Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.COC1C=CC(C[N:30](CC2C=CC(OC)=CC=2)[C:31]2[N:36]=[C:35]([CH3:37])[C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][N:32]=2)=CC=1.COC1C=CC(CN(CC2C=CC(OC)=CC=2)C2N=CC(B3OC(C)(C)C(C)(C)O3)=CN=2)=CC=1>>[CH3:37][C:35]1[C:34]([C:2]2[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:4]=3[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=2)=[CH:33][N:32]=[C:31]([NH2:30])[N:36]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)c(C)n2)cc1
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1ccncc1
Agent: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)cc1
Product: Cc1nc(N)ncc1-c1nc(N2CCOCC2)nc2c1CCN2c1ccncc1
Yield: 24.2 %

Procedure:
Using 4-chloro-2-morpholin-4-yl-7-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (64 mg) obtained in Step C in Example 1-B-01 and bis-(4-methoxy-benzyl)-[4-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-yl]-amine (105 mg) obtained in Step A in Example 1-D-260 instead of bis-(4-methoxy-benzyl)-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-yl]amine used in Step D in Example 1-B-01, the same operation as Step D in Example 1-B-01 was carried out, to obtain the desired compound (D-261) as a colorless powder (19 mg, 25%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][C:4]=1[O:18][CH2:19][O:20][CH3:21].[C-:22]#[N:23].[Na+].CCOC(C)=O>CN(C=O)C.O>[O:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][C:22]#[N:23])=[C:4]([O:18][CH2:19][O:20][CH3:21])[CH:5]=1
Reactant: [C-]#N
Reactant: COCOc1cc(-c2nc3ccccc3o2)ccc1CBr
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COCOc1cc(-c2nc3ccccc3o2)ccc1CC#N

Procedure:
2-[4-(Bromomethyl)-3-(methoxymethoxy)phenyl]-1,3-benzoxazole (250 mg, 0.72 mmol) was treated with sodium cyanide (150 mg, 2.2 mmol) in DMF/H2O (15 mL/1.5 mL) at 90° C. for 3 h and EtOAc (150 mL) was added. The EtOAc solution was washed with H2O (2×20 mL), brine (2×20 mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue was eluted with flash column (silica gel, hexanes:EtOAc 4:1) to afford the desired [4-(1,3-benzoxazol-2-yl)-2-(methoxymethoxy)phenyl]acetonitrile as a yellow solid. 1H NMR (CD3OD, 300 MHz), δ 8.02 (d, 2H), 7.95 (m, 1H), 7.80 (m, 1H), 7.63 (m, 1H), 7.57 (d, 2H), 7.40 (m, 2H). MS (ESI) 295 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([S:5]([O:8]CCCC)(=[O:7])=[O:6])[CH2:4][CH2:3]1.[S-]C#N.[K+:16]>O1CCOCC1.O>[CH3:1][C:2]1([S:5]([O-:8])(=[O:7])=[O:6])[CH2:4][CH2:3]1.[K+:16]
Reactant: CCCCOS(=O)(=O)C1(C)CC1
Agent: N#C[S-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(S(=O)(=O)[O-])CC1
Temperature: 25 °C

Procedure:
A mixture of butyl 1-methylcyclopropane-1-sulfonate (0.80 g, 4.2 mmol) and potassium thiocyanate (0.404 g, 4.16 mmol) in 1,4-dioxane/water (1:1, 10 mL) was heated at reflux for about 8 h. The reaction was cooled to ambient temperature and the solvents were concd under reduced pressure to yield crude potassium 1-methylcyclopropane-1-sulfonate which was suspended in thionyl chloride (7 mL). DMF (0.05 mL) was added and the mixture was heated at reflux for about 8 h and then cooled. The volatiles were removed under reduced pressure and the residue was dissolved in DCM (20 mL), washed with water (15 mL), dried over anhydrous MgSO4 and concd under reduced pressure to yield 1-methylcyclopropane-1-sulfonyl chloride (0.56 g, 86%) as a yellow oil. 1H NMR (DMSO-d6) δ 1.82 (br s, 2H), 1.79 (s, 3H), 1.15 (m, 2H).
Reaction SMILES: [NH:1]1C2C(=CC(C#N)=CC=2)C=[CH:2]1.[C:12]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21](OC(F)(F)F)[CH:22]=2)[N:17]([CH2:29][C:30]([OH:32])=[O:31])[CH:16]=1)(=[O:14])[CH3:13]>>[C:12]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:2]#[N:1])[CH:22]=2)[N:17]([CH2:29][C:30]([OH:32])=[O:31])[CH:16]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)c1cn(CC(=O)O)c2ccc(OC(F)(F)F)cc12
Reactant: N#Cc1ccc2[nH]ccc2c1
Product: CC(=O)c1cn(CC(=O)O)c2ccc(C#N)cc12

Procedure:
was prepared from 1H-indole-5-carbonitrile in a similar manner as described in Scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl)-acetic acid. MS (LC/MS): 241.2 [M−H]−; 243.2 [M+H]+; tR (HPLC conditions a): 2.62 min.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].I[C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1>>[CH3:8][C:7]1[O:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[C:1]#[C:2][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: NS(=O)(=O)c1ccc(I)cc1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Product: Cc1onc(-c2ccccc2)c1C#Cc1ccc(S(N)(=O)=O)cc1
Yield: 71 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 4-iodobenzenesulphonamide instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 120 mg, 71%) which was obtained as a white solid. MS: m/e=339.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:15]([OH:17])=O.[C:18](N1C=CN=C1)([N:20]1C=CN=C1)=O.C(N(CC)CC)C.Cl.CN>CN(C=O)C>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:15]([NH:20][CH3:18])=[O:17]
Reactant: COc1ccc(-n2ncc(C(=O)O)c2Cl)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1cnn(-c2ccc(OC)cc2)c1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 51.5 %

Procedure:
To a solution of 1.2 g of 5-chloro-1-(4-methoxyphenyl)-1H-pyrazole-4-carboxylic acid in 150 ml DMF was added 1.1 g of carbonyldiimidazole and the mixture was allowed to stir at room temperature for 20 minutes. One gram of triethylamine and 0.6 g of methylamine hydrochloride were next added to the reaction mixture and the solution was stirred at room temperature for 20 hours. The mixture was poured into ice water and extracted with ethyl acetate. The organic phase was separated and washed with water, dried, and concentrated under vacuum to dryness. The residue was recrystallized from toluene/hexane to afford 650 mg of 5-chloro-1-(4-methoxyphenyl)-N-methyl-1H-pyrazole-4-carboxamide. Yield 71%. mp=144°-146° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])[OH:9])=[CH:4][C:3]=1[CH2:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Cu](C#N)[C:41]#[N:42]>CN1C(=O)CCC1>[O:33]([CH2:32][C:3]1[CH:4]=[C:5]([C:8]2([O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])[OH:9])[CH:6]=[CH:7][C:2]=1[C:41]#[N:42])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: N#C[Cu]C#N
Reactant: CC(=O)OC[C@H]1OC(O)(c2ccc(Br)c(COc3ccccc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CN1CCCC1=O
Product: CC(=O)OC[C@H]1OC(O)(c2ccc(C#N)c(COc3ccccc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A flask charged with a stir bar, 1-bromo-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-2-(phenoxymethyl)-benzene (14.7 g), copper cyanide (4.1 g), and NMP (100 mL) is heated at reflux temperature for 8 h. After dilution with water (600 mL), the precipitate is separated, washed a few times with water and subsequently dissolved in ethyl acetate (200 mL). The resultant solution is filtered through a plug of silica gel using ethyl acetate (300 mL) as the eluent. The filtrate is concentrated under reduced pressure and the residue is dissolved in dichloromethane (100 mL) to reacetylate the oxygen groups deprotected during the cyanation. Accordingly, pyridine (4 mL), 4-dimethylaminopyridine (0.3 g) and acetic anhydride (4.4 mL) are added in succession. The resulting solution is stirred at room temperature for 1 h. Then, the reaction mixture is diluted with dichloromethane (50 mL) and washed thrice with 1 M aqueous hydrochloric acid, once with aqueous sodium hydrogen carbonate solution and once with water. The organic phase is dried (sodium sulphate) and the solvent is removed. The residue is recrystallized from ethanol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][O:11][C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=3)[C:15]([O:17][CH3:18])=[O:16])[N:7]([CH3:22])[C:6]=2[CH:23]=1.[Br:24][C:25]1[C:26](F)=[N:27][CH:28]=[C:29]([Br:32])[C:30]=1[Cl:31].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu](I)I.CN(C=O)C>[Br:24][C:25]1[C:26]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[N:9]=[C:8]([CH2:10][O:11][C:12]4[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=4)[C:15]([O:17][CH3:18])=[O:16])[N:7]([CH3:22])[C:6]=3[CH:23]=2)=[N:27][CH:28]=[C:29]([Br:32])[C:30]=1[Cl:31]
Reactant: COC(=O)c1cccc(OCc2nc3ccc(O)cc3n2C)c1
Reactant: Fc1ncc(Br)c(Cl)c1Br
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OCc2nc3ccc(Oc4ncc(Br)c(Cl)c4Br)cc3n2C)c1
Yield: 53.6 %

Procedure:
The reaction and post-treatment were carried out according to Example (1f) using methyl 3-[(6-hydroxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzoate produced in Example (1e) (1.69 g, 5.00 mmol), 3,5-dibromo-4-chloro-2-fluoropyridine produced in Example (14b) (1.59 g, 5.50 mmol), copper iodide (0.10 g, 0.50 mmol), 1,10-phenanthroline (0.09 g, 0.50 mmol), cesium carbonate (4.89 g, 15.0 mmol) and DMF (30 mL) to obtain the title compound (1.56 g, 54%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].[Cl:14][C:15]1[CH:20]=[C:19](I)[CH:18]=[CH:17][N:16]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:14][C:15]1[CH:20]=[C:19]([N:10]2[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:13])[CH:18]=[CH:17][N:16]=1
Reactant: Clc1cc(I)ccn1
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccnc(Cl)c2)C1=O
Yield: 82.8 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 600 mg, 3.3898 mmol) was reacted with 2-chloro-4-iodo-pyridine (974 mg, 4.067 mmol), 1,4-dioxane (60 mL), copper iodide (65 mg, 0.3398 mmol), trans-1,2-diamino cyclohexane (0.12 mL, 1.0169 mmol) and potassium phosphate (2.15 g, 10.1694 mmol) to afford 810 mg of the product (83% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH2:15][CH2:16][O:17][CH3:18].[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:24](Cl)=[O:25]>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:24](=[O:25])[C:23]1[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=[C:21]([C:20]([F:19])([F:34])[F:35])[CH:22]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COCCNc1cnccc1-c1ccccc1Cl
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COCCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(2-chloro-phenyl)-pyridin-3-yl]-(2-methoxy-ethyl)-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Yellow solid (53%). MS (ESI): m/z=503.095 [M+H]+.
Reaction SMILES: NC1N=[C:7]([C:9]2C(OC)=CC(C)=C[C:10]=2[O:18]C)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2N(C)C1=O.C([NH:33][C@@H](C(O)=O)CC1C=CC=CC=1)(OC(C)(C)C)=O.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.O>[C:6]1([CH2:7][CH2:9][C:10]([NH2:33])=[O:18])[CH:20]=[CH:21][CH:22]=[CH:23][CH:5]=1
Reactant: COc1cc(C)cc(OC)c1C1=NC(N)C(=O)N(C)c2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)CCc1ccccc1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
1.73 g of 3-amino-1,3-dihydro-5-(2,6-dimethoxy-4-methylphenyl)-1-methyl-1,4-benzodiazepin-2-one are dissolved in 30 ml of dimethylformamide in the presence of 1.42 g of BOC-D-phenylalanine, followed by cooling to 5° C. and addition of 1.07 ml of triethylamine and then 2.4 g of BOP. The reaction mixture is allowed to return to room temperature and is left stirring overnight. It is then poured into water and extracted with ethyl acetate. The organic phase is washed with water, separated out after settling of the phases, dried over Na2SO4, filtered and concentrated under vacuum. An oily residue of 2-tertbutoxycarbonylamino-N-]2,3-dihydro-5-(2,6-dimethoxy-4-methylphenyl)-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl!-3-phenylpropionamide, obtained in quantitative yield, is used as it is for the following step (Compound 16).
Reaction SMILES: [C:1]([C:3]1[C:4]([F:14])=[CH:5][C:6]([O:12][CH3:13])=[C:7]([CH:11]=1)[C:8]([OH:10])=O)#[N:2].C(Cl)(=O)C(Cl)=O.C(N(C(C)C)CC)(C)C.Cl.[N+:31]([C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][NH2:38])([O-:33])=[O:32]>ClCCl.CN(C=O)C>[C:1]([C:3]1[C:4]([F:14])=[CH:5][C:6]([O:12][CH3:13])=[C:7]([CH:11]=1)[C:8]([NH:38][CH2:37][C:36]1[CH:39]=[CH:40][CH:41]=[C:34]([N+:31]([O-:33])=[O:32])[CH:35]=1)=[O:10])#[N:2]
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: COc1cc(F)c(C#N)cc1C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(F)c(C#N)cc1C(=O)NCc1cccc([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a stirring slurry of 5-cyano-4-fluoro-2-methoxy-benzoic acid (1.92 g, 9.8 mmol) in dichloromethane (20 mL, 0.5 M) was added oxalyl chloride (2.57 mL, 29.5 mmol) and DMF (1 drop). The mixture was heated to 40° C. until the solution was clear (1–2 h). Next, the mixture was allowed to cool to room temperature, concentrated under reduced pressure, and then diluted with dichloromethane (20 mL, 0.5 M). To the stirring mixture at 0° C. was added diisopropylethyl amine (4.3 mL, 24.6 mmol) followed by 3-nitrobenzylamine hydrochloride salt (2.78 g, 14.8 mmol). The stirring under nitrogen, the solution was gradually warmed to room temperature and stirred overnight. The mixture was then diluted with dichloromethane and washed with 2N HCl (3×25 mL) and saturated aq NaCl (2×25 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to afford a yellow oil. Purification by MPLC (10–100% ethyl acetate in heptane, 23 mL/min, 75 min) provided [5-cyano-4-fluoro-2-methoxy-N-(3-nitro-benzyl)-benzamide (2.0 g, 63%) as a yellow solid: 1H NMR (DMSO-d6, 300 MHz) δ 8.55 (d, J=7.5 Hz, 1 H), 8.19 (9, 1 H), 8.15 (d, J=8.4 Hz, 1 H), 7.96 (bd s, 1 H), 7.70 (d, J=6.3 Hz, 1H), 7.54 (t, J=8.0 Hz, 5 H), 6.86 (d, J=10.5 Hz, 1 H), 4.76 (d, J=5.4 Hz, 1H), 4.07 (d, J=1.2 Hz, 3 H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].CCCCCC.[CH2:17]([C@H:24]1[CH2:28][O:27][C:26](=[O:29])[N:25]1[C:30](=[O:33])[CH2:31][CH3:32])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Br[CH2:35]/[CH:36]=[CH:37]/[CH2:38][O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:17]([C@H:24]1[CH2:28][O:27][C:26](=[O:29])[N:25]1[C:30](=[O:33])[C@H:31]([CH3:32])[CH2:35]/[CH:36]=[CH:37]/[CH2:38][O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: BrC/C=C/COCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[C@H](C/C=C/COCc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
164 ml of a solution of sodium bis(trimethylsilyl)amide in n-hexane (1.03 mol/l) (169 mmol) was added to a solution of 32.9 g of (S)-4-benzyl-3-propionyloxazolidin-2-one (141 mmol) in tetrahydrofuran (330 ml) under a nitrogen atmosphere and at −78° C. over 45 minutes, and the mixture was stirred at the same temperature for 30 minutes. Then, a solution of 35.5 g of [(E)-4-bromobut-2-enyloxymethyl]benzene obtained in Reference Example 4 (148 mmol) in tetrahydrofuran (80 ml) was added to the solution over 30 minutes, and the mixture was stirred at the same temperature for 30 minutes. Thereafter, the mixture was raised to −40° C. and further stirred for four hours. 100 ml of a saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was further stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure and diluted with 500 ml of water, followed by extraction with ethyl acetate. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=7/1-2/1) to obtain 37.9 g of the title compound (yield: 69%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:31]([O:32][CH3:33])=[CH:30][C:6]2[S:7][C:8](/[CH:19]=[C:20](\[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)/[C:21]([O-:23])=[O:22])=[C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:5]=2[CH:4]=1.[Na+].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]1[C:31]([O:32][CH3:33])=[CH:30][C:6]2[S:7][C:8]([CH2:19][CH:20]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:21]([OH:23])=[O:22])=[C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:5]=2[CH:4]=1
Reactant: [H][H]
Reactant: COc1ccc(Oc2c(/C=C(/C(=O)[O-])c3ccccc3)sc3cc(OC)c(OC)cc23)cc1
Agent: [Pd]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Oc2c(CC(C(=O)O)c3ccccc3)sc3cc(OC)c(OC)cc23)cc1

Procedure:
The compound obtained in Example 6 after Step F is used as substrate, which is treated with a stream of hydrogen in the presence of 10% Pd/C in methanol for 24 hours. Filtration, at the end of the reaction, followed by chromatography over silica gel enables the expected product to be isolated.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][C:8]([F:12])([F:11])[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Li+].CCC[CH2-].C(O[B:22]1[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]1)(C)C.C(OCC)C>O1CCCC1>[Cl:1][C:2]1[C:10]2[O:9][C:8]([F:12])([F:11])[O:7][C:6]=2[C:5]([B:22]2[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]2)=[CH:4][CH:3]=1
Reactant: FC1(F)Oc2cccc(Cl)c2O1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(C)OB(c2ccc(Cl)c3c2OC(F)(F)O3)OC1(C)C
Temperature: -75 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
4-Chloro-2,2-difluorobenzo[d][1,3]dioxole (3 g, 15.58 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to −75° C. N-Butyllithium (2.5 M in hexanes; 6.86 mL, 17.14 mmol) was added dropwise keeping the temperature below −65° C. The reaction mixture was then stirred at −75° C. for 1 h to ensure complete deprotonation. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.19 g, 17.14 mmol) was then added to the reaction mixture dropwise keeping the temperature below −65° C. The reaction mixture was then allowed to warm to room temperature, added to diethyl ether (200 mL) and extracted with water (2×100 mL). The aqueous phases were combined and acidified to pH 4 with concentrated HCl. The product was extracted with diethyl ether and the organic phase was dried and concentrated under vacuum to provide the title compound as an off-white solid (3.82 g, 77%): 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J=8.4 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 1.36 (s, 12H); EIMS m/z 318.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]([C:16]([OH:18])=O)=[C:13]([CH3:15])[N:14]=3)[C:6]2=[O:19])[CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[F:51][C:52]1[CH:53]=[C:54]([CH2:58][NH2:59])[CH:55]=[N:56][CH:57]=1>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([CH2:4][N:5]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]([C:16]([NH:59][CH2:58][C:54]4[CH:55]=[N:56][CH:57]=[C:52]([F:51])[CH:53]=4)=[O:18])=[C:13]([CH3:15])[N:14]=3)[C:6]2=[O:19])[CH2:2][CH2:3]1
Reactant: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)O
Reactant: NCc1cncc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)NCc1cncc(F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 47 %

Procedure:
To a solution of 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid (1.00 g, 3.55 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 1.70 g, 4.47 mmol) and triethylamine (1.00 mL, 7.17 mmol) in N,N-dimethylformamide (15 mL) was added (5-fluoropyridin-3-yl)methanamine (0.55 g, 4.36 mmol). The reaction mixture was stirred at ambient temperature for 20 h, diluted with ethyl acetate (200 mL) and washed with water and brine. The organic solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was recrystallized from ethyl acetate to afford the title compound as a white powder in 47% yield (0.65 g): mp 144-145° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.53 (J=6.0 Hz, 1H), 8.43-8.38 (m, 2H), 7.59-7.56 (m, 1H), 4.39 (d, J=6.0 Hz, 2H), 4.00-3.95 (m, 2H), 3.64-3.59 (m, 2H), 3.06 (d, J=6.0 Hz, 2H), 2.44 (s, 3H), 0.95-0.87 (m, 1H), 0.48-0.42 (m, 2H), 0.20-0.16 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 162.4, 161.1, 157.9, 155.2, 145.5, 137.9, 136.6, 122.5, 122.3, 117.6, 48.2, 42.5, 42.3, 40.8, 17.6, 9.3, 3.6; MS (ES+) m/z 389.9 (M+1).
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:19][C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][N:21]=4)[S:16][C:17]=3[CH3:18])[CH:10]=[N:9]2)=CC=1.C([O-])([O-])=O.[Na+].[Na+].O>C(O)(C(F)(F)F)=O>[F:26][C:24]1[CH:23]=[CH:22][N:21]=[C:20]([NH:19][C:15]2[S:16][C:17]([CH3:18])=[C:13]([C:11]3[CH:12]=[N:8][NH:9][CH:10]=3)[N:14]=2)[CH:25]=1
Reactant: COc1ccc(Cn2cc(-c3nc(Nc4cc(F)ccn4)sc3C)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1sc(Nc2cc(F)ccn2)nc1-c1cn[nH]c1
Yield: 51.5 %

Procedure:
According to Scheme 3 Step 3: A solution of N-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-methylthiazol-2-yl)-4-fluoropyridin-2-amine (0.33 mmol, 132 mg) in TFA (1.5 mL) was microwaved for 2 minutes at 150° C. A precipitate was formed after addition of a saturated solution of Na2CO3 and water. After filtration, the solid was washed with water and recrystallized in Et2O to yield N-(4-fluoropyridin-2-yl)-5-methyl-4-(1H-pyrazol-4-yl)thiazol-2-amine (0.17 mmol, 47 mg, 51%) as a beige solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][C@H:14]2[C:29](=[O:30])[N:16]3[C:17]([C:26]([O-:28])=[O:27])=[C:18]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:19][S:20][C@H:15]23)=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]>FC(F)(F)C(O)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][C@H:14]2[C:29](=[O:30])[N:16]3[C:17]([C:26]([OH:28])=[O:27])=[C:18]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:19][S:20][C@H:15]23)=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cc1ccc([N+](=O)[O-])cc1)N[C@H]1C(=O)N2C(C(=O)[O-])=C(C3CCCC3)CS[C@H]12
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1ccc([N+](=O)[O-])cc1)N[C@H]1C(=O)N2C(C(=O)O)=C(C3CCCC3)CS[C@H]12

Procedure:
A solution of 244 mg of the ester of Step A in 2.5 ml of trifluoroacetic acid stood at room temperature for 8 minutes and was then evaporated to dryness under reduced pressure. The residue was taken up in benzene and was evaporated to dryness. The residue was triturated with ether and crystallization was effected. The crystals were vacuum filtered, washed with ether and dried to obtain 174 mg of DL cis 7-p-nitrophenylacetamido-3-cyclopentyl-3-cepheme-4-carboxylic acid melting at 170° C. The product occurred as colorless crystals slightly soluble in ethanol and insoluble in ether and water.