Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[CH:10]([OH:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].O>ClCCl.O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:29][S:30]([O:18][CH:10]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:19])(=[O:32])=[O:31]
Reactant: O=C(Nc1ccc(Br)cc1)C(O)Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OC(Cc1ccccc1)C(=O)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of N-(4-bromophenyl)-2-hydroxy-3-phenylpropanamide (1.5 g) in dichloromethane (60 mL) and tetrahydrofuran (30 mL) were added diisopropylethylamine (908 mg) and 4-dimethylaminopyridine (114 mg), followed by dropwise addition of methanesulfonyl chloride (805 mg) at 5° C. and the mixture was stirred at ambient temperature for 20 hours. The mixture was poured into water and concentrated in vacuo. The residue was extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, and evaporated in vacuo to afford crude 1-benzyl-2-[(4-bromophenyl)amino]-2-oxoethyl methanesulfonate. The crude methanesulfonate was dissolved in N,N-dimethylformamide (30 mL) and 4-piperidinol (1.19 g) was added. The mixture was stirred at 80° C. for 5 hours and poured into water. The mixture was extracted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate to afford N-(4-bromophenyl)-2-(4-hydroxypiperidin-1-yl)-3-phenylpropanamide (894 mg) as a powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:17][NH:18][C:19]3[N:24]=[C:23]([N:25]4[CH2:30][CH2:29][C:28](C)([OH:31])[CH2:27]C4)[CH:22]=[CH:21][N:20]=3)=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.ClC1C=CC2N(C(CNC3N=CC=CN=3)=C(C3C=CC([F:49])=CC=3)N=2)C=1.N1CCC(O)C1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:17][NH:18][C:19]3[N:24]=[C:23]([N:25]4[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27]4)[CH:22]=[CH:21][N:20]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:49])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: CC1(O)CCN(c2ccnc(NCc3c(-c4ccccc4)nc4ccc(Cl)cn34)n2)CC1
Reactant: Fc1ccc(-c2nc3ccc(Cl)cn3c2CNc2ncccn2)cc1
Agent: OC1CCNC1
Product: OC1CCN(c2ccnc(NCc3c(-c4ccc(F)cc4)nc4ccc(Cl)cn34)n2)C1

Procedure:
The title compound was prepared in the same fashion as that described for compound 187 from N-((6-chloro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2-amine and pyrrolidin-3-ol. 1H-NMR (CDCl3, 400 MHz, δ) 8.72 (d, J=11.6 Hz, 1H), 8.32 (s, 1H), 7.78 (dd, J=5.7, 8.3 Hz, 2H), 7.66 (s, 1H), 7.61 (d, J=9.6 Hz, 2H), 7.41 (d, J=9.6 Hz, 1H), 7.26 (t, J=8.7 Hz, 2H), 6.13 (dd, J=6.3, 21.2 Hz, 1H), 5.10 (s, 2H), 4.88 (, 1H), 4.48 (d, J=36.5 Hz, 1H), 3.60 (m, 1H), 3.52 (m, 1H), 3.42 (m, 1H), 2.42 (m, 2H) ppm; m/e 439 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[CH:4][N:3]=1.[CH3:20][C@:21]12[C:27]([CH3:29])([CH3:28])[C@H:24]([CH2:25][CH2:26]1)[CH2:23][C@@H:22]2[NH2:30].O1CCOCC1>O>[N:14]1([C:12]([C:5]2[C:6]([C:8]([F:11])([F:10])[F:9])=[N:7][C:2]([NH:30][C@H:22]3[CH2:23][C@@H:24]4[C:27]([CH3:29])([CH3:28])[C@@:21]3([CH3:20])[CH2:26][CH2:25]4)=[N:3][CH:4]=2)=[O:13])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: O=C(c1cnc(Cl)nc1C(F)(F)F)N1CCOCC1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)[C@@H](N)C2
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)[C@@H]2CC[C@@]1(C)[C@@H](Nc1ncc(C(=O)N3CCOCC3)c(C(F)(F)F)n1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.2 %

Procedure:
A mixture of 4-{[2-chloro-4-(trifluoromethyl)pyrimidin-5-yl]carbonyl}morpholine (100 mg), (1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-amine (207 mg), and 1,4-dioxane (2 mL) was stirred at room temperature for 3 hours. To the reaction mixture was added water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate), and the obtained colorless oily substance was solidified from hexane-ethyl acetate to obtain 5-(morpholin-4-ylcarbonyl)-4-(trifluoromethyl)-N-[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]pyrimidin-2-amine (98 mg) as a white solid.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1.[CH2:17]([NH2:20])[CH:18]=[CH2:19]>CCO>[CH3:16][S:13]([C:10]1[CH:11]=[CH:12][C:6]2[CH2:5][O:4][CH:3]([CH2:2][NH:20][CH2:17][CH:18]=[CH2:19])[O:8][C:7]=2[CH:9]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc2c(c1)OC(CBr)OC2
Reactant: C=CCN
Solvent: CCO
Product: C=CCNCC1OCc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 22 using 2-(bromomethyl)-7-(methylsulfonyl)-4H-1,3-benzodioxine (30 mg, 0.10 mmol), prop-2-en-1-amine (0.50 ml, 6.7 mmol) and EtOH (1.0 ml). MS m/z (rel. intensity, 70 eV) 283 (M+, 1), 123 (6), 77 (7), 71 (5), 70 (bp).
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][CH:12]([CH2:15]Cl)[C:13]#[N:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:8]1[C:13](=[NH:14])[C:12](=[CH2:15])[NH:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC(CCl)NC(=O)NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C1NC(=O)N(Cc2ccccc2)C1=N

Procedure:
A solution of 4.75 g. (20 mmol) 2-(benzylaminocarbonylamino)-3-chloropropionitrile and 6 ml. triethylamine in 50 ml. dry tetrahydrofuran is heated to reflux for 5 hours. Subsequently, the precipitate formed is filtered off, the filtrate is evaporated to dryness and the residue is chromatographed on silica gel (elution agent: ethyl acetate) to give 2.5 g. (62.2% of theory) of the title compound; m.p. 139°-141° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C:12]([C:13]3[CH2:14][CH2:15][CH:16]4[C@:21]([C:23]=3[CH2:24][CH2:25]2)([CH3:22])[CH2:20][CH2:19][C@H:18](O)[CH2:17]4)=[CH:11][CH2:10]1)[CH3:8])[CH3:3].C(N(S(F)(F)F)CC)C.O>C(Cl)Cl>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C:12]([C:13]3[CH2:14][CH2:15][CH:16]4[C@:21]([C:23]=3[CH2:24][CH2:25]2)([CH3:22])[CH2:20][CH:19]=[CH:18][CH2:17]4)=[CH:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)CC1CC3
Agent: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(C)CCC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC=CCC1CC3
Temperature: -78 °C

Procedure:
The title compound was prepared by using a method analogous to a method described in J Chemical Research (miniprint) (1979) 4714-4755. Cholesta-8,14-diene-3β-ol (1.17 g, 3 mmol) was dissolved in 10 ml of methylenechloride and cooled to −78° C. Over 10 min a solution of diethylaminosulfur trifluoride (1.4 g, 8,7 mmol) in 10 ml of methylenechloride was added at −78° C. The mixture was stirred and was then slowly heated to the room temperature. The reaction mixture was added 15 ml water while stirring was continued. The organic phase was separated and washed with 30 ml of 5% NaHCO3 and then with water. The organic phase was dried with MgSO4 and evaporated to dryness. The residue was purified by column chromatography using heptane for a first fraction A giving cholesta-2,8,14-triene, 0.23 g. Melting point: 104.7° C. Elementary analysis: Cal C: 88.45; H: 11.55. Found C: 88.58; H: 11.89. NMR: Hd: 5.64 (m 2H; C2—H; C3—H)d 5.35 (s,1H C 15H). Cd: 125.95 (C3), 125.67 (C2).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16]C)[CH:11]=2)=[O:9])=[CH:4][C:3]=1[F:18].[Al+3].[Cl-].[Cl-].[Cl-].Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)=[O:9])=[CH:4][C:3]=1[F:18]
Reactant: COc1cccc(C(=O)c2ccc(Br)c(F)c2)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C(c1cccc(O)c1)c1ccc(Br)c(F)c1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
The demethylation procedure described for 2 was employed. To a stirred solution of (4-bromo-3-fluorophenyl)[3-(methyloxy)phenyl]methanone (1.0 g, 2.5 mol) in toluene (50 mL) was slowly added AlCl3 (1.3 g, 9.7 mol) via a powder addition funnel under a nitrogen atmosphere at room temperature. The stirred reaction mixture was heated at reflux for 3 h. The reaction mixture was allowed to cool to room temperature and then poured into 10% aqueous HCl (200 mL). Standard work-up yielded 0.935 g (100%) of the title compound 196 as a tan solid. 1H NMR (300 MHz, CDCl3): δ 7.71 and 7.68 (dd, J1=6.6 Hz, J2=6.6 Hz, 1H), 7.60 and 7.57 (dd, J1=8.7 Hz, J2=1.5 Hz, 1H), 7.50 and 7.47 (dd, J1=8.1 Hz, J2=1.2 Hz, 1H), 7.41-7.31 (m 3H), 7.15 and 7.13 (dd, J1=7.8 Hz, J2=1.8 Hz, 1H), 5.93(s, 1H).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:9](=[N:22][C:23]1[CH:24]=[C:25]([OH:30])[CH:26]=[CH:27][C:28]=1[CH3:29])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.I[C:32]1[CH:40]=[C:39]2[C:35]([C:36](/[CH:49]=[CH:50]/[C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[N:37][N:38]2[CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])=[CH:34][CH:33]=1.C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C>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].CC1C=CC=CC=1C>[C:9](=[N:22][C:23]1[CH:24]=[C:25]([O:30][C:32]2[CH:40]=[C:39]3[C:35]([C:36](/[CH:49]=[CH:50]/[C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)=[N:37][N:38]3[CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:46])([CH3:47])[CH3:48])=[CH:34][CH:33]=2)[CH:26]=[CH:27][C:28]=1[CH3:29])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C[Si](C)(C)CCOCn1nc(/C=C/c2ccccc2)c2ccc(I)cc21
Reactant: Cc1ccc(O)cc1N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1C
Product: Cc1ccc(Oc2ccc3c(/C=C/c4ccccc4)nn(COCC[Si](C)(C)C)c3c2)cc1N=C(c1ccccc1)c1ccccc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 146.4 %

Procedure:
A round bottom flask was charged with potassium phosphate (5.5 g, 26.0 mmol, 2.0 eq), 3-(benzhydrylidene-amino)-4-methyl-phenol (3.9 g, 13.6 mmol, 1.1 eq), 6-iodo-3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole (6.2 g, 13.0 mmol, 1.0 eq) and o-xylene (130 mL). The resultant slurry was degassed, purged with argon and treated with a mixture of tris(dibenzylideneacetone)dipalladium(0) (916 mg, 1.1 mmol, 8 mol %) and biphenyl-2-yl-di-tert-butyl-phosphane (656 mg, 2.2 mmol, 16 mol %). The flask was immersed in an oil bath and stirred at 100° C. for 18 hours. The black slurry was cooled to room temperature, filtered through celite and concentrated. The black oil was dissolved in chloroform, washed with water, brine, dried over magnesium sulfate, filtered and concentrated to give a black oil (12.1 g). The crude product was purified by flash chromatography on silica gel using 10–15% ether-cyclohexane as the eluant to give_benzhydrylidene-{2-methyl-5-[3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-6-yloxy]-phenyl}-amine as a yellow foam from ether (1.4 g, 16%): HPLC Rt=24.3 min.; TLC Rf=0.5 (20% ether-cyclohexane); 1H NMR (300 MHz, DMSO-d6) δ 8.10 (d, 1H, J=8.8 Hz), 7.75–7.66 (m, 4H), 7.53–7.31 (m, 11H), 7.14–7.08 (m, 4H), 6.62 (dd, 1H, J=8.8, 2.0 Hz), 6.55 (dd, 1H, J=8.2, 2.5 Hz), 6.20 (d, 1H, J=2.4 Hz), 5.64 (s, 2H), 3.51 (t, 2H, J=7.8 Hz), 2.12 (s, 3H), 0.78 (t, 2H, J=7.7 Hz), −0.14 (s, 9H).
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].O[CH2:20][C:21](=[O:23])[CH3:22].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[O:23]=[C:21]([CH3:22])[CH2:20][O:4][C:3]([C@@H:2]1[CH2:6][CH2:7][CH2:8][N:1]1[C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])=[O:5]
Reactant: CC(=O)CO
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)COC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
To a solution of 2.0 g Z-Pro-OH n 20 ml dichloromethane were added 0.58 ml hydroxyl-acetone and 10 mg DMAP. The solution was cooled to 0° C. and a solution of 1.7 g DCC in 20 ml dichloromethane was added dropwise. The suspension was allowed to warm to RT for 16 h before being filtered over a short plug of Celite. The reaction mixture was washed with dichloro-methane and the combined wash solutions evaporated. The residue thus obtained was purified by chromatography on silica using heptane/ethyl acetate 1:1 as eluent.
Reaction SMILES: ClC(OC)=O.C(N(CC)CC)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=2[C:29]([OH:31])=[O:30])=O)=[C:16]([F:32])[CH:15]=1>C(Cl)Cl>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]2[C:23]3[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=3[C:29](=[O:31])[O:30]2)=[C:16]([F:32])[CH:15]=1
Reactant: O=C(O)C1=C(C(=O)Nc2ccc(Cl)cc2F)CCCC1
Agent: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1OC(=Nc2ccc(Cl)cc2F)C2=C1CCCC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.59 Parts of methyl chloroformate was added dropwise during 15 minutes to a stirred solution of 1.87 parts of triethylamine and 5 parts of 2-(4-chloro-2-fluorophenylaminocarbonyl)-1-cyclohexene-1-carboxylic acid in 200 parts of methylene chloride cooled to 0° C. The reaction mixture was allowed to come to ambient temperature during 1 hour after which it was washed successively with 100 parts of water (twice) and 100 parts of a saturated aqueous sodium chloride solution. After drying with anhydrous sodium sulfate, the solution was evaporated under reduced pressure of 300 mm. Hg at 25° C to 5.6 parts of a yellow semisolid. Analysis of the semisolid by high pressure liquid chromatography indicates the presence of 3-(4-chloro-2-fluorophenylimino)-4,5,6,7-tetrahydro-1-(3H)-isobenzofuranone in 51% concentration.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([C:13]([N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][CH2:17][CH2:16]2)=O)[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].N>O1CCCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH2:13][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(C(=O)N2CCCCc3ccccc32)cc1OC
Agent: N
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN2CCCCc3ccccc32)cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 76 %

Procedure:
To an ice-bath-cooled solution of methyl 2-methoxy-4-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonylbenzoate (350 mg) in tetrahydrofuran (15 ml) was added dropwise a 1M solution of borane-tetrahydrofuran complex (3.1 ml), and the mixture was stirred at room temperature for 6 hours. After quenching the reaction with 1N hydrochloric acid (10 ml), the mixture was adjusted to pH 8-9 with concentrated ammonia solution and extracted with chloroform. The solution was washed with brine. The organic layer was dried over magnesium sulfate and the solvent was evaporated in vacuo. The crude product was purified by silica gel column chromatography (10% ethyl acetate in hexane) to give methyl 2-methoxy-4-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)methylbenzoate (255 mg).
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1.[F-:25].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)C>O1CCCC1.C(Cl)Cl>[F:25][CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CBr)c3c2)c1=O
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CF)c3c2)c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 3-[3-(bromomethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (1.00 g, 0.00240 mol), 14.4 mL of a 1 M tetrabutylammonium fluoride in tetrahydrofuran solution (0.0144 mol) and anhydrous p-toluenesulfonic acid (1.36 g, 0.00790 mol) in tetrahydrofuran is stirred at room temperature for 30 minutes, refluxed for three hours, stirred at room temperature for three days, refluxed for 22 hours, partially concentrated in vacuo, and diluted with ethyl acetate. The resultant mixture is washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain an orange solid. Column chromatography of the solid using silica gel and a 2.5% diethyl ether in methylene chloride solution gives the title product as a white solid (0.42 g, mp 201-202° C.).
Reaction SMILES: O.O.O.C([O-])(=O)C.[Na+:8].CC(C)=O.[CH3:13][C:14]([O:16][CH2:17][C:18]1[CH2:39][S:38][C@@H:21]2[C@H:22]([NH:25][C:26](/[C:28](/[C:32]3[N:36]=[C:35]([NH2:37])[S:34][CH:33]=3)=[N:29]\[O:30][CH3:31])=[O:27])[C:23](=[O:24])[N:20]2[C:19]=1[C:40]([OH:42])=[O:41])=[O:15]>O>[CH3:13][C:14]([O:16][CH2:17][C:18]1[CH2:39][S:38][C@@H:21]2[C@H:22]([NH:25][C:26](/[C:28](/[C:32]3[N:36]=[C:35]([NH2:37])[S:34][CH:33]=3)=[N:29]\[O:30][CH3:31])=[O:27])[C:23](=[O:24])[N:20]2[C:19]=1[C:40]([O-:42])=[O:41])=[O:15].[Na+:8]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Reaction time: 1 h

Procedure:
6 g of sodium acetate trihydrate are dissolved in 20 ml of water. 40 ml of acetone and 20 g of cefotaxime in free acid form are added to the stirred solution. The mixture is cooled to 0°. A solution is obtained within 2 to 5 minutes. The solution is filtered through a filter bed and subsequently through a sterile filter. The filters are washed with a chilled mixture of 3 ml of water and 15 ml of acetone. The filtrate is seeded with 0.2 g of seed crystals (Claforan®) and warmed to 20°. The mixture is stirred for 60 minutes. The sodium salt of cefotaxime partially crystallises. In order to compete crystallisation, 300 ml of acetone are added dropwise within 3 hours, and stirring is effected for a further 30 minutes at 20°. The sodium salt of cefotaxime is separated off by filtration, washed with acetone and dried overnight in a vacuum drying chamber at 40° and for 1.5 hours in a stream of dry nitrogen gas at 70°. Crystalline sodium cefotaxime substantially in form of needles is obtained.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.[O:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1>C1COCC1>[CH3:2][O:3][CH:4]=[C:32]1[CH2:33][CH2:34][O:29][CH2:30][CH2:31]1
Reactant: O=C1CCOCC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC=C1CCOCC1
Temperature: 25 °C
Yield: 35.2 %

Procedure:
To a stirred suspension of (methoxymethyl)triphenyl-phosphonium chloride (24.82 g, 72.41 mmol) in THF (250 mL) cooled in an ice-water bath was added n-BuLi (24.76 mL or 2.42 M solution in hexane, 59.93 mmol). The reaction mixture was allowed to warm to room temperature for 1 h and then recooled in an ice-water bath and a solution of tetrahydro-4H-pyran-4-one (5.00 g, 49.94 mmol) in THF (10 mL) added. After 20 min the reaction mixture was concentrated to an oily reside, the residue was triturated with Et2O (150 mL), and the supernatant was decanted. This process was repeated (6×75 mL), and the combined supernatants were concentrated to give crude title compound (7.3 g) as an orange oil. Flash chromatography (10×18 cm) eluting with a gradient (5-10%) of EtOAc/hexane gave the title compound (2.25 g, 35%) as a volatile, colorless oil. TLC: Rf 0.13 (5:95 EtOAc:hexane). 1H NMR: δ5.85 (s, 1H, vinyl), 3.69-3.61 (m, 4H, CH2OCH2), 3.56 (s, 3H, OCH3), 2.32 and 2.06 (pr t, 4H, 2×CH2).
Reaction SMILES: [F:1][C:2]1[C:10]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:20])=O>>[F:1][C:2]1[C:10]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:20])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: CCCS(=O)(=O)Nc1cccc(C(=O)O)c1F
Product: CCCS(=O)(=O)Nc1cccc(C(=O)Cl)c1F

Procedure:
To 2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid (50, 1.17 g, 4.5 mmol) was added thionyl chloride (10.0 mL). The reaction was heated to reflux for 3 hours. The reaction was concentrated to give crude compound 51 that was used in the next step.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:20][C:19]=3[CH3:33])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[H][H]>[Pd].CO.CCOC(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])=[CH:20][C:19]=3[CH3:33])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: [H][H]
Reactant: Cc1cc(C=CC(=O)OC(C)(C)C)ccc1-c1nsc(-c2ccc(OC(C)C)c(C#N)c2)n1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(CCC(=O)OC(C)(C)C)ccc1-c1nsc(-c2ccc(OC(C)C)c(C#N)c2)n1

Procedure:
A mixture of 120 mg (0.26 mmol) of tert-butyl 3-(4-(5-(3-cyano-4-isopropyloxyphenyl)-1,2,4-thiadiazol-3-yl)-3-methylphenyl)-2-propenoate (from Step C) and 41 mg of palladium on activated carbon (10% w/w; 0.025 mmol) in 15 mL of methanol/EtOAc (1/1) was hydrogenated under atmospheric pressure of hydrogen for 2 h. The heterogeneous mixture was filtered through a disposable frit to remove palladium and the filtrate was concentrated. The crude product was found to be pure by ESI-MS and 1H NMR analyses and used in subsequent step without purification: 1H NMR (500 MHZ, CDCl3) δ 1.46 (s, 9H), 1.49 (d, J=6.5, 6H), 2.61 (t, J=7.5, 2H), 2.65 (s, 3H), 2.97 (t, J=7.5, 2H), 4.79 (sep, J=6.5, 1H), 7.11 (d, J=9.0, 1H), 7.18 (d, J=9.0, 1H), 7.23 (s, 1H), 7.69 (d, J=8.0, 1H), 8.18 (d, J=2.0, 1H), 8.24 (dd, J=8.0, 2.0, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:11]N(C)C)=[CH:5][NH:6]2.[OH-].[Na+].C(O)(=O)C.[N+:21]([CH:24]([CH3:26])[CH3:25])([O-:23])=[O:22]>C(OCC)(=O)C.[Cl-].[Na+].O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:11][C:24]([CH3:26])([N+:21]([O-:23])=[O:22])[CH3:25])=[CH:5][NH:6]2
Reactant: CC(C)[N+](=O)[O-]
Reactant: CN(C)Cc1c[nH]c2cccc(F)c12
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(Cc1c[nH]c2cccc(F)c12)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
A slurry of 4-fluoro-3-(dimethylaminomethyl)-1H-indole (4.3 g, 22.4 mmol) in 14.1 ml of 2-nitropropane is treated with solid NaOH (941 mg, 23.5 mmol), and the resulting mixture is heated at reflux overnight. After cooling to ambient temperature, the reaction mixture is acidified with 10% aqueous acetic acid (25 ml) and stirring is continued for 30 minutes. The reaction mixture is diluted with ethyl acetate (50 ml) and brine (50 ml). The layers are separated, and the organic layer is washed with brine (50 ml), dried over Na2SO4 and concentrated in vacuo to give 3.71 g of 4-fluoro-3-(2-methyl-2-nitropropyl)-1H-indole (76%).