Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][C:3]1=[O:14].[H-].[Na+].BrC[C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C=O)C>[N+:11]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[C:2]([CH2:1][C:25]([O:27][CH2:28][CH3:29])=[O:26])([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:3](=[O:14])[NH:4]2)([O-:13])=[O:12]
Reactant: CCOC(=O)CC1(C)C(=O)Nc2cccc([N+](=O)[O-])c21
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1(CC(=O)OCC)C(=O)Nc2cccc([N+](=O)[O-])c21
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-nitro-1,3-dihydro-2H-indol-2-one (5.25 g, 29.5 mmol, described in Intermediate 16) in DMF (200 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil; 1.24 g, 30.9 mmol) and the resulting mixture was stirred for 30 min. Ethyl bromoacetate (3.60 mL, 32.4 mmol) was added dropwise and the mixture was stirred at 0° C. for 1 h. A further equivalent of sodium hydride (60% dispersion in mineral oil; 1.24 g, 30.9 mmol) was added, stirring was continued for 1 h, then ethyl bromoacetate (3.00 mL, 27.1 mmol) was added dropwise. The reaction mixture was stirred for 1 h, then quenched with saturated aqueous NH4Cl (125 mL) and H2O (500 mL). The mixture was extracted with EtOAc (3×300 mL) and the combined organic extracts were washed with brine (100 mL), then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 50:50, to give the title compound. MS: m/z=351 (M+1).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]1([CH2:10][C:11](Cl)=[O:12])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1C=CC=CC=1>[CH3:1][N:2]([CH3:3])[C:11](=[O:12])[CH2:10][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CNC
Solvent: c1ccccc1
Product: CN(C)C(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In 204 ml of anhydrous benzene was dissolved 77.5 g (0.5 mole) of commercially available phenylacetyl chloride, and the solution was added dropwise to a 50% aqueous solution of 180 g (2.0 moles) of dimethyl amine, 50 g of ice and 100 ml of benzene at an inner temperature of 5° to 25° C. After completion of the dropwise addition, the mixture was agitated for 1 hour at the same temperature.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]([NH:17]C(=O)OCC1C=CC=CC=1)[CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:14][C:13](=[O:15])[NH:12][C:11]=2[CH:16]=1)=[O:4].[H][H]>[Pd].CO>[NH2:17][C@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:14][C:13](=[O:15])[NH:12][C:11]=2[CH:16]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: [H][H]
Reactant: COC(=O)[C@@H](Cc1ccc2[nH]c(=O)[nH]c2c1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](N)Cc1ccc2[nH]c(=O)[nH]c2c1
Yield: 99.2 %

Procedure:
Benzyl(R)-1-(methoxycarbonyl)-2-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-6-yl)ethylcarbamate (265 mg, 0.72 mmol) and 10% palladium on carbon (30 mg) in methanol (15 mL) were agitated for 1.5 h under 50 psi hydrogen using a Parr apparatus. The reaction mixture was purged with 3 vacuum/nitrogen purge cycles. The reaction mixture was then filtered through a pad of Celite® and the pad was rinsed with several portions of methanol. The methanol filtrate was evaporated to give the title compound (168 mg, quantitative yield). 1H-NMR (CD3OD, 300 MHz) δ 6.97 (d, J=8.1 Hz, 1H), 6.87 (s, 1H), 6.86 (d, J=8.2 Hz, 1H), 3.71-3.64 (m, 1H), 3.67 (s, 3H), 3.04-2.89 (m, 2H). LC/MS: tR=0.87 min, 236 (MH)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:28]=[CH:27][C:15]2[C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[CH:26])=[CH:21][CH:20]=3)=[N:17][S:18][C:14]=2[CH:13]=1)[CH2:4][CH2:5][OH:6])[CH3:2]>CCOC(C)=O.[Pd]>[CH2:1]([N:3]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:28]=[CH:27][C:15]2[C:16]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][S:18][C:14]=2[CH:13]=1)[CH2:4][CH2:5][OH:6])[CH3:2]
Reactant: C#Cc1ccc(-c2nsc3cc(OCCCCN(CC)CCO)ccc23)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1ccc(-c2nsc3cc(OCCCCN(CC)CCO)ccc23)cc1

Procedure:
150 mg (0.4 mmol) 2-(Ethyl-{4-[3-(4-ethynyl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amino)-ethanol in 6 ml EtOAc were hydrogenated in the presence of 50 mg 10% Pd/C, filtration over decalite, followed by purification by preparative HPLC yielded 2-(Ethyl-{4-[3-(4-ethyl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amino)-ethanol as light yellow oil, MS: 399 (MH+).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:6].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]23[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][CH2:20][N:19]2[CH2:18][CH2:17][C:16](=O)[CH2:15]3)=[CH:10][CH:9]=1.[BH3-]C#N.[Na+]>CO>[ClH:6].[ClH:6].[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]23[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][CH2:20][N:19]2[CH2:18][CH2:17][CH:16]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:15]3)=[CH:12][CH:13]=1
Reactant: Cc1ccc(C23CC(=O)CCN2CCc2ccccc23)cc1
Reactant: C1CCNC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(C23CC(N4CCCC4)CCN2CCc2ccccc23)cc1

Procedure:
A solution of 14 ml of pyrrolidine (168 mmoles) in 75 ml of methanol is neutralized with HCl gas while the solution is cooled in an ice bath. 13 ml more (156 mmoles) of yrrolidine is added along with 100 ml of methanol. Thereafter is added 16.0 g (54.9 mmoles) of 11b-(4-methylphenyl)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizin-2-one, 3.47 g (55.2 mmoles) of NaBH3CN and molecular sieves. A drying tube is attached and the reaction conditions of EXAMPLE 7 are employed. The work-up procedures of EXAMPLE 8 are used to obtain 11b-(4-methylphenyl)-1,3,4,6,7,11b-hexahydro-2-pyrrolidin-1-yl-2H-benzo[a]quinolizine dihydrochloride.
Reaction SMILES: [C:1]1(=[O:13])[O:10][C:8](=O)[CH:7]2[CH2:11][CH2:12][C:2]1([C:4]2([CH3:6])[CH3:5])[CH3:3].[NH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>N1C=CC=CC=1>[CH3:3][C:2]12[C:4]([CH3:5])([CH3:6])[CH:7]([CH2:11][CH2:12]1)[C:8](=[O:10])[N:14]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[C:1]2=[O:13]
Reactant: NCCc1ccccn1
Reactant: CC12CCC(C(=O)OC1=O)C2(C)C
Solvent: c1ccncc1
Product: CC12CCC(C(=O)N(CCc3ccccn3)C1=O)C2(C)C

Procedure:
A mixture of (-) camphoric anhydride 5 g (0.029 mol), 2-(2-aminoethyl)pyridine 3.6 (0.03 mol) and 50 ml of pyridine was refluxed overnight. The solvent is removed under reduced pressure and the remaining oil boiled in 20 ml of ethanol and allowed to cool.
Reaction SMILES: O=O.[CH3:3][O:4]/[C:5](=[CH:9]\[C:10]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:12][CH:11]=1)/[C:6]([OH:8])=[O:7].C1([C@@H](N)C)C=CC=CC=1.[H][H]>ClCCl>[CH3:3][O:4][C@H:5]([CH2:9][C:10]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: CO/C(=C\c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Reactant: [H][H]
Agent: C[C@H](N)c1ccccc1
Agent: O=O
Solvent: ClCCl
Product: CO[C@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a glove box (O2 content≦2 ppm), a 50-ml stainless steel autoclave was charged with 0.66 mg of [Ru(η5-2,4-DMP)((R)—(S)—PPF—PtBu2)(NCMe)]BF4 (0.0008 mmol, S/C 3,000) and 5 ml of dichloromethane. The resulting violet solution was stirred for 2 h at r.t. Then, 1.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (2.30 mmol), 10 ml of dichloromethane and 0.06 ml of (S)-1-phenylethylamine (0.47 mmol) were added. The autoclave was sealed and the hydrogenation was run under stirring at 40° C. under 30 bar of hydrogen. After 16 h the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford (R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 99.5% (99.9% conversion) and an enantiomeric purity of 90%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[H-].[Na+].Cl[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[N:17]=[C:16]([CH3:30])[N:15]=1.O>CN(C)C=O>[CH3:29][O:28][C:22]1[CH:21]=[C:20]([C:18]2[N:17]=[C:16]([CH3:30])[N:15]=[C:14]([O:10][C:3]3[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])[CH:19]=2)[CH:25]=[CH:24][C:23]=1[O:26][CH3:27]
Reactant: COc1ccc(-c2cc(Cl)nc(C)n2)cc1OC
Reactant: Cc1cc(C)c(O)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(Oc3c(C)cc(C)cc3C)nc(C)n2)cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71.2 %

Procedure:
To a solution of 2,4,6-trimethylphenol (1.03 g) in N,N-dimethylformamide (20 ml) was added sodium hydride (60% in oil, 0.30 g), and stirred at ambient temperature for 5 minutes. To the solution was added 4-chloro-6-(3,4-dimethoxyphenyl)-2-methylpyrimidine (2.0 g), and the mixture was stirred at ambient temperature for 18 hours. The solution was poured into water (300 ml), and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel eluting with chloroform to give 6-(3,4-dimethoxyphenyl)-2-methyl-4-(2,4,6-trimethylphenoxy)pyrimidine (1.96 g).
Reaction SMILES: [Na].[N+]([C:5]1[CH:6]=[C:7]([CH3:12])[N+:8]([O-:11])=[CH:9][CH:10]=1)([O-])=O.[CH3:13][OH:14]>>[CH3:12][C:7]1[CH:6]=[C:5]([O:14][CH3:13])[CH:10]=[CH:9][N+:8]=1[O-:11]
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Reactant: CO
Agent: [Na]
Product: COc1cc[n+]([O-])c(C)c1
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of sodium (4.6 g, 0.2 mole) in anhydrous methanol (140 ml) at 25° C. was added 4-nitro-2-picoline-N-oxide (31 g, 0.2 mole). The mixture was stirred for 11/2 hours and then filtered. The filtrate was evaporated and the residue extracted with ethyl acetate. The solution was filtered, evaporated and the oily residue distilled to give the title compound (25.7 g, 92%) b.p. 150° C. at 0.2 mm mercury.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[CH:10]=[N:11][N:12]([CH:19]([CH3:21])[CH3:20])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([Cl:32])[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=1>CCOC(C)=O>[Cl:32][C:26]1[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=[C:24]([NH:23][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2[CH:10]=[N:11][N:12]([CH:19]([CH3:21])[CH3:20])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:25]=1
Reactant: CCOC(=O)c1c(C(O)c2ccc(Cl)cc2)cnn1C(C)C
Reactant: Cn1cc(N)cc(Cl)c1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C(Nc2cc(Cl)c(=O)n(C)c2)c2ccc(Cl)cc2)cnn1C(C)C

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-isopropyl-1H-pyrazole-5-carboxylate (Step 36.3) and 5-amino-3-chloro-1-methylpyridin-2(1H)-one (Step 5.2). tR: 5.17 min (HPLC 1); tR: 1.17 min (LC-MS 2); ESI-MS: 463 [M+H]+ (LC-MS 2); Rf=0.53 (EtOAc).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[S:19]1[CH:23]=[CH:22][C:21]([C:24](Cl)=[O:25])=[CH:20]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH:12][C:24]([C:21]3[CH:22]=[CH:23][S:19][CH:20]=3)=[O:25])=[N:9][C:8]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: O=C(Cl)c1ccsc1
Reactant: Cc1nc(-c2sc(N)nc2-c2ccccc2)no1
Product: Cc1nc(-c2sc(NC(=O)c3ccsc3)nc2-c2ccccc2)no1

Procedure:
Prepared from 5-(5-methyl-[1,2,4]oxadiazol-3-yl)-4-phenyl-thiazol-2-ylamine and thiophene-3-carbonyl chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:11])[NH:9][N:10]=[C:4]2[C:3]=1I.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:7]=[CH:6][N:5]3[C:8](=[O:11])[NH:9][N:10]=[C:4]3[C:3]=2[C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)=[CH:16][CH:15]=1
Reactant: O=c1[nH]nc2c(I)c(Br)ccn12
Reactant: OB(O)c1ccc(Cl)cc1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)ccn12
Temperature: 150 °C
Yield: 51.7 %

Procedure:
To a stirring mixture of 7-bromo-8-iodo-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (1.0 g, 2.9 mmol) in 15 mL dioxane and 5 mL of water at 20° C. was added 4-chlorophenylboronic acid (1.4 g, 8.8 mmol), K2CO3 (0.8 g, 5.9 mmol), and tetrakis(triphenylphosphine)palladium (0.17 g, 0.15 mmol). The resulting reaction mixture was degassed and then heated in a microwave reactor at 150° C. for 40 min under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was allowed to cool to room temperature and was concentrated under reduced pressure. The crude product was purified by trituration with methylene chloride to obtain the title compound (0.52 g, 1.5 mmol) as a light yellow solid. MS: [M+H]+=356. 1H NMR (CD3OD): δ 7.89 (d, J=1.9 Hz, 1H), 7.37-7.24 (m, 8H), 5.48 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([NH:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[N:5]2[N:20]=[CH:21][N:22]=[C:4]2[N:3]=1.CN.[CH2:25]([N:27](CC)CC)C>C1(C)C=CC=CC=1>[CH3:25][NH:27][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([NH:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[N:5]2[N:20]=[CH:21][N:22]=[C:4]2[N:3]=1
Reactant: Clc1nc2ncnn2c(NC2CCCC2)c1-c1ccccc1
Reactant: CCN(CC)CC
Agent: CN
Solvent: Cc1ccccc1
Product: CNc1nc2ncnn2c(NC2CCCC2)c1-c1ccccc1
Yield: 75 %

Procedure:
A mixture of 5-chloro-6-phenyl-7-cyclopentylamino-1,2,4-triazolo[1,5-a]pyrimidine (3.1 g, 10 mmol) prepared by a method analogous to Example 2, methylamine (5 ml), triethylamine (5 ml) and toluene (50 ml) was refluxed for 10 hours. After cooling, the reaction mixture was washed with water (50 ml) and the organic layer separated, dried over sodium sulphate and evaporated. Recrystallization of the solid residue from diisopropyl ether gave 2.3 g 5-methylamino-6-phenyl-7-cyclopentylamino-1,2,4-triazolo[1,5-a]pyrimidine as colourless crystals, m.pt. 158°-160° C. Yield: 75% of theoretical 1H-NMR: δ=1.25-1.7 (mm, 8H); 2.95 (d,3H); 3.42 (m,1H); 4.48 (m,1H); 5.55 (d,1H); 7.3-7.5 (m,5H); 8.03 (s,1H)
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:57]([CH3:59])[CH3:58])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]3[C:31]4[C:26](=[C:27]5[CH:35]=[CH:34][C:33]([C:36]6[NH:40][C:39]([C@@H:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](OCC7C=CC=CC=7)=[O:47])=[N:38][CH:37]=6)=[CH:32][C:28]5=[CH:29][CH:30]=4)[O:25][CH2:24][C:23]=3[CH:56]=2)=[CH:17][N:18]=1)=[O:8])=[O:4].Br.[CH3:61][O:62][C:63]([NH:65][C@H:66]([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)C(O)=O)=[O:64].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(O)(=O)C.ClCCl.C(OCC)(=O)C.CN(C)C=O>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:57]([CH3:59])[CH3:58])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]3[C:31]4[C:26](=[C:27]5[CH:35]=[CH:34][C:33]([C:36]6[NH:40][C:39]([C@@H:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](=[O:47])[C@H:66]([NH:65][C:63](=[O:64])[O:62][CH3:61])[C:70]7[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=7)=[N:38][CH:37]=6)=[CH:32][C:28]5=[CH:29][CH:30]=4)[O:25][CH2:24][C:23]=3[CH:56]=2)=[CH:17][N:18]=1)=[O:8])=[O:4]
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)COc2c-3ccc3cc(-c4cnc([C@@H]5CCCN5C(=O)OCc5ccccc5)[nH]4)ccc23)[nH]1)C(C)C
Agent: Br
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)COc2c-3ccc3cc(-c4cnc([C@@H]5CCCN5C(=O)[C@H](NC(=O)OC)c5ccccc5)[nH]4)ccc23)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
A mixture of (S)-benzyl 2-(5-(8-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (260 mg, 0.33 mmol), 33% HBr in acetic acid (1 mL) and dichloromethane (4 mL) was vigorously stirred at room temperature for 30 minutes and then thoroughly concentrated. The crude material was diluted with dichloromethane and concentrated, letting the resulting residue sit under vacuum overnight. To this residue were sequentially added dichloromethane (2.4 mL), dimethylformamide (0.6 mL), (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (88 mg, 0.42 mmol), and COMU (154 mg, 0.36 mmol) and diisopropylethylamine (0.16 mL, 0.9 mmol). After stirring for 30 minutes at room temperature the reaction was diluted with ethyl acetate and washed sequentially with saturated aqueous NaHCO3 solution, water and brine. The organic layer was dried (MgSO4), then filtered through a freebasing column (Stratospheres™ PL-HCO3MP SPE, Part #: PL3540-C603). The filtrate was concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H2O+0.1% HCO2H) to yield methyl (R)-2-((S)-2-(5-(8-(2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate (72 mg, 26%). LCMS-ESI+: calculated for C48H50N8O7: 850.96; observed [M+1]+: 851.93.
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.[F:10][C:11]1[CH:12]=[C:13]([CH:36]=[CH:37][CH:38]=1)[CH2:14][N:15]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]3[C:30]4=[C:31]([CH2:34]O)[CH:32]=[CH:33][N:29]4[N:28]=[CH:27][N:26]=3)=[CH:21][CH:22]=2)[CH:17]=[N:16]1.C(N(CC)CC)C.[F:46][C:47]1([F:54])[CH2:53][NH:52][CH2:51][CH2:50][NH:49][CH2:48]1>C(Cl)Cl.ClCCCl>[F:46][C:47]1([F:54])[CH2:53][N:52]([CH2:34][C:31]2[CH:32]=[CH:33][N:29]3[C:30]=2[C:25]([NH:24][C:20]2[CH:19]=[C:18]4[C:23](=[CH:22][CH:21]=2)[N:15]([CH2:14][C:13]2[CH:36]=[CH:37][CH:38]=[C:11]([F:10])[CH:12]=2)[N:16]=[CH:17]4)=[N:26][CH:27]=[N:28]3)[CH2:51][CH2:50][NH:49][CH2:48]1
Reactant: FC1(F)CNCCNC1
Reactant: OCc1ccn2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Fc1cccc(Cn2ncc3cc(Nc4ncnn5ccc(CN6CCNCC(F)(F)C6)c45)ccc32)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 9.5 %

Procedure:
A solution of methanesulfonic anhydride (114 mg, 3.2 equiv.) in DCM (0.6 mL) was added to a solution of {4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methanol (78 mg, 2 mmole) in dry DCM (1.4 mL) at 0° C. under nitrogen followed by triethylamine (0.140 mL, 5 equiv.). After stirring at 0° C. for 1 hr, 6,6-difluoro-[1,4]diazepane (82 mg, 3 equiv.) and 1,2 dichloroethane (2 mL) were added. The reaction mixture was transferred to a microwave reactor (Personal Chemistry's Smith Creator) and irradiated at 65° C. for 50 min. Removal of the solvent followed by preparative HPLC afforded the title compound as a solid (29 mg, 29%). MS: 507 (M+H+); HPLC Ret Time: 1.47 min (YMC Xterra ODS S7 3.0×50 mm column, 2 min gradient, 5 ml/min).
Reaction SMILES: C1(CC([NH:10][CH:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([OH:25])=[O:24])=[C:15](/[CH:18]=[CH:19]\[CH:20]4[CH2:22][CH2:21]4)[CH2:16][S:17][C@H:12]23)=O)C=CC=CC=1.N.CC1(C)S[C@@H]2[C@H](NC(CC3C=CC=CC=3)=O)C(=O)N2[C@H]1C([O-])=O.[K+]>O>[NH2:10][CH:11]1[C:26](=[O:27])[N:13]2[C:14]([C:23]([OH:25])=[O:24])=[C:15](/[CH:18]=[CH:19]\[CH:20]3[CH2:22][CH2:21]3)[CH2:16][S:17][C@H:12]12
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)=C(/C=C\C3CC3)CS[C@H]12
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Agent: N
Agent: [K+]
Solvent: O
Product: NC1C(=O)N2C(C(=O)O)=C(/C=C\C3CC3)CS[C@H]12
Temperature: 37 °C
Reaction time: 5 h

Procedure:
6 g (0.0156 mol) of 7-phenylacetamido-3-[(Z)-2-cyclopropyl-viny]-3-cephem-4-carboxylic acid are suspended in 320 ml of water and the suspension is brought to pH 7.8 with half-concentrated ammonia solution, whereupon an almost clear solution forms. The solution is warmed to 37° C. and 35 g of penicillin-acylase resin are added. The reaction solution is titrated further to pH 7.8 with ammonia and kept at 37° C. for 5 hours. The resin is then filtered off with suction and the filtrate is concentrated down to a volume of 50 ml. The concentrated solution is brought to pH 4.2 with 2N HCl, whereupon the product precipitates out and is filtered off with suction and washed with water and acetone.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH2:26][CH2:25][CH2:24]1.CCN(CC)CC>CS(C)=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:23]2[CH2:26][CH2:25][CH2:24]2)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: C1CNC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(N2CCC2)c(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example B5), azetidine and Et3N in DMSO at 23° C. according to the general procedure C. Obtained as a yellow solid (6.925 g).
Reaction SMILES: IC.[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:15][C:16]#[N:17])[C:12]([OH:14])=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:18]1CCN2C(=NCCC2)CC1.OS([O-])(=O)=O.[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[CH3:18][O:13][C:12](=[O:14])[C@@H:11]([NH:10][C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])[CH2:15][C:16]#[N:17]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC#N)C(=O)O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@H](CC#N)NC(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 86.3 %

Procedure:
Iodomethane (2.18 ml, 35.01 mmol) was added to a mixture of (S)-2-(tert-butoxycarbonylamino)-3-cyanopropanoic acid (5.00 g, 23.34 mmol) and DBU (3.67 ml, 24.51 mmol) in toluene (20 mL) at rt. The reaction was stirred at 50 C for 2 days. Water (20 mL), saturated KHSO4 (20 mL) and ethyl acetate (50 mL) were added. The organic layer was separated, washed with brine and dried over sodium sulfate. After removal of solvent, the residue was purified by chromatography (hexane:Ethyl acetate=2:1) to give the (S)-methyl-2-(tert-butoxycarbonylamino)-3-cyanopropanoate as white solid (4.6 g, 86%). 1H NMR (400 MHz, d6-DMSO) δ7.64 (d, J=8.8 Hz, 1H), 4.39 (m, 1H), 3.66 (s, 3H), 2.96 (dd, J=16.8 Hz & 5.1 Hz, 1H), 2.85 (dd, J=16.8 Hz & 5.2 Hz, 1H), 1.40 (s, 9H).