Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@:20]([O:52][CH3:53])([NH:21][C:22](=[O:51])[C:23](=[N:30][O:31]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:19](=[O:54])[N:10]2[C:11]=1[C:12]([O:14]C(C)(C)C)=[O:13])(=[O:3])[CH3:2].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@@:20]([NH:21][C:22](=[O:51])[C:23](=[N:30][OH:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([O:52][CH3:53])[C:19](=[O:54])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CO[C@@]1(NC(=O)C(=NOC(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccccc2)C(=O)N2C(C(=O)OC(C)(C)C)=C(COC(C)=O)CS[C@@H]21
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CO[C@@]1(NC(=O)C(=NO)c2ccccc2)C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@@H]21

Procedure:
t-Butyl (6R,7S)-3-acetoxymethyl-7-methoxy-7-[2-triphenylmethoxyimino-2-phenylacetamido]-ceph-3-em-4-carboxylate (syn isomer) (400 mg, 0.535 mmole) was treated with anisole (2 ml) and trifluoroacetic acid (8 ml) as described in Example 1(b) to give (6R,7S)-3-acetoxymethyl-7-[2-hydroxyimino-2-phenylacetamido]-7-methoxyceph-3-em-4-carboxylic acid (syn isomer) as an electrostatic white solid. (135 mg, 0.30 mmole). This acid was converted into the title compound by dissolving it in water containing sodium bicarbonate (25 mg, 0.298 mmole), filtering the solution and freeze-drying the filtrate to give the product as an amorphous solid (120 mg, 0.255 mmole, 51%), paper chromatography Rf 0.40 Rf/Rf cephaloram 0.78, λmax (pH6 buffer) 254 nm (ε 10,400).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:22]=[C:23]([NH:31][C:32](=[O:46])/[CH:33]=[CH:34]/[C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][C:36]=2[Cl:45])[CH:24]=[CH:25][C:26]=1[CH2:27][CH2:28][CH2:29]O.[Br:47]C(Br)(Br)Br>ClCCl>[Br:47][CH2:29][CH2:28][CH2:27][C:26]1[CH:25]=[CH:24][C:23]([NH:31][C:32](=[O:46])/[CH:33]=[CH:34]/[C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][C:36]=2[Cl:45])=[CH:22][C:21]=1[Cl:20]
Reactant: BrC(Br)(Br)Br
Reactant: O=C(/C=C/c1ccc(C(F)(F)F)cc1Cl)Nc1ccc(CCCO)c(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(C(F)(F)F)cc1Cl)Nc1ccc(CCCBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
0.577 g (2.200 mmol) triphenylphosphine was added batchwise to a suspension of 0.836 g (2.000 mmol) (E)-N-[3-chloro-4-(3-hydroxy-propyl)-phenyl]-3-(2-chloro-4-trifluoromethyl-phenyl)-acrylamide and 0.730 g (2.200 mmol) tetrabromomethane in 10 mL dichloromethane and the mixture was stirred for 48 h at RT. The reaction mixture was purified by column chromatography (silica gel, dichloromethane) and the residue was triturated with petroleum ether.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.CC(C)=O.C(=O)=O.[Li]CCCC.[N:26]1([C:32]([CH:34]2[CH2:37][C:36](=[O:38])[CH2:35]2)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C1COCC1>[OH:38][C:36]1([C:2]2[CH:13]=[CH:12][C:5]([CH2:6][N:7]3[CH2:11][CH2:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=2)[CH2:37][CH:34]([C:32]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:33])[CH2:35]1
Reactant: O=C1CC(C(=O)N2CCOCC2)C1
Reactant: Brc1ccc(CN2CCCC2)cc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: O=C(C1CC(O)(c2ccc(CN3CCCC3)cc2)C1)N1CCOCC1
Yield: 20.4 %

Procedure:
To a stirring solution of 1-(4-bromo-benzyl)-pyrrolidine (1.6 g, 6.5 mmol) in THF (20 mL) at −78° C. (acetone/dry ice bath) was added slowly down the side of the flask a solution of nBuLi (2.6 mL, 6.5 mmol, 2.5 M THF). After 15 minutes a solution of Intermediate 7, 3-(morpholin-4-ylcarbonyl)cyclobutanone (1.0 g, 5.4 mmol, in 7 mL of THF) precooled to −78° C. was added slowly. After 30 minutes the reaction was quenched cold with 1N HCl (20 mL). This mixture was diluted with EtOAc and then the layers were separated and the organic layer was discarded. The aqueous layer was basified with 1N NaOH and extracted with CHCl3/iPrOH (3:1). The organic layer was dried over MgSO4, filtered and concentrated to give a yellow oil. This material was purified by flash column chromatography using a 40 g ISCO™ column, eluting with a gradient of 3%, 5%, 10%, 20%, 30%/0 MeOH/CHCl3 with 0.1% NH4OH. The product containing fraction were collected and concentrated under reduced pressure to give the title compound (379 mg, 20% yield): Rf=0.3 (30% MeOH/CH2Cl2); LRMS m/z Calcd for C20H28N2O3, 344.4, found, 345 (M+1) APCI; 400 MHz 1H NMR (CDCl3) δ 7.42 (d, J=8.3 Hz, 2H), 7.29 (d, J=8.3 Hz, 2H), 4.58 (brs, 1H), 3.62-3.55 (m, 8H), 3.34-3.32 (m, 2H), 2.87 (dddd, J=8.3, 8.3, 8.3, 8.3 Hz, 1H), 2.77-2.71 (m, 2H), 2.64-2.59 (m, 2H), 2.48-2.45 (m, 4H), 1.75-1.70 (m, 4H); 100 MHz 13C NMR (CDCl3) δ 173.8, 144.4, 137.8, 129.3, 125.3, 72.9, 67.0, 66.9, 60.3, 54.2, 46.0, 42.6, 40.9, 28.1, 23.5.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:18]3=[N:19][C:20]4[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([CH:27]([O:32][CH:33]([F:35])[F:34])[C:28]([F:31])([F:30])[F:29])[C:21]=4[N:17]3[CH2:16][CH2:15][CH2:14]2)=[C:9]([CH3:36])[N:8]=1)(=O)=O.[NH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>CN(C)C=O.O>[Cl:26][C:25]1[C:20]2[N:19]=[C:18]3[N:13]([C:10]4[C:9]([CH3:36])=[N:8][C:7]([N:39]5[CH2:43][CH2:42][CH2:41][CH2:40]5)=[CH:12][CH:11]=4)[CH2:14][CH2:15][CH2:16][N:17]3[C:21]=2[C:22]([CH:27]([O:32][CH:33]([F:35])[F:34])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:24]=1
Reactant: Cc1nc(OS(=O)(=O)C(F)(F)F)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Reactant: C1CCNC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(N2CCCC2)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 87980.8 %

Procedure:
To a solution of 5-{9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-3,4-dihydropyrimido[1,2-a]benzimidazol-1(2H)-yl}-6-methylpyridin-2-yl trifluoromethanesulfonate (123.7 mg, 0.208 mmol) in N,N-dimethylformamide (2.5 mL) was added pyrrolidine (86.8 μL, 1.04 mmol). The reaction mixture was stirred at 80° C. for 2.5 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2) and brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-60% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from ethyl acetate/n-hexane to give a title compound as a colorless powder (94.6 mg, 0.183 mol, 88%).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[C:9]1([NH:15]N)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[CH2:6]1[C:1]2[NH:15][C:9]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:2]=2[C:3](=[O:7])[CH2:4][CH2:5]1
Reactant: NNc1ccccc1
Reactant: O=C1CCCC(=O)C1
Solvent: O
Product: O=C1CCCc2[nH]c3ccccc3c21
Yield: 91.5 %

Procedure:
To a solution of 1,3-cyclohexane dione (1.99 g, 17.7 mmol) in water (55 mL) is added phenylhydrazine (1.92 g, 17.7 mmol) in 10 mL of water. A gummy solid quickly formed, which after completion of the addition is scrapped with a spatula to give a solid. The solid is collected, washed with water, and dried in a vacuum oven to give 3.0 g of a tan solid. After drying, the tan solid is stirred at reflux in TFA (25 mL) overnight. Upon cooling, TFA is removed in vacuo and water is added to the residue. The resulting solid is collected, washed with water, and dried to give 1.82 g (55%) of the title compound; mp 218-220° C.; IR (drift) 3150, 3130, 3104, 3093, 3056, 2976, 2954, 2944, 1607, 1577, 1466, 1413, 1251, 1178, 755 cm−1; 1H NMR (CDCl3) δ2.26, 2.64, 3.00, 7.26, 7.35, 8.21, 8.74. Anal. Calcd for C12H11NO: C, 77.81; H, 5.99; N, 7.56. Found: C, 77.82; H, 6.15; N, 7.54.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)N)=[CH:4][CH:3]=1.CO[CH:21](OC)[CH2:22][CH2:23][CH2:24][NH:25][CH3:26]>>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:8]([CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:21]=[C:22]2[CH2:23][CH2:24][NH:25][CH3:26]
Reactant: CNCCCC(OC)OC
Reactant: NN(CCCc1ccccc1)c1ccc(Cl)cc1
Product: CNCCc1cn(CCCc2ccccc2)c2ccc(Cl)cc12

Procedure:
The title compound is prepared by General Method 10 using 1-(4-chlorophenyl)-1-(3-phenylpropyl)hydrazine (Example 9) and 4,4-dimethoxy-N-methylbutan-1-amine.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[F:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:31])=[C:25]([S:27](Cl)(=[O:29])=[O:28])[CH:26]=1>>[F:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:31])=[C:25]([S:27]([NH:15][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][O:7][C:6]3[CH:16]=[CH:17][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:4][CH:5]=3)[N:14]=2)(=[O:29])=[O:28])[CH:26]=1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Reactant: Nc1cccc(COc2ccc(C(F)(F)F)cc2)n1
Product: Cc1ccc(F)cc1S(=O)(=O)Nc1cccc(COc2ccc(C(F)(F)F)cc2)n1

Procedure:
This material was prepared in analogy to example 1 from 6-(4-trifluoromethyl-phenoxymethyl)-pyridin-2-ylamine (0.08 g) and 5-fluoro-2-methyl-benzenesulfonyl chloride (0.07 g) as a light yellow solid (0.1 g). MS (ESI−): 439.1 ([M−H]−)
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:13]1[N:14]=[N:15][CH:16]=[C:17]2[C:21]([CH3:22])=[C:20]([CH3:23])[N:19]([CH2:24][C@H:25]3[CH2:27][C@@H:26]3[CH3:28])[C:18]=12>O1CCCC1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][C:13]2[N:14]=[N:15][CH:16]=[C:17]3[C:21]([CH3:22])=[C:20]([CH3:23])[N:19]([CH2:24][C@H:25]4[CH2:27][C@@H:26]4[CH3:28])[C:18]=23)=[CH:4][CH:3]=1
Reactant: Cc1c(C)n(C[C@H]2C[C@@H]2C)c2c(Cl)nncc12
Reactant: OCc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(C)n(C[C@H]2C[C@@H]2C)c2c(OCc3ccc(F)cc3)nncc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
A solution of p-fluorobenzyl alcohol (1.45 g, 11.5 mmol) in tetrahydrofuran (2 ml) was added dropwise to a solution of sodium hydride (0.26 g, 10.8 mmol) in tetrahydrofuran (6 ml) and the mixture was stirred at room temperature for 30 minutes. A solution of 7-chloro-2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]pyridazine (2.50 g, 10.0 mmol) in tetrahydrofuran (13 ml) was added dropwise to the reaction mixture at room temperature and the mixture was heated under reflux for 3 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated in vacuo. Hexane was added to the concentrated solution, and the precipitate was collected by filtration and then recrystallized from a mixture of ethyl acetate and hexane to afford the title compound (2.25 g, 66.4%) as pale brown crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-])=O)[N:8]=[CH:7][NH:6][C:5]2=[O:15].[NH4+].[Cl-]>CO.O.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH2:12])[N:8]=[CH:7][NH:6][C:5]2=[O:15]
Reactant: O=c1[nH]cnc2cc([N+](=O)[O-])c(Cl)cc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1cc2nc[nH]c(=O)c2cc1Cl
Temperature: 65 °C
Yield: 100.7 %

Procedure:
To a suspension of 6-chloro-7-nitroquinazoline-4-one (7.5 g, 33 mmol) in MeOH (250 mL) was added NH4Cl (17.7 g, 0.33 mol) dissolved in water (75 mL). Iron powder (18.5 g, 330 mmol) was added and the suspension was heated at 65° C. for 2 h. The warm reaction mixture was filtered over diatomaceous earth and washed several times with THF (1 L) and methanol (500 mL). The filtrate was concentrated, washed with water and dried under vacuum at 50° C. to afford the title compound (6.5 g, 90%) as a brown solid. ESI-MS m/z 196 [C8H6ClN3O+H]+.
Reaction SMILES: [O:1]([C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[CH:19]=[C:20]([C:22]4[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=4)[NH2:25])[O:21][C:14]=23)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:37](Cl)(=[O:40])[CH2:38][CH3:39]>O>[O:1]([C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[CH:19]=[C:20]([C:22]4[CH:23]=[C:24]([NH:25][C:37](=[O:40])[CH2:38][CH3:39])[CH:26]=[CH:27][CH:28]=4)[O:21][C:14]=23)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)Cl
Reactant: Nc1cccc(-c2cc3nccc(Oc4ccc(Oc5ccccc5)cc4)c3o2)c1
Solvent: c1ccncc1
Solvent: O
Product: CCC(=O)Nc1cccc(-c2cc3nccc(Oc4ccc(Oc5ccccc5)cc4)c3o2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 77.7 %

Procedure:
To a 20-mL glass vial was added 3-[7-(4-phenoxyphenoxy)furo[3,2-b]pyridin-2-yl]aniline (30.00 mg; 0.08 mmol) and pyridine (1.00 ml). The resulting mixture was cooled to 0° C. and stirred for 5 minutes. Then propanoyl chloride (0.01 ml; 0.08 mmol) was added. The ice bath was left to melt. The reaction mixture was stirred at room temperature overnight. Water was added to the mixture which was then extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude mixture was purified using Biotage column chromatography (50-100% EtOAc/Hexanes) to afford the title compound as a white solid (28.00 mg, 82%). HPLC (method F): 92%, RT=4.530 min. 1H NMR (DMSO-d6) δ [ppm] 7.52 (d, 1H), 7.45 (d, 1H), 6.85-6.80 (dd, 2H), 6.70-6.64 (q, 1H), 6.60-6.49 (m, 6H), 6.36-6.34 (m, 3H), 6.26 (d, 2H), 6.01 (d, 1H), 1.63 (q, 2H), 0.42 (t, 3H). MS: m/z=451 [M+H]+, RT=4.08 min.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]3[CH2:20][CH2:21][O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:18]=3[N:17]=[C:16]([NH2:29])[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:11]1([C:14]2[C:19]3[CH2:20][CH2:21][O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:18]=3[N:17]=[C:16]([NH2:29])[N:15]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N)nc3c2CCOc2ccccc2-3)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc2c(c(N3CCNCC3)n1)CCOc1ccccc1-2
Temperature: 60 °C

Procedure:
A solution of Example 30A (38 mg, 0.096 mmol) in CH2Cl2 (1 mL) was treated with TFA (2 mL), heated at 60° C. for 2 minutes, cooled, concentrated under reduced pressure and chromatographed on silica gel eluting with a gradient of 2, 3.5, 5 and 10% (9:1 MeOH: saturated aqueous NH4OH) in CH2Cl2 to provide the title compound. 1H NMR (CDCl3) δ 2.72 (t, J=5.93 Hz, 2H), 2.91-3.09 (m, 4H), 3.26-3.46 (m, 4H), 4.54 (t, J=5.93 Hz, 2H), 4.79 (s, 2H), 7.09 (dd, J=7.97, 1.19 Hz, 1H), 7.17-7.26 (m, 1H), 7.34-7.41 (m, 1H), 7.89 (dd, J=7.63, 1.86 Hz, 1H); MS (M+H)+ m/z 298.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)[NH:10][CH:11]=2)[CH:2]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>CN(C=O)C.C1COCC1>[CH3:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([S:32]([N:10]2[CH:11]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:8]=[C:9]2[C:12]2[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=2)(=[O:34])=[O:33])=[CH:30][CH:31]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(-c2cc(-c3cccnc3)c[nH]2)cc(OC)c1OC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)n2cc(-c3cccnc3)cc2-c2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred solution of 4-(3-pyridyl)-2-(3,4,5-trimethoxyphenyl)-pyrrole (155 mg, 0.5 mmol, Example 76a) in dry DMF or THF (1.5 ml) NaH dispersion (48 mg, 2 equiv.) and p-methoxyphenylsulfonyl chloride (103 mg, 0.5 mmol) is added under a stream of nitrogen at 4° C. The reaction mixture is subsequently stirred for 12-18 h at room temperature and extracted with saturated aqueous NaHCO3 solution and ethyl acetate. The organic layer is dried and purified by flash chromatography and preparative HPLC. RT (program 1) 3.79. MS: 480.7.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([CH3:21])([O:13][Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.Cl[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]([F:32])([F:31])[CH3:30])[N:24]=1>>[F:31][C:29]([C:25]1[N:26]=[C:27]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([CH3:21])([O:13][Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:12])=[N:10][C:5]3=[N:4][CH:3]=2)[CH:28]=[CH:23][N:24]=1)([F:32])[CH3:30]
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(Br)cnc2n1
Reactant: CC(F)(F)c1nccc(Cl)n1
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(C(C)(F)F)n3)cnc2n1

Procedure:
3-Bromo-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine (567 mg, 1.4 mmol) and 4-chloro-2-(1,1-difluoroethyl)pyrimidine (209 mg, 1.17 mmol) were reacted together as described in Example 39, Step 1. Purification by column chromatography on silica using 3% MeOH/CH2Cl2 gave 3-[2-(1,1-difluoroethyl)pyrimidin-4-yl]-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:10]([C:12]([O:14]C(OCC)C)=[O:13])[OH:11])=O)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].CS(Cl)(=O)=O.[CH2:43]1[CH2:47][O:46][CH2:45][CH2:44]1>CCCCCC.C(OCC)(=O)C>[C:1]([O:5][C:6]1[O:13][C:12](=[O:14])[CH:10]([O:11][CH:45]([O:46][CH2:47][CH3:43])[CH3:44])[C:9]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(C)OC(=O)C(O)C(NC(=O)OC(C)(C)C)(c1ccccc1)c1ccccc1
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(C)OC1C(=O)OC(OC(C)(C)C)=NC1(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
To a solution of 497 mg (1.16 mmol) of N-tertbutoxycarbonyl-O-(1-ethoxyethyl)-3,3-diphenylisoserine (3) in 20 mL of THF is added 261 mg (2.33 mmol) of solid potassium tert-butoxide and the mixture is stirred at 25° C. for 30 min. A solution of 134 mg (1.16 mmol) of methanesulfonyl chloride in 3.2 mL of THF is added and the mixture is stirred at 25° C. for 1.5 hour. The mixture is diluted with 80 mL of hexane and ethyl acetate, and this solution is extracted with 20 mL of saturated aqueous sodium bicarbonate solution and 10 mL of brine. The organic phase is dried over sodium sulfate and concentrated to give 243 mg (59%) of 2-tertbutoxy-4,4-diphenyl-5-(1-ethoxyethoxy)-4,5-dihydro-1,3-oxazin-6-one as a colorless oil. N-debenzoykl-N-tertbutoxycarbonyl-3'-phenyl taxol. To a small reaction vessel is added 90 mg (0.218 mmol) of 2-tertbutoxy-4,4-diphenyl-5-(1-ethoxyethoxy)-4,5-dihydro-1,3-oxazin-6-one, 40 mg (0.057 mmol) of 7-O-triethylsilyl baccatin III, 6.9 mg (0.057 mmol) of 4-dimethylamino pyridine (DMAP), and 0.029 mL of pyridine. The mixture is stirred at 25° C. for 12 hours and diluted with 100 mL of ethyl acetate. The ethyl acetate solution is extracted with 20 mL of 10% aqueous copper sulfate solution, dried over sodium sulfate and concentrated. The residue is filtered through a plug of silica gel eluted with ethyl acetate. Flash chromatography on silica gel eluted with ethyl acetate/hexane followed by recrystallization from ethyl acetate/hexane gives 44 mg (66%) of N-debenzoyl-N-tertbutoxycarbonyl-2 -(1-ethoxyethyl)3'-phenyl-7-O-triethylsilyl taxol as a ca 3:1 mixture of diastereomers
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:31])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=N)[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][CH2:5]2.C(O)(=[O:34])C.Cl.C(=O)(O)[O-].[Na+]>O>[OH:1][C:2]1[C:3]([CH3:31])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:34])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][CH2:5]2
Reactant: CC(=O)O
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc(CC3SC(=N)NC3=O)cc1)O2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Temperature: 25 °C

Procedure:
15.5 g of 5-[4-(6-hydroxy-2,5,7,8-tetramethyl chroman-2-yl-methoxy) benzyl]-2-iminothiazolidine-4-one, prepared by the process as described in Example-1, was added to a mixture of 225 ml of acetic acid, 75 ml of conc. hydrochloric acid and 40 ml of water and the mixture was refluxed for 12 hrs. The reaction mixture was cooled to room temperature and 66.2 g of sodium bicarbonate was added and once the evolution of carbondioxide had ceased, the solvent was distilled off applying high vacuum. A 10:1 by volume mixture of benzene and ethyl acetate was added to the residue and the crude product was washed with a mixture of equal volumes of a saturated aq. sodium bicarbonate solution & water. The organic layer was dried over anhydrous sodium sulphate and the solvent was distilled off. The resulting crude product was quickly eluted from a silica gel column with 50% ethylacetate-hexane to furnish 12.5 g of the required 5-{4-(6-hydroxy-2, 5, 7, 8-tetramethylchroman-2-yl-methoxy) benzyl) thiazolidine-2,4-dione (Troglitazone) with a HPLC purity of ~67-70%.
Reaction SMILES: [C:1]([O:4][C@@H:5]([C:7]1[N:12]=[C:11](OS(C)(=O)=O)[CH:10]=[CH:9][N:8]=1)[CH3:6])(=[O:3])[CH3:2].[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>O1CCCC1>[C:1]([O:4][C@@H:5]([C:7]1[N:12]=[C:11]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:10]=[CH:9][N:8]=1)[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)c1nccc(OS(C)(=O)=O)n1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: CC(=O)O[C@H](C)c1nccc(N2CCNCC2)n1
Yield: 88 %

Procedure:
A mixture of (R)-1-(4-methanesulfonyloxy-pyrimidin-2-yl)-ethyl acetate (prepared according to the method of Preparation Six, 24.1 g, 92 mmol) and piperazine (16.0 g, 184 mmol) in tetrahydrofuran (200 mL) was heated at reflux for 1 h. This mixture was cooled, filtered, concentrated, and purified by flash column chromatography (9:1 dichloromethane/methanol) to give 24.4 g (88%) of the title compound as an oil. 1H NMR (CDCl3, 300 MHz) δ 1.56 (d, 3H), 2.25 (s, 3H), 2.83 (m, 4H), 3.63 (m, 4H), 5.54 (q, 1H), 6.38 (d, 1H), 8.24 (d, 1H); MS (Cl) 251 (MH+).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]1([NH2:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>>[C:12]1([NH:22][C:4](=[O:5])[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:1]([OH:6])=[O:11])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1cccc2ccccc12
Product: O=C(O)c1ccccc1C(=O)Nc1cccc2ccccc12
Reaction time: 0.02 h
Yield: 96 %

Procedure:
To a 30 mm co-rotating twin screw extruder (Werner & Pfleiderer ZSK type) was added at barrel 1 (of 14) 2370 g (16 mol) per hour phthalic anhydride in the form of crushed pellets, and at barrel 2 molten 1-naphthylamine at a rate of 2234 g (15.62 mol) per hour while maintaining a temperature profile of: zone 1=75°, zone 2=83°, zone 3=95°, zone 4= 75° and zone 5=45° C. At a screw speed of 300 rpm, the residence time was about 60 seconds, resulting in a product containing N-1-naphthylphthalamic acid (4365 g, ca. 96% yield based on 1-naphthylamine).
Reaction SMILES: O[Li].O.O.[OH:5][C:6]1([C:18]([O:20]C)=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1>C1COCC1>[OH:5][C:6]1([C:18]([OH:20])=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C1(O)CCCc2ccc(OC)cc21
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)C(O)(C(=O)O)CCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
LiOH.H2O (0.41 g; 9.8 mmol) and water (4 mL) were added to a solution of 1-hydroxy-7-methoxytetralin-1-yl-carboxylic acid, methyl ester (1.16 g; 4.9 mmol; from step (i) above) in THF (10 mL). The reaction mixture was stirred at room temperature for 3 h, the THF was evaporated, and the water phase was washed with methylene chloride. The reaction mixture was acidified with HCl (2M) and some NaCl was added. After extraction with methylene chloride, the organic phase was dried and concentrated. Yield: 765 mg (70%).