157 mg, 0.482 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under Ar and stirred at 135° C. overnight. The suspension was cooled, 9:0.9:0.1 CH2Cl2/MeOH/NH4OH (10 mL) was added and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel and the filtrate was washed with brine. The resulting solution was dried over Na2SO4 and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH2Cl2/MeOH/NH4OH), 100:0 to 0:100) afforded the title compound (74 mg, 30%) as a viscous oil: 1H NMR (300 MHz, CDCl3) δ 8.10 (d, J=8.7 Hz, 1H), 7.97 (d, J=8.7 Hz, 1H), 7.65 (d, J=6.9 Hz, 1H), 7.62-7.53 (m, 1H), 7.33 (br s, 1H), 7.30-7.21 (overlapping with solvent peak, 2H), 7.08 (d, J=8.1 Hz, 1H), 3.71-3.62 (m, 7H), 3.11-2.98 (m, 4H), 1.49 (s, 9H).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:15]2[CH2:18][C@@H:17]([OH:19])[C@@H:16]2[CH3:20])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[S:27](Cl)([CH3:30])(=[O:29])=[O:28]>ClCCl>[C:21]1([CH:14]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:15]2[CH2:18][C@@H:17]([O:19][S:27]([CH3:30])(=[O:29])=[O:28])[C@@H:16]2[CH3:20])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: C[C@H]1[C@H](O)CN1C(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1[C@H](OS(C)(=O)=O)CN1C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 95.9 %

Procedure:
50 g (0.495 mol) of triethylamine are added to a solution of 77.33 g (0.329 mol) of trans-1-diphenylmethyl-3-hydroxy-2-methylazetidine in 600 ml of dichloromethane and the mixture is cooled to 0° C. The temperature is maintained, a solution of 50 g (0.437 mol) of mesyl chloride is added dropwise and the mixture is left for 24 hours at room temperature. The resulting solution is washed twice with water (300 ml), dried with anhydrous sodium sulphate and evaporated, and an oil is obtained which, when crystallized with petroleum ether, gives 104.6 g (96%) of trans-1-diphenylmethyl-2-methyl-3-methylsulphonyloxyazetidine, melting point 68°-71° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C@H:5]1[N:8](C(CC2C=CC(OC)=CC=2)CC2C=CC(OC)=CC=2)[C:7](=[O:28])[C@@H:6]1[C@H:29]([O:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH3:30])=[CH2:4]>C(#N)C.O.CO>[Cl:1][CH2:2][C:3]([C@H:5]1[NH:8][C:7](=[O:28])[C@@H:6]1[C@H:29]([O:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH3:30])=[CH2:4]
Reactant: C=C(CCl)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Solvent: O
Solvent: CC#N
Solvent: CO
Product: C=C(CCl)[C@H]1NC(=O)[C@@H]1[C@@H](C)OC(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of (3S,4S)-4-(1-chloromethylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (320 g) in a mixture of acetonitrile and water (9 : 1) (3.8 liters) was added a solution of ceric ammonium nitrate (702 g) in a mixture of acetonitrile and water (9 : 1) (2 liters) at 5° C. or lower, followed by stirring for 30 minutes. The reaction mixture was diluted with water (5.2 liters) and extracted with ethyl acetate (3.4 liters). The aqueous layer was extracted with a mixture of ethyl acetate (1.7 liters), diethyl ether (1.7 liters) and benzene (1.7 liters). The combined extracts were washed successively with brine, 5l% sodium bicarbonate and brine, and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave an oily residue, which was dissolved in methanol (1.5 liters) with warming and allowed to cool gradually. After filtration to remove crystals, the filtrate was concentrated in vacuo to give an oily residue, which was purified by silica gel chromatography to yield (3S,4S)-4-(1-chloromethylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-2-azetidinone.
Reaction SMILES: [CH3:1][Si:2]([CH3:52])([O:7][C@@H:8]1[C@H:12]([O:13][Si:14]([CH3:20])([CH3:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C@@H:11]([CH2:21][O:22][Si:23]([CH3:29])([CH3:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[O:10][C@H:9]1[N:30]1[CH:38]=[N:37][C:36]2[C:31]1=[N:32][C:33]([C:40]1[CH:41]=[N:42][N:43]([CH2:45]C3C=CC=CC=3)[CH:44]=1)=[N:34][C:35]=2[NH2:39])[C:3]([CH3:6])([CH3:5])[CH3:4].IC1C(C)=NNC=1.IC1C=CC(CC2C=CNN=2)=CC=1>>[CH3:52][Si:2]([CH3:1])([O:7][C@@H:8]1[C@H:12]([O:13][Si:14]([CH3:20])([CH3:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[C@@H:11]([CH2:21][O:22][Si:23]([CH3:28])([CH3:29])[C:24]([CH3:27])([CH3:26])[CH3:25])[O:10][C@H:9]1[N:30]1[CH:38]=[N:37][C:36]2[C:31]1=[N:32][C:33]([C:40]1[CH:41]=[N:42][N:43]([CH3:45])[CH:44]=1)=[N:34][C:35]=2[NH2:39])[C:3]([CH3:4])([CH3:5])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(N)nc(-c4cnn(Cc5ccccc5)c4)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: Cc1n[nH]cc1I
Agent: Ic1ccc(Cc2cc[nH]n2)cc1
Product: Cn1cc(-c2nc(N)c3ncn([C@@H]4O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]4O[Si](C)(C)C(C)(C)C)c3n2)cn1

Procedure:
Compound 15 was prepared in the manner of compound 11 substituting 4-iodo-methylpyrazole for 4-iodo-benzylpyrazole to afford compound 15: 1H NMR(CDCl3) 0.00 (s, 3H, CH3), 0.01 (s, 3H, CH3), 0.04 (s, 3H, CH3), 0.07 (s, 3H, CH3), 0.11 (s, 3H, CH3), 0.14 (s, 3H, CH3), 0.78 (s, 9H, t-bu), 0.83 (s, 9H, t-bu), 0.91 (s, 9H, t-bu), 3.8 (d, 1H), 3.90 (s, 3H, N—CH3) 4.05 (d, 1H), 4.08-4.12 (m, 1H), 4.30-4.32 (m, 1H), 4.55-4.60 (m, 1H), 5.60 (bs, 1H, D2O exchangeable), 6.00-6.05 (m, 1H), 7.99 (s, 1H), 8.05 (s, 1H), 8.15 (s, 1H)
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][C:16](=[O:32])[CH2:17][C@@H:18]([NH2:31])[C:19]([NH:21][C@H:22]([C:27](=[O:30])[NH:28][CH3:29])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CO[CH:35]1[CH:39]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:38][CH:37](OC)O1.FC(F)(F)C(O)=O.O>ClCCCl>[CH2:8]([O:15][C:16](=[O:32])[CH2:17][C@@H:18]([N:31]1[CH:37]=[CH:38][C:39]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:35]1)[C:19]([NH:21][C@H:22]([C:27](=[O:30])[NH:28][CH3:29])[C:23]([CH3:25])([CH3:26])[CH3:24])=[O:20])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CNC(=O)[C@@H](NC(=O)[C@H](N)CC(=O)OCc1ccccc1)C(C)(C)C
Reactant: COC1CC(c2ccccc2)C(OC)O1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccccc2)c1)C(C)(C)C
Reaction time: 20 h
Yield: 36.7 %

Procedure:
A solution of crude 3(R)-amino-N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]-succinamic acid benzyl ester trifluoroacetate salt (2.33 mmol), 2,5-dimethoxy-3-phenyl-tetrahydrofuran (583 mg, 2.80 mmol), trifluoroacetic acid (216 μL, 2.80 mmol), and water (50 μL, 2.8 mmol) in 1,2-dichloroethane (1 mL) was heated at 70° C. After 20 hours, the mixture was allowed to cool and concentrated in vacuo to give a brown oil, which was purified via flash column chromatography with 0.5% HOAc/35% EtOAc/hex as eluant to afford 407 mg (37%) of N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)-3(R)-(3-phenyl-1H-pyrrol-1-yl)succinamic acid benzyl ester as a yellow foam. 1H NMR: a 7.52-7.44 (m, 2H), 7.38-7.15 (m, 3H), 7.04 (dd, 1H, J=1.8, 1.8 Hz), 6.78 (t, 1H, J=2.5 Hz), 6.56 (dd, 1H, J=1.6, 2.5 Hz), 6.42 (d, 1H, J=9.0 hz), 5.95 (bd, J=4.0 Hz), 5.18-5.04 (m, 3H), 4.30 (d, 1H, J=9.0 Hz), 3.38 (dd, 1H, J=5.9, 16.8 Hz), 3.10 (dd, 1H, J=8.4, 16.8 hz), 2.72 (d, 3H, J=5.0 Hz), 0.93 (s, 9H). IR: 3301, 2960, 1736, 1645, 1542, 1166, 752, 695 cm-. HRFABMS: Calculated for C28H33N3O4Cs (M+Cs+): 608.1525. Found: 608.1549. Anal. Calculated for C28H33N3O4.0.2H2O: C, 70.18; H 7.03; N, 8.77. Found: C, 70.45; H, 6.99; N, 8.84.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:23]=[C:14]3[CH2:15][N:16]([C:19](=[O:22])[CH2:20][CH3:21])[CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:24]([O:27][CH2:28][C:29]1[C:30]([N:38]2[CH2:49][CH2:48][N:47]3[C:40](=[CH:41][C:42]4[CH2:43][C:44]([CH3:51])([CH3:50])[CH2:45][C:46]=43)[C:39]2=[O:52])=[N:31][CH:32]=[CH:33][C:34]=1B(O)O)(=[O:26])[CH3:25].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[C:24]([O:27][CH2:28][C:29]1[C:30]([N:38]2[CH2:49][CH2:48][N:47]3[C:40](=[CH:41][C:42]4[CH2:43][C:44]([CH3:51])([CH3:50])[CH2:45][C:46]=43)[C:39]2=[O:52])=[N:31][CH:32]=[CH:33][C:34]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:23]=[C:14]3[CH2:15][N:16]([C:19](=[O:22])[CH2:20][CH3:21])[CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: CCC(=O)N1CCn2nc(Nc3cc(Br)cn(C)c3=O)cc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CCC(=O)N1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CC(C)(C)C7)C5=O)c4COC(C)=O)cn(C)c3=O)cc2C1
Temperature: 100 °C
Yield: 28.9 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 265c (200 mg, 0.53 mmol), {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (834 mg, 2.10 mmol), Pd(dppf)Cl2 (19 mg, 0.0263 mmol), K3PO4 (223 mg, 1.052 mmol), sodium acetate (86 mg, 1.052 mmol), acetonitrile (10 mL), and water (5 drops). After three cycles of vacuum/argon flush, the reaction mixture was heated at 100° C. for 3 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The reaction mixture was cooled down to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 60:1 dichloromethane/methanol to afford 265d (100 mg, 29%) as yellow oil. MS-ESI: [M+H]+ 653.3
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:17].C1C[O:21][CH2:20]C1>CO>[ClH:17].[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13](=[NH:14])[O:21][CH3:20])=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: N#Cc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CO
Product: COC(=N)c1ccc(OCc2ccccc2)cc1
Reaction time: 16 h

Procedure:
A solution of 560 mg of 4-benzyloxybenzonitrile in 16 ml of THF and 0.2 ml of methanol, cooled to 0° C., was saturated with hydrogen chloride and kept at 4° C. for 16 hours. The precipitate was filtered off, washed with diethyl ether and dried to give 357 mg of methyl 4-benzyloxybenzimidate hydrochloride, m.p. 179°-180° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:34]1[N:41]=[CH:40][C:39]([CH2:42][N:43]2[CH2:48][CH2:47][N:46]([CH:49]([CH3:51])[CH3:50])[CH2:45][CH2:44]2)=[CH:38][C:35]=1[C:36]#[N:37].C(=O)([O-])O.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC>[C:36]([C:35]1[C:34]([C:20]2[CH:19]=[CH:18][C:17]([C:16]([NH:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:32])=[CH:22][CH:21]=2)=[N:41][CH:40]=[C:39]([CH2:42][N:43]2[CH2:44][CH2:45][N:46]([CH:49]([CH3:51])[CH3:50])[CH2:47][CH2:48]2)[CH:38]=1)#[N:37]
Reactant: CC(C)N1CCN(Cc2cnc(Cl)c(C#N)c2)CC1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: COCCOC
Product: CC(C)N1CCN(Cc2cnc(-c3ccc(C(=O)Nc4ccccc4NC(=O)OC(C)(C)C)cc3)c(C#N)c2)CC1
Temperature: 80 °C

Procedure:
1,1′-Bis(diphenylphosphino)ferrocenedichloropalladium (II) chloride (58 mg, 0.072 mmol) was added to a mixture of N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (626 mg, 1.43 mmol prepared as described in International Patent Publication Number WO03/087057, Method 13, page 60), 2-chloro-5-[(4-isopropylpiperazin-1-yl)methyl]nicotinonitrile (398 mg, 1.43 mmol; see Method 20), saturated aqueous sodium hydrogen carbonate solution (5 ml) and 1,2-dimethoxyethane (10 ml). The mixture was heated at 80° C. for 1 hour then allowed to cool to room temperature and partitioned between dichloromethane (75 ml) and water (50 ml). The aqueous layer was extracted with further dichloromethane (2×75 ml). The combined organics were dried over magnesium sulfate, filtered and then evaporated to dryness. The residue was purified by flash chromatography on silica, eluting with methanol (5-10%) in dichloromethane to afford the title compound as a yellow gum which crystallised on trituration with diethyl ether, (652 mg, 82%).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C(N(CC)CC)C.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[S:25](Cl)(=[O:27])=[O:26]>C1COCC1>[CH3:3][O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([S:25]([C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)(=[O:27])=[O:26])[CH2:9][CH2:8]1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COCCN1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCN1CCN(S(=O)(=O)c2cccs2)CC1
Reaction time: 0.17 h
Yield: 66.4 %

Procedure:
To a suspension of 1-(2-methoxyethyl)piperazine dihydrochloride (2.61 g, 12.0 mmol) in THF (100 mL) was added triethylamine (10 mL) and the resulting mixture was stirred for 10 min. Then a solution of 2-thiophenesulfonyl chloride (1.98 g, 10.84 mmol) was added in THF (3 mL) over 5 min. The reaction mixture was allowed to stir at room temperature for 1 h, the volatiles were evaporated and the residue was extracted with ethyl acetate (3×100 mL). The combined extracts were washed with a saturated sodium bicarbonate solution (50 mL), brine and dried over molecular sieves. Evaporation to dryness gave a viscous oil (2.09 g, 75%).
Reaction SMILES: C[N+](C)=CCl.[Cl-].P(Cl)(Cl)(Cl)=O.[CH2:12]([O:19][C:20]([CH2:22][O:23][N:24]=[C:25]([C:29](=[O:32])[CH2:30][Br:31])[C:26]([OH:28])=O)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.[NH2:34][CH:35]1[C:60](=[O:61])[N:37]2[C:38]([C:44]([O:46][CH:47]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:45])=[C:39]([CH:42]=[CH2:43])[CH2:40][S:41][C@H:36]12.C[Si](CC(N)=O)(C)C>O1CCCC1.C(Cl)Cl.C(OCC)(=O)C.CN(C)C=O>[CH2:12]([O:19][C:20]([CH2:22][O:23][N:24]=[C:25]([C:29](=[O:32])[CH2:30][Br:31])[C:26]([NH:34][CH:35]1[C:60](=[O:61])[N:37]2[C:38]([C:44]([O:46][CH:47]([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)[C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[O:45])=[C:39]([CH:42]=[CH2:43])[CH2:40][S:41][C@H:36]12)=[O:28])=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(CON=C(C(=O)O)C(=O)CBr)OCc1ccccc1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Agent: C[N+](C)=CCl
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OCc3ccccc3)C(=O)CBr)[C@H]2SC1
Yield: 74.5 %

Procedure:
Vilsmeier reagent prepared from N,N-dimethylformamide (0.67 ml) and phosphorus oxychloride (0.79 ml) was suspended in dry tetrahydrofuran (25 ml). Thereto was added 2-benzyloxycarbonylmethoxyimino-4-bromo-3-oxobutyric acid (2.8 g) at 0° C. with stirring, and the stirring was continued at 0° to 5° C. for an hour to prepare the activated acid solution. This activated acid solution was added at a time to a solution of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (2.2 g) and trimethylsilylacetamide (7.0 g) in methylene chloride (30 ml) at -35° C., and the mixture was stirred at -10° to -5° C. for 30 minutes. The reaction mixture was poured into ethyl acetate (200 ml), and the separated organic solution was washed with a saturated aqueous sodium bicarbonate and a saturated aqueous sodium chloride, followed by drying over magnesium sulfate. Removal of the solvent gave benzhydryl 7-(2-benzyloxycarbonylmethoxyimino-4-bromo-3-oxobutyramido)-3-vinyl-3-cephem-4-carboxylate (2.8 g).
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][N:7]=1)(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:48][C@@H:49]([CH2:63][C:64]1[CH:69]=[C:68]([F:70])[CH:67]=[C:66]([F:71])[CH:65]=1)[C@H:50]([OH:62])[CH2:51][NH:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([CH2:60][CH3:61])[CH:55]=1>C(Cl)Cl>[F:70][C:68]1[CH:69]=[C:64]([CH:65]=[C:66]([F:71])[CH:67]=1)[CH2:63][C@H:49]([NH:48][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:6]([CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])=[N:7][CH:8]=1)[C@H:50]([OH:62])[CH2:51][NH:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([CH2:60][CH3:61])[CH:55]=1
Reactant: CS(=O)(=O)Cc1ccc(C(=O)O)cn1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2ccc(CS(C)(=O)=O)nc2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 36.9 %

Procedure:
To a stirred solution of 6-[(methylsulfonyl)methyl]nicotinic acid (181 mg), diisopropylethylamine (116 mg), and HBTU (341 mg) in methylene chloride (5 mL) was added a mixture of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (326 mg) and N,N-diisopropylethylamine (233 mg) in methylene chloride (5 mL). The mixture was stirred at room temperature for 15 h and concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 mL), washed with saturated sodium bicarbonate, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 5:95 to 10:90 methanol/methylene chloride) provided 165 mg of the title compound: ESI MS m/z 532 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]=[N:22][NH:23][CH:24]=1)=[CH:16][CH:15]=3.[H-].[Na+].C1OCCOC2C(=CC=CC=2)OCCOCCOC2[C:35](=CC=CC=2)[O:34][CH2:33]1.COCBr>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]=[N:22][N:23]([CH2:33][O:34][CH3:35])[CH:24]=1)=[CH:16][CH:15]=3
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4c[nH]nn4)ccc3n(C)c21
Reactant: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Agent: COCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCn1cc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)nn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
209 mg (0.49 mmol) of compound from Example 47, 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(1H-[1,2,3]triazol-4-yl)-1,9-dihydropyrido[2,3-b]indol-2-one, are dissolved in 3 ml of DMF. 30 mg (0.74 mmol) of 60% NaH and a spatula tip of dibenzo-18-crown-6 are added. 80 μl of bromomethyl methyl ether are then added. The mixture is stirred at ambient temperature for 16 hours. The reaction medium is poured into water and then extracted with EtOAc and the organic phase is dried over MgSO4, filtered and evaporated to dryness, adsorbing onto silica. Purification is carried out on a silica column, elution being carried out with a gradient of EtOAc/50% cyclohexane, then with EtOAc/40% cyclohexane and, finally, 100% EtOAc. The residue is triturated in MeOH so as to obtain a beige solid.