Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3F)[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[NH2:1][C@@H:2]([CH3:5])[CH2:3][O:4][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:31]=1[C:22]([NH:21][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[C:7]([Cl:6])[CH:8]=1)=[N:23][CH:24]=[N:25]2
Reactant: Fc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: C[C@H](N)CO
Product: C[C@H](N)COc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 51 %

Procedure:
The procedure described in Example 2.4 (preparation of starting materials) was repeated using (2S)-2-aminopropan-1-ol and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-fluoroquinazolin-4-amine (obtained as described in Example 1, preparation of starting materials) to give 5-{[(2S)-2-aminopropyl]oxy}-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine in 51% yield; Mass spectrum MH+ 436.4.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13]>[Cu]I.C(N(CC)CC)C>[CH3:11][Si:12]([C:15]#[C:16][C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1)([CH3:14])[CH3:13]
Reactant: O=[N+]([O-])c1cccc(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccc([N+](=O)[O-])c1
Temperature: 82.5 °C
Yield: 102.4 %

Procedure:
A mixture of 1-bromo-3-nitrobenzene (10.0 g, 49.45 mmol) and trimethylsilylacetylene (8.4 mL, 59.34 mmol) was treated with triethylamine (33 mL), giving a small amount of white precipitate. The resultant mixture was treated with dichlorobis(triphenylphonsphone)palladium II (7 mgs, 0.01 mmol) and copper (I) iodide (8.5 mgs, 0.04 mmol) and heated at 80-85° C. (oil bath temperature) for 4 hours. The resultant bright yellow mixture was allowed to cool to room temperature and the solid was removed by filtration with the aid of triethylamine (33 mL). The clear yellow solution was concentrated by evaporation and dried in vacuo at room temperature overnight to give the title product (11.11 g, 102%) as a dark brown oil. gc/mass spectroscopy indicated that the final compound was 100% pure m/e 219 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([OH:13])[C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2[OH:19].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O.O>[CH2:26]([O:13][C:10]1[C:11]([F:12])=[C:2]([F:1])[CH:3]=[C:4]2[C:9]=1[N:8]=[CH:7][C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2[OH:19])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)c1cnc2c(O)c(F)c(F)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(OCc3ccccc3)c(F)c(F)cc2c1O
Reaction time: 11 h

Procedure:
To a stirred solution of ethyl 6,7-difluoro-4,8-dihydroxy-3-quinolinecarboxylate (300 mg) in dry dimethylformamide (6 ml), was added anhydrous potassium carbonate (308 mg) and then benzyl chloride (145 μl). The mixture was stirred at 55°-65° C. for 11 hours. The reaction mixture was diluted with water (30 ml) and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel (7 g) using acetone/chloroform (1:20) as an eluent to give 113 mg of ethyl 8-benzyloxy-6,7-difluoro-4-hydroxy-3-quinolinecarboxylate, mp 200°-201° C.; MS m/z 359 (M+), after recrystallization from methanol.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[C:4]([CH3:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.CC(C1C=CC=CC=1)=C.COC1CCCC1.CCCCCC.C([Li])CCC.[C:38]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(O)(=O)C>O.C(OCC)C.CCCCCC>[CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:38]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[OH:45]
Reactant: Cc1ccccc1N(C)C
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: C=C(C)c1ccccc1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: COC1CCCC1
Solvent: CCOCC
Product: CN(C)c1ccccc1CC(O)(c1ccccc1)c1ccccc1
Reaction time: 13 h

Procedure:
In a 30 ml Schlenk flask, 0.514 g (3.80 mmol) of N,N-dimethyl-o-toluidine, 0.898 g (7.60 mmol) of α-methylstyrene, 6.60 g of hexane and 4.43 ml (38.0 mmol) of cyclopentyl methyl ether were placed. Then, 4.78 ml (7.60 mmol) of a 1.59M n-butyllithium hexane solution was dropwise added at 25° C., and the mixture was stirred for 13 hours. To the reaction mixture, a diethyl ether solution containing 1.34 g (7.50 mmol) of benzophenone was dropwise added, and the mixture was stirred for 30 minutes. The resulting reaction mixture was added to a diethyl ether solution containing 0.500 g (8.3 mmol) of acetic acid, and the mixture was stirred for 5 minutes. Thereafter, 5 ml of water was added, and the mixture was further stirred for 5 minutes. After the aqueous phase was separated, the organic phase was extracted with 10% hydrochloric acid, and the resulting aqueous phase was neutralized, whereby 2-(2-(dimethylamino)phenyl)-1,1-diphenylethanol was obtained as a white crystal. The yield was 0.680 g and was 56%. Identification was carried out by a 1H-NMR spectrum. The results of the measurement are given below.
Reaction SMILES: Cl.C([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[CH2:22][CH2:21][CH2:20][NH:19][C:18]=3[N:17]=2)[CH2:10]1)(OC(C)(C)C)=O>CCOC(C)=O>[N:17]1[C:18]2[NH:19][CH2:20][CH2:21][CH2:22][C:23]=2[CH:24]=[CH:25][C:16]=1[CH2:15][CH:11]1[CH2:12][CH2:13][CH2:14][NH:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCCC(Cc2ccc3c(n2)NCCC3)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1cc2c(nc1CC1CCCNC1)NCCC2
Reaction time: 0.25 h

Procedure:
HCl gas was bubbled through a solution of 2-5 (0.8 g, 2.5 mmol) and EtOAc (15 mL) at 0° C. for 15 min. After an additional 15 min argon was passed through the solution for 15 min followed by concentration. The residue was azeotroped twice with ether to give 2-6 as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[Cl:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[C:18]([NH2:25])[CH:19]=[CH:20][CH:21]=2)[N:16]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[C:18]([NH:25][S:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[CH:19]=[CH:20][CH:21]=2)[N:16]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: Nc1cccc2ccc(Cl)nc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1cccc2ccc(Cl)nc12
Yield: 80 %

Procedure:
In a similar fashion using route 14 general procedure 27, 2-nitrobenzene-1-sulfonyl chloride (800 mg, 3.65 mmol), 2-chloro-quinolin-8-ylamine (Intermediate 26), pyridine (0.67 ml, 0.8 mmol) and DMAP (cat.) in DCM (30 ml) gave the title compound (800 mg, 80%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Br:9]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:9])=[CH:4][N:3]=1
Reactant: Cc1ccc(Br)nc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(Br)nc1
Yield: 110.3 %

Procedure:
A solution of 296.3 g (1.72 mol) of 2-bromo-5-picoline from step 3 in 6 L of carbon tetrachloride was treated with 306.5 g (1.72 mol) of N-bromosuccinimide (NBS) and 28.3 g 173 mmol) of azobisisobutyronitrile (AIBN). The reaction was stirred at reflux under nitrogen for 3 h, filtered, and concentrated in vacuo providing 476 g of crude 2-bromo-5-bromomethylpyridine as a brownish yellow solid (NMR indicates that this material is only 60% monobromomethyl product): NMR (CDCl3)δ4.42 (s, 2 H), 7.48 (d, J=9 Hz, 1 H), 7.60 (dd, J=9 and 3 Hz, 1 H), 8.37 (d, J=3 Hz, 1 H).
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[CH2:16][S:17][C:5]=2[CH:4]=[CH:3][CH:2]=1)=[CH:13][C:12]([OH:18])=[CH:11][CH:10]=4.N1C=CN=C1.[CH3:24][C:25]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])[CH3:26]>CN(C=O)C>[C:25]([Si:28]([CH3:30])([CH3:29])[O:18][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]1[C:6]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[S:17][CH2:16][C:15]2=1)([CH3:27])([CH3:26])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2[nH]c3c(c2c1)CSc1ccccc1-3
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]c3c(c2c1)CSc1ccccc1-3
Reaction time: 2 h

Procedure:
6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-ol (820 mg, 3.24 mmoL) in DMF (10 mL) was treated with imidazole (331 mg, 4.862 mmoL) followed by TBSCl (733 mg, 4.862 mmoL) at room temperature. The reaction was stirred for 2 hours. The reaction mixture was then partitioned between CH2Cl2 and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The crude material (the oil) was then purified by column chromatography (silica gel, hexanes:EtOAc 4:1 as eluent) to yield the title compound as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:25]=[CH:24][C:15]([CH2:16][S:17]([CH2:20][C:21](O)=[O:22])(=[O:19])=[O:18])=[CH:14][C:13]=1[N+:26]([O-:28])=[O:27]>C(O)(=O)C>[Cl:11][C:12]1[CH:25]=[CH:24][C:15]([CH2:16][S:17]([C:20]2[C:21](=[O:22])[O:10][C:5]3[C:6]([CH:7]=2)=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=3)(=[O:18])=[O:19])=[CH:14][C:13]=1[N+:26]([O-:28])=[O:27]
Reactant: O=C(O)CS(=O)(=O)Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=Cc1cc(Cl)ccc1O
Solvent: CC(=O)O
Product: O=c1oc2ccc(Cl)cc2cc1S(=O)(=O)Cc1ccc(Cl)c([N+](=O)[O-])c1
Yield: 93 %

Procedure:
A solution of 5-chlorosalicylaldehyde (1 mmol) and 2-(4-chloro-3-nitrobenzylsulfonyl)acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 2, Method A to generate a 93% yield of the title compound; m.p. 272-275° C.
Reaction SMILES: [CH:1]1[C:9](=[N:10]O)[CH:8]=[CH:7][C:5](=[O:6])[C:3](=[O:4])[CH:2]=1.[Sn](Cl)Cl>C(O)C>[CH:1]1[C:9]([NH2:10])=[CH:8][CH:7]=[C:5]([OH:6])[C:3](=[O:4])[CH:2]=1
Reactant: O=C1C=CC(=NO)C=CC1=O
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccc(O)c(=O)cc1
Yield: 9.9 %

Procedure:
To a stirred solution of 0.39 g of 5-nitrosotropolone (2.6 mmole, obtained from the previous example) and 10 mL of absolute ethanol was added 2.92 g of Tin (II) chloride (12.9 mmole). After 40 minutes at reflux the solution was cooled, filtered, and the liquefied portion was partitioned between ethyl acetate and water. The organic fraction was concentrated in vacuo to give 35 mg (10%) of 5-aminotropolone as a yellow solid. IR spectroscopy of the product (neat) found the following characteristic IR absorption frequencies: 3319 cm−1, 3181 cm−1, 2925 cm−1, 1511 cm−1, 1410 cm−1, 1261 cm−1, 837 cm−1, 781 cm−1, and 739 cm−1.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[N:15]1([C:21]#[N:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:12][C:11]([F:14])([F:13])[C:8]1[N:6]2[N:7]=[C:2]([N:18]3[CH2:19][CH2:20][N:15]([C:21]#[N:22])[CH2:16][CH2:17]3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: N#CN1CCNCC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CN1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Yield: 92.2 %

Procedure:
A stirred solution of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (3.48 g, 15.65 mmol), piperazine-1-carbonitrile (2 g, 17.99 mmol) and DIPEA (3.54 mL, 20.34 mmol) in DMF (20 mL) was heated at 70° C. for 1 hour. The solution was evaporated and partitioned between DCM and 1M aqueous K2CO3. The organic phase was washed with brine, dried over MgSO4, evaporated and triturated with ether. The precipitate was collected by filtration, washed with ether and dried under vacuum to afford 4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazine-1-carbonitrile (4.29 g, 92%) as a cream crystalline solid.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:36][CH2:37][C:38]([NH:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1)=[O:39]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:36][CH2:37][C:38]([NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=2)=[O:39])=[O:18])=[CH:19][CH:20]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4]
Reactant: NCC(=O)Nc1ccccn1
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)NCC(=O)Nc2ccccn2)cc1
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
4-geranyloxybenzoic acid(1.81 g) was dissolved in chloroform(40 ml) and triethylamine(1.84 ml), and then diphenylphosphinic chloride(1.26 ml) was added thereto while being cooled with ice. After being stirred for 30 minutes, the mixture, with 2-(aminoacetylamino)pyridine(1.00 g) added thereto, was stirred for 2 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 1.84 g of the aimed compound.
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]([C:7]1[C:8]([O:14][CH3:15])=[N:9][CH:10]=[C:11]([F:13])[CH:12]=1)[CH2:5][OH:6].[OH-].[K+].Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[F:13][C:11]1[CH:12]=[C:7]([C@H:4]2[CH2:5][O:6][C:19](=[O:21])[NH:3]2)[C:8]([O:14][CH3:15])=[N:9][CH:10]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ncc(F)cc1[C@H](N)CO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ncc(F)cc1[C@H]1COC(=O)N1
Temperature: 0 °C
Reaction time: 16 h
Yield: 34.6 %

Procedure:
To a solution of (S)-2-amino-2-(5-fluoro-2-methoxypyridin-3-yl)ethanol dihydrochloride (897 mg, 3.46 mmol) in KOH (10 mL, 24.2 mmol, 2.42 M in water) was added THF (10 mL). The mixture was cooled to 0° C. and treated with triphosgene (1.03 g, 3.46 mmol). The mixture was allowed to warm to ambient temperature with stirring over 16 hours then partitioned between EtOAc (50 mL) and water (50 mL), and the layers were separated. The aqueous layer was extracted with EtOAc (2×30 mL) and the combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was triturated with Et2O, filtered and dried under reduced pressure to afford (S)-4-(5-fluoro-2-methoxypyridin-3-yl)oxazolidin-2-one (254 mg, 35% yield) as a white powder. 1H NMR (CDCl3) δ 7.98 (m, 1H), 7.44 (m, 1H), 5.61 (Br S, 1H), 5.13 (m, 1H), 4.83 (m, 1H), 4.16 (m, 1H), 3.96 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][CH3:12])[CH:5]=[CH:4][C:3]=1[O:13][CH3:14].B(OC(C)C)(OC(C)C)OC(C)C.C([Li])CCC.B(O)O.[N:36]1[CH:41]=[CH:40][CH:39]=[C:38]([NH:42][C:43]([N:45]2[CH2:48][CH:47]([O:49][C:50]3[CH:55]=[CH:54][C:53](I)=[CH:52][N:51]=3)[CH2:46]2)=[O:44])[N:37]=1.C(=O)(O)[O-].[Na+]>C1COCC1.C(Cl)Cl.CN(C=O)C>[N:36]1[CH:41]=[CH:40][CH:39]=[C:38]([NH:42][C:43]([N:45]2[CH2:46][CH:47]([O:49][C:50]3[CH:55]=[CH:54][C:53]([C:2]4[CH:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][CH3:12])[CH:5]=[CH:4][C:3]=4[O:13][CH3:14])=[CH:52][N:51]=3)[CH2:48]2)=[O:44])[N:37]=1
Reactant: COCCOc1ccc(OC)c(Br)c1
Reactant: O=C(Nc1cccnn1)N1CC(Oc2ccc(I)cn2)C1
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: O=C([O-])O
Agent: OBO
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCCOc1ccc(OC)c(-c2ccc(OC3CN(C(=O)Nc4cccnn4)C3)nc2)c1
Temperature: 25 °C
Yield: 44.9 %

Procedure:
A solution of 2-bromo-1-methoxy-4-(2-methoxy-ethoxy)-benzene (110 mg, 0.42 mmol) in anhydrous THF (2 mL) was cooled to −78° C. with a CO2— acetone bath under a nitrogen atmosphere. Triisopropyl borate (0.19 mL, 0.842 mmol) was added, followed by n-butyl lithium solution (2.5M in hexanes, 0.22 mL, 0.55 mmol). The mixture was allowed to warm to ambient temperature the solvents were removed in vacuo to afford a colourless solid. To the crude boronic acid was added 3-(5-iodo-pyridin-2-yloxy)-azetidine-1-carboxylic acid pyridazin-3-ylamide (Example 7, step 1) (150 mg, 0.38 mmol), 1N aqueous sodium bicarbonate solution (1.26 mL), DMF (7 mL) and 1,1′-bis[(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with CH2Cl2 (15 mg). Nitrogen gas bubbled through mix for 5 minutes and reaction mixture heated at 80° C. for 2 hr. Mix was allowed to cool, partitioned between ethyl acetate (30 mL) and water (30 mL). Organic phase was separated then washed with sat. aqueous sodium chloride solution (60 mL) and dried over sodium sulphate. Solvents were removed in vacuo to afford a crude oil which was purified by flash chromatography on silica gel, eluting with a gradient of 0-10% ethyl acetate in hexane to afford the title compound (77 mg, 41%) as a pale yellow foam.
Reaction SMILES: [K].[C:2]([CH:5]([NH:12]/C(/C)=C\C(OCC)=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([OH:4])=O.CN1CCOCC1.ClC(OCC)=O.[NH2:34][CH:35]1[C:46](=[O:47])[N:37]2[C:38]([C:43]([OH:45])=[O:44])=[C:39]([Cl:42])[CH2:40][S:41][C@H:36]12>O.C(#N)C.O.C(N(CC)CC)C.C(#N)C.CN(C)C=O>[CH:9]1[CH:10]=[CH:11][C:6]([C@@H:5]([NH2:12])[C:2]([NH:34][C@@H:35]2[C:46](=[O:47])[N:37]3[C:38]([C:43]([OH:45])=[O:44])=[C:39]([Cl:42])[CH2:40][S:41][C@H:36]23)=[O:4])=[CH:7][CH:8]=1
Reactant: CCOC(=O)/C=C(/C)NC(C(=O)O)c1ccccc1
Reactant: NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12
Agent: CCOC(=O)Cl
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: N[C@@H](C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1ccccc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
To a mixture of 162 g of ethyl 3-α-carboxybenzylaminocrotonate potassium salt, 450 ml of dimethylformamide and 900 ml of acetonitrile, cooled to -40° C., 1.5 ml of 4-methylmorpholine and 54 ml of ethyl chloroformate are added. The mixture is stirred one hour at -40° C., then a previously cooled solution of triethylamine salt of 7-amino-3-chloro-3-cephem-4-carboxylic acid (corresponding to 99 g of free acid) in 900 ml of a mixture acetonitrile/water 1/1 (v/v) is added thereinto. The solution is kept in the cool for about 3 hours, then it is treated with 630 ml of water and filtered. The filtrate is made acid to pH 1.5 with 6N hydrochloric acid, then the pH is adjusted to 4.5 with triethyl amine. The suspension thus obtained is kept to 0° C. overnight, then it is filtered. The product thus obtained is washed with acetonitrile/water 1/1 (v/v) and dried under vacuum at 35° C. Thus, 120 g of amorphous raw cefaclor are obtained.
Reaction SMILES: [Br-].C(CCCCC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(O)=O.CC([O-])(C)C.[K+].CO.[CH:37]1([CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]([C:50]([NH:52][C:53]([C:55]2[CH:60]=[CH:59][C:58](/[C:61](/[C:70]3[CH:71]=[N:72][CH:73]=[CH:74][CH:75]=3)=[CH:62]\[CH2:63][CH2:64][CH2:65][CH2:66][C:67]([OH:69])=[O:68])=[CH:57][CH:56]=2)=[O:54])=[CH2:51])=[O:49])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>C1COCC1>[CH:37]1([CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]([C@@H:50]2[CH2:51][O:54][C:53]([C:55]3[CH:56]=[CH:57][C:58](/[C:61](/[C:70]4[CH:71]=[N:72][CH:73]=[CH:74][CH:75]=4)=[CH:62]\[CH2:63][CH2:64][CH2:65][CH2:66][C:67]([OH:69])=[O:68])=[CH:59][CH:60]=3)=[N:52]2)=[O:49])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: C=C(NC(=O)c1ccc(/C(=C\CCCCC(=O)O)c2cccnc2)cc1)C(=O)NCCCCC1CCCCC1
Agent: CC(C)(C)[O-]
Agent: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCCC/C=C(\c1ccc(C2=N[C@H](C(=O)NCCCCC3CCCCC3)CO2)cc1)c1cccnc1
Yield: 38 %

Procedure:
Using the method described above at Example 18-G, 1.472 g (3.4 mmol) of (4S)-4,5-dihydro-2-[4-(3-pyridylcarbonyl)phenyl]oxazole-4-[N-(4-cyclohexylbutyl)]-L-serinamide was treated with 3.08 g (6.8 mmol) of (5-carboxypentyl)triphenylphosphonium bromide and 13.6 mL (13.6 mmol) of 1.0 M t-BuOK in 10.0 mL of THF at 0° C. for 2.5 hr. Preparative HPLC with MeOH--AcOH--CH2Cl2 (3:0.5:96.5) yielded ~700 mg (38%) of the title product and -670 mg (37%) of the β-elimination Wittig product (less polar material)(E)-7-[4-[[[1-[[(4-cyclohexylbutyl)amino]carbonyl]-eth-1-enyl]amino]carbonyl]phenyl]-7-(3-pyridyl)-hept-6-enoic acid (311030): mp 61-63° C.; 1H NMR (CDCl3) δ 9.05 (s, 1H), 8.58 (s, 1H), 8.48 (d, J=3.3 Hz, 1H), 7.89 (d, J=8.2 Hz, 2H), 7.43 (br d, J=8.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 2H), 7.25 (buried, 1H), 6.63 (d, J=1.1 Hz, 1H), 6.55 (br s, 1H), 6.21 (t, J=7.4 Hz, 1H), 5.35 (s, 1H), 3.37 (dt, J=6.8, 6.3 Hz, 2H), 2.32 (dd, J=7.1, 6.9 Hz, 2H), 2.18 (ddd, J=7.3, 7.2, 7.1 Hz, 2H), 1.69-0.83 (m, 21H); FDMS 532 (M+1). Anal. (C32H41N3O4) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[C:4](I)=[N:5][NH:6]2.[H-].[Na+].C([Mg]Cl)(C)C.[CH2:20]([Sn:24]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:26][CH2:27][CH2:28][CH3:29])Cl)[CH2:21][CH2:22][CH3:23]>C1COCC1>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[C:4]([Sn:24]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:20][CH2:21][CH2:22][CH3:23])=[N:5][NH:6]2
Reactant: Fc1cc(F)c2c(I)n[nH]c2c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(F)cc(F)c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.1 %

Procedure:
To a solution of 4,6-difluoro-3-iodo-1H-indazole (2.11 g, 7.53 mmol) in THF (45 mL) at 0° C. was slowly added sodium hydride (60% in mineral oil, 362 mg, 9.04 mmol). The reaction mixture was stirred at room temperature for 10 min then cooled to −10° C. and isopropylmagnesium chloride (2.0 M in THF, 4.52 mL, 9.04 mmol) was added. The reaction mixture was stirred at −10° C. for 30 min then tributylchlorostannane (2.66 mL, 9.8 mmol) was added dropwise. Stirring was continued at −10° C. for 20 min then at room temperature for 3 h. The reaction mixture was quenched with saturated aqueous NH4Cl then diluted with water and extracted with EtOAc (2×). The combined organics were washed with brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 10% to 20% EtOAc/heptane (0.5% Et3N) to afford 1.94 g (58%) of 4,6-difluoro-3-tributylstannanyl-1H-indazole as a pale yellow viscous oil. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.03 (dd, J=8.9, 2.1 Hz, 1H), 6.60 (td, J=9.8, 2.1 Hz, 1H), 1.51-1.64 (m, 6H), 1.29-1.42 (m, 6H), 1.20-1.29 (m, 6H), 0.88 (t, J=7.4 Hz, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][C:11](=[O:17])[NH:12]2.[CH2:18]([N:20]([CH2:35][CH3:36])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:35]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[NH:12][C:11]2=[O:17])[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:36]
Reactant: O=C1Cc2c(cccc2-c2ccccc2F)N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4ccccc4F)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.6 %

Procedure:
To a solution of 4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (69.0 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 5-[4-(2-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (98 mg, 83%).