Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)=[N+]=[N-].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[NH2:1][CH2:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1
Reactant: [N-]=[N+]=NCc1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.2 %

Procedure:
A solution of 4-(4-azidomethylbenzyl)-nitrobenzene (5.835 g) in tetrahydrofuran (175 mL) was treated with water (0.43 mL) and triphenylphosphine (6.45 g, 1.1 eg). The mixture was stirred at room temperature for 18 hours, and the solvent was evaporated. The residue was suspended in water, and suspension madeacidic by the dropwise addition of hydrochloric acid to about pH 1, then extracted with diethyl ether (3×). The aqueous phase was made alkaline with 50% aqueous sodium hydroxide, extracted with dichloromethane (3×) to afford a crude brown oil (5.66 g). Chromatography on silica gel, eluting with dichloromethane/methanol/ammonium hydroxide, gave 4-(4-aminomethylbenzyl)-nitrobenzene (3.91 g, 79%) as a yellow solid.
Reaction SMILES: C([O:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C@@H:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][C@H:15]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.O1CCCC1.[Pd]>[OH:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C@@H:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][C@H:15]2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: CN1CC[C@@H](Oc2ccc(OCc3ccccc3)cc2)[C@H](c2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CC[C@@H](Oc2ccc(O)cc2)[C@H](c2ccccc2)C1

Procedure:
A solution of 8.59 g of trans-4-(4-benzyloxyphenoxy)-1-methyl-3-phenylpiperidine in a mixture of 100 ml of absolute ethanol and 50 ml of tetrahydrofuran is hydrogenated overnight over 5% palladium-on-carbon at room temperature under 45 pounds per square inch of hydrogen. The catalyst is filtered and washed with ethanol and ether. The filtrate is concentrated in vacuo to a nearly colorless, partially solidified foam. Trituration of the foam with ether followed by recrystallization from 270 ml of chloroform gives product as a colorless solid, mps 169.5° C., 170°-172° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[S:25][C:24]([NH2:26])=[N:23][C:22]=3[Cl:27])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33]([CH:36]=O)=[CH:32][CH:31]=1.C([BH3-])#N>C(O)C.C(O)(=O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[S:25][C:24]([NH:26][CH2:36][C:33]4[CH:34]=[N:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=4)=[N:23][C:22]=3[Cl:27])=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1nc(Cl)c(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)s1
Reactant: COc1ccc(C=O)cn1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(CNc2nc(Cl)c(Cc3cn(S(=O)(=O)c4ccccc4)c4ncc(Cl)cc34)s2)cn1

Procedure:
5-(1-Benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-ylamine (592, 30 mg, 0.083 mmol, prepared as described in Example 66, Scheme 183) was combined with 6-methoxy-pyridine-3-carbaldehyde (618, 26.2 mg, 0.165 mmol) in a 2 mL microwave reaction vial. The mixture was dissolved in ethanol: acetic acid (95:5, 0.6 mL). Silica supported cyanoborohydride (1.0 mmol/g, 83 mg, 0.083 mmol) was added and the mixture was irradiated with microwave on 300 watts for 5 minutes at 100° C. The silica was separated by centrifuging and the supernatant solution was decanted. The silica residue was rinsed with ethanol (0.500 mL) and centrifuged. The solvents were combined and removed under reduced pressure to give the desired compound 619, which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:18][N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21]>>[N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:20](=[O:21])[N:19]([CH3:18])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(O)cc2)cc1
Product: CN(C(=O)Oc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-(4-nitro-phenoxy)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (71%, white crystals). HPLC-MS m/z=365.0 (M+1), Rt: 4.83 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([SH:10])=[C:6]([CH:9]=1)[CH:7]=O.[F:11][C:12]([F:21])([F:20])/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16].C([O-])([O-])=O.[K+].[K+].Cl>C(OCC)(=O)C.CN(C=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH:13]([C:12]([F:11])([F:21])[F:20])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:9]=1
Reactant: Cc1ccc(S)c(C=O)c1
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2cc(C)ccc2SC1C(F)(F)F
Yield: 69.4 %

Procedure:
The 5-methyl-2-mercaptobenzaldehyde (Step 1) (3.25 g, 21.3 mmol) was added to DMF (5 mL) and ethyl 4,4,4-trifluorocrotonate (4.32 g, 25.7 mmol). With stirring, K2CO3 (3.78 g, 27.3 mmol) was added causing the reaction to become a deep red. The reaction was stirred at room temperature for 20 hours, acidified with 3N HCl, diluted with ethyl acetate and washed with water, saturated NaHCO3 solution, brine, dried over MgSO4, filtered and concentrated in vacuo yielding an oil. The oil was crystallized from diethyl ether-petroleum ether to give ethyl 6-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylate as a light yellow solid (4.47 g, 69%),: mp 93.1–94.7° C. 1H NMR (acetone-d6/300 MHz) 7.94 (s, 1H), 7.41 (s, 1H), 7.31 (d, 1H, J=7.9 Hz), 7.25 (d, 1H, J=7.9 Hz), 4.96 (q, 1H, J=8.5 Hz), 4.33 (m, 2H), 2.34 (s, 3H), 1.35 (t, 3H, J=7.0 Hz). FABLRMS m/z 309 (M+Li).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:14]2[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=[C:16]([NH:29][NH2:30])[CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[OH:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1>C(O)C>[OH:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[N:30][NH:29][C:16]2[CH:15]=[C:14]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=2)=[CH:34][CH:33]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: Oc1ccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccccc4)cc3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
There was dissolved, in ethanol (2 mL), trifluoroacetic acid salt of (7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (25.0 mg, 0.0464 mM), then 4-hydroxy-benzaldehyde (6.2 mg, 0.051 mM) was added to the solution and the mixture was stirred at room temperature for one hour. This reaction liquid was filtered and the resulting solid was purified by the NH-silica gel column chromatography (methanol/methylene chloride=1/20) to thus give the title compound (19.2 mg, yield: quantitative).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:6](OC)=[O:7])#[N:2].[BH4-].[Li+].O1CCCC1>O1CCOCC1>[CH:13]1([C:12]2[CH:11]=[CH:10][C:5]([CH2:6][OH:7])=[CH:4][C:3]=2[C:1]#[N:2])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: COC(=O)c1ccc(C2CCCCC2)c(C#N)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: N#Cc1cc(CO)ccc1C1CCCCC1
Temperature: 0 °C
Yield: 72 %

Procedure:
To a solution of methyl 3-cyano-4-cyclohexylbenzoate (299.0 mg, 1.229 mmol) in 1,4-dioxane (30 mL) was added 2 M lithium borohydride solution in tetrahydrofuran (1.23 mL, 2.46 mmol). The mixture was heated under reflux for 2.5 h. The mixture was cooled to 0° C. and quenched with 1 N aqueous HCl solution slowly to pH 5. After the addition of brine solution, the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography to provide the title compound as a white solid (190.5 mg). LCMS m/z=216.5 [M+H]+; NMR (400 MHz, CDCl3) δ ppm 1.23-1.33 (m, 1H), 1.41-1.52 (m, 4H), 1.76-1.83 (m, 1H), 1.84-1.92 (m, 4H), 2.90-3.05 (m, 1H), 4.70 (d, J=5.81 Hz, 2H), 7.36 (d, J=8.21 Hz, 1H), 7.53 (dd, J=8.27, 1.71 Hz, 1H), 7.61 (d, J=1.39 Hz, 1H).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([S:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:17].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](Cl)=[O:27])=[CH:21][CH:20]=1>>[C:13]([S:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:17])[N:2]([NH:1][C:26](=[O:27])[CH2:25][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)[N:11]=1)([CH3:14])([CH3:16])[CH3:15]
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CC(C)(C)Sc1nn(N)c(=O)c2ccccc12
Product: CC(C)(C)Sc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12

Procedure:
The product from Example 198B and 2-(4-chlorophenyl)acetyl chloride were processed using a method similar to that described in Example 4C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ 11.74 (s, 1H), 8.32 (d, J=7.9, 1H), 8.12 (d, J=8.0, 1H), 8.01 (t, J=7.6, 1H), 7.93 (t, J=7.5, 1H), 7.44-7.37 (m, 4H), 3.70 (s, 2H), 1.43 (s, 9H); MS (DCI+) M/Z 419 (M+NH4)+.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(N(CC)CC)C.[Br:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]=O)=[N:21][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][NH:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])=[N:21][CH:22]=1
Reactant: CCOC(=O)CN
Reactant: O=Cc1ccc(Br)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)CNCc1ccc(Br)cn1
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
Glycine ethyl ester hydrochloride (9C2) (161 mmol, 22.51 g) was dried under vacuum then dissolved in methanol (200 ml). Triethylamine (137 mmol, 13.87 g) was added with stirring and the resulting solution was added dropwise to a solution of 5-bromo-2-formylpyridine (9B1) (81 mmol, 15 g) in methanol (200 ml) under nitrogen. After 30 min, sodium triacetoxyborohydride (194 mmol, 41.0 g) was added portionwise over 30 min and the reaction was then stirred at room temperature under nitrogen overnight. The reaction was quenched with saturated sodium bicarbonate solution and extracted three times with DCM. The combined organic layers were washed with water, brine and dried using a hydrophobic frit, then concentrated under reduced pressure. The reside was purified on silica eluting with heptane/EtOAc/EtOH 8/1.6/0.4 to 5/4/1 to give ethyl 2-((5-bromopyridin-2-yl)methylamino)acetate (9J1) 11.4 g (51.6%); 1H NMR (400 MHz, CDCl3) 8.61 (s, 1H) 7.78 (d, 1H) 7.27 (d, 1H) 4.20 (q, 2H) 3.91 (s, 2H) 3.46 (s, 2H) 2.31 (bs, 1H) 1.27 (t, 3H).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.ClC1N=CN=C2C=1NC=N2.[OH:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31].C(N(CC)CC)C>C(O)CC>[OH:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH:31][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1
Reactant: NCc1ccccc1O
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: Clc1ncnc2nc[nH]c12
Solvent: CCN(CC)CC
Solvent: CCCO
Product: Oc1ccccc1CNc1ncnc2c1ncn2C1CCCCO1
Yield: 90 %

Procedure:
A mixture of 10 mmol (2387 mg) 6-chloro-9-(tetrahydropyran-2-yl)purine (prepared from 10 mmol (1546 mg) of 6-chloropurine), 12 mmol (1478 mg) 2-hydroxybenzylamine, and 5 mL of triethylamine was refluxed in n-propanol for 3 hrs. After removal of the n-propanol by vacuum evaporation, the resulting material was treated with water and extracted into ethyl acetate. The ethyl acetate solvent was evaporated and the residuum subsequently washed with 30 ml of diethylether. The solid residue was filtered off and the crude product crystallized from methanol. Yield 90%, white solid. TLC (EtOAc:hexane (1:1) (v:v): single spot; HPLC: purity>98%. 1H-NMR (400 MHZ, DMSO): 1.58m (2H); 1.70m (1H); 1.95m (2H); 2.26qq (1H, Ja=11.8 Hz, Jb=4.0 Hz); 3.67m (1H); 4.0d (1H, J=11.3 Hz); 4.64bs (2H); 5.63dd (1H, Ja=11.3 Hz, Jb=1.8 Hz); 6.73t (1H, J=7.5 Hz); 6.82 (d, 1H, J=7.9 Hz); 7.06t (1H, J=7.5 Hz); 7.14d (1H, J=7.5 Hz); 8.21s (1H); 8.35bs (1H); 8.37bs (1H); 9.82bs (1H). MS (ES): [M+H]+=326 (100).
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:11]3([CH2:15][CH2:14][N:13]([CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[C:12]3=[O:22])[CH2:10][C@@H:9]([OH:23])[CH2:8]2)=[CH:4][CH:3]=1.O1CCOCC1.CN[C@H]1CCCC[C@@H]1NC.[F:42][C:43]([F:50])([F:49])[C:44]1[CH:48]=[CH:47][NH:46][N:45]=1>[Cu]I>[CH:16]1([N:13]2[CH2:14][CH2:15][C:11]3([N:7]([CH2:6][C:5]4[CH:24]=[CH:25][C:2]([N:46]5[CH:47]=[CH:48][C:44]([C:43]([F:50])([F:49])[F:42])=[N:45]5)=[CH:3][CH:4]=4)[CH2:8][C@H:9]([OH:23])[CH2:10]3)[C:12]2=[O:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: O=C1N(C2CCCCC2)CCC12C[C@@H](O)CN2Cc1ccc(Br)cc1
Agent: [Cu]I
Agent: CN[C@H]1CCCC[C@@H]1NC
Solvent: C1COCCO1
Product: O=C1N(C2CCCCC2)CCC12C[C@@H](O)CN2Cc1ccc(-n2ccc(C(F)(F)F)n2)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a solution of (3R)-1-(4-bromobenzyl)-7-cyclohexyl-3-hydroxy-1,7-diazaspiro[4.4]nonan-6-one (25.0 mg, 0.0000614 mol; prepared as in Example 37) in 1,4-dioxane (0.8 mL, 0.01 mol) was added (1S,2S)—N,N′-dimethylcyclohexane-1,2-diamine (1.7 mg, 0.000012 mol), copper(I) iodide (1.2 mg, 0.0000061 mol), and 3-(trifluoromethyl)-1H-pyrazole (17 mg, 0.00012 mol). After stirring the resulting mixture at 100° C. for 16 h, the crude reaction mixture was purified by prep.-HPLC under pH=10 conditions to afford the desired product. LC-MS: 463.2 (M+1H)+.
Reaction SMILES: C[Sn](C)C.C[Sn](C)C.[Cl:9][C:10]1[CH:11]=[CH:12][C:13](Br)=[N:14][CH:15]=1.Br[C:18]1[O:22][C:21]([C:23]2[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=2)[C:26]#[N:27])=[CH:20][CH:19]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:18]2[O:22][C:21]([C:23]3[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=3)[C:26]#[N:27])=[CH:20][CH:19]=2)=[N:14][CH:15]=1
Reactant: N#Cc1cccc(-c2ccc(Br)o2)c1
Reactant: Clc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)C
Product: N#Cc1cccc(-c2ccc(-c3ccc(Cl)cn3)o2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 17.5 %

Procedure:
Pd(PPh3)4 (5 mg, 0.004 mmol) was added to a solution of hexamethylditin (160 mg, 0.49 mmol) and 5-chloro-2-bromopyridine (76 mg, 0.395 mmol) in toulene (1 mL) under argon. The resulting solution was stirred at 80° C. for 16 h. After cooling to room temperature, a second portion of Pd(PPh3)4 (20 mg, 0.019 mmol) and 3-(5-bromofuran-2-yl)-benzonitrile (79 mg, 0.32 mmol) were added and the resulting solution was stirred at 110° C. for 14 h. After cooling to room temperature, the solvent was removed in vacuo. Chromatography (5 g silica gel SPE tube, 25–50% chloroform in hexane to 2% ethyl acetate in 1:1 chloroform:hexane) followed by triturating with hexanes and purification by preparative TLC (90% dichloromethane in hexane) afforded 15.7 mg (17%) of 3-(5-(5-choro-2-pyridyl)-2-furyl)-benzonitrile (97.5% pure by GC/MS, contaminated with 2.5% dimer). 1H-NMR (CDCl3), δ (ppm): 8.55 (d, 1H), 8.03 (s, 1H), 7.94 (dd, 1H), 7.73 (s, 2H), 7.54 (m, 12), 7.16 (d, 1H), 6.88 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:26]/[OH:27])/[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([OH:23])=[O:22])=[C:15](/[CH:18]=[CH:19]\[CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1.[C:52]([O:58][CH:59](I)[CH3:60])(=[O:57])[C:53]([CH3:56])([CH3:55])[CH3:54]>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:26]/[OH:27])/[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([O:23][CH:59]([O:58][C:52](=[O:57])[C:53]([CH3:56])([CH3:55])[CH3:54])[CH3:60])=[O:22])=[C:15](/[CH:18]=[CH:19]\[CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(I)OC(=O)C(C)(C)C
Reactant: C/C=C\C1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C/C=C\C1=C(C(=O)OC(C)OC(=O)C(C)(C)C)N2C(=O)C(NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1
Reaction time: 0.75 h
Yield: 22 %

Procedure:
To a mixture of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-1-propenyl]-3-cephem-4-carboxylic acid (250 mg, 0.61 mmol), K2CO3 (124 mg, 0.90 mmol) and 18-crown-6 (24 mg) in DMF (2.5 ml) was added 1-pivaloyloxyethyl iodide (461 mg, 1.8 mmol) at 5° C. and the mixture was stirred for 45 min at the same temperature. The mixture was diluted with ethyl acetate, washed with water and evaporated under reduced pressure. The residue was chromatographed on a column of silica gel (10 g) and the column was eluted with chloroform containing 1% methanol. The fractions containing the desired product were combined and evaporated under reduced pressure. The residue was dissolved in a small amount of benzene and freeze-dried to give 72 mg (21%) of the product as an amorphous powder.
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[NH:5][C:4]=2[CH2:3]1.[H-].[Na+].[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:27][O:26]2)=[CH:21][CH:20]=1>CN(C=O)C>[CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[N:5]([CH2:27][CH:25]([C:22]3[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=3)[OH:26])[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)C3
Reactant: Fc1ccc(C2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2ccc(F)cc2)CN(C)CC1
Reaction time: 0.17 h
Yield: 35.5 %

Procedure:
2,6-Dimethyl-2,3,4,9-tetrahydro-1H-β-carboline (500 mg, 2.5 mmol) was dissolved in 5 mL DMF and sodium hydride (250 mg, 6.24 mmol) was added portionwise at 0° C. and the mixture stirred for 10 min. 2-(4-Fluoro-phenyl)-oxirane (450 mg, 3.26 mmol) was added dropwise at same temperature and stirred for 12 h at RT. The reaction was monitored by TLC & LCMS. After consumption of starting material, the reaction mixture was quenched with ice cold water. The resultant solid was filtered and washed with water (100 mL) and hexane (100 mL), and the crude product was crystallized in EtOH:hexane (5:95 ratio) to obtain 300 mg of 2-(2,6-dimethyl-1,2,3,4-tetrahydro-β-carbolin-9-yl)-1-(4-fluoro-phenyl)-ethanol. 1H NMR (CDCl3, Free base) δ (ppm): 7.30 (m, 2H), 7.20 (d, 1H), 7.05 (m, 3H), 7.0 (d, 1H), 5.0 (t, 1H), 4.05 (d, 2H), 3.62 (d, 1H), 3.30 (d, 1H), 2.80 (m, 3H), 2.70 (m, 1H), 2.50 (s, 3H), 2.44 (s, 3H). Separation by chiral HPLC provided enantiomers 18a and 18b. Optical rotations: Compound No. 18a, (−) 6.97 (c 0.56, Chloroform, 89.35% HPLC purity); Compound No. 18b, (+) 13.03 (c 0.51, Chloroform, 99.51% HPLC purity).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([NH:13][CH2:14][C:15]([OH:17])=[O:16])(=O)[CH3:11].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:14]2[C:15](=[O:16])[O:17][C:10]([CH3:11])=[N:13]2)=[CH:4][CH:3]=1
Reactant: CC(=O)NCC(=O)O
Reactant: O=Cc1ccc(Br)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC1=NC(=Cc2ccc(Br)cc2)C(=O)O1
Reaction time: 1 h
Yield: 64 %

Procedure:
A mixture of 4-bromobenzaldehyde (2.88 g, 35.10 mmol), N-acetyl-glycine (3.80 g, 32.40 mmol) and sodium acetate (2.88 g, 35.1 mmol) in acetic anhydride (13.79 g, 135 mmol), was refluxed for 1 h with continuous stirring. After cooling, the reaction was quenched with ice and vigorously stirred for 1 h in an ice bath to allow precipitation. Filtration afforded compound in 64% yield.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.C(N(CC)CC)C.Cl.[F:15][C:16]([F:50])([F:49])[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[N:20]=[C:19]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39]3[CH:40]=[C:41]([S:45](Cl)(=[O:47])=[O:46])[CH:42]=[CH:43][CH:44]=3)[CH:34]=2)[N:18]=1>C1COCC1>[F:50][C:16]([F:15])([F:49])[C:17]1[CH:22]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=2)[N:20]=[C:19]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39]3[CH:40]=[C:41]([S:45]([N:1]4[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]4)(=[O:47])=[O:46])[CH:42]=[CH:43][CH:44]=3)[CH:34]=2)[N:18]=1
Reactant: OC1CCNC1
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1)N1CCC(O)C1
Temperature: 0 °C
Yield: 82.4 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of (RS)-3-pyrrolidinol (0.27 g, 3.0 mmol), triethylamine (0.29 ml, 2.1 mmol) and THF (4 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example I.1) (0.58 g, 1.0 mmol) in THF (6 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH/hexane) yielded the title compound as a white solid (0.49 g, 88%). MS (ISP) 594.6 [(M+H)+]; mp 234° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:5]2.CN(C)CCN(C)CCN(C)C.C([Li])(CC)C.[I:39]I>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[C:10]=1[I:39])[N:7]([Si:12]([CH:16]([CH3:18])[CH3:17])([CH:19]([CH3:21])[CH3:20])[CH:13]([CH3:14])[CH3:15])[CH:6]=[CH:5]2
Reactant: II
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(F)cc(F)c21
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(F)c(I)c(F)c21
Temperature: -70 °C
Reaction time: 3 h

Procedure:
5,7-difluoro-1-(triisopropylsilyl)-1H-indole (1.4 g, 4.5 mmol) and pentamethyldiethylene-triamine (830 mg, 4.8 mmol) were combined in 10 mL dry THF, cooled to −70° C. and treated in portions with sec-butyl lithium (3.4 mL, 1.4 M, 4.8 mmol) and stirred for 3 h at this temperature. Iodine (1.3 g, 5.0 mmol) in 5 mL THF was added, the mixture was stirred for 50 min, quenched by addition of 3 mL sat. NH4Cl and partitioned between diethyl ether and water. The organic phase was washed with sat. NaCl, dried (Na2SO4), evaporated and purified by flash chromatography (SiO2; hexanes) the title compound as a clear oil which solidified on standing (1.9 g, 90%). 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J=3.1 Hz, 1H), 7.14 (dd, J=7.7, 0.9 Hz, 1H), 6.60 (t, J=3.1 Hz, 1H), 1.67 (m, 3H), 1.13 (d, J=7.6 Hz, 18H). 19F NMR (376 MHz, CDCl3) δ −101.37, −105.33. MP: 74-76° C.