Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([O:15][CH2:16][CH2:17][CH:18]=[CH2:19])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])[O:26][C:27]=1[CH3:28]>>[CH2:16]([O:15][CH:4]([CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:22][C:23]1[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])[O:26][C:27]=1[CH3:28])[CH:10]=[CH:9]2)[C:3]([OH:2])=[O:20])[CH2:17][CH:18]=[CH2:19]
Reactant: C=CCCOC(Cc1ccc2[nH]ccc2c1)C(=O)OC
Reactant: COc1ccccc1-c1nc(CCl)c(C)o1
Product: C=CCCOC(Cc1ccc2c(ccn2Cc2nc(-c3ccccc3OC)oc2C)c1)C(=O)O

Procedure:
In analogy to the procedure described in example 44, rac-2-but-3-enyloxy-3-(1H-indol-5-yl)-propionic acid methyl ester (preparation 9) was reacted with 4-chloromethyl-2-(2-methoxy-phenyl)-5-methyl-oxazole to give rac-2-but-3-enyloxy-3-{1-[2-(2-methoxy-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-5-yl}-propionic acid as light brown oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.Cl.[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH2:31])[CH3:27].C(N(CC)CC)C>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]([NH:31][CH2:30][C:29]([O:28][CH2:26][CH3:27])=[O:32])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCCc1ccccc1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)CCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
4-Phenylbutyric acid (2.46 g, 15 mmol) was dissolved in distilled tetrahydrofuran (70 ml) in an argon atmosphere. After cooling in an ice bath, carbonyl diimidazole (2.43 g, 15 mmol) was added and the mixture was stirred cold 1 hour and at room temperature 1 hour. The mixture was then cooled and glycine ethyl ester.hydrochloride (2.09 g, 15 mmol) and distilled triethylamine (2.1 ml, 15 mmol) were added. The mixture was left stirring overnight at room temperature. After removal of the solvent in vacuo, ethyl ether (200 ml) was added. The solution was washed with 1 N hydrochloric acid (70 ml), 0.5 N sodium hydroxide (70 ml) and saturated sodium chloride solution (70 ml), dried over anhydrous magnesium sulfate and freed of solvent in vacuo leaving the title I compound (3.13 g) as white crystalline material.
Reaction SMILES: Cl[O-].[Na+].[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]=[N:11][OH:12].[C:13]([O:17][C:18]([NH:20][CH2:21][C:22]#[CH:23])=[O:19])([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl>[C:13]([O:17][C:18]([NH:20][CH2:21][C:22]1[O:12][N:11]=[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]=2)[CH:23]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: ON=Cc1ccccn1
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1cc(-c2ccccn2)no1
Temperature: 25 °C
Yield: 42.7 %

Procedure:
Sodium hypochlorite (16 ml of a 14% w/v aqueous solution, 29.5 mmol) was added dropwise to a solution of 2-pyridinealdoxime (2 g, 16.4 mmol) and N-tert-butoxycarbonyl-propargylamine (5.6 g, 36.1 mmol) in DCM (30 ml) cooled in an ice bath. The mixture was stirred vigorously and allowed to warm to ambient temperature and stirred for 18 hours. The aqueous layer was separated and extracted with DCM. The combined organic extracts were combined, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography on silica gel eluting with diethyl ether/isohexane (1:1) to give the title compound (1.93 g, 43%). NMR (CDCl3) 1.45 (s, 9H), 4.5 (m, 2H), 5.03 (bs, 1H), 6.8 (s, 1H), 7.35 (m, 1H), 7.8 (m, 1H), 8.05 (d, 1H), 8.67 (m, 1H).
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([CH:15]=O)=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[Br:17][C:18]1[N:19]=[CH:20][C:21]([NH2:24])=[N:22][CH:23]=1>ClCCCl.CC(O)=O>[Br:17][C:18]1[N:19]=[CH:20][C:21]([NH:24][CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([CH3:2])=[CH:4][CH:5]=2)=[N:22][CH:23]=1
Reactant: Cc1ccc(-c2ccccc2C=O)cc1
Reactant: Nc1cnc(Br)cn1
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1ccc(-c2ccccc2CNc2cnc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
Sodium tiracetoxyl borohydride (215 mg, 1.02 mmol) was added to the solution of 4′-methyl-biphenyl-2-carbaldehyde and 5-bromo-pyrazin-2-ylamine in 5 ml of DCE, 0.1 ml of HOAc was added and the mixture was stirred overnight at room temperature, followed by addition of 5 ml of DCE. The organic phase was washed with water, and purified with column (silica gel, hexane:EtOAc 6:1) to give 100 mg of (5-bromo-pyrazin-2-yl)-(4′-methyl-biphenyl-2-ylmethyl)-amine, yield 55%.
Reaction SMILES: C([NH:6][C:7](=[S:11])[S:8][CH2:9][CH3:10])(OCC)=O.[CH3:12][O-:13].[K+].Cl[CH2:16][C:17]#[N:18].O>CO.[I-].[K+]>[CH2:9]([S:8][C:7]1[S:11][C:16]([C:17]#[N:18])=[C:12]([OH:13])[N:6]=1)[CH3:10]
Reactant: C[O-]
Reactant: N#CCCl
Reactant: CCOC(=O)NC(=S)SCC
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCSc1nc(O)c(C#N)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.8 %

Procedure:
A suspension of 40 g of ethyl N-carbethoxy-dithiocarbamate, 14 g of potassium methylate, 15 g of chloroacetonitrile and 1 g of potassium iodide in 250 ml of methanol was stirred for 3 hours at room temperature under an inert atmosphere and then 14 g of potassium methylate were added. The reaction mixture was refluxed for one hour and water was then added thereto. The aqueous phase was washed with ethyl acetate and then acidified with concentrated hydrochloric acid. The aqueous phase was extracted with ethyl acetate and the extracts were dried, filtered and evaporated to dryness. The residue was empasted with isopropyl ether and then filtered to obtain 14 g of 2-ethylthio-4-hydroxy-5-cyano-thiazole in the form of cream crystals melting at 160° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[CH2:29]([N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[CH3:30].C(OCC)(=O)C>CN(C=O)C>[Cl-:1].[CH2:29]([N+:31]1([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][C:16]([C:22]5[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=5)=[CH:17][CH:18]=4)[CH:13]=3)=[O:11])=[CH:5][CH:4]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[CH3:30]
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Reactant: CCN1CCCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[N+]1(Cc2ccc(NC(=O)C3=Cc4cc(-c5ccc(C)cc5)ccc4CC3)cc2)CCCCC1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 20 h

Procedure:
In DMF (3 ml) was dissolved N-[4—(chloromethyl)-phenyl]-7—(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (150 mg), and to the mixture was added 1-ethylpiperidine (159 μl). The mixture was stirred at room temperature for 20 hours. To the reaction mixture was added ethyl acetate (100 ml), and the resulting precipitate was filtered to give 1-ethyl-1-[4-[7—(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamido]benzyl]piperidinium chloride (Compound 34) (156 mg) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:30])[CH2:15][CH:16]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:17]([O:19]CC)=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:32]1[O:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[O:33]1[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=[C:32]1[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14](=[O:30])[CH2:15][CH:16]([CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:17]([OH:19])=[O:18])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CCc1ccccc1)CC(=O)c1ccc(-c2ccc(N)cc2)cc1
Reactant: Clc1nc2ccccc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(CC(CCc1ccccc1)C(=O)O)c1ccc(-c2ccc(Nc3nc4ccccc4o3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.6 %

Procedure:
A solution of ethyl 4-(4′-amino-1,1′-biphenyl-4-yl)-4-oxo-2-(2-phenylethyl)butanoate (100 mg, 0.25 mmol) and 2-chlorobenzoxazole (38.3 mg, 0.25 mmol) in toluene (1.0 mL) was heated at reflux for 16 h. Solvent was removed under reduced pressure, and the residue was dissolved in dichloromethane. The solution was washed with water, solvent was again removed under reduced pressure, and the residue was dissolved in methanol (1 mL) and tetrahydrofuran (1 mL). A 1 N aqueous solution of sodium hydroxide (0.77 mL, 0.77 mmol) was added, and the mixture was stirred at rt for 16 h and then concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford 4-[4′-(1,3-benzoxazol-2-ylamino)-1,1′-biphenyl-4-yl]-4-oxo-2-(2-phenylethyl)butanoic acid (40 mg, 33% yield). LC-MS ret. time 4.14 min, m/z 519.5 (MH+); 1H NMR (300 MHz, DMSO-d6) δ 1.82-1.90 (m, 2 H), 2.68 (m, 2 H), 2.80-2.85 (m, 1 H), 3.16 (dd, 1 H), 3.41 (m, 1 H), 7.10-7.30 (m, 8 H), 7.48 (t, 2 H), 7.78-7.86 (m, 4 H), 7.89 (d, 2 H), 8.02 (d, 2 H), 10.83 (br s, 1 H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH3:13][NH2:14].[BH4-].[Na+].O>CO>[CH3:13][NH:14][CH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[CH:3]=[CH:4]2
Reactant: Cn1ccc2cc(C=O)ccc21
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNCc1ccc2c(ccn2C)c1
Reaction time: 3 h
Yield: 99.6 %

Procedure:
N-Methylindole-5-carbaldehyde (800 mg, 5.1 mmol) was dissolved in anhydrous methanol (15 mL). Methylamine (7.15 mL of 2M solution in methanol, 15.3 mmol) was added and the reaction was stirred for 3 hr. The solution was concentrated to a yellow oil and then dissolved into anhydrous methanol (15 mL). Sodium borohydride (194 mg, 5.1 mmol) was added and the mixture was stirred overnight. Water (1 mL) was added and the solution was concentrated to an orange oil. Sodium hydroxide (5 mL, 1N) was added and the product was extracted with ethyl acetate (3×20 mL), dried over MgSO4 and concentrated to afford the title compound as an orange oil (885 mg, 100%). 1H NMR (200 MHz, CDCl3) δ 7.57(s, 1H), 7.35-7.11(m, 3H), 6.51 (d, J=2.9 Hz, 1H), 3.85 (s, 2H), 3.79 (s, 3H), 2.48 (s, 3H).
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:15]([C:17]1[C:22](=[O:23])[C:21]([C:24]#[N:25])=[C:20]([C:26]#[N:27])[C:19](=[O:28])[C:18]=1[C:29]#[N:30])#[N:16]>C(#N)C>[CH:4]1[C:5]2[C:14](=[CH:13][C:12]3[C:7]([CH:6]=2)=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:1]=[CH:2][CH:3]=1.[C:29]([C:18]1[C:19](=[O:28])[C:20]([C:26]#[N:27])=[C:21]([C:24]#[N:25])[C:22](=[O:23])[C:17]=1[C:15]#[N:16])#[N:30]
Reactant: c1ccc2c(c1)Cc1ccccc1C2
Agent: N#CC1=C(C#N)C(=O)C(C#N)=C(C#N)C1=O
Solvent: CC#N
Product: c1ccc2cc3ccccc3cc2c1
Temperature: -20 °C

Procedure:
A solution of 9,10-dihydroanthracene (35 mg; 0.192 mmol) dissolved in 1 mL dry acetonitrile was reacted with tetracyano-1,4-benzoquinone (40 mg; 0.192 mmol) also dissolved in 1 mL dry acetonitrile. After reducing the volume in half and cooling to -20° C. crystals precipitated and were collected. The infrared spectra of the precipitate was identical to that obtained from a mixture of authentic anthracene and tetracyano-1,4-hydroquinone (ν(C≡N)=2239 and 2263 cm-1) verifying that tetracyano-1,4-benzoquinone dehydrogenates 9,10-dihydroanthracene.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=O)=[CH:4][C:3]=1[F:17].[C:18]1(=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[F:17]
Reactant: O=C1CCCCCC1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Br)c(F)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: Oc1ccc(C(=C2CCCCCC2)c2ccc(Br)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 75.5 %

Procedure:
To a stirred suspension of zinc powder (0.90 g, 13.8 mmoL) in anhydrous THF (20 mL) was slowly added TiCl4 (0.75 mL, 1.3 g, 6.8 mmoL) via syringe at RT under a nitrogen atmosphere. (Note: significant fuming occurred upon addition of TiCl4.) The reaction mixture was heated at reflux with stirring under nitrogen for 2.25 h. A solution of (4-bromo-3-fluorophenyl)(4-hydroxyphenyl)methanone (186) (0.50 g, 1.7 mmoL) and cycloheptanone (0.6 mL, 0.57 g, 5.09 mmoL) in THF (10 mL) was added to the reaction mixture via syringe. The reaction mixture was heated at reflux for 2 h. The oil bath was removed and the reaction mixture was allowed to cool at RT. To the reaction mixture was added H2O (10 mL) followed by 10% K2CO3 (10 mL). The quenched reaction mixture was filtered through a pad of Celite with the aid of EtOAc and H2O. The pad washed with EtOAc and the filtrate was transferred to a separatory funnel. The layers were separated and the organic phase was allowed to stand at RT over the weekend. The organic phase was dried over MgSO4, filtered, and the filtrate was concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography on silica gel with a hexanes:EtOAc gradient (100:0 to 50:50) to give 0.48 g (75%) of compound 187 as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.50 (m, 8 H), 2.20 (m, 4 H), 6.67 (d, J=8.4 Hz, 2 H), 6.88 (dd, J=1.9 Hz, 8.3 Hz, 1 H), 6.92 (d, J=8.4 Hz, 2 H), 7.08 (dd, J=1.8 Hz, 10.0 Hz, 1 H), 7.59 (t, J=7.9 Hz, 1 H), 9.33 (s, 1 H). LRMS (ESI): m/z 373 (M−H)−.
Reaction SMILES: C(=O)([O-])OC1C=CC([N+]([O-])=O)=CC=1[CH2:12][CH:13]1[C:25]2[C:20](=[C:21]3[CH:33]=[CH:32][CH:31]=[CH:30][C:22]3=[C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]3=2)[C:19]2[C:14]1=[C:15]1[CH:41]=[CH:40][CH:39]=[CH:38][C:16]1=[C:17]1[CH:37]=[CH:36][CH:35]=[CH:34][C:18]1=2.[C:44]([OH:47])(=[O:46])C.[C:48]([O:52][C:53](=[O:63])[C@H:54]([CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[NH2:55])([CH3:51])([CH3:50])[CH3:49].O.OS([O-])(=O)=O.[K+]>ClCCl>[C:48]([O:52][C:53](=[O:63])[C@H:54]([CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[NH:55][C:44]([O:47][CH2:12][CH:13]1[C:14]2[C:19](=[C:18]3[CH:34]=[CH:35][CH:36]=[CH:37][C:17]3=[C:16]3[CH:38]=[CH:39][CH:40]=[CH:41][C:15]3=2)[C:20]2[C:25]1=[C:24]1[CH:26]=[CH:27][CH:28]=[CH:29][C:23]1=[C:22]1[CH:30]=[CH:31][CH:32]=[CH:33][C:21]1=2)=[O:46])([CH3:51])([CH3:49])[CH3:50]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C([O-])Oc1ccc([N+](=O)[O-])cc1CC1c2c(c3ccccc3c3ccccc23)-c2c1c1ccccc1c1ccccc21
Reactant: CC(=O)O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2c(c3ccccc3c3ccccc23)-c2c1c1ccccc1c1ccccc21
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of 17-tetrabenzo(a,c,g,i)fluorenylmethyl-para-nitrophenyl carbonate (139.4 mg, 0.248 mmol) and L-phenylalanine tert-butyl ester acetate (83.9 mg, 0.298 mmol; 1.2 equiv) in dichloromethane (5 ml) was added N,N′-dimethylaniline (63 μl, 0.497 mmol; 2 equiv). The reaction mixture was stirred at room temperature under nitrogen for 120 h. After addition of water (10 ml) and acidification with KHSO4 (2M) to pH=1, the reaction mixture was extracted with dichloromethane (3×20 ml). The combined organic phases were washed with water (2×15 ml) to pH 6-7 and dried over MgSO4. After filtration the solvent was evaporated under reduced pressure to give an orange oil. After purification by flash chromatography using toluene as the eluent, the fractions containing material of Rf=0.04 were evaporated to give a yellow solid. Recrystallization from ether/petrol (b.p. 40-60° C.) gave compound (54) as a pale yellow solid which was filtered, washed with petrol and finally dried (73.9 mg, 46%);
Reaction SMILES: [Si](OCC(C)C[C@H:12]1[C:17](=[O:18])[NH:16][C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[O:13]1)(C(C)(C)C)(C)C.CCCC[N+](C[CH2:38][CH2:39][CH3:40])(CCCC)CCCC.[F-].C1C[O:45][CH2:44]C1>>[OH:45][CH2:44][C@@H:39]([CH3:38])[CH2:40][N:16]1[C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[O:13][CH2:12][C:17]1=[O:18]
Reactant: C1CCOC1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CC(CO[Si](C)(C)C(C)(C)C)C[C@@H]1Oc2ccccc2NC1=O
Agent: [F-]
Product: C[C@H](CO)CN1C(=O)COc2ccccc21
Yield: 98 %

Procedure:
The compound (S)-4-[3-(tert-Butyldimethylsilanyloxy)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (108LM24-21) (3.92 g, 11.7 mmol) and TBAF (4.78 g, 15.2 mmol) in THF (30 mL) were reacted according to GP3 to give the title compound (108LM26-23) (2.52 g, 98%). 1H NMR (CDCl3) δ 7.05-6.95 (m, 4H), 4.63 (s, CH2), 4.23 (dd, J=10.3 Hz, J=13.9 Hz, 1H), 3.56 (dd, J=4.8 Hz, J=13.9 Hz, 1H), 3.52-3.49 (m, 1H), 3.46-3.38 (m, 1H), 2.92-2.85 (m, 1H), 2.09-1.97 (m, 1H), 1.06 (d, J=7.3 Hz, CH3).
Reaction SMILES: [C:1](Br)(=[O:4])[CH2:2][CH3:3].[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:48]([F:51])([F:50])[F:49])=[C:11]([N:13]2[C:17](=[O:18])[N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[S:32](=[O:42])(=[O:41])[NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:22][C:21]=3[F:43])[C:15]([CH2:44][CH2:45][CH2:46][CH3:47])=[N:14]2)[CH:12]=1>>[C:37]([O:36][C:34]([NH:33][S:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:16]2[C:15]([CH2:44][CH2:45][CH2:46][CH3:47])=[N:14][N:13]([C:11]3[CH:12]=[C:7]([NH:6][C:1](=[O:4])[CH2:2][CH3:3])[CH:8]=[CH:9][C:10]=3[C:48]([F:50])([F:51])[F:49])[C:17]2=[O:18])=[C:21]([F:43])[CH:22]=1)(=[O:42])=[O:41])=[O:35])([CH3:38])([CH3:39])[CH3:40]
Reactant: CCCCc1nn(-c2cc(N)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1F
Reactant: CCC(=O)Br
Product: CCCCc1nn(-c2cc(NC(=O)CC)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1F
Yield: 95 %

Procedure:
Propionyl bromide was reacted with 2-[5-amino-2-(trifluoromethyl)phenyl]-4-[[2'-[N-(t-butoxycarbonyl)sulfamoyl]-3-fluorobiphenyl-4-yl]methyl]-5-n-butyl-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step D) according to the procedure of Example 26 to give a 95% yield of the title compound as a white solid, mp 167°-169° C.; homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 726 (M+Li)+.
Reaction SMILES: F[C:2]1[CH:15]=[N:14][C:5]2[N:6]=[CH:7][C:8](=[O:13])[N:9]([CH2:10][CH:11]=[CH2:12])[C:4]=2[CH:3]=1.[CH3:16][O-:17].[Na+].O>CO>[CH3:16][O:17][C:2]1[CH:15]=[N:14][C:5]2[N:6]=[CH:7][C:8](=[O:13])[N:9]([CH2:10][CH:11]=[CH2:12])[C:4]=2[CH:3]=1
Reactant: C[O-]
Reactant: C=CCn1c(=O)cnc2ncc(F)cc21
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=CCn1c(=O)cnc2ncc(OC)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 407.4 %

Procedure:
A solution of 7-fluoro-1-(2-propen-1-yl)pyrido[2,3-b]pyrazin-2(1H)-one (196 mg, 0.956 mmol) in MeOH (5 ml) was treated with sodium methoxide (25% w/v in MeOH, 1.03 ml. 4.780 mmol) and stirred at rt for 1 h. The reaction was repeated with more 7-fluoro-1-(2-propen-1-yl)pyrido[2,3-b]pyrazin-2(1H)-one (657 mg, 3.204 mmol) in MeOH (15 ml) and sodium methoxide (25% w/v in MeOH, 3.45 ml. 16.02 mmol). This reaction was also stirred for 1 h after which time both reaction mixtures were combined and treated with water (100 ml). The mixture was then extracted with DCM (3×100 ml). The combined organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give a yellow solid which was purified by column chromatography on silica with ethyl acetate to give the desired product as a brown solid (846 mg, 94%).
Reaction SMILES: [N+](=[CH2:3])=[N-].[Br:4][CH2:5][C:6]([C:8](=[N:34][OH:35])[C:9]([NH:11][CH:12]1[C:32](=[O:33])[N:14]2[C:15]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[O:20])=[CH:16][CH2:17][S:18][C@H:13]12)=[O:10])=[O:7]>C(OCC)C.O1CCCC1>[Br:4][CH2:5][C:6]([C:8](=[N:34][O:35][CH3:3])[C:9]([NH:11][CH:12]1[C:32](=[O:33])[N:14]2[C:15]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[O:20])=[CH:16][CH2:17][S:18][C@H:13]12)=[O:10])=[O:7]
Reactant: O=C(CBr)C(=NO)C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12

Procedure:
A solution of diazomethane in diethyl ether was added little by little to a solution of 4-nitrobenzyl 7-[2-(2-bromoacetyl)-2-hydroxyiminoacetamido]-3-cephem-4-carboxylate (0.9 g.) in tetrahydrofuran (30 ml.) under ice-cooling until the reaction terminated, and then acetic acid was added to the resultant solution to decompose excess diazomethane. The resultant solution was concentrated under reduced pressure to give the foamy product of 4-nitrobenzyl 7-[2-(2-bromoacetyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer: 0.9 g.)
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:27][CH2:26][CH2:25][C@H:6]1[C:7]([N:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])([OH:3])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH:43]1([NH2:48])[CH2:47][CH2:46][CH2:45][CH2:44]1>C(#N)C>[CH:43]1([NH:48][C:1](=[O:3])[CH2:4][N:5]2[CH2:27][CH2:26][CH2:25][C@H:6]2[C:7]([N:9]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])[CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: NC1CCCC1
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)NC1CCCC1
Yield: 79.9 %

Procedure:
A -5° C. solution of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide (0.212 g, 0.56 mmol, 1.0 eq), and triethylamine (96 uL, 65 mg, 0.65 mol, 1.15 eq), in acetonitrile (10 mL) was treated with isobutyl chloroformate (77 uL, 86 mg, 0.59 mmol, 1.05 eq) followed by cyclopentylamine (111 uL, 96 mg, 1.13 mmol, 2.0 eq). Workup as above provided 198 mg (79%) of L-isoleucine, N-[1-[2-(N-cyclopentylamino)-2-oxoethyl]-L-prolyl] benzylamide.
Reaction SMILES: C(OC(=O)[N:7]([C:19]1[CH:24]=[CH:23][C:22]([CH:25](O)[C:26]2[C:34]3[C:29](=[N:30][CH:31]=[C:32]([O:35][Si:36]([CH:43]([CH3:45])[CH3:44])([CH:40]([CH3:42])[CH3:41])[CH:37]([CH3:39])[CH3:38])[CH:33]=3)[NH:28][CH:27]=2)=[CH:21][N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[F:17][C:15]([F:16])([F:18])[C:12]1[CH:13]=[CH:14][C:9]([CH2:8][NH:7][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]3[C:34]4[C:29](=[N:30][CH:31]=[C:32]([O:35][Si:36]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:38])[CH3:39])[CH:43]([CH3:44])[CH3:45])[CH:33]=4)[NH:28][CH:27]=3)=[CH:21][N:20]=2)=[CH:10][CH:11]=1
Reactant: CC(C)[Si](Oc1cnc2[nH]cc(C(O)c3ccc(N(Cc4ccc(C(F)(F)F)cc4)C(=O)OC(C)(C)C)nc3)c2c1)(C(C)C)C(C)C
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[Si](Oc1cnc2[nH]cc(Cc3ccc(NCc4ccc(C(F)(F)F)cc4)nc3)c2c1)(C(C)C)C(C)C
Temperature: 0 °C
Yield: 103 %

Procedure:
A mixture of {5-[hydroxy-(5-triisopropylsilanyloxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl}-(4-trifluoromethyl-benzyl)-carbamic acid tert-butyl ester (84, 0.05 g, 0.07 mmol), trifluoroacetic acid (0.5 mL, 0.006 mol), and triethylsilane (1 mL, 0.006 mol) in acetonitrile (10 mL) was refluxed for 2 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with saturated sodium bicarbonate, brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a viscous liquid (85, 0.04 g, 97%). MS (ESI) [M+H+]+=555.38.