Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[F:12].[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][N:35]=1.ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[F:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([F:12])[C:5]=1[C:4]1[N:30]=[C:29]([C:28]2[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[C:26]([O:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:42])([F:43])[F:41])=[CH:36][N:35]=3)[CH:27]=2)[N:2]([CH3:1])[N:3]=1
Reactant: COc1ccc(C#N)cc1Oc1ccc(C(F)(F)F)cn1
Reactant: CN(N=C(Cl)c1c(F)cccc1F)S(=O)(=O)c1ccccc1
Agent: Cl[Fe](Cl)Cl
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2nc(-c3c(F)cccc3F)nn2C)cc1Oc1ccc(C(F)(F)F)cn1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2,6-difluorobenzohydrazonoyl chloride (0.70 g), 4-methoxy-3-(5-trifluoromethylpyridine-2-yloxy)benzonitrile (0.80 g), anhydrous iron (III) chloride (0.50 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (100 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.30 g of desired compound.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=2)[N:9]=1)([OH:7])=[O:6].[C:20]1(C)C=CC=CC=1>CO.C(OCC)C.C(OCC)(=O)C>[CH3:19][O:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:5]([O:7][CH3:20])=[O:6])[CH:17]=[CH:16]2
Reactant: COc1ccc2nc(C(=O)O)ccc2c1
Reactant: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc2cc(OC)ccc2n1
Reaction time: 0.5 h

Procedure:
230 ml (3.17 mol) of thionyl chloride are run dropwise onto a suspension of 129 g (0.635 mol) of 2-carboxy-6-methoxyquinoline in 1200 ml of toluene, and the mixture is heated for 3 h 30 min. After concentrating the solution under reduced pressure, the solid obtained is dissolved in 300 ml of methanol. The mixture is stirred for 30 min, the solvent is then evaporated off under reduced pressure, and the product obtained is taken up in diethyl ether and isolated by filtration. The solid obtained is taken up in ethyl acetate and dilute aqueous ammonia, and the organic phase is then separated out, treated with animal black, filtered and concentrated under reduced pressure. 90 g of product are thus obtained.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([C@H:28]([CH3:32])[C:29]([OH:31])=[O:30])[CH:22]=[CH:21]2.[N+:33]([C:36]([CH3:41])([CH2:39]O)[CH2:37][OH:38])([O-:35])=[O:34]>C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([C@H:28]([CH3:32])[C:29]([O:31][CH2:39][C:36]([CH3:41])([N+:33]([O-:35])=[O:34])[CH2:37][OH:38])=[O:30])[CH:22]=[CH:21]2
Reactant: CC(CO)(CO)[N+](=O)[O-]
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc2cc([C@H](C)C(=O)OCC(C)(CO)[N+](=O)[O-])ccc2c1

Procedure:
A solution of 1,3-dicyclohexylcarbodiimide (4.23 g, 20.5 mmol), (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 4.34 g, 18.9 mmol), and 2-nitro-2-methyl-1,3-propanediol (2.56 g, 19.0 mmol) in CH2Cl2 (50 mL) and TEF (50 mL) was stirred at ambient temperature overnight. The solvent was evaporated and EtOAc (100 mL) was added to the resulting crude material, cooled in a dry-ice bath and the byproduct, dicyclohexyl urea was removed by filtration. The product was separated by silica gel column chromatography eluting with ethyl acetate/hexane (1:3, Rf=0.1) to give the title compound (a mixture of diasteromers) as an oil (2.77 g, 42% yield). 1H NMR (300 MHz, CDCl3) δ 7.69–7.60 (m, 3H), 7.34–7.3 (m, 1H), 7.14–7.08 (m, 2H), 4.44 (d, J=4.2 Hz, 2H), 3.86 (s, 3H), 3.85 (q, J=7.2 Hz, 1H), 3.7 (m, 1H), 1.55 (d, J=7.2 Hz, 3H), 1.36 & 1.40 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 174.14, 174.02, 157.57, 134.53, 134.51, 133.64, 129.13, 128.7, 127.17, 125.87, 125.84, 119.0, 105.47, 89.53, 89.42, 64.67, 64.52, 64.19, 55.12, 45.04, 18.25, 18.03, 17.82, 17.79. Mass spectrum (API-TIS) m/z 348 (MH)+.
Reaction SMILES: [O:1]([C:8]1[C:17]2[N:18]=[CH:19][N:20]([CH2:21][CH2:22][OH:23])[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31]Cl>>[O:1]([C:8]1[C:17]2[N:18]=[CH:19][N:20]([CH2:21][CH2:22][O:23][CH2:31][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=3)[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCn1cnc2c(Oc3ccccc3)nc3ccccc3c21
Reactant: ClCc1ccccn1
Agent: Cl
Product: c1ccc(Oc2nc3ccccc3c3c2ncn3CCOCc2ccccn2)cc1
Yield: 55.6 %

Procedure:
Using the general method of Example 13 Part F, 2-(4-phenoxy-1H-imidazo[4,5-c]quinolin-1-yl)ethanol (0.9 g, 2.95 mmol) was reacted with 2-picolyl chloride hydrogen chloride (0.53 g, 3.24 mmol) and the product purified to provide 0.65 g of 4-phenoxy-1-[2-(pyridin-2-ylmethoxy)ethyl]-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [O-][Mn](=O)(=O)=O.[K+].[N:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH2:16][OH:17].C([O-])([O-])=[O:19].[Na+].[Na+]>O>[N:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[C:16]([OH:19])=[O:17]
Reactant: O=C([O-])[O-]
Reactant: OCc1nc2cccnc2[nH]1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1nc2cccnc2[nH]1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a boiling solution of KMnO4 (0.38 g, 2.4 mmol) in water (8 mL), a boiling solution of 3H-imidazo[4,5-b]pyridin-2-ylmethanol (0.20 g, 1.4 mmol) and Na2CO3 (0.19 g, 1.5 mmol) in water (6 mL) is added. The resulting mixture is heated at reflux for 4 hr. The hot mixture is filtered, the filtrate is cooled to rt, and the pH adjusted to 2 using conc. HCl. The resulting precipitate is collected by vacuum filtration to afford 3H-imidazo[4,5-b]pyridine-2-carboxylic acid in 100% yield: MS for C7H5N3O2: m/z 164 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[C:13]([NH2:14])=[C:12]([C:15](O)=[O:16])[S:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.C(N1C=CN=C1)([N:22]1C=CN=C1)=O.[OH-].[NH4+]>CN(C=O)C>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[C:13]([NH2:14])=[C:12]([C:15]([NH2:22])=[O:16])[S:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1c(-c2cccc(C(F)(F)F)c2)nsc1C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: NC(=O)c1snc(-c2cccc(C(F)(F)F)c2)c1N
Temperature: 0 °C
Reaction time: 2.25 h

Procedure:
One gram of 3-(3-trifluoromethylphenyl)-4-amino-5-isothiazolecarboxylic acid and 0.7 g. of carbonyldiimidazole were dissolved in 25 ml. of DMF at ambient temperature. The solution was stirred for 2.25 hours; 3 ml. of 14 N aqueous ammonium hydroxide were added and the resulting mixture stirred overnight at ambient temperature after which time it was poured into an ice-water mixture. 3-(3-Trifluoromethylphenyl)-4-amino-5-isothiazolecarboxamide formed in the above reaction precipitated and the precipitate was collected by filtration and was dried. 3-(3-Trifluoromethylphenyl)-4-amino-5-isothiazole carboxamide, thus prepared and purified, melted at about 124° C. after recrystallization from an ethyl acetate-hexane solvent mixture; yield 0.4 g.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[CH:9]([C:25]1[CH:37]=[CH:36][C:28]([C:29]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1)[C:10]1[CH:15]=[C:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH:13]=[CH:12][C:11]=1[F:24].[CH2:38](Br)[CH:39]=[CH2:40].C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:40]([N:6]1[C@H:5]([CH3:8])[CH2:4][N:3]([CH:9]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=2)[C:10]2[CH:15]=[C:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH:13]=[CH:12][C:11]=2[F:24])[C@@H:2]([CH3:1])[CH2:7]1)[CH:39]=[CH2:38]
Reactant: C=CCBr
Reactant: CCN(CC)C(=O)c1ccc(C(c2cc(O[Si](C)(C)C(C)(C)C)ccc2F)N2C[C@@H](C)NC[C@@H]2C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C=CCN1C[C@H](C)N(C(c2ccc(C(=O)N(CC)CC)cc2)c2cc(O[Si](C)(C)C(C)(C)C)ccc2F)C[C@H]1C
Yield: 78 %

Procedure:
The benzhydrylpiperazine from above (0.44 g, 0.83 mmol) was treated with allyl bromide (0.074 mL, 0.85 mmol) and anhydrous sodium carbonate (0.44 g, 4.2 mmol) as in Example 1. The product was purified by preparative thin layer chromatography (silica gel with dichloromethane:methanol:ammonium hydroxide/90:10:1) to give 0.37 g (78%) of (±)-4-(α-(trans-4-allyl-2,5-dimethyl-1-piperazinyl)-5-(tert-butyldimethylsilyloxy)-2-fluorobenzyl)-N,N-diethylbenzamide as a yellow oil. Reaction with tetraethylammonium fluoride hydrate in acetonitrile as in Example 1, followed by chromatography on silica gel with dichloromethane:methanol/4:1 gave 0.24 g (77%) of (±)-4-α-(trans-4-allyl-2,5-dimethyl-1-piperazinyl)-2-fluoro-5-hydroxybenzyl)-N,N-diethylbenzamide as a light amber resin. NMR (CDCl3): δ 1.0-1.3 (m, 12H); 2.0-2.3 (m, 2H); 2.5-3.05 (m, 5H); 3.2-3.6 (br m, 5H); 5.1-5.3 (m, 2H); 5.25 and 5.55 (s, 1H); 5.7-6.0 (m, 1H); 6.5-7.2 (m, 3H); 7.25 (d, J=8 Hz, 2H); 7.4 (d, J=8 Hz, 2H). A solution of the product in absolute ethanol was titrated to pH 4 with ethanolic hydrochloric acid, concentrated and treated with diethyl ether to precipitate 0.21 g (63%) of the monohydrochloride as an off-white powder. Calc. for C27H36FN3O2HCl 1.25 H2O: C, 63.27; H, 7.77; N, 8.20; Cl, 6.92. Found: 63.33; H, 7.78; N, 8.24; Cl, 7.00. Mass spectrum (Cl--CH4) m/z: 454 (M+1, 100%), 453 (M, 6%), 300 (17%), 153 (95%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]=[N:42][N:43]([CH2:45][CH2:46][CH3:47])[CH:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]=[N:42][N:43]([CH2:45][CH2:46][CH3:47])[CH:44]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cn(CCC)nn4)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cn(CCC)nn4)cc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 69.3 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-propyl-1,2,3-triazol-4-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.55 g) was dissolved in methylene chloride (16.5 ml), and a solution of m-chloroperbenzoic acid (213 mg) in methylene chloride (11 ml) was added dropwise to the solution at −78° C. The mixture was stirred for 15 minutes, and an aqueous solution of saturated sodium thiosulfate was added to the mixture. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-propyl-1,2,3-triazol-4-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 280) (0.39 g).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=[O:4].[N-:15]=[N+]=[N-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[C:39]1([CH3:49])[CH:44]=[CH:43][C:42]([S:45]([OH:48])(=[O:47])=[O:46])=[CH:41][CH:40]=1>C1COCC1.O>[NH2:15][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=[O:4].[CH3:49][C:39]1[CH:44]=[CH:43][C:42]([S:45]([OH:48])(=[O:47])=[O:46])=[CH:41][CH:40]=1
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Charge 2-bromo-1-[3(trifluoromethyl)phenyl]-1-ethanone (1664.7 g; 1.00 equiv; 6.23 moles) and tetrahydrofuran (7500 mL) to a 12 L 3-necked round bottom flask (fitted with water-cooled condenser, nitrogen blanket, mechanical stirrer and cooling bath. Charge sodium azide (425.6 g; 1.05 equiv; 6.55 moles) in one portion. Rinse into the flask with water (135 mL). Stir the pale yellow slurry at RT under nitrogen. After 6 hours, add water (260 mL) and continue to stir overnight. Filter the resulting orange slurry over a thin pad of Celite® and rinse with THF (1 L). Divide the resulting solution into two equal portions (5146.5 g each). Charge two identical 22 L 3-necked round bottom flask (fitted with addition funnel, water-cooled condenser, nitrogen blanket, mechanical stirrer and cooling bath) with triphenylphosphine (889 g, 3.43 mol, 1.1 eq), p-toluenesulfonic acid monohydrate (1304 g, 6.86 mol, 2.2 eq) and THF (5.6 L). Add the two portions of intermediate mixture via addition funnels to the individual flasks over four hours, controlling the foaming from nitrogen evolution by addition rate and the temperature by use of an ice bath. On completion of addition stir the slurry at ambient temperature for two hours, then filter solids from both reactors onto the same filter. Wash both flasks and the combined cake with a total THF (4 L). Dry in a vacuum oven at 40° C. overnight to afford (2-Amino-1-(3-trifluoromethyl-phenyl)-ethanone)-, p-toluene sulfonate (1:1) as a white, crystalline solid (2340 g, 6.23 mol, 72%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1>>[OH:22][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:9]2[S:8][C:6]3[C:5]([N:10]=2)=[CH:4][CH:3]=[C:2]([C:28]2[CH:27]=[N:26][N:25]([CH3:24])[CH:29]=2)[N:7]=3)=[O:23])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: CC(C)(O)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Cn1cc(-c2ccc3nc(NC(=O)c4ccc(C(C)(C)O)cc4)sc3n2)cn1
Yield: 37 %

Procedure:
The titled compound (yield=37%, white solid) was prepared using a procedure analogous to that described in connection with 9 (Example 9) except 1D (Example 1) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 6H) 3.90 (s, 3H) 7.66 (d, J=8.08 Hz, 2H) 7.78 (d, J=8.59 Hz, 1H) 8.04-8.14 (m, 4H) 8.38 (s, 1H) 12.89 (br. s., 1H); ESI-MS: m/z 394.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:4])[CH:2]=[CH2:3].[CH:10]([Si:13]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[N:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1)([CH3:12])[CH3:11].C(OOC(C)(C)C)(=O)C1C=CC=CC=1>C(O)(=O)C.O1CCOCC1.CS(C)=O.C(OCC)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:22]([Si:13]([CH:10]([CH3:12])[CH3:11])([CH:19]([CH3:21])[CH3:20])[N:14]1[CH:18]=[CH:17][C:16](/[CH:3]=[CH:2]/[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4])=[CH:15]1)([CH3:24])[CH3:23]
Reactant: C=CC(=O)OCCCC
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)OOC(=O)c1ccccc1
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)O
Product: CCCCOC(=O)/C=C/c1ccn([Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 35 °C
Reaction time: 24 h
Yield: 133.5 %

Procedure:
Palladium(II) acetate (0.05 equiv.) was added to a solution of n-butyl acrylate (0.27 mL, 1.5 mmol, 0.50 equiv.), 1-(triisopropylsilyl)-1H-pyrrole (1.34 g, 3.00 mmol), and tert-butyl peroxybenzoate (0.56 mL, 1.5 mmol, 0.50 equiv.), in acetic acid/dioxane/dimethylsulfoxide (0.23/0.69/0.08 mL). The mixture was stirred at 35° C. for 24 h, diluted with diethyl ether (200 mL) and water (20 mL), and filtered through a plug of celite. The organic phase was separated and washed with saturated NaHCO3 solution (2×30 mL) and water (30 mL). The combined aqueous layers were further extracted with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by CC (SiO2, EtOAc/petroleum ether 1:20) to give (E)-butyl 3-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]acrylate (0.70 g, 67%) as a light-yellow oil.
Reaction SMILES: O.O.Cl[Sn]Cl.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=1[C:17]1[N:21]([CH3:22])[N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1>CCO>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[C:17]1[N:21]([CH3:22])[N:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1cc(C(F)(F)F)nn1C
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(N)cc1-c1cc(C(F)(F)F)nn1C
Yield: 97 %

Procedure:
SnCl2.2H2O (0.15 g, 0.66 mmol, 4.0 eq.) was added to a stirred solution of 5-(2-methoxy-5-nitro-phenyl)-1-methyl-3-trifluoromethyl-1H-pyrazole, see Example 1.99, (0.05 g, 0.16 mmol) in EtOH (2.0 mL). The mixture was stirred at reflux for 4 hrs and EtOH was removed under vacuum. The resulting solid was dissolved in EtOAc and 1N NaOH was added until the pH was adjusted to 6. The mixture was stirred overnight and filtered through celite. The aqueous phase was extracted with EtOAc (3×50 mL). The combined organic phase was dried over anhydrous MgSO4, filtered and evaporated to give 4-methoxy-3-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-phenylamine (0.04 g, 0.15 mmol, 97% yield): LCMS m/z (%)=272 (M+H, 100). 1H NMR (400 MHz, CDCl3) δ: 6.82 (dd, J=16.0, 4.0 Hz, 1H), 6.79 (dd, J=10.0, 2.0 Hz, 1H), 6.61 (d, 1H), 6.46 (s, 1H), 3.76 (s, 3H), 3.74 (s, 3H).
Reaction SMILES: C([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[OH:12])[CH:7]=[O:8])C.Cl.C1(C)C=CC=CC=1>O.[Cl-].[Zn+2].[Cl-]>[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[OH:12])[CH:7]=[O:8]
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 17 h
Yield: 72.7 %

Procedure:
A mixture of 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (20.0 g), zinc chloride (60.0 g) and hydrochloric acid (37%, 15 mL) was stirred at 90° C. for 17 h. The mixture was diluted with water (100 mL) and then cooled to 3° C. After 1 h the product was filtered and washed with cold water. The product was dried in vacuo at 100° C. to give 16.5 g (95.1%) of crude product. The crude product was mixed with toluene (275 mL) and activated carbon (2,0 g) and the resulting mixture was refluxed for 45 min. The hot solution was filtered and then cooled to 3° C. After 1 h the product was filtered and washed with cold toluene. It was dried in vacuo at 50° C. to give 12.6 g (72.6%) of pure 3,4-dihydroxy-5-nitrobenzaldehyde (mp. 146°-8° C.).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]([C:9]([OH:11])=[O:10])[N:7]2[C:12](=[O:23])[CH:13]([NH:14][C:15](=[O:22])[CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C@H:6]2[S:5][CH:4]=1.[C:24](=O)(O)[O-:25].[Na+].C(OCC)(=O)C>CO.C(Cl)(Cl)Cl>[CH3:24][O:25][CH2:2][C:3]1[CH:8]([C:9]([OH:11])=[O:10])[N:7]2[C:12](=[O:23])[CH:13]([NH:14][C:15](=[O:22])[CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C@H:6]2[S:5][CH:4]=1
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)O)C(CBr)=CS[C@H]12
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COCC1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)O
Reaction time: 0.33 h

Procedure:
The benzyl ester of 3-bromomethyl-7-(2-thienylacetamido)-2-cephem-4-carboxylic acid is dissolved in methanol. After standing at room temperature for 20 minutes the reaction mixture is poured into a dilute sodium bicarbonate solution and extracted with methylene chloride. The organic layer is washed with aqueous sodium chloride and dried. Removal of the solvent affords 35 mg. of crude product. The pure benzyl ester of 3-methoxymethyl-7-(2-thienylacetamido)-2-cephem-4-carboxylic acid is then isolated by preparative thin layer chromatography (15% ethyl acetate in chloroform as eluant).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([O:17][C:18]3[CH:32]=[CH:31][C:21]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:20][CH:19]=3)=[C:15](Br)[S:14][C:13]=2[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][C:41]=1[S:42]([CH3:45])(=[O:44])=[O:43].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([O:17][C:18]3[CH:32]=[CH:31][C:21]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:20][CH:19]=3)=[C:15]([C:38]3[CH:39]=[CH:40][C:41]([S:42]([CH3:45])(=[O:43])=[O:44])=[C:36]([F:35])[CH:37]=3)[S:14][C:13]=2[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1sc2cc(OCc3ccccc3)ccc2c1Oc1ccc(OCCN2CCCCC2)cc1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1F
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: C1COCCO1
Product: CS(=O)(=O)c1ccc(-c2sc3cc(OCc4ccccc4)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1F
Yield: 36.5 %

Procedure:
Dissolve 1-{2-[4-(6-benzyloxy-2-bromo-benzo[b]thiophen-3-yloxy)-phenoxy]-ethyl}-piperidine (350 mg, 0.65 mmol) and 3-fluoro-4-methanesulfonyl-phenyl-boronic acid (213 mg, 0.98 mmol) in dioxane (10 mL) and add 10% aqueous sodium carbonate (9 mL) and Pd(PPh3)4 (75 mg, 0.065 mmol). Heat to reflux for 3 hours. Partition the reaction mixture between dichloromethane (20 mL) and saturated aqueous ammonium chloride (20 mL). Wash the organic layer with brine (30 mL), dry with sodium sulfate, and concentrate in vacuo. Chromatograph the residue on a SiO2 column eluting with methanol in dichloromethane (0 to 5%) to give 150 mg of the title compound contaminated with a 2-H reduced byproduct. Take the mixture on to the next step without further purification.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([O-:24])=[O:23])=[CH:20][CH:19]=3)[CH:14]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[K+].O1CCCC1.Cl>O>[CH2:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:25][CH:26]=3)[CH:14]=2)=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOc1ccc(-c2cc(-c3ccc(C(=O)[O-])cc3)no2)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCOc1ccc(-c2cc(-c3ccc(C(=O)O)cc3)no2)cc1
Temperature: 50 °C

Procedure:
The pure potassium 4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoate obtained in Example 2, tetrahydrofuran (131 L) and water (131 L) were put into a 1000 L glass-lined reaction chamber, heated to 45 to 55° C., and 1N hydrochloric acid (82 L) was added to this reaction mixture for 20 or more minutes. Furthermore, water (607 L) was added to the reaction mixture for 30 or more minutes at the same temperature. This reaction mixture was cooled to 25 to 35° C. and its pH was adjusted to 3 or less with 6N hydrochloric acid. The product was isolated by a centrifugal separator and washed with water (164 L) and acetone (82 L) and dried by a vacuum drier to obtain pure 4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoic acid (14.9 kg).