Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][N:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17](B4OC(C)(C)C(C)(C)O4)[C:16]=3[CH3:30])[C:11]2=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:32]1[CH:33]=[C:34]([NH:39][C:40]2[CH:49]=[C:43]3[CH2:44][N:45]([CH3:48])[CH2:46][CH2:47][N:42]3[N:41]=2)[C:35](=[O:38])[NH:36][N:37]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>C(OCC)(=O)C.O.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.O1CCOCC1>[C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][N:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:32]4[CH:33]=[C:34]([NH:39][C:40]5[CH:49]=[C:43]6[CH2:44][N:45]([CH3:48])[CH2:46][CH2:47][N:42]6[N:41]=5)[C:35](=[O:38])[NH:36][N:37]=4)[C:16]=3[CH3:30])[C:11]2=[O:14])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2ccc(C(C)(C)C)cc2C1=O
Reactant: CN1CCn2nc(Nc3cc(Cl)n[nH]c3=O)cc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Cc1c(-c2cc(Nc3cc4n(n3)CCN(C)C4)c(=O)[nH]n2)cccc1N1Cc2ccc(C(C)(C)C)cc2C1=O
Yield: 27 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with 107e (890 mg, 2.20 mmol), 101m (441 mg, 1.57 mmol), sodium carbonate (832 mg, 7.85 mmol), DMF (5 mL), water (5 mL) and 1,4-dioxane (15 mL). After bubbling nitrogen through the resulting suspension for 30 min, tetrakis(triphenylphosphine)palladium(0) (363 mg, 0.314 mmol) was added. A reflux condenser was attached to the flask, and the reaction mixture was heated at reflux for 16 h. After this time, the mixture was diluted with ethyl acetate (100 mL) and water (50 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×100 mL), and the combined organic layers were washed with brine (100 mL) and dried over sodium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography (silica, 95:5 methylene chloride/methanol) to afford 107 in 27% yield (222 mg) as an amorphous white solid: mp 208-210° C.; 1H NMR (500 MHz, DMSO-d6) δ 12.97 (s, 1H), 9.21 (s, 1H), 7.79 (s, 1H), 7.75 (s, 1H), 7.75-7.73 (m, 1H), 7.60 (d, J=9.0 Hz, 1H), 7.48 (dd, J=7.5, 2.0 Hz, 1H), 7.40-7.38 (m, 2H), 5.96 (s, 1H), 4.84 (s, 2H), 3.97 (t, J=5.5 Hz, 2H), 3.51 (s, 2H), 2.79 (t, J=6.0 Hz, 2H), 2.35 (s, 3H), 2.10 (s, 3H), 1.36 (s, 9H); MS (ESI+) m/z 524.3 (M+H).
Reaction SMILES: S(C)C.[C:4]([O:8][C:9]([N:11]1[CH2:16][CH:15]([N:17]2[C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:27])[C:21]=3[C:20]3=[N:28][O:29][C:30]([CH3:31])=[C:19]3[C:18]2=[O:32])[CH2:14][CH:13]([C:33](O)=[O:34])[CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>C1COCC1>[C:4]([O:8][C:9]([N:11]1[CH2:12][CH:13]([CH2:33][OH:34])[CH2:14][CH:15]([N:17]2[C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:27])[C:21]=3[C:20]3=[N:28][O:29][C:30]([CH3:31])=[C:19]3[C:18]2=[O:32])[CH2:16]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: Cc1onc2c1c(=O)n(C1CC(C(=O)O)CN(C(=O)OC(C)(C)C)C1)c1cccc(Cl)c21
Solvent: CSC
Solvent: C1CCOC1
Product: Cc1onc2c1c(=O)n(C1CC(CO)CN(C(=O)OC(C)(C)C)C1)c1cccc(Cl)c21
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
Add BH3.SMe2 (3.2 mL, 6.4 mmol, 2.0 M in THF) to a solution of 5-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (1.5 g, 3.2 mmol) in THF (20 mL) at 0° C. Remove the ice bath and stir for 30 min. Quench dropwise with MeOH and concentrate to dryness. Partition between 20% iPrOH/CHCl3 and water. Wash 2× sat. aq NaHCO3, wash 2× brine, dry over Na2SO4, filter and concentrate to dryness. Purify by radial chromatography using MeOH/CHCl3 as eluant and concentrate to dryness to afford the title compound (0.95 g, 66%) as a white foam as a mixture of cis isomers. MS(IS) 448.2 (M+); HPLC (40% IPA 60% heptane on a Chiralpak AD (0.46×25 cm) 1.5 mL/min flow; 25 μL Inj.; 225 nM) Rt=3.28 min (72.1%), 4.48 min (27.8%).
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=7)=[C:24]([C:34]([NH:36][CH3:37])=[O:35])[C:23]=6[CH:38]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH:11]([CH2:45][OH:46])[N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1.[C:47]([NH:54][C@H:55]([C:59](O)=[O:60])[CH:56]([CH3:58])[CH3:57])([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48].CCN=C=NCCCN(C)C.CCN(CC)CC>ClCCl.CN(C1C=CN=CC=1)C.O>[C:50]([O:49][C:47]([NH:54][C@@H:55]([CH:56]([CH3:58])[CH3:57])[C:59]([O:46][CH2:45][CH:11]1[N:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[C:3]=3[CH:4]=[C:5]2[C:14]2[N:15]=[C:16]([C:19]3[C:20]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:21][C:22]4[O:26][C:25]([C:27]5[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=5)=[C:24]([C:34](=[O:35])[NH:36][CH3:37])[C:23]=4[CH:38]=3)[CH:17]=[CH:18][C:13]=2[O:12]1)=[O:60])=[O:48])([CH3:53])([CH3:52])[CH3:51]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(CO)O4)cc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)O4)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
To a solution of 5-(11-fluoro-6-(hydroxymethyl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (30 mg, 0.05 mmol, Compound 87, single enantiomer) and N-Boc-L-Valine (20 mg, 0.09 mmol) in dichloromethane, EDCI (20 mg, 0.10 mmol), DMAP (8 mg, 0.06 mmol) and Et3N (0.01 mL) were added. The reaction mixture was stirred at room temperature overnight. Then H2O was added, and extracted with dichloromethane. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified using prep-TLC (dichloromethane:MeOH=40:1) to provide (2S)-(11-fluoro-2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-6-yl)methyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (30 mg, yield: 76%). 1H-NMR (CDCl3, 400 MHz) δ 7.98˜8.02 (m, 3H), 7.67 (s, 1H), 7.46˜7.54 (m, 2H), 7.19˜7.25 (m, 5H), 6.84˜6.89 (m, 1H), 6.62˜6.65 (m, 1H), 5.98 (br s, 1H), 4.91 (d, J=8.4 Hz, 1H), 4.42˜4.48 (m, 1H), 4.30˜4.35 (m, 1H), 4.18 (br s, 1H), 3.38 (s, 3H), 3.01 (d, J=4.8 Hz, 3H), 2.72 (s, 3H), 1.90˜1.95 (m, 1H), 1.45 (s, 9H), 0.88 (d, J=6.4 Hz, 3H), 0.79 (d, J=6.4 Hz, 3H). MS (M+H)+: 844.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[C:20]([CH3:22])[C:19]([CH3:23])=[CH:18][C:17]=3[CH3:24])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][C:26]1=[O:30]>>[CH3:24][C:17]1[CH:18]=[C:19]([CH3:23])[C:20]([CH3:22])=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([N:25]3[CH2:29][CH2:28][CH2:27][C:26]3=[O:30])=[N:7][CH:6]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: O=C1CCCN1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)nc3)CC2)cc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCC4=O)nc3)CC2)cc1C

Procedure:
Using (6-bromopyridin-3-yl)[4-(2,4,5-trimethylphenyl)piperazin-1-yl]methanone (310 mg) described in Preparation Example 173 and pyrrolidin-2-one (93 μL) and by the reaction and treatment in the same manner as in Example 1, the title compound (187 mg) was obtained.
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].Cl[C:6]1[N:11]=[C:10]([C:12]2[C:20]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=[CH:23][CH:22]=3)=[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N:14]3[N:13]=2)[CH:9]=[CH:8][CH:7]=1>CN(C=O)C>[CH3:1][O:2][C:6]1[N:11]=[C:10]([C:12]2[C:20]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=[CH:23][CH:22]=3)=[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N:14]3[N:13]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: CO
Reactant: Clc1cccc(-c2nn3ccccc3c2-c2ccnc3ccccc23)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2nn3ccccc3c2-c2ccnc3ccccc23)n1
Temperature: 110 °C
Yield: 72.1 %

Procedure:
Add methanol (19 mg, 0.59 mmol) and sodium hydride (14 mg, 60% dispersion, 0.35 mmol) to a solution of 4-[2-(6-chloro-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline (42 mg, 0.118 mmol) in DMF (0.6 mL) at room temperature. Heat to 110° C. for 3 hours, cool to room temperature, and quench with saturated aqueous ammonium chloride (0.5 mL). Concentrate in vacuo, filter, and purify by flash column chromatography (Silica Gel, 20-40% acetone/hexanes) to provide the title compound 30 mg (73%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=3)=[O:26])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1nc(C(=O)O)c(-c2cccc(C(F)(F)F)c2)o1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)s2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(C(F)(F)F)c3)n2)s1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-(3-trifluoromethyl-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:27])[CH2:11][CH2:12][C:13]1[N:14]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([OH:26])[CH:19]=2)[O:16][CH:17]=1)[CH3:2].Cl[CH:29]([F:31])[F:30]>>[F:30][CH:29]([F:31])[O:26][C:20]1[CH:19]=[C:18]([C:15]2[O:16][CH:17]=[C:13]([CH2:12][CH2:11][C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:3][CH2:1][CH3:2])=[O:27])[N:14]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: FC(F)Cl
Reactant: CCOc1ccccc1C(=O)CCc1coc(-c2ccc(OC)c(O)c2)n1
Product: CCOc1ccccc1C(=O)CCc1coc(-c2ccc(OC)c(OC(F)F)c2)n1

Procedure:
Using the compound obtained in Example 101 and chlorodifluoromethane, white powdery 3-[2-(3-difluoromethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one was obtained following the procedure of Example 4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[C:5]#[N:6].[F:11][C:12]([F:24])([F:23])[O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:10][C:9]1[C:2]([C:17]2[CH:16]=[CH:15][C:14]([O:13][C:12]([F:11])([F:23])[F:24])=[CH:19][CH:18]=2)=[CH:3][C:4]([C:5]#[N:6])=[CH:7][CH:8]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: N#Cc1ccc(F)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: N#Cc1ccc(F)c(-c2ccc(OC(F)(F)F)cc2)c1
Temperature: 80 °C
Reaction time: 0.13 h
Yield: 100.4 %

Procedure:
A 100 mL 3-necked flask equipped with a stir bar, a condenser, and a nitrogen inlet was flushed with nitrogen and then charged with 3-bromo-4-fluorobenzonitrile (2.507 g, 1.23×10−2 mol), 4-trifluoromethoxyphenyl boronic acid (2.825 g, 1.23×10−2mol, 1.01 equiv), bis(triphenylphosphine)-palladium(II) chloride (2.0 mg, 2.85×10−6 mol, 0.02 mol %), and sodium bicarbonate (1.577 g, 1.82×10−2 mol, 1.5 equiv). The flask was then evacuated and purged with nitrogen three times, and charged with deoxygenated toluene (6 mL) and deoxygenated water (6 mL). The mixture was heated to 80° C. until HPLC analysis indicated the disappearance of the aryl bromide (less than 16 hours; HPLC conditions: Eclipse XDB-C8 (4.6 mm×150 mm), flow rate: 1.5 mL/min.; mobile phase: 80:20 water(0.1%H3PO4)/CH3CN to 20:80 in 8 minutes, hold to 15 minutes with the column at 35° C. and UV detection: 210 nm. Retention time for the product is 8.88 min, retention time for aryl bromide is 6.47 min, retention time for excess boronic acid is 5.64 min, and retention time for homocoupled product is 10.58 minutes). The reaction was cooled to room temperature and the phases were separated. The organic phase was filtered through a plug of silica (2.5 g) and the silica plug was washed with toluene (25 mL). The filtrate was concentrated to provide the desired product (3.472 g, 92% potency, 93% potency adjusted yield). HRMS (FAB) calcd. for C14H7F4NO (M+H)+: 282.0542, found 282.0536; 1H NMR (CDCl3) δ 7.76 (dd, 1H), 7.68 (ddd, 1H), 7.56 (m, 2H), 7.34 (m, 2H), 7.30 (dd, 1H); 13C (CDCl3) δ 161.9, 149.5, 134.9, 133.5, 131.9, 130.4, 129.5, 121.2 (2), 120.4, 117.8, 117.7, 109.1; IR (KBr) 2230, 1514, 1490, 1265, 1256, 1223, 1210, 1157; Analytical: Pd 6 ppm, B <30ppm, Na <1ppm; mp 63.5-64.2° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@H:15]3[C@H:19]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][N:17](CC4C=CC=CC=4)[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)=O.CO.[Pd]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@H:15]3[C@H:19]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][NH:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(OC)c(OC2CCCC2)c1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: COC(=O)[C@@H]1CNC[C@H]1c1ccc(OC)c(OC2CCCC2)c1
Temperature: 25 °C
Yield: 83.7 %

Procedure:
trans-3-(3-Cyclopentoxy-4-methoxyphenyl)-4-methoxycarbonyl-1-(phenylmethyl)pyrrolidine (3.5 g, 8.6 mmol) was dissolved in 20 mL of 4% HCO2H:methanol. While stirring at room temperature, 10% Pd/C (450 mg) was added in small portions. After several hours the reaction was diluted with methanol. Filtration through Celite followed by concentration under reduced pressure yielded a yellow oil residue. This residue was partitioned between CH2Cl2 and sat. NaHCO3. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×). The organic layers were combined, dried (K2CO3), filtered, and concentrated under reduced pressure to afford a pale oil. Chromatography on silica gel (8:1:1, CH2Cl2 :ethyl acetate:methanol) provided trans-3-(3-cyclopentoxy-4-methoxyphenyl)-4-(methoxycarbonyl)pyrrolidine as a colorless oil (2.3 g, 84%). 1H-NMR (300 MHz): δ 2.86-3.04 (m, 2), 3.29-3.52 (m, 4), 3.68 (s, 3), 3.83 (s, 3).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5](/[N:8]=[C:9](\Cl)/[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1.C[O:16][NH2:17]>O1CCCC1>[Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8]/[C:9](=[N:17]\[OH:16])/[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1
Reactant: CON
Reactant: FC(F)(F)/C(Cl)=N/c1ccc(Cl)nn1
Solvent: C1CCOC1
Product: O/N=C(\Nc1ccc(Cl)nn1)C(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of 4.5 g (18 mmol) of the crude product of Step B in 150 mL tetrahydrofuran was carefully added 2 mL aqueous 50% methoxyamine. The resulting solution was stirred under nitrogen at ambient temperature. After 1 h the solution was concentrated in vacuo then dissolved in 100 mL ethyl acetate and washed sequentially with saturated aqueous sodium bicarbonate solution and saturated aqueous brine (100 mL each). The organic phase was then dried over magnesium sulfate, filtered, and evaporated in vacuo to yield a crude oil.
Reaction SMILES: C(OC1C(N)=CC(O)=C([N+]([O-])=O)C=1)CCCCCC.N([O-])=O.[Na+].Cl.C(O)C.C[C@H:29]([O:36][C:37]1[C:42]([N:43]=[N:44][C:45]2[CH:50]=[C:49]([O:51][C@@H:52]([CH3:59])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[C:48]([N:60]([CH3:62])[CH3:61])=[CH:47][C:46]=2[OH:63])=[CH:41][C:40]([OH:64])=[C:39]([N+:65]([O-:67])=[O:66])[CH:38]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>N1C=CC=CC=1>[CH2:29]([O:36][C:37]1[C:42]([N:43]=[N:44][C:45]2[CH:50]=[C:49]([O:51][C@@H:52]([CH3:59])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[C:48]([N:60]([CH3:61])[CH3:62])=[CH:47][C:46]=2[OH:63])=[CH:41][C:40]([OH:64])=[C:39]([N+:65]([O-:67])=[O:66])[CH:38]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCC[C@H](C)Oc1cc([N+](=O)[O-])c(O)cc1N=Nc1cc(O[C@@H](C)CCCCCC)c(N(C)C)cc1O
Agent: CCCCCCCOc1cc([N+](=O)[O-])c(O)cc1N
Agent: Cl
Agent: O=N[O-]
Solvent: CCO
Solvent: c1ccncc1
Product: CCCCCCCOc1cc([N+](=O)[O-])c(O)cc1N=Nc1cc(O[C@@H](C)CCCCCC)c(N(C)C)cc1O
Yield: 46 %

Procedure:
Compound 43a (388 mg, 1.46 mmol), compound 51b (392 mg, 1.46 mmol), 0.1M aqueous sodium nitrite (14.5 ml), and pyridine (4.5 ml) in 39 ml of a 15% HCl/ethanol solution were reacted according to the procedure for compound 52a. The crude product was adsorbed onto silica gel and purified via flash chromatography with gradual elutions. from 90/5/5 to 75/20/5 (Hex/EtOAc/dichloromethane). Recrystallization from hexanes yielded 370 mg (46%) of a metallic green solid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>C(#N)C>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:16]2[O:15][CH2:14][CH:13]([CH2:12][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[O:18][C:17]=2[CH:19]=1)(=[O:24])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: C1CCNC1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc2c(c1)OC(CN1CCCC1)CO2
Temperature: 120 °C

Procedure:
A mixture of [7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.4 g, 0.9 mmol), pyrrolidine (1 ml) and ACN (3 ml) was heated under microwave radiation at 120° C. for 20 min. Purification on SCX-3 column (TEA/MeOH) and twice on flash column chromatography (Isooctane/EtOAc/MeOH). Yield: 0.2 g, 75%. The amine was converted to the hydrochloric acid salt and crystallized from MeOH/Et2O. M.p. 221° C. MS m/z (rel. intensity, 70 eV) 297 (M+, 1), 85 (6), 84 (bp), 79 (2), 55 (4).
Reaction SMILES: [NH2:1][CH:2]([CH3:5])[CH2:3][OH:4].[CH:6]1([C:9]2[N:14]=[C:13]([C:15]([NH:17][C:18]3[CH:26]=[N:25][CH:24]=[CH:23][C:19]=3[C:20](O)=[O:21])=[O:16])[C:12]([NH:27][C:28]3[CH:29]=[N:30][CH:31]=[N:32][CH:33]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1>>[OH:4][CH2:3][CH:2]([NH:1][C:20]([C:19]1[CH:23]=[CH:24][N:25]=[CH:26][C:18]=1[NH:17][C:15]([C:13]1[C:12]([NH:27][C:28]2[CH:29]=[N:30][CH:31]=[N:32][CH:33]=2)=[CH:11][CH:10]=[C:9]([CH:6]2[CH2:8][CH2:7]2)[N:14]=1)=[O:16])=[O:21])[CH3:5]
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: CC(N)CO
Product: CC(CO)NC(=O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 32 %

Procedure:
According to the general method described in step 3 of example 53, reaction of 2-amino-propan-1-ol with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (32%) as amorphous yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.O=[C:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[C:15]#[N:16].[Cl-].[Ca+2].[Cl-]>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]2[CH2:14][CH2:13][CH2:12][C:11]=2[C:15]#[N:16])=[CH:4][CH:3]=1
Reactant: N#CC1CCCC1=O
Reactant: Nc1ccc(Br)cc1
Agent: [Ca+2]
Agent: [Cl-]
Product: N#CC1=C(Nc2ccc(Br)cc2)CCC1

Procedure:
4-Bromo-aniline (Aldrich Chemicals) (3.5 g, 20 mmol), cyano-ketone (Example 11) (2.2 g, 20 mmol), calcium chloride (2.5 g, 23 mmol) and T.H.F. (30 ml) were heated under reflux for 7 hours. After being allowed to cool, the mixture was filtered and the solvent evaporated. Kugelrohr distillation (150° C., 0.07 mmHg) gave the product as a brown-grey powder.
Reaction SMILES: [CH3:1][Si:2]([CH3:5])([CH3:4])Cl.C(N(CC)CC)C.[Cl:13][CH:14](Cl)[C:15]([NH:17][CH:18]1[C:36](=[O:37])[N:20]2[C:21]([C:33]([OH:35])=[O:34])=[C:22]([CH2:25][S:26][C:27]3[N:31]([CH3:32])[N:30]=[N:29][N:28]=3)[CH2:23][S:24][C@H:19]12)=[O:16]>C(Cl)(Cl)Cl>[CH3:1][Si:2]([O:35][C:33]([C:21]1[N:20]2[C:36](=[O:37])[CH:18]([NH:17][C:15](=[O:16])[CH2:14][Cl:13])[C@H:19]2[S:24][CH2:23][C:22]=1[CH2:25][S:26][C:27]1[N:31]([CH3:32])[N:30]=[N:29][N:28]=1)=[O:34])([CH3:5])[CH3:4]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(Cl)Cl)[C@H]2SC1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cn1nnnc1SCC1=C(C(=O)O[Si](C)(C)C)N2C(=O)C(NC(=O)CCl)[C@H]2SC1
Reaction time: 1.5 h

Procedure:
Trimethylchlorosilane(0.32 ml) and triethylamine (0.14 ml) were added to a solution of 7-dichloroacetamido-3-(1-methyl-1H-tetrazole-5-yl)thiomethyl-3-cephem-4-carboxylic acid(374 mg) in chloroform(10 ml) and the reaction mixture was stirred at 5 - 7°C. for 1.5 hours to give 7-chloroacetamido-3-(1-methyl-1H-tetrazole-5-yl) thiomethyl-3-cephem-4-carboxylic acid trimethylsilyl ester. The resulting solution was added to a mixture of phosphorus pentachloride(176 mg), quinoline(0.12 ml) and chloroform(15 ml) at -50°C. The reaction mixture was stirred at -50°C for 3 hours and diluted with tetrahyrofuran(20 ml), which was cooled to -78°C. To this solution was added a methanol solution of lithium methoxide prepared from lithium(140 mg) and methanol (15 ml) at -78°C. The mixture was stirred at -78°C. for 30 minutes and treated with acetic acid(1.2 ml). The solution was poured into water and extracted with chloroform. The chloroform solution was washed with water, dried (Na2SO4) and evaporated to give a residue. The aqueous layer in the extraction of chloroform was again extracted with ethyl acetate. The extracts were washed with water, dried (Na2SO4) and the solvent was removed by distillation under reduced pressure to afford a residue. The residual fractions obtained above were combined and dissolved in a small amount of chloroform, to which was added excess hexane to precipitate the desired product. This precipitation process was repeated three times to give 200 mg of pure 7β-(2'-chloro-1'-methoxyethylidenimino)-7α-methoxy-3-(1-methyl-1H- tetrazole-5-yl)thiomethyl-3-cephem-4-carboxylic acid. NMR(CDCl3) δ ppm: 3.38 and 3.56(2H, AB-quartet, J=19 Hz), 3.46(3H, singlet), 3.78(3H, singlet), 3.82(3H, singlet), 4.20 and 4.55(2H, AB-quartet, J=12 Hz), 4.47(2H, singlet), 5.07(1H, singlet).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:32]([C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]Br)#[N:33]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:37][C:36]2[CH:39]=[CH:40][CH:41]=[C:34]([C:32]#[N:33])[CH:35]=2)[C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:27]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1cccc(CBr)c1
Reactant: COC(=O)c1ccc(Oc2ccc(NC3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Product: COC(=O)c1ccc(Oc2ccc(N(Cc3cccc(C#N)c3)C3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Yield: 89.7 %

Procedure:
Using general procedure H, 4-[4-(4-methoxycarbonyl-phenoxy)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 96) (440 mg, 1.07 mmol) and 3-cyanobenzyl bromide (314 mg, 1.6 mmol) afforded 4-{(3-cyano-benzyl)-[4-(4-methoxycarbonyl-phenoxy)-phenyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester as a white solid (520 mg, 90%).