Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[NH:8][C:7]2[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:6]=2[O:5][CH2:4]1)[CH3:2].O.[F:17][C:18]([F:22])([F:21])[CH:19]=O.[BH3-]C#N.[Na+]>>[CH2:1]([CH:3]1[N:8]([CH2:19][C:18]([F:22])([F:21])[F:17])[C:7]2[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:6]=2[O:5][CH2:4]1)[CH3:2]
Reactant: O=CC(F)(F)F
Reactant: CCC1COc2cc([N+](=O)[O-])ccc2N1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Product: CCC1COc2cc([N+](=O)[O-])ccc2N1CC(F)(F)F
Yield: 35.9 %

Procedure:
This compound was prepared by General Method 7 (EXAMPLE 5) from (±)-3-ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine (200 mg, 0.96 mmol), 2,2,2-trifluoroacetaldehyde monohydrate (1.12 g, 9.6 mmol) and NaBH3CN (292 mg, 4.6 mmol) to afford 100 mg (36%) of 3-ethyl-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine, a yellow solid. Data for (±)-3-ethyl-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine: Rf 0.69 (2:3 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 7.80 (dd, 1H, J=8.9, 2.6), 7.71 (d, 1H, J=2.6), 6.72 (d, 1H, J=9.0), 4.34 (dd, 1H, J=10.9, 1.4), 4.19-4.05 (m, 1H), 4.02 (dd, 1H, J=11.0, 2.3), 3.87-3.72 (m, 1H), 1.72-1.62 (m, 2H), 1.00 (t, 34H, J=7.4).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:18][C@H:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21]>>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][NH:18][C@H:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](C)N
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Agent: Cl
Product: COC(=O)[C@@H](C)NCc1cccc(O[Si](C)(C)C(C)(C)C)c1
Yield: 82 %

Procedure:
Prepared as in Example 12-1b from 3-(tert-butyldimethylsilyloxy)benzaldehyde (Example 12-1c) and (R)-methyl 2-aminopropanoate hydrochloride. Yield 82%, colorless liquid. MS 324 (MH+).
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:44]2([CH3:45])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:43]2[CH2:42][CH2:41][C@@:40]2([CH3:46])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:24]/[CH:25]=[CH:26]/[C:27]([CH2:38][CH3:39])([O:30][Si](CC)(CC)CC)[CH2:28][CH3:29])[CH3:22])[CH2:12][C@@H:11]([O:47][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@@H:9]1[C@@:44]2([CH3:45])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:43]2[CH2:42][CH2:41][C@@:40]2([CH3:46])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:24]/[CH:25]=[CH:26]/[C:27]([CH2:38][CH3:39])([OH:30])[CH2:28][CH3:29])[CH3:22])[CH2:12][C@@H:11]([OH:47])[CH2:10]1
Reactant: CCC(/C=C/CO[C@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)(CC)O[Si](CC)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(O)(/C=C/CO[C@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C)CC
Yield: 42.1 %

Procedure:
By the same procedure as in Example 9, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-{(E)-(4-ethyl-4-triethylsilyloxy-2-hexenyloxy)}pregna-5,7,16-triene (60.3 mg, 0.0754 mmol), tetrahydrofuran (3 ml) and 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) were reacted (heating under reflux for 5.5 hours) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×1, dichloromethane:ethyl acetate:ethanol=20:80:1, developed once) to give the title compound as a pale yellow oil (14.5 mg, 42%).
Reaction SMILES: [CH:1]1([CH2:4][C:5]([F:25])([F:24])[CH2:6][C@H:7]([NH:11][C@@H:12]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:13]([F:16])([F:15])[F:14])[C:8]([OH:10])=O)[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:49][C@@H:50]([CH2:59][CH3:60])[CH:51]([OH:58])[C:52]([NH:54][CH:55]1[CH2:57][CH2:56]1)=[O:53].CN1CCOCC1>ClCCl>[CH:1]1([CH2:4][C:5]([F:25])([F:24])[CH2:6][C@H:7]([NH:11][C@@H:12]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:13]([F:15])([F:14])[F:16])[C:8]([NH:49][C@@H:50]([CH2:59][CH3:60])[CH:51]([OH:58])[C:52]([NH:54][CH:55]2[CH2:56][CH2:57]2)=[O:53])=[O:10])[CH2:2][CH2:3]1
Reactant: CC[C@H](N)C(O)C(=O)NC1CC1
Reactant: O=C(O)[C@H](CC(F)(F)CC1CC1)N[C@@H](c1ccc(F)cc1)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC[C@H](NC(=O)[C@H](CC(F)(F)CC1CC1)N[C@@H](c1ccc(F)cc1)C(F)(F)F)C(O)C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 66.4 %

Procedure:
A solution of (S)-5-cyclopropyl-4,4-difluoro-2-(((S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)amino)-pentanoic acid (0.5 g; 1.35 mmol) in dry dichloromethane (16 mL) under nitrogen was treated with HOBt (228 mg; 1.49 mmol; 110 mol %), EDC hydrochloride (286 mg; 1.49 mmol; and (3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide hydrochloride (311 mg; 1.49 mmol; 110 mole %). N-methylmorpholine (NMM; 210 μL; 301 mg; 2.97 mmol; 220 mole %) was added and resulting mixture was stirred for 20 h at ambient temperature. The dichloromethane was removed by distillation and the residue partitioned between ethyl acetate (50 mL) and washed in sequence with 10% aqueous citric acid (20 mL), saturated aqueous sodium bicarbonate (20 mL), and saturated aqueous sodium chloride (20 mL). The organic phase was dried (MgSO4) and concentrated in vacuo to give 740 mg of the crude product which was chromatographed on silica gel (5 g), eluting with ethyl acetate/hexane, 1:2 followed by 1:1, to give 469 mg (66.2%) of (25)-5-cyclopropyl-N-((3S)-1-(cyclopropylamino)-2-hydroxy-1-oxopentan-3-yl)-4,4-difluoro-2-(((S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)amino)pentanamide. LC-MS, positive ion mode: m/z=524 [M+H]+ (100%). Methods for the preparation of starting materials are disclosed in U.S. Pat. Nos. 7,488,848 and 7,893,112.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][C:30]1[C:35]([F:36])=[CH:34][C:33]([F:37])=[CH:32][C:31]=1[F:38]>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:29][C:30]3[C:35]([F:36])=[CH:34][C:33]([F:37])=[CH:32][C:31]=3[F:38])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1cc(F)c(CBr)c(F)c1
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc(C)cc1
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)c(C)nc3c2ccn3Cc2c(F)cc(F)cc2F)cc1

Procedure:
The title compound was prepared from methyl 2-(tert-butoxy)-2-(6-methyl-4-(p-tolyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 2-(bromomethyl)-1,3,5-trifluorobenzene in a manner similar to that described in Example 25 as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=7.63 (d, J=7.6 Hz, 1 H), 7.40-7.30 (m, 3 H), 7.07 (d, J=3.5 Hz, 1 H), 6.78-6.69 (m, 2 H), 6.25 (d, J=3.5 Hz, 1 H), 5.71-5.56 (m, 2 H), 5.53 (s, 1 H), 2.84 (s, 3 H), 2.47 (s, 3 H), 0.95 (s, 9 H); LCMS (m/z) ES+=497 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C@H:6]2[CH2:11][CH2:10][C@H:9]([C:12]([O:14]CC)=[O:13])[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.CO.[OH-].[Na+].C1(CO[C@H]2CC[C@H](C(O)=O)CC2)CC1>C1COCC1>[CH:1]1([CH2:4][O:5][CH:6]2[CH2:11][CH2:10][CH:9]([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)[C@H]1CC[C@H](OCC2CC2)CC1
Agent: O=C(O)[C@H]1CC[C@H](OCC2CC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1CCC(OCC2CC2)CC1

Procedure:
Ethyl 4-[(cyclopropylmethyl)oxy]cyclohexanecarboxylate (D99, 20.8 g, 45.8 mmol) was taken up in THF (50 mL)/methanol (50 mL). Sodium hydroxide (20 mL, 250 mmol, concentrated) was added to the solution which was left to stir o/n. The THF/methanol was evaporated and the crude residue washed with Et2O. The aqueous layer was acidified with 5 M HCl and extracted with EtOAc (2×). The EtOAc organics were combined, dried (Na2SO4) and the solvent evaporated to give a mixture of cis and trans 4-[(cyclopropylmethyl)oxy]cyclohexanecarboxylic acid (D100, 9.47 g, 94%) as a yellow oil.
Reaction SMILES: C(N([CH2:12][C@@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:22]([CH3:25])(=[O:24])=[O:23])[CH:16]=1)[OH:14])CCO)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O>C(Cl)Cl>[CH2:26]([N:21]([C:17]1[CH:16]=[C:15]([CH:13]([OH:14])[CH3:12])[CH:20]=[CH:19][CH:18]=1)[S:22]([CH3:25])(=[O:24])=[O:23])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CS(=O)(=O)N(Cc1ccccc1)c1cccc([C@@H](O)CN(CCO)Cc2ccccc2)c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(O)c1cccc(N(Cc2ccccc2)S(C)(=O)=O)c1
Temperature: -20 °C

Procedure:
(R)-2-[N′-Benzyl-N′-(2-hydroxyethyl)amino]-1-[3-(N-benzyl-N-methylsulfonylamino)phenyl]ethanol (273 mg; synthesized according to the process described in WO 01/04092) and triphenylphosphine (162 mg) were dissolved in dehydrated methylene chloride (8 mL) under an argon atmosphere, followed by stirring at −20° C. After adding N-bromosuccinimide (110 mg) at a stretch, the resulting mixture was stirred for 10 minutes. The reaction mixture was purified by silica gel column chromatography (5:1-3:1 hexane/ethyl acetate) to yield (R)-2-[N′-benzyl-N′-(2-bromoethyl)amino])-1-[3-(N-benzyl-N-methylsulfonylamino)phenyl]ethanol. This was immediately dissolved in acetonitrile (4 mL), to which the compound (116 mg; obtained in the above step E) and an aqueous 1 N sodium hydroxide solution (521 μL) were added. The resulting mixture was stirred at room temperature for 16 hours and the reaction mixture was then concentrated. The residue was purified by silica gel column chromatography (5:1-1:1 hexane/ethyl acetate) to yield the title compound (243 mg).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH:3]=1.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>CN(C)C=O>[CH3:18][N:19]([CH3:21])[CH:20]=[CH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1cc(-n2cncn2)ncc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CN(C)C=Cc1cc(-n2cncn2)ncc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 99.9 %

Procedure:
To a suspension of 4-methyl-5-nitro-2-(1,2,4-triazol-1-yl)pyridine (4.1 g, 20 mmol) in dry dimethylformamide (30ml) was added dimethylformamide dimethyl acetal (5.9ml, 44 mmol) and the mixture heated at 90° C. for 20 min. The solvent was evaporated in vacuo using toluene as an azeotrope to give the title compound (5.2 g, 100%) as a dark red solid; mp 225°-228° C. 1H NMR (360 MHz, CDCl3) δ 3.10 (6H, s), 6.13 (1H, J=13.1 Hz), 7.54 (1H, J=13.1 Hz), 7.81 (1H, s), 8.04 (1H, s), 8.92 (1H, s), 9.17 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][CH:3]=1.[CH:24]1([C:30](O)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C.P(Cl)(Cl)(Cl)=O>ClCCl>[CH:24]1([C:30]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]3[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=4)[NH:9]3)=[CH:6][CH:7]=2)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)C1CCCCC1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(N)cc1)N2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(NC(=O)C3CCCCC3)cc1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 53 %

Procedure:
To a solution of methyl 2-(4-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxy late (50 mg, 0.16 mmol), cyclohexanecarboxylic acid (0.03 mL, 0.24 mmol) and N,N-diisopropylethylamine (0.05 mL, 0.32 mmol,) in dichloromethane (5 mL) was added phosphorus oxychloride (0.02 mL, 0.24 mmol) via syringe below 0° C. The mixture was stirred at room temperature for 16 h under nitrogen. The solvent was removed and the residue was washed with dichloromethane/petroleum ether, the precipitate was collected to afford methyl 2-(4-(cyclohexane carboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a yellow solid, 42 mg, yield: 53%.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][CH2:16][NH:17][CH2:18][C:19]([CH3:27])=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([O:41][CH3:42])[C:38]=1[O:39][CH3:40])[C:33](O)=[O:34].S(Cl)(Cl)=O>C(N(CC)CC)C>[CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][CH2:16][N:17]([CH2:18][C:19]([CH3:27])=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:33](=[O:34])[C:32]2[CH:31]=[C:30]([O:29][CH3:28])[C:38]([O:39][CH3:40])=[C:37]([O:41][CH3:42])[CH:36]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Reactant: CC(=Cc1ccccc1)CNCCCN1CCN[C@@H](Cc2ccccc2)C1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N(CCCN2CCN[C@@H](Cc3ccccc3)C2)CC(C)=Cc2ccccc2)cc(OC)c1OC
Yield: 7 %

Procedure:
Experimental condition similar to Example 18 were used with [3-(S)-(3-benzyl-piperazin-1-yl)-propyl]-(2-methyl-3-phenyl-allyl)-amine (prepared from (S)-2-benzyl piperazine described on scheme 11) 0.08 g (0.24 mmol), 3,4,5-trimethoxy benzoic acid 0.05 g (0.24 mmol), thionyl chloride 0.02 ml (0.46 mmol) and triethylamine. The free amine after purification was transformed to HCl salt, yielding 45 mg of a brown, semi-solid salt. Yield: 7%.
Reaction SMILES: [CH:1]1([C@@H:7]([NH:31]C(=O)OC(C)(C)C)[C:8](=[O:30])[NH:9][C:10]2[CH:11]=[C:12]3[C:28](=[O:29])[NH:27][N:26]=[CH:25][C:14]4=[C:15]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[NH:16][C:17]([CH:18]=2)=[C:13]34)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>O1CCOCC1>[NH2:31][C@H:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:8]([NH:9][C:10]1[CH:11]=[C:12]2[C:28](=[O:29])[NH:27][N:26]=[CH:25][C:14]3=[C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[NH:16][C:17]([CH:18]=1)=[C:13]23)=[O:30]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O)C1CCCCC1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O)C1CCCCC1
Yield: 87.8 %

Procedure:
The title compound of Example 59 (210 mg, 0.41 mmol) was treated with 4M HCl in dioxane and allowed to stir tightly capped as a slurry for about 4 hours after which the volatile components were evaporated and diethyl ether was added and evaporated several times. The resulting solids were dissolved in methanol, precipitated with diethyl ether, and collected to afford the title compound (161 mg, 0.36 mmol) as a yellow powder in 87% yield.
Reaction SMILES: CC([O-])(C)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23].[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26]1>COCCOC.CCOCC.CCCCCCCCCCCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N+:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26]1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: c1ccc2[nH]ccc2c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: COCCOC
Solvent: CCCCCCCCCCCC
Product: O=[N+]([O-])c1ccccc1-n1ccc2ccccc21
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A solution of Pd2(dba)3 [92 mg, 0.1 mmol (4.6 mg, 0.005 mmol, 2 mol % Pd per reaction)], ligand 1 (see FIG. 1) [168 mg, 0.4 mmol (8.4 mg, 0.02 mmol, 4 mol % per reaction)] and NaOt-Bu [40 mg, 0.4 mmol (2 mg, 0.02 mmol, 4 mol % per reaction)] were stirred in 10 mL DME (anhy). After 10 minutes, 0.5 mL of the solution was added via syringe to a test tube containing (under an Argon atmosphere) K3PO4 (148 mg, 0.7 mmol), 2-chloronitrobenzene (79 mg, 0.5 mmol), and indole (70 mg, 0.6 mmol). The test tube was capped (with a proper cap-no rubber septa) and heated at 100° C. for 18 hours. The reaction mixture was allowed to cool to r.t., diluted with ether and dodecane was added as an internal standard. The GC yield was calculated to be 3%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][CH:3]=1.[CH:24]1([C:28](O)=[O:29])[CH2:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C.P(Cl)(Cl)(Cl)=O>ClCCl>[CH:24]1([C:28]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]3[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=4)[NH:9]3)=[CH:6][CH:7]=2)=[O:29])[CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)C1CCC1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(N)cc1)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(NC(=O)C3CCC3)cc1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
To a solution of methyl 2-(4-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (50 mg, 0.16 mmol), cyclobutanecarboxylic acid (0.025 mL, 0.24 mmol) and N,N-diisopropylethylamine (0.05 mL, 0.32 mmol) in dichloromethane (5 mL) was added phosphorus oxychloride (0.02 mL, 0.24 mmol) via syringe below 0° C. The mixture was stirred at room temperature for 16 hrs under nitrogen. The solvent was removed and the residue was washed with dichloromethane/petroleum ether, the precipitate was collected to afford methyl 2-(4-(cyclobutane carboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a yellow solid, 42 mg, yield: 67%.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[C:34]2[N:33]=[C:32]([Br:35])[N:31]=[C:23]([NH:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:22]=2[N:21]=[CH:20]1)(=O)C>N>[Br:35][C:32]1[N:31]=[C:23]([NH:24][N:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)[C:22]2[N:21]=[CH:20][N:19]([C:34]=2[N:33]=1)[C@@H:6]1[O:7][C@H:8]([CH2:14][OH:15])[C@@H:9]([OH:10])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NN4CCCCC4)nc(Br)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Product: OC[C@H]1O[C@@H](n2cnc3c(NN4CCCCC4)nc(Br)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The above 2',3',5'-tri-O-acetyl-2-bromo-N-(1-piperidinyl)adenosine was treated with methanolic ammonia (10 ml) (previously saturated at -10° C.) and stirred at room temperature for 16 hours after which time TLC investigation indicated that the starting material was consumed and a new product was present [rf 0.24 (SiO2, ethyl acetate/methanol (90/10)]. The reaction mixture was evaporated and the resultant residue was treated with water (25 ml) and the suspension was extracted with ethyl acetate (2×25 ml). The combined extracts were dried (MgSO4) and coevaporated with dichloromethane; 1H NMR (400 MHz, Me2SO-d6) δ3.54, 3.65 (2H, ABX, H-5'a and H-5'b), 3.94 (1H, q, H-4'), 4.12 (1H, m, H-3'), 4.50 (1H, m, H-2'), 5.82 (1H, d, H-1'), 8.38 (1H, s, H-8). HPLC retention time 14.25 (gradient elution, 5-25% acetonitrile/0.1M pH 3.3 ammonium sulphate buffer: 214 nm detector).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:35]1[N:36]=[C:37]([NH2:40])[S:38][CH:39]=1)[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([O:19]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:18])=[C:12]([C:15]#[CH:16])[CH2:13][S:14][C@H:9]12)=[O:6].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(OC(C)C)(C)C>[CH3:1][O:2][N:3]=[C:4]([C:35]1[N:36]=[C:37]([NH2:40])[S:38][CH:39]=1)[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([OH:19])=[O:18])=[C:12]([C:15]#[CH:16])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: C#CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Solvent: COc1ccccc1
Product: C#CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Yield: 59 %

Procedure:
To a suspension of benzhydryl 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-ethynyl-3-cephem-4-carboxylate (syn isomer) (3.70 g) and anisole (5.58 g) was added trifluoroacetic acid (14.71 g) under ice-cooling and the resultant mixture was stirred at the same temperature for 30 minutes. The reaction mixture was dropwise added to diisopropylether (200 ml) and the precipitates were collected by filtration. The precipitates were added to water and ethyl acetate and the mixture was adjusted to pH 7.0 with saturated aqueous sodium bicarbonate. The separated aqueous layer was acidified to pH 3.0 with 10% hydrochloric acid and the precipitates were collected by filtration to give 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-ethynyl-3-cephem-4-carboxylic acid (syn isomer) (1.55 g).
Reaction SMILES: [N:1]1([CH2:10][C:11]([OH:13])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(OC(Cl)=O)C(C)C.[NH2:22][CH:23]1[C:30](=[O:31])[N:29]2[CH:24]1[S:25][CH2:26][C:27]([Cl:35])=[C:28]2[C:32]([OH:34])=[O:33].O1CCCC1.O>O1CCCC1.C(N(CC)CC)C>[N:1]1([CH2:10][C:11]([NH:22][CH:23]2[C:30](=[O:31])[N:29]3[CH:24]2[S:25][CH2:26][C:27]([Cl:35])=[C:28]3[C:32]([OH:34])=[O:33])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)Cn1ccc2ccccc21
Reactant: NC1C(=O)N2C(C(=O)O)=C(Cl)CSC12
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cn1ccc2ccccc21)NC1C(=O)N2C(C(=O)O)=C(Cl)CSC12
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
(1H-Indol-1-yl)acetic acid (0.05 m) is added to tetrahydrofuran. The temperature is lowered to about -10° C. and 1 equivalent of isobutylchloroformate in tetrahydrofuran is added. This mixture is stirred for about 30 minutes. A solution of 7-amino-3-chloro-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid in 1:1 tetrahydrofuran/water containing 1 equivalent of triethylamine is added to the previously formed solution maintained at -10° C. The resulting solution is stirred for about 60 minutes at -10° C. to 0° C. and then stirred for 60 minutes at 30° C. to 30° C. The solvents are removed at reduced pressure to give a residue which is extracted with ethyl acetate. The ethyl acetate is dried over magnesium sulfate, filtered and evaporated to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1N.N([O-])=O.[Na+].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=1
Reactant: Nc1ccccc1Br
Reactant: c1ccncc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Brc1ccccc1-c1ccccn1
Temperature: 80 °C

Procedure:
2-Bromobenzenamine (18.77 g) in 50 ml of conc HCl and 50 ml of water, was cooled in an ice bath and treated dropwise with stirring with a solution of sodium nitrite (8.28 g) in water (35 ml). After the addition was complete, the mixture was stirred in the ice bath for a further 30 minutes and then added portionwise (over 5 minutes) to pyridine (275 ml) stirred in an oil bath at 80° C. The mixture was heated (at 80° C.) for a further 1 hour, when the excess of pyridine was distilled off under reduced pressure. The residue was basified (aqueous sodium hydrogen carbonate) and extracted with ethyl acetate (3×). The extracts were washed with water (2×), dried (sodium sulphate) and evaporated to give a dark oil, which was flash chromatographed on silica using methylene chloride/ethyl acetate (20/1) as eluant. Pure sub-title compound (6.56 g) was obtained as a dark brown oil.