Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2]N.Br.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[NH:14])[NH2:13])=[CH:8][CH:7]=1.[C:15]([NH:18][CH:19]([CH3:27])[C:20](=O)[C:21](OCC)=[O:22])(=[O:17])[CH3:16]>C(O)C>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][C:21](=[O:22])[C:20]([CH:19]([NH:18][C:15](=[O:17])[CH3:16])[CH3:27])=[N:2][N:14]=2)=[CH:8][CH:7]=1
Reactant: NN
Reactant: N=C(N)c1ccc(Br)cc1
Reactant: CCOC(=O)C(=O)C(C)NC(C)=O
Agent: Br
Solvent: CCO
Solvent: O
Product: CC(=O)NC(C)c1nnc(-c2ccc(Br)cc2)[nH]c1=O
Reaction time: 1 h

Procedure:
3.50 ml of hydrazine hydrate (3.60 g, 27.5 mmol) are added to 4-bromobenzenecarboximidamide hydrobromide from example 3A (11.8 g) in 150 ml of ethanol, and the mixture is stirred for 1 h. After this time, ethyl 3-(acetylamino)-2-oxobutanoate from example 4A (16.8 g) in 76 ml of ethanol is added dropwise and the reaction mixture is stirred for 3 h at a bath temperature of 80° C., subsequently overnight at 20° C. The mixture is concentrated and the residue is purified by flash chromatography (eluent: dichloromethane/methanol 95:5).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.[N:10]1[CH:15]=[C:14](B(O)O)[CH:13]=[N:12][CH:11]=1.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:8][C:6]1[N:7]=[C:2]([C:14]2[CH:15]=[N:10][CH:11]=[N:12][CH:13]=2)[CH:3]=[C:4]([NH2:9])[N:5]=1
Reactant: OB(O)c1cncnc1
Reactant: Cc1nc(N)cc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(N)cc(-c2cncnc2)n1
Temperature: 160 °C

Procedure:
To a microwave vial were added 6-chloro-2-methylpyrimidin-4-amine (700 mg, 4.88 mmol), pyrimidin-5-ylboronic acid (725 mg, 5.86 mmol), PdCl2(PPh3)2 (684 mg, 0.97 mmol), dioxane (10 mL) and Na2CO3 (2 M, 7 mL, 14 mmol) under Argon. The vial was microwave heated for 1 h at 160° C. Water was added, and extracted with 10% MeOH/CHCl3 (3*50 mL). The organic layers were combined and concentrated under reduced pressure and the crude was purified by silica gel chromatography to yield the title compound as a white solid; MS (m/z): [M+H]+188.2.
Reaction SMILES: S1C=CC(C2[S:10][C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[N:8]C=2)=C1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH:27]=O>C(Cl)Cl.CO>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[S:10][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:8][CH:27]=1
Reactant: O=CCc1ccccc1Cl
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)cc1
Solvent: ClCCl
Solvent: CO
Product: Oc1ccc(Nc2ncc(-c3ccccc3Cl)s2)cc1

Procedure:
The title compound is prepared as described in Example 12 (Procedure B) for 4-(5-thiophen-3-yl-thiazol-2-yl-amino)-phenol but starting from (2-chlorophenyl)-acetaldehyde. The title compound: ES-MS: 303.0 [M+H]+; single peak at tR=3.59 min (System 2); Rf=0.21 (CH2Cl2/MeOH, 95/5).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]([CH3:30])=[C:20]([CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][C@H:25]3[CH3:29])[N:21]=2)=[CH:13][CH:12]=1>>[C:11]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]([CH3:30])=[C:20]([CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][C@H:25]3[CH3:29])[N:21]=2)=[CH:13][CH:12]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC[C@H]1C
Reactant: OB(O)c1ccccc1
Product: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCN1CCC[C@H]1C

Procedure:
The title compound is prepared in a manner substantially analogous to example 133 starting from phenyl boronic acid (174 mg, 1.43 mmol) and 2-(4-Bromo-phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-oxazole (100 mg, 0.287 mmol) to give 16 mg (16%). MS (m/e) 347.3 (M+1)
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.CCCCCC.[CH:19]1([C:24]([OH:26])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1.[C:27]1([CH2:33][CH2:34][C:35](=[CH2:43])[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[C:39]([O:38][C:36]([CH:35]([CH2:34][CH2:33][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:43][C:19]1([C:24]([OH:26])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:37])([CH3:40])([CH3:41])[CH3:42]
Reactant: O=C(O)C1CCCC1
Reactant: C=C(CCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)C(CCc1ccccc1)CC1(C(=O)O)CCCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To diisopropylamine (5.13 g, 50.9 mmol) in tetrahydrofuran (THF) (20 ml) at -60° C., add n-BuLi hexane solution (20.3 ml of 2.5M, 50.9 mmol). Warm to 0° C., cool again to -60° C. and add cyclopentanecarboxylic acid (2.89 g, 25.4 mmol). Warm to 0° C. for 2.5 hr., cool again and add t-butyl 2-(2-phenylethyl)acrylate (5.90 g, 25.4 mmol) in THF (10 ml). After 2 h., warm to 0° C., quench with 5N HCl, extract with hexane, wash with 1N NaHCO3, and concentrate to a solid. Chromatograph on silica, eluting with hexane-ether-HOAc 60:40:1 to obtain an oil.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=[C:12]2[N:23](CC1C=CC=CC=1)CC1C=CC=CC=1)C1C=CC=CC=1>CO.[Pd]>[CH3:22][O:21][C:19]([C:15]1[C:16]2[C:11](=[CH:10][C:9]([OH:8])=[CH:18][CH:17]=2)[C:12]([NH2:23])=[CH:13][CH:14]=1)=[O:20]
Reactant: COC(=O)c1ccc(N(Cc2ccccc2)Cc2ccccc2)c2cc(OCc3ccccc3)ccc12
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(N)c2cc(O)ccc12
Reaction time: 20 h

Procedure:
Pd on carbon (5 wt %, 0.350 g) was added to a solution of methyl 6-(benzyloxy)-4-(dibenzylamino)-1-naphthoate (3.409 g, 6.834 mmol) in MeOH (70 mL). The system was evacuated and purged with argon and then stirred under a H2 (g) atmosphere for 20 h. The mixture was filtered through a pad of Celite and concentrated to afford methyl-4-amino-6-hydroxy-1-naphthoate as a light brown solid. MS (ESI, pos. ion) m/z: 218.1 (M+H). Mass Calc'd for C12H11NO3: 217.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@H:2]([C@@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[NH2:11][CH:12]1[CH2:16][CH2:15][NH:14][CH2:13]1>O.CO>[C:6]([C@H:4]([C@@H:2]([C:1]([OH:10])=[O:9])[OH:3])[OH:5])([OH:8])=[O:7].[NH2:11][C@@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1
Reactant: NC1CCNC1
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: O
Solvent: CO
Product: N[C@@H]1CCNC1
Reaction time: 8 h

Procedure:
D(-)-tartaric acid (17 g) is dissolved in a mixture of water (30 ml) and methanol (120 ml), and to the solution is gradually added (3RS)-3-aminopyrrolidine (19 g), and the mixture is stirred. When exothermic reaction is finished, methanol (60 ml) is added to the mixture, and the mixture is allowed to stand at 0°-2° C. overnight. The precipitated crude (3R)-3-aminopyrrolidine D(-)-tartrate (20.6 g) is taken by filtration. This product is recrystallized from a mixture of methanol-water (2:3) four times to give (3R)-3-aminopyrrolidine D(-)-tartrate (6.8 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([CH3:14])(O)[CH3:12])=[C:4]([O:15][CH3:16])[CH:3]=1.S(=O)(=O)(O)O>O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([CH2:8][CH2:9][CH2:10][C:11]2([CH3:14])[CH3:12])=[C:4]([O:15][CH3:16])[CH:3]=1
Reactant: COc1cc(Br)ccc1CCCC(C)(C)O
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1cc(Br)cc2c1CCCC2(C)C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
5-(4-Bromo-2-methoxy-phenyl)-2-methyl-pentan-2-ol (Intermediate 62, 7.3 g, 24.6 mmol) was treated with 85% sulfuric acid (25 mL) at ambient temperature. After 30 minutes, the reaction mixture Was diluted with cold water and extracted with diethyl ether. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product (5.6 g, 83%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[CH:6]=[O:7])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C.O.CC(=O)OCC>[CH2:19]([O:11][C:10]1[C:9]([CH3:12])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH2:1][CH3:2])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: CCc1cc(C=O)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CCc1cc(C=O)cc(C)c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 70.4 %

Procedure:
To a solution of 3-ethyl-4-hydroxy-5-methyl-benzaldehyde (25.0 g, 152 mmol) in acetonitrile (250 mL), K2CO3 (42.1 g, 305 mmol) followed by benzyl bromide (26.0 g, 152 mmol) is added. The suspension is stirred at 60° C. for 18 h. The mixture is diluted with water (150 mL) and EA (150 mL). The org. extract is separated and the aq. phase is extracted once more with EA (100 mL). The combined org. extracts are washed with water (150 mL) and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 4-benzyloxy-3-ethyl-5-methyl-benzaldehyde (27.2 g) as a yellow oil; LC-MS: tR=1.09 min; 1H NMR (D6-DMSO): δ1.19 (t, J=7.5 Hz, 3H), 2.35 (s, 3H), 2.70 (q, J=7.5 Hz, 2H), 4.90 (s, 2H), 7.37-7.41 (m, 1H), 7.42-7.46 (m, 2H), 7.49-7.52 (m, 2H), 7.65-7.69 (m, 2H), 9.92 (s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[C:18]2[N:17]=[C:16]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[N:15]([CH2:28][CH2:29][CH2:30][CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[C:14]=2[CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[C:43]1([CH2:49][CH2:50][CH2:51]Br)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C)C=O>[CH3:8][O:9][C:10]1[C:18]2[N:17]=[C:16]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[N:15]([CH2:28][CH2:29][CH2:30][CH:31]3[CH2:32][CH2:33][N:34]([CH2:51][CH2:50][CH2:49][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH2:35][CH2:36]3)[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: BrCCCc1ccccc1
Reactant: COc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCN(CCCc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 72 %

Procedure:
A solution of 4-methoxy-2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-4-yl)propyl]benzimidazole trifluoroacetate (177 mg, 0.29 mmol, 1 eq) in anhydrous N,N-dimethylformamide (2 ml) was treated with potassium carbonate (120 mg, 0.87 mmol, 3 eq) and 3-phenylpropyl bromide (87 mg, 0.43 mmol, 1.5 eq). The resulting mixture was stirred at 80° C. for six hours. The reaction was quenched by the addition of water (5 ml). The aqueous fraction was extracted with ethyl acetate (3×10 ml). The organic fractions were combined, washed with water (3×10 ml), and brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The residue was further purified by column chromatography to yield the title product as a white crystalline solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[N:10][CH:11]=[C:12]([O:21][CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:13]=3)[O:8][C:5]2=[CH:6][CH:7]=1.CN(C=O)C.C(NC(C)C)(C)C.C[Si](C)(C)[C:41]#[C:42][C:43]1([CH3:47])[CH2:46][O:45][CH2:44]1>[Cu](I)I.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>[CH3:47][C:43]1([C:42]#[C:41][C:2]2[CH:3]=[C:4]3[C@@:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:14]4[C:9](=[N:10][CH:11]=[C:12]([O:21][CH2:22][C:23]([CH3:26])([CH3:24])[CH3:25])[CH:13]=4)[O:8][C:5]3=[CH:6][CH:7]=2)[CH2:46][O:45][CH2:44]1
Reactant: CC(C)(C)COc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(Br)ccc1O2
Reactant: CC1(C#C[Si](C)(C)C)COC1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)COc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(C#CC3(C)COC3)ccc1O2
Temperature: 90 °C

Procedure:
A sealable tube was charged with (S)-7-bromo-3-(neopentyloxy)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (75 mg, 0.179 mmol), copper iodide (3.38 mg, 0.018 mmol), tetrakis(triphenylphosphine)palladium (20.53 mg, 0.018 mmol). To this mixture was added DMF (355 μL, 0.178 mmol), diisopropylamine (498 μL, 3.55 mmol) and trimethyl((3-methyloxetan-3-yl)ethynyl)silane (90 mg, 0.533 mmol). The tube was flushed with argon, sealed and heated to 90° C. for 12 hours. The reaction was diluted with water (100 mL) and poured into a separatory funnel containing ethyl acetate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water and then brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide a brown oil that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (12 g), 0-10% methanol in methylenechloride with 0.1% ammonium hydroxide) to provide (S)-7-((3-methyloxetan-3-yl)ethynyl)-3-(neopentyloxy)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a yellow solid.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](OCC[Cl:20])[CH:15]=2)[O:10][C:9]([C:21]2[N:26]=[CH:25][N:24]3[CH:27]=[CH:28][CH:29]=[C:23]3[CH:22]=2)=[CH:8]1)(C)(C)C.[F:30][C:31]1([F:37])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[ClH:20].[F:30][C:31]1([F:37])[CH2:36][CH2:35][N:34]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:21]2[N:26]=[CH:25][N:24]4[CH:27]=[CH:28][CH:29]=[C:23]4[CH:22]=2)=[CH:8][C:7]3=[N:6][OH:5])[CH2:33][CH2:32]1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCl)cc12
Reactant: FC1(F)CCNCC1
Product: Cl
Product: ON=c1cc(-c2cc3cccn3cn2)oc2ccc(N3CCC(F)(F)CC3)cc12

Procedure:
6-(4,4-difluoro-piperidin-1-y)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime, hydrochloride was prepared in 48% overall yield using the method described in example 87, starting from 6-(2-chloro-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 87B) and 4,4-difluoropiperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:27])[C:7]3[C:14](=[O:15])[N:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=4)[C:12](=[O:26])[C:8]=3[NH:9][C:10]=2[CH:11]=1.CS(O)(=O)=O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:27])[C:7]3[C:14]([OH:15])=[N:13][N:16]([C:17]4[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=4)[C:12](=[O:26])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: CC(C)c1ccc(NN2C(=O)c3[nH]c4cc(Cl)ccc4c(=O)c3C2=O)cc1
Agent: CS(=O)(=O)O
Solvent: CO
Product: CC(C)c1ccc(-n2nc(O)c3c(=O)c4ccc(Cl)cc4[nH]c3c2=O)cc1
Temperature: 25 °C
Yield: 35.5 %

Procedure:
A stirred suspension of 6-chloro-2-(4-isopropylanilino)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-trione (1.13 g, 2.98 mM) in a solution of methanol (90 mL) and methanesulfonic acid (23 mL) was refluxed for 7 hours and cooled to room temperature. The mixture was filtered (the filtrate was saved for use in Example 21), and the collected yellow solids were washed with methanol and ether to give the title compound (0.401 g, 35%) as a yellow powder, mp 393-394° C.; MS(CI): 382 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:39]1[N:40]=[C:41]([NH:44][CH:45]=[O:46])[S:42][CH:43]=1)[C:12]([NH:14][CH:15]1[C:37](=[O:38])[N:17]2[C:18]([C:24]([O:26]CC3C=CC([N+]([O-])=O)=CC=3)=[O:25])=[C:19]([O:22][CH3:23])[CH2:20][S:21][C@H:16]12)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.C(O)(=O)C>[C].[Pd].O>[C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:39]1[N:40]=[C:41]([NH:44][CH:45]=[O:46])[S:42][CH:43]=1)[C:12]([NH:14][CH:15]1[C:37](=[O:38])[N:17]2[C:18]([C:24]([OH:26])=[O:25])=[C:19]([O:22][CH3:23])[CH2:20][S:21][C@H:16]12)=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(NC=O)n3)[C@H]2SC1
Agent: [Pd]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: COC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(NC=O)n3)[C@H]2SC1
Yield: 69.8 %

Procedure:
4-Nitrobenzyl 7-[2-(tert-butoxycarbonylmethoxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-methoxy-3-cephem-4-carboxylate (syn isomer, 6.8 g), methanol (60 ml) tetrahydrofuran (60 ml), acetic acid (6 ml), water (10 ml) and 10% palladium carbon (3.5 g) were treated in a similar manner to that of Example 3 to give 7-[2-(tert-butoxycarbonylmethoxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-methoxy-3-cephem-4-carboxylic acid (syn isomer, 3.8 g).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].CS(Cl)(=O)=O.C(N(CC)CC)C.[CH3:26][NH:27][CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31]>C(Cl)Cl>[CH2:28]([N:27]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:26])[CH2:29][CH:30]([CH3:32])[CH3:31]
Reactant: CNCCC(C)C
Reactant: COC(=O)c1cc(C)cc(CO)c1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C)cc(CN(C)CCC(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To methyl 3-(hydroxymethyl)-5-methylbenzoate prepared by the method in Example SP-198, Step 2 in anhydrous methylene chloride at −30° C. is added methanesulfonyl chloride (601 μL, 7.8 mmol), then triethylamine (1.5 mL, 11.1 mmol), and the reaction is stirred at 0° C. 15 min. The resulting precipitate is filtered, and the filtrate is added to N-methylisoamylamine (2.1 mL, 16.7 mmol). The reaction stirred at room temperature 16 h. The solution is concentrated under reduced pressure, redissolved in ethyl acetate and washed with saturated sodium bicarbonate, brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 20% ethyl acetate/hexanes) provides the title compound. ESI MS m/z 264.2 [M+H]+.
Reaction SMILES: Br[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].[Mg].[Cl:11][CH2:12][C:13]([C:15]1([Cl:18])[CH2:17][CH2:16]1)=[O:14].[Cl-].[NH4+]>C(OCC)C.O>[Cl:11][CH2:12][C:13]([C:15]1([Cl:18])[CH2:17][CH2:16]1)([OH:14])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3]
Reactant: O=C(CCl)C1(Cl)CC1
Reactant: C=C(Br)c1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: C=C(c1ccccc1)C(O)(CCl)C1(Cl)CC1
Temperature: 25 °C
Yield: 97.2 %

Procedure:
##STR20## A solution of 5 g (25 mmol) of α-bromostyrene in 10 ml of absolute diethyl ether is added dropwise to a mixture of 0.7 g (30 mmol) of magnesium filings and 10 ml of diethyl ether under an argon atmosphere and with stirring at room temperature. After the addition has ended, the reaction mixture is refluxed for 1 hour. The resulting Grignard solution is added dropwise at room temperature with stirring to a solution of 3 g (20 mmol) of 1-chlorocyclopropyl chloromethyl ketone in 10 ml of diethyl ether. After the addition has ended, the mixture is refluxed for another 4 hours. The reaction mixture is subsequently treated with a saturated, aqueous ammonium chloride solution, the resulting mixture is poured into water, and this mixture is extracted repeatedly using diethyl ether. The combined organic phase are washed with saturated, aqueous sodium chloride solution, dried over sodium sulphate, and then concentrated by stripping off the solvent under reduced pressure. 5.0 g (97% of theory) of 1-chloro-2-(1-chlorocyclopropyl)-3-phenyl-but-3-en-2-ol are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[CH2:11]([NH:13][CH2:14][C:15](O)=[O:16])[CH3:12].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:11]([N:13]1[CH2:14][C:15](=[O:16])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:9]1=[S:10])[CH3:12]
Reactant: CCNCC(=O)O
Reactant: Fc1ccc(N=C=S)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN1CC(=O)N(c2ccc(F)cc2)C1=S
Yield: 55.5 %

Procedure:
The title compound was prepared by the procedure described in Example 16 using 7.65 g of 4-fluorophenyl-isothiocyanate, 9.32 g of N-ethyl glycine, 10 g of triethyl amine, and 250 mL of chloroform. Purification was achieved through crystallization from ethanol. The title compound (6.6 g) was obtained as a pink solid, m.p. 149°-151° C. Anal. Calcd. for. C11H11F N2O S: C, 55.45; H, 4.65; N, 11.76. Found: C, 55.31; H, 4.51; N, 10.82. Mass spectrum (EI, M.+) m/z 238.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=2)[N:10]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][N:19]=2)[CH:9]=1)=[O:7]>O1CCCC1.O>[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=2)[N:10]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][N:19]=2)[CH:9]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1cn(-c2nccc3ccccc23)c2ccc(C)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)c(C(=O)O)cn2-c1nccc2ccccc12
Reaction time: 24 h
Yield: 87.3 %

Procedure:
0.319 g (7.59 mmol) of lithium hydroxide monohydrate and 60 cm3 of water are added at 25° C. to 1.2 g (3.79 mmol) of 3-methoxycarbonyl-1-(isoquinol-1-yl)-5-methyl-1H-indole dissolved in 60 cm3 of tetrahydrofuran. After stirring at the reflux point of the solvent for 24 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 30 cm3 of water and then triturated with 11.4 cm3 of N hydrochloric acid. After filtering off and drying the solid residue under reduced pressure (2.7 kPa) at 40° C., 1 g of 3-carboxy-1-(isoquinol-1-yl)-5-methyl-1H-indole is obtained in the form of a white solid. Mass spectrum (EI): m/e 302 (M+·), m/e 257.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([C:13]2[N:14]=[CH:15][N:16]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)([OH:12])[CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:42]1[O:43][CH:44]=[CH:45][CH:46]=1)CCC>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>[O:43]1[CH:44]=[CH:45][CH:46]=[C:42]1[C:2]1[CH:3]=[C:4]([C:8]([C:13]2[N:14]=[CH:15][N:16]([C:18]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:17]=2)([OH:12])[CH:9]([CH3:10])[CH3:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: CC(C)C(O)(c1cccc(Br)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(C)C(O)(c1cccc(-c2ccco2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
By the reaction in the same manner as in Example 28-(i) using 1-(3-bromophenyl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (1.70 g), tri-n-butyl(2-furyl)tin (1.29 ml) and tetrakis(triphenylphosphine)palladium((0) (110 mg), the title compound (1.62 g) was obtained as colorless powder crystals.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[N+:9]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[NH:18][C@@H:19]([CH3:22])[CH2:20][OH:21])([O-:11])=[O:10]>C(#N)C>[Br:1][C:16]1[N:15]=[CH:14][C:13]([NH:18][C@@H:19]([CH3:22])[CH2:20][OH:21])=[C:12]([N+:9]([O-:11])=[O:10])[CH:17]=1
Reactant: C[C@@H](CO)Nc1cnccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: C[C@@H](CO)Nc1cnc(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 40 %

Procedure:
N-Bromosuccinimide (0.090 g, 0.507 mmol) was added in one portion to a 0° C. solution of (S)-2-(4-nitropyridin-3-ylamino)propane-1-ol (0.100 g, 0.507 mmol) in acetonitrile (2.0 mL). The mixture stirred at 0° C. and was allowed to warm to room temperature over 16 h. The solution was then concentrated to remove most (>90%) of the acetonitrile. Ethyl acetate was added, and the solution was washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-50% ethyl acetate-hexane) to afford (S)-2-(6-bromo-4-nitropyridin-3-ylamino)propane-1-ol (0.056 g, 40%) as an orange solid. MS (ESI, pos. ion) m/z 276, 278.