Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:2]2[N:3]([CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:5][N:6]=1.Cl.[CH2:11]=[O:12].[OH-].[Na+]>O>[CH:1]1[C:2]2[N:3]([C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: c1cc2cnccn2c1
Reactant: C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=Cc1ccc2cnccn12
Temperature: 60 °C
Reaction time: 240 h
Yield: 19.3 %

Procedure:
Pyrrolo[1,2-a]pyrazine (1.92 g, 16.3 mmol) was dissolved in water (16 mL) and treated with conc. aq. HCl (4 mL, 46.4 mmol) and 37% wt aqueous formaldehyde (5.6 mL, 67 mmol). The solution was heated to 60° C. for 4 h, allowed to cool to RT and the pH adjusted to 10. The solution was extracted with EtOAc (3×50 mL) and the combined fractions dried over Na2SO4 and concentrated to dryness under vacuum. The organic residue was purified (SGC using DCM:MeOH:NH4OH eluant in 96:3:1 ratio). Recovered starting material was dissolved in water (20 mL) and conc. HCl (5 mL, 0.6 mol) and formaldehyde (7 mL, 0.9 mol). The solution was heated to 60° C. for 120 h, and then allowed to stir at RT for 240 h. The solution pH was then brought to 12 with sodium hydroxide solution (30% w/v aq) and extracted with EtOAc (4×30 mL). The organic fractions were combined, dried over Na2SO4, and concentrated to dryness under vacuum. The product was purified (SGC using DCM:MeOH:NH4OH eluant in 95:4:1 ratio) yielding the title compound (0.46 g). MS (ESI+) for m/z 149 (M+H)+. 1H NMR (CDCl3) δ 8.46 (s, 1H), 7.85 (dd,1H), 7.19 (d, 1H), 6.72 (d, 1H), 6.63 (d, 1H), 4.83 (s, 1H), 4.78 (bs,1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[O:20])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:27].O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:83][C@H:84]1[O:89][C@@H:88]([CH3:90])[CH2:87][NH:86][CH2:85]1>CN(C=O)C.[Pd]>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([N:86]3[CH2:85][C@H:84]([CH3:83])[O:89][C@H:88]([CH3:90])[CH2:87]3)=[C:3]([F:27])[CH:4]=2)(=[O:10])=[O:9])=[C:13]([C:19]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[O:20])[CH:14]=1
Reactant: O=C(c1cccnc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(Br)c(F)c1
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CN(c2ccc(S(=O)(=O)Nc3ccc(Cl)cc3C(=O)c3cccnc3)cc2F)C[C@H](C)O1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of heterocyclyl and heteroaryl substituted phenylsulfonyl derivatives previously described, using 4-Bromo-N-[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-3-fluoro-benzenesulfonamide 0.2 g (0.42 mmol), potassium phosphate tribasic monohydrate 0.58 g (2.56 mmol), rac-2,2′-bis (diphenylphosphino)-1,1′-binaphthyl 0.079 g (0.12 mmol), cis-2,6-dimethyl-morpholine 0.24 g (2.13 mmol) and Pd (dba)3 0.057 g (0.06 mmol) in 2 ml DMF. HPLC purification gave a pale yellow compound.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[CH2:12]([O:14][C:15]([C:17]([C:34]1[CH:44]=[CH:43][C:37]([O:38][CH2:39][C:40](=O)[CH3:41])=[CH:36][CH:35]=1)([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:16])[CH3:13].C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH2:32]([O:31][C:29]([C:17]([C:34]1[CH:44]=[CH:43][C:37]([O:38][CH2:39][CH:40]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])[CH3:41])=[CH:36][CH:35]=1)([C:15]([O:14][CH2:12][CH3:13])=[O:16])[CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:30])[CH3:33]
Reactant: CCOC(=O)C(C(=O)OCC)C(C(=O)OCC)(C(=O)OCC)c1ccc(OCC(C)=O)cc1
Reactant: NCC(O)c1cccc(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: CCOC(=O)C(C(=O)OCC)C(C(=O)OCC)(C(=O)OCC)c1ccc(OCC(C)NCC(O)c2cccc(Cl)c2)cc1
Yield: 11 %

Procedure:
Following a procedure similar to that described in Example 6, but using 1 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 8), 3 g of 4-[1,1,2,2-tetrakis(ethoxycarbonyl)ethyl]phenoxyacetone (prepared as described in Preparation 22), 100 ml of dry benzene, 50 ml of absolute methanol and 920 mg of sodium cyanoborohydride, and then purifying the reaction product by column chromatography through silica gel, using a 10:1 by volume mixture of ethyl acetate and hexane as the eluent, 0.4 g of the title compound was obtained having an Rf=0.35 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.Cl[CH:19]([CH3:23])[C:20](=[O:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C.O>[CH3:1][C:2]1[N:3]([CH:19]([C:20](=[O:22])[CH3:21])[CH3:23])[C:4]2[C:9]([C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CC(=O)C(C)Cl
Reactant: Cc1[nH]c2ccccc2c1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2ccccc21
Temperature: 90 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
To a solution of tert-butyl 2-methyl-1H-indole-3-carboxylate (2 g, 8.65 mmol) and 3-chlorobutan-2-one (1.1 g, 10.38 mmol) in acetonitrile (18 mL) were added potassium carbonate (3.2 g, 25.8 mmol) and potassium iodide (1.4 g, 8.65 mmol). The reaction mixture was stirred at 90° C. overnight. To the reaction mixture was added water (20 mL). The aqueous layer was extracted with ethyl acetate (50 mL×4). The combined organic layers were dried over sodium sulfate and concentrated. The crude product was purified by silica gel column (petroleum ether/ethyl acetate 100:1 to 80:1) to give tert-butyl 2-methyl-1-(3-oxobutan-2-yl)-1H-indole-3-carboxylate (600 mg, yield: 23%) as a yellow oil. LRMS (M+H+) m/z: calcd 301.17. found 302.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][CH2:8][Li])[CH2:4][CH3:5])[CH3:2].[Cl-].[CH3:11][Ga+:12][CH3:13]>CCCCC>[CH2:1]([N:3]([CH2:6][CH2:7][CH2:8][Ga:12]([CH3:13])[CH3:11])[CH2:4][CH3:5])[CH3:2]
Reactant: [Li]CCCN(CC)CC
Reactant: C[Ga+]C
Agent: [Cl-]
Solvent: CCCCC
Product: CCN(CC)CCC[Ga](C)C
Reaction time: 24 h

Procedure:
3.6 g (30 mmol) of diethylaminopropyllithium dissolved in 100 ml of pentane are added to a solution of 4 g (30 mmol) of dimethylgallium chloride in 50 ml of pentane at -78°. The solution is allowed to come to room temperature and is stirred for a further 24 hours. The working up is carried out analogously to Example 1. Instead of the distillation, a sublimination is carried out. Diethylaminopropyl(dimethyl)gallium with an M.p. of 43°-45° is obtained.
Reaction SMILES: [P:1]([O-:18])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:19](=[O:24])[CH2:20][CH2:21][CH2:22][CH3:23]>C(Cl)(Cl)Cl>[OH:24][CH:19]([P:1](=[O:18])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCC=O
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCCC(O)P(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
The general method of F. Texier-Boullet and A. Foucaud [Synthesis, 1982, 916] was employed. A mixture of dibenzyl phosphite (7.73 ml, 0.035 mole) and valeraldehyde (11.15 ml, 0.105 mole) was stirred at room temperature and basic alumina (35 g) added in one portion. After standing overnight at room temperature chloroform was added and the alumina collected and washed with chloroform. The filtrate was evaporated to dryness and the resulting oil chromatographed on silica gel with gradient elution (50% pentane/ethyl acetate-ethyl acetate) to give the title compound as a colourless oil (9.17 g, 76%).
Reaction SMILES: [CH:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[N:11]=[C:12]([O:22][CH:23]3[CH2:40][CH:39]4[N:25]([C:26](=[O:46])[N:27]([CH3:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH:33][CH:34]5[C:36]([C:42](O)=[O:43])([NH:37][C:38]4=[O:41])[CH2:35]5)[CH2:24]3)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][CH3:21])=[CH:15][CH:14]=3)[N:9]=1)([CH3:3])[CH3:2].ClC1N=C(OC2CC3N(C(=O)N(C)CCCCC=CC4C(C([NH:82][S:83]([CH:86]5[CH2:88][CH2:87]5)(=[O:85])=[O:84])=O)(NC3=O)C4)C2)C2C(C=1)=CC(OC)=CC=2>>[CH:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[N:11]=[C:12]([O:22][CH:23]3[CH2:40][CH:39]4[N:25]([C:26](=[O:46])[N:27]([CH3:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH:33][CH:34]5[C:36]([C:42]([NH:82][S:83]([CH:86]6[CH2:88][CH2:87]6)(=[O:85])=[O:84])=[O:43])([NH:37][C:38]4=[O:41])[CH2:35]5)[CH2:24]3)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][CH3:21])=[CH:15][CH:14]=3)[N:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nc(-c3csc(NC(C)C)n3)cc2c1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nc(Cl)cc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nc(-c3csc(NC(C)C)n3)cc2c1

Procedure:
The title product 72 was prepared from 17-[3-(2-isopropylaminothiazol-4-yl)-6-methoxyisoquinolin-1-yloxy]-13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo-[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (71) following the same procedures described for the preparation of N-[17-(3-chloro-6-methoxyisoquinolin-1-yloxy)-13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl]-(cyclopropyl)sulfonamide (43, Example 11): m/z=752 (M+H)+. 1H NMR (CDCl3): 0.93-1.03 (m, 1H), 1.05-1.15 (m, 1H), 1.18-1.28 (m, 3H), 1.32 (d, J=6.6 Hz, 3H), 1.34 (d, J=6.6 Hz, 3H), 1.36-1.67 (m, 4H), 1.93-2.07 (m, 2H), 2.22-2.36 (m, 1H), 2.45-2.65 (m, 3H), 2.85 (s, 3H), 2.91-3.00 (m, 1H), 3.05-3.17 (m, 1H), 3.64-3.80 (m, 3H), 3.89 (s, 3H), 4.08 (dd, J=3.8 Hz, J=10.9 Hz, 1H), 4.78 (t, J=8.1 Hz, 1H), 5.15 (t, J=10.4 Hz, 1H), 5.21-5.36 (broad s, 1H), 5.73 (dd, J=8.1 Hz, J=18.4 Hz, 1H), 5.94-6.02 (m, 1H), 6.92-6.99 (broad s, 1H), 7.00-7.07 (m, 2H), 7.22 (s, 1H), 7.74 (s, 1H), 7.95 (d, J=8.6 Hz, 1H), 10.54-10.99 (broad s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].I[CH2:21][CH2:22][C:23]#[C:24][CH3:25].C([O-])([O-])=O.[K+].[K+]>>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:25][CH2:24][C:23]#[C:22][CH3:21])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC#CCCI
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC#CCCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Yield: 10.7 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (3 g) is alkylated using 1-iodo-3-pentyne (4.42 g; 22.8 mmol) and K2CO3 (4.29 g; 30.4 mmol) at 40° C. for 5 d. After aqueous work-up and purification by RP chromatography a part of the material (0.4 g) is de-acetylated in MeOH (30 ml) using DBU (0.4 ml) at reflux. After aqueous work-up 5-amino-3,3-dimethyl-6-nitro-1-pent-3-ynyl-1,3-dihydro-indol-2-one (0.35 g) is obtained and used without further purification.
Reaction SMILES: [C-:1]#[N:2].[K+].[C-]#N.[Na+].C1OCCOCCOCCOCCOCCOC1.Br[CH2:26][C@@H:27]1[N:31]([CH3:32])[C:30](=[O:33])[CH2:29][CH2:28]1>CC#N>[CH3:32][N:31]1[C:30](=[O:33])[CH2:29][CH2:28][C@@H:27]1[CH2:26][C:1]#[N:2]
Reactant: [C-]#N
Reactant: CN1C(=O)CC[C@@H]1CBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: CN1C(=O)CC[C@@H]1CC#N

Procedure:
KCN (1.26 g, 25.7 mmols), NaCN (2.78 mg, 42.7 mmols) and 18-crown-6 (793 mg, 3 mmols) were added to a CH3CN (60 ml) solution of the (5R)-5-(bromomethyl)-1-methylpyrrolidin-2-one (2.67 g, 13.9 mmols), and the mixture was heated for 44 hours under reflux. The inorganic matter was filtered off, and the filtrate was diluted with AcOEt (50 ml). The dilution was washed with a saturated aqueous solution (30 ml) of NaCl, and dried over MgSO4. The solvent was distilled off under reduced pressure, and then the residue was subjected to silica gel column chromatography (SiO2 100 g, MeOH—CHCl3 1:9 v/v) to obtain 2-((2R)-1-methyl-5-oxopyrrolidin-2-yl)ethanenitrile as a mixture (1.49 g) with impurities difficult to separate.
Reaction SMILES: C[N:2]([CH3:12])[CH:3]=[C:4]([N+:10]#[C-:11])[C:5]([O:7]CC)=O.[Si:13]([O:20][C@H:21]1[CH2:26][CH2:25][C@H](N)[CH2:23][CH2:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[Cl-].[NH4+]>O1CCCC1.C(OCC)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>[Si:13]([O:20][C@H:21]1[CH2:26][CH2:25][C@H:12]([N:2]2[CH:3]=[C:4]([CH2:5][OH:7])[N:10]=[CH:11]2)[CH2:23][CH2:22]1)([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N)CC1
Reactant: [C-]#[N+]C(=CN(C)C)C(=O)OCC
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2cnc(CO)c2)CC1
Temperature: 85 °C
Reaction time: 12 h

Procedure:
Ethyl 3-(dimethylamino)-2-isocyanoacrylate (300 mg) and trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexylamine (Synthetic Communications, 1990, Vol. 20, p. 1073) (1.02 g) were mixed and stirred at 85° C. for 12 hours. To the reaction solution, saturated aqueous ammonium chloride was added, and organic matter was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: hexane/ethyl acetate-4/1-1/1). Lithium aluminum hydride (92%, 105 mg) was suspended in tetrahydrofuran (8 mL). The produced crude product was dissolved in tetrahydrofuran (6 mL), and this solution was slowly added dropwise to the suspension at 0° C. After stirring at 0° C. for 1 hour, the reaction solution was diluted with diethyl ether, and saturated aqueous sodium sulfate was added thereto. After stirring at room temperature for 1 hour, the formed inorganic salt was removed by filtration through celite. The filtrate was concentrated under reduced pressure to obtain a crude product. This crude product was washed with a mixed solvent of hexane and ethyl acetate (2:1) to obtain the title compound (260 mg).
Reaction SMILES: [F:1][C:2]([F:54])([F:53])[C:3]1[CH:4]=[C:5]([C:13]([CH3:52])([CH3:51])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[C@H:41]([CH2:42][O:43][Si](C(C)(C)C)(C)C)[CH2:40][N:39]4[C@H:34]([CH2:35][O:36][CH2:37][CH2:38]4)[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH]Cl>CO>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]([CH3:52])([CH3:51])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[C@H:41]([CH2:42][OH:43])[CH2:40][N:39]4[C@H:34]([CH2:35][O:36][CH2:37][CH2:38]4)[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:54])[F:53])[CH:8]=1
Reactant: Cc1ccc(F)cc1-c1cc(N2C[C@H]3COCCN3C[C@H]2CO[Si](C)(C)C(C)(C)C)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [CH]Cl
Solvent: CO
Product: Cc1ccc(F)cc1-c1cc(N2C[C@H]3COCCN3C[C@H]2CO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-[(7S,9aS)-7-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-4-(5-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (D56, 110 mg) was dissolved in dry MeOH (2 mL), cooled in an ice-salt bath before adding cHCl solution (0.2 mL), and stirring at R.T. for 2 hours. Poured directly onto a 5 g SCX column. Washed with MeOH (2×10 mL), before eluting the compound with NH3 in MeOH 94×10 mL). Solvent evaporated. Residue purified on a 5 g sek-pak column eluting with Pent to EtOAc to 10% MeOH/EtOAc. Solvent evaporated to afford the title compound as a white solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(C1NC=CN=1)(C1NC=CN=1)=O>>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:13])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc2nccnc2c1
Reactant: C1CCNCC1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Product: O=C(c1ccc2nccnc2c1)N1CCCCC1

Procedure:
The coupling of 6-quinoxalinecarboxylic acid to piperidine is accomplished in a manner similar to that used for the preparation of Invention Compound XIII, or by any other method known in the art for activation of aromatic carboxylic acids, such as, for example, activation by carbonyl diimidazole. 1H NMR δ 1.56 and 1.73 (br, 6), 3.40 (br s, 2), 3.79 (br s, 2), 7.82 (dd, 1, J=8.8, 1.9Hz), 8.13 (d, 1, J=1.6 Hz), 8.17 (d, 1, 8.6 Hz), and 8.9 ppm (m, 2).
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:17][CH2:18][CH3:19])[CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][C:11]2=O.BrBr.[NH2:22][C:23]([NH2:25])=[S:24].C(=O)([O-])O.[Na+]>C(O)C.CO.C(Cl)(Cl)Cl>[CH3:1][O:2][CH:3]([CH2:17][CH2:18][CH3:19])[CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][C:10]1[S:24][C:23]([NH2:25])=[N:22][C:11]=12
Reactant: CCCC(CCc1cccc2c1CCCC2=O)OC
Reactant: NC(N)=S
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCC(CCc1cccc2c1CCc1sc(N)nc1-2)OC
Reaction time: 1 h
Yield: 42.1 %

Procedure:
To a 10% methanol-chloroform (60 mL) solution of 5-(3-methyloxyhexyl)tetralone (6) (9.0 g) was added bromine (5.5 g), and the reaction mixture was stirred for 1 h. After the solvent was evaoprated, the residue was dissolved in ethanol (60 mL), and to the residue was added thiourea (2.65 g). After the mixture was heated at reflux for 7 h, the reaction solvent was evported. To the residue was added a saturated sodium hydrogencarbonate aqueous solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate=4:1) to obtain the compoumd (7) 4.6 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][C@@H:18]2[C:24](=[O:25])[NH:23][C:22]3[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:21]=3[O:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:16])[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Br[CH2:39][CH:40]1[CH2:42][CH2:41]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH:40]1([CH2:39][N:23]2[C:22]3[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:21]=3[O:20][C@H:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@H:18]([NH:17][C:15](=[O:16])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]3[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=3)[C:24]2=[O:25])[CH2:42][CH2:41]1
Reactant: BrCC1CC1
Reactant: COc1ccc2c(c1)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)[C@@H](c1ccccc1)O2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)N(CC1CC1)C(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)[C@@H](c1ccccc1)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of N2-[(3,5-difluorophenyl)acetyl]-N1-[(2,3-cis)-7-methoxy-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]-L-alaninamide (68) (95 mg, 0.186 mmol) in DMF (1 mL) under nitrogen was added (bromomethyl)cyclopropane (70 mg, 0.518 mmol) and powdered cesium carbonate (170 mg, 0.521 mmol). The mixture was stirred overnight at ambient temperature then diluted with water and extracted with ethyl acetate. The residue obtained from the organic extract was purified by flash chromatography on silica gel eluting with diethyl ether to afford the title compound in a 1:1 mixture with the 2S,3R diastereomer (65 mg, 62%) as a white solid. TLC Rf=0.26 (diethyl ether). 1H NMR (300 MHz, CDCl3) δ0.23 (m, 1H), 0.37-0.65 (m, 3H), 1.07 (d 1.5H, J=7.0 Hz), 1.21)d, 1.5H, J=7.0 Hz), 3.43 (s, 1H), 3.47 (s, 1H), 3.83 (s, 3H), 4.09 (m, 1H), 4.25 (m, 1H), 5.05 (m, 1H), 5.61 (m, 1H), 5.89 (br d, 1H), 5.99 (br d, 1H), 6.20 (br t, 1H), 6.66-6.85 (m, 5H), 7.19 (d, 1H), 8.3 Hz), 7.30-7.42 (m, 6H). MS APCI, m/z=564 (M+1). LC/MS: 2.77 min.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:27](=[O:28])[N:13]3[C:14]([C:24]([OH:26])=[S:25])=[C:15]([C:18]4[S:19][C:20]([CH3:23])=[N:21][N:22]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:35]([O:41][CH2:42]I)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37].O>CN(C)C(=O)C.C(OCC)(=O)C>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:27](=[O:28])[N:13]3[C:14]([C:24]([O:26][CH2:42][O:41][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[S:25])=[C:15]([C:18]4[S:19][C:20]([CH3:23])=[N:21][N:22]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1nnc(C2=C(C(O)=S)N3C(=O)[C@@H](NC(=O)Cc4ccccc4)[C@H]3SC2)s1
Reactant: CC(C)(C)C(=O)OCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nnc(C2=C(C(=S)OCOC(=O)C(C)(C)C)N3C(=O)[C@@H](NC(=O)Cc4ccccc4)[C@H]3SC2)s1
Reaction time: 1.5 h
Yield: 79.1 %

Procedure:
To a solution of 7β-(2-phenylacetamido)-3-(5-methyl-1,3,4-thiadiazol-2-yl)thio-3-cephem-4-carboxylic acid (492 mg) in N,N-dimethylacetamide (4 ml) was added cesium carbonate (200 mg) under ice-cooling, stirred at the same temperature for 1.5 hours. To the mixture was added iodomethyl pivalate (297 mg), stirred for 1 hour at the same temperature. To the mixture were added water (50 ml) and ethyl acetate (50 ml). The organic layer was separated, washed with water and saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether to give pivaloyloxymethyl 7β-(2-phenylacetamido)-3-(5-methyl-1,3,4-thiadiazol-2-yl)thio-3-cephem-4-carboxylate (492 mg).
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:8]=[CH:9][C:10]2[O:16][CH2:15][CH2:14][CH2:13][CH:12]([OH:17])[C:11]=2[CH:18]=1.[CH:19](N1CCOCC1)=[O:20]>CCCCC.C1COCC1.C(OCC)C>[CH:19]([C:7]1[CH:8]=[CH:9][C:10]2[O:16][CH2:15][CH2:14][CH2:13][CH:12]([OH:17])[C:11]=2[CH:18]=1)=[O:20]
Reactant: OC1CCCOc2ccc(Br)cc21
Reactant: O=CN1CCOCC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: CCOCC
Product: O=Cc1ccc2c(c1)C(O)CCCO2
Temperature: -78 °C
Reaction time: 1 h
Yield: 105.9 %

Procedure:
254 ml (0.6 mole) of a 1.7 molar solution of tert.-butyllithium in n-pentane is slowly added dropwise under argon to a stirred solution of 48.6 g (0.2 mole) of 7-bromo-5-hydroxy-2,3,4,5-tetrahydro-1-benzoxepin in 550 ml of absolute THF at -90° C. to -100° C. The mixture is subsequently stirred at -78° C. for 1 hour and then, at this temperature, a solution of 24 ml (0.24 mole) of N-formylmorpholine in 180 ml of absolute THF is added dropwise while stirring vigorously. The mixture is stirred at -78° C. for 1 hour and subsequently allowed to warm to 0° C., and is diluted with diethyl ether and hydrolyzed with ice-water. After extraction several times with diethyl ether, the combined organic extracts are washed with water and saturated brine and dried over sodium sulfate, and the solvent is stripped off in vacuo. 40.7 g of yellowish oil are obtained and reacted further without purification.