Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H][H].[Si:3]([O:10][CH2:11][C@@H:12]([CH3:44])[C@H:13]([NH:24]C1(C2C=CC=CC=2)C2C=CC=CC=2C2C1=CC=CC=2)[C:14]([O:16]CC1C=CC=CC=1)=[O:15])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>CCOC(C)=O.C(Cl)Cl.[Pd]>[NH2:24][C@@H:13]([C@H:12]([CH3:44])[CH2:11][O:10][Si:3]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4])[C:14]([OH:16])=[O:15]
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)[C@H](NC1(c2ccccc2)c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A balloon of hydrogen was attached to a mixture of (2S,3S)-benzyl 4-(tert-butyldimethylsilyloxy)-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate (836 mg, 1.447 mmol) and 10% Pd/C (213 mg) in EtOAc (16 mL) and the mixture was stirred at room temperature for ˜21 hr, where the balloon was recharged with H2 as necessary. The reaction mixture was diluted with CH2Cl2 and filtered through a pad of diatomaceous earth (CELITE®-545), and the pad was washed with EtOAc (200 mL), EtOAc/MeOH (1:1 mixture, 200 mL) and MeOH (750 mL). The combined organic phase was concentrated, and a silica gel mesh was prepared from the resulting crude material and submitted to a flash chromatography (8:2:1 mixture of EtOAc/1-PrOH/H2O) to afford (2S,3S)-2-amino-4-(tert-butyldimethylsilyloxy)-3-methylbutanoic acid as a white fluffy solid (325 mg). (2S,3R)-benzyl 4-(tert-butyldimethylsilyloxy)-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate was similarly elaborated to (2S,3R)-2-amino-4-(tert-butyldimethylsilyloxy)-3-methylbutanoic acid. (2S,3S)-amino acid isomer: 1H NMR (Methanol-d4, δ=3.29 ppm, 400 MHz), 3.76 (dd, J=10.5, 5.2, 1H), 3.73 (d, J=3.0, 1H), 3.67 (dd, J=10.5, 7.0, 1H), 2.37 (m, 1H), 0.97 (d, J=7.0, 3H), 0.92 (s, 9H), 0.10 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.[CH3:26][O:27][C@H:28]([CH3:32])[CH2:29][CH2:30][NH2:31]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:31][CH2:30][CH2:29][C@H:28]([O:27][CH3:26])[CH3:32])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: CO[C@H](C)CCN
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Agent: Cl
Product: CO[C@H](C)CCNC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3C)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-3-methoxybutan-1-amine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11 (d, J=6.32 Hz, 3 H) 1.58-1.79 (m, 2 H) 2.43 (s, 3 H) 3.24 (s, 3 H) 3.30-3.42 (m, 3 H) 7.66 (dd, J=7.83, 1.26 Hz, 1 H) 7.73 (s, 1 H) 7.77 (br. s., 1 H) 8.18 (br. s., 1 H) 8.29-8.59 (m, 2 H) 8.68 (t, J=5.31 Hz, 1 H) 8.87-8.94 (m, 1 H) 13.17 (br. s., 1 H); ESI-MS m/z [M+H]+ 406.2.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=2)[CH:5]=[CH:6][N:7]=1)[CH3:2].[BrH:16]>C(O)(=O)C>[BrH:16].[CH2:1]([C:3]1[N:4]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:5]=[CH:6][N:7]=1)[CH3:2]
Reactant: CCc1nccn1-c1ccc(OC)cc1
Agent: Br
Solvent: CC(=O)O
Product: CCc1nccn1-c1ccc(O)cc1
Yield: 100 %

Procedure:
A mixture of 5.2 parts of 2-ethyl-1-(4-methoxyphenyl)-1H-imidazole and 75 parts of hydrobromic acid solution 48% in glacial acetic acid is stirred and refluxed overnight. The solvent is evaporated and the residue is triturated in 2-propanone. The product is filtered off and dried, yielding 6.1 parts (100%) of 4-(2-ethyl-1H-imidazol-1-yl)phenol monohydrobromide.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:6][C:5]([C:12]([NH2:14])=O)=[N:4]1)[CH3:2].P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:1]([N:3]1[C:7]([CH:8]=[C:9]([CH3:10])[CH3:11])=[CH:6][C:5]([C:12]#[N:14])=[N:4]1)[CH3:2]
Reactant: CCn1nc(C(N)=O)cc1C=C(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCn1nc(C#N)cc1C=C(C)C
Temperature: 90 °C

Procedure:
A mixture of 1-ethyl-5-(2-methylprop-1-enyl)-1H-pyrazole-3-carboxamide (5.0 g, 25.9 mmol) and phosphorous oxychloride (18.5 mL) was heated at 90° C. for 20 minutes. The reaction vessel was cooled in an ice bath and reaction mixture was poured over ice (100 mL) The quenched reaction mixture was made basic with 2 M aqueous sodium carbonate and was extracted with chloroform. The organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 1-ethyl-5-(2-methylprop-1-enyl)-1H-pyrazole-3-carbonitrile, all of which was used in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([N:7]([CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:6])[CH3:2].[C:26](ON1C(=O)CCC1=O)([O:28][CH2:29][CH:30]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]2[C:31]1=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:27].C([O-])(O)=O.[Na+]>O1CCOCC1.O>[CH2:1]([O:3][C:4](=[O:25])[C:5]([N:7]([CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)[CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:26]([O:28][CH2:29][CH:30]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=3[C:37]3[C:42]2=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:27])[CH2:11][CH2:10]1)=[O:6])[CH3:2]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: CCOC(=O)C(=O)N(Cc1ccc(C(=O)O)cc1)CC1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C(=O)N(Cc1ccc(C(=O)O)cc1)CC1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Reaction time: 1.25 h
Yield: 39.8 %

Procedure:
To a solution of 4-{[[ethoxy(oxo)acetyl](piperidin-4-ylmethyl)amino]methyl}benzoic acid (7.650 g, 16.54 mmol) in dioxane/H2O (1/1) (120 mL) was added Fmoc-OSu (6.697 g, 19.85 mmol) and a 1 M aqueous solution of NaHCO3 (10 mL). The resulting reaction mixture was stirred for 1.25 h, then concentrated under vacuum. The oily residue dissolved in DCM (120 mL) was washed with a 1 N aqueous solution until pH 1, dried over MgSO4, filtered and the solvents were evaporated under vacuum. This crude product was purified by column chromatography over silica gel (AcOEt/c-Hex 1/4 to 1/1 in about 1 h) to give the title compound as a white powder (3.755 g, 40%). 1H NMR (CDCl3, 300 MHz) δ 8.1 (m, 2H), 7.75 (d, 2H, J=7.6 Hz), 7.55 (d, 2H, J=7.2 Hz), 7.38 (m, 4H), 7.29 (t, 2H, J=7.3 Hz), 4.70 (s, 1H), 4.56 (s, 1H), 4.45-4.07 (m, 7H), 3.0 (m, 2H), 2.45 (m, 2H), 1.7-1.5 (m, 1H), 1.40 (m, 2H), 1.38 (t, 1H, J=7.0 Hz), 1.31-1.21 (m, 3H), 1.0-0.8 (m, 2H). M−(LC/MS (ESI)): 569.4; M+(LC/MS (ESI)): 571.8. HPLC (Condition A), Rt: 4.83 min (HPLC purity: 99.3%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.NC1C(C#N)=C(N2CCC(C3N(C[CH2:66][N:67]4[CH2:70][CH2:69][CH2:68]4)C=C(C4C=CC(F)=C(C(F)(F)F)C=4)N=3)CC2)N=CN=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH2:33][CH2:66][N:67]4[CH2:70][CH2:69][CH2:68]4)[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1
Reactant: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN2CCC2)CC1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Product: NC(=O)c1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=533, obsd.=533).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]1[N:12]=[N:13][N:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])=[CH:18][CH:17]=2)[CH:15]=1.[CH2:30]([N:37]1[CH2:42][CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH2:39][CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH2:30]([N:37]1[CH2:38][CH:39]=[C:40]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[C:5]3[C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)=[O:23])=[CH:18][CH:17]=3)[CH:15]=2)[CH2:41][CH2:42]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC1(C)OB(C2=CCN(Cc3ccccc3)CC2)OC1(C)C
Reactant: O=C(c1ccc(-n2cc(-c3n[nH]c4ccc(Br)cc34)nn2)cc1)N1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1ccc(-n2cc(-c3n[nH]c4ccc(C5=CCN(Cc6ccccc6)CC5)cc34)nn2)cc1)N1CCOCC1
Temperature: 150 °C

Procedure:
A suspension of {4-[4-(5-Bromo-1H-indazol-3-yl)-[1,2,3]triazol-1-yl]-phenyl}-morpholin-4-yl-methanone (100 mg; 0.22 mmol; 1.0 eq.), 1-Benzyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,6-tetrahydro-pyridine; hydrochloride (J&W Pharm Lab, 222 mg; 0.66 mmol; 3.00 eq.), Pd2Cl2(PPh3)2(15 mg; 0.02 mmol; 0.1 eq.), potassium carbonate (91 mg; 0.66 mmol; 3.0 eq.) in dioxane (2 mL) and water (1 mL) was degassed with nitrogen flow and heated in MW at 150° C. for 10 min. The reaction mixture was filtered through a celite pad, water was added to the filtrate. Aqueous phase was extracted three times with DCM using separators tubes. Combined organic phases were concentrated under reduced pressure and the crude was purified by flash chromatography on silica (DCM/MeOH, gradient from 100:0 to 90:10) to give the title compound as yellow powder. 1H NMR (300 MHz, DMSO-d6) δ 13.37 (brs, 1H), 9.39 (s, 1H), 8.30 (s, 1H), 8.22-8.10 (m, 2H), 7.76-7.65 (m, 2H), 7.65-7.50 (m, 2H), 7.42-7.31 (m, 4H), 7.31-7.22 (m, 1H), 6.30-6.10 (m, 1H), 3.78-3.50 (m, 8H), 3.47-3.37 (m, 2H), 3.18-3.07 (m, 2H), 2.77-2.56 (m, 4H). HPLC (Condition A): Rt 2.87 min (purity 97.5%). MS (ESI+): 546.4, MS (ESI−): 544.3.
Reaction SMILES: F[C:2]1(F)[CH2:5][CH:4]([CH2:6][O:7][C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][CH2:13][C:14]3=[O:17])=[CH:10][CH:9]=2)[CH2:3]1.[OH:19][C:20]1[CH:28]=[C:27]2C(CCC2=O)=[CH:22][CH:21]=1.C1(CO)CCC1>>[CH:4]1([CH2:6][O:7][C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][C:13]4([CH2:27][CH2:28][C:20](=[O:19])[CH2:21][CH2:22]4)[C:14]3=[O:17])=[CH:10][CH:9]=2)[CH2:5][CH2:2][CH2:3]1
Reactant: O=C1CCc2ccc(OCC3CC(F)(F)C3)cc21
Reactant: O=C1CCc2ccc(O)cc21
Agent: OCC1CCC1
Product: O=C1CCC2(CC1)Cc1ccc(OCC3CCC3)cc1C2=O
Temperature: 45 °C
Yield: 58 %

Procedure:
The title compound (2.56 g, 58% yield) was prepared using the procedure described for Intermediate 11, starting from 6-hydroxy-2,3-dihydro-1H-inden-1-one (3.0 g, 20.3 mmol) and cyclobutylmethanol (2.10 mL, 22.3 mmol). The mixture was heated to 45° C. and left stirring over a weekend. 1H NMR (500 MHz, CDCl3) δ ppm 1.81-2.03 (m, 4H), 2.11-2.20 (m, 2H), 2.69-2.74 (m, 2H), 2.78 (dt, 1H), 3.04-3.12 (m, 2H), 3.96 (d, 2H), 7.17-7.22 (m, 2H), 7.36 (d, 1H); MS (ES+) m/z 217 [M+H]+.
Reaction SMILES: [CH:1]1([C:5]2[N:13]3[C:8]([C:9]([NH2:14])=[N:10][CH:11]=[N:12]3)=[C:7](I)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][C:26](B4OC(C)(C)C(C)(C)C4)=[CH:27][CH:28]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH:1]1([C:5]2[N:13]3[C:8]([C:9]([NH2:14])=[N:10][CH:11]=[N:12]3)=[C:7]([C:26]3[CH:25]=[C:24]4[C:29]([CH:30]=[CH:31][C:22]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[N:23]4)=[CH:28][CH:27]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)CB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Reactant: Nc1ncnn2c(C3CCC3)nc(I)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Nc1ncnn2c(C3CCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Temperature: 75 °C

Procedure:
A flask was charged with 7-cyclobutyl-5-iodo-imidazo[5,1-f][1,2,4]triazin-4-ylamine (30 mg, 0.095 mmol), 2-phenyl-7-(4,4,5,5-tetramethyl-[2,3,2]dioxaborolan-2-yl)-quinoline (38 mg, 0.110 mmol), and sodium carbonate (Na2CO3) (30 mg, 0.286 mmol) was evacuated and charged with nitrogen (N2) (3×). To this mixture was quickly added tetrakis(triphenylphosphine)palladium(0) and evacuated and charged with N2 (2×). This mixture was charged with a previously degassed solvent DME/H2O (5:1) (2 mL) and heated overnight at 75° C. The reaction mixture was filtered through an autovial (0.45 μM frit) and washed with MeOH (3×). The filtrate was concentrated in vacuo and purified by mass directed purification (MDP) resulting in the title compound as a pale yellow solid; 1H NMR (CDCl3, 400 MHz) δ 1.96-2.10 (m, 1H), 2.10-2.25 (m, 1H); 2.40-2.56 (m, 2H); 2.60-2.78 (m, 2H); 4.12-4.29 (m, 1H); 5.99 (brs, 2H); 7.42-7.58 (m, 3H); 7.84-8.05 (m, 4H); 8.18 (d, J=7.2 Hz, 2H); 8.28 (d, J=8.4 Hz, 1H); 8.39 (s, 1H); MS (ES+): m/z 393.14 (100) [MH+], HPLC: tR=3.51 min (MicromassZQ, polar—5 min).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=1[CH2:8]P(=O)(OC)OC)([O-:5])=[O:4].[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O.O>O1CCCC1>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=[CH:8][C:7]1[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=1[N+:3]([O-:5])=[O:4]
Reactant: COP(=O)(Cc1ccccc1[N+](=O)[O-])OC
Reactant: O=Cc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1C=Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 68.4 %

Procedure:
1.63 g of 60 wt % sodium hydride were added to 20 ml of tetrahydrofuran under stirring at room temperature, followed by cooling thereof to 0° C. and drop-wise addition thereto of a solution of 8 g of dimethyl 2-nitrobenzylphosphonate in 20 ml of tetrahydrofuran. After completion of the drop-wise addition, the reaction mixture was stirred at 0° C. for 30 minutes, followed by drop-wise addition thereto of 6.2 g of 2-chlorobenzaldehyde. After completion of the drop-wise addition, the resulting mixture was gradually heated up to room temperature, at which stirring was then continued for 17 hours. The reaction mixture was poured into water, subjected to extraction with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was purified twice by silica gel column chromatography (first developing solvent:methylene chloride:hexane=7:3, and second developing solvent:methylene chloride:hexane=3:1) to obtain 5.8 g of 2-chloro-2'-nitrostilbene.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=1.Cl[C:15]1[N:20]=[CH:19][N:18]=[C:17]([NH:21][S:22]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:24])=[O:23])[C:16]=1[C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1>COCCOC>[Br:3][C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10][O:11][C:15]2[N:20]=[CH:19][N:18]=[C:17]([NH:21][S:22]([CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:23])=[O:24])[C:16]=2[C:33]2[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=2)=[CH:6][CH:5]=1
Reactant: OCCOc1ccc(Br)cc1
Reactant: Cc1ccc(-c2c(Cl)ncnc2NS(=O)(=O)CCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(-c2c(NS(=O)(=O)CCc3ccccc3)ncnc2OCCOc2ccc(Br)cc2)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 86.7 %

Procedure:
To a suspension of NaH (17 mg, 60% in mineral oil) in DME (5 ml) was added 2-(4-bromo-phenoxy)-ethanol (111 mg). The mixture was stirred at 50° C. for 1 h before 2-phenyl-ethanesulfonic acid (6-chloro-5-p-tolyl-pyrimidin-4-yl)-amide (100 mg, Referential Example 1f) and K-tert.-butylate (25 mg) was added. The mixture was stirred at 70° C. for 16 h. A further portion of K-tert.-butylate (50 mg) was added and stirring was continued at 70° C. for 12 h and at rt for 72 h. The solvent was evaporated. The residue was treated with water (40 ml), acidified with 10% aq. citric acid and extracted twice with EA (50 ml). The organic phase was washed with water and evaporated. The crude product was crystallised from 2-propanol to give 2-phenyl-ethanesulfonic acid {6-[2-(4-bromo-phenoxy)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-amide (127 mg) as a beige powder. LC-MS: tR=6.14 min, [M+1]+=568.38, [M−1]−=570.15.
Reaction SMILES: [OH-:1].[K+].Cl[C:4]1[N:12]=[C:11]([N:13]2[C:17]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=3[N:15]=[CH:14]2)[N:10]=[C:9]2[C:5]=1[NH:6][C:7](=[O:30])[N:8]2[C@H:23]1[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:22][C:19]1[CH:20]=[CH:21][C:16]2[N:15]=[CH:14][N:13]([C:11]3[N:10]=[C:9]4[C:5]([NH:6][C:7](=[O:30])[N:8]4[C@H:23]4[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]4)=[C:4]([OH:1])[N:12]=3)[C:17]=2[CH:18]=1
Reactant: [OH-]
Reactant: O=c1[nH]c2c(Cl)nc(-n3cnc4ccc(F)cc43)nc2n1[C@H]1CC[C@H](O)CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [K+]
Solvent: C1COCCO1
Product: O=c1[nH]c2c(O)nc(-n3cnc4ccc(F)cc43)nc2n1[C@H]1CC[C@H](O)CC1
Temperature: 100 °C
Reaction time: 0.05 h

Procedure:
An oven dried vial containing a stirbar was charged with Pd2 dba3 (2 mg, 0.002 mmol, 0.02 equiv.), 2-di-t-butylphosphino-2′,4′,6′-tri-isopropyl-1,1′-diphenyl (Strem, 3.5 mg, 0.008 mmol, 0.08 equiv.), KOH (17 mg, 0.3 mmol, 3 equiv.) and 6-chloro-2-(6-fluoro-1H-benzo[d]imidazol-1-yl)-9-(trans-4-hydroxycyclohexyl)-7H-purin-8(9H)-one (40 mg, 0.1 mmol, 1 equiv.), followed by 1,4-dioxane (0.3 mL) and degassed water (0.3 mL). A stream of argon was passed through the reaction mixture for 3 min; the vial was then closed and heated at 100° C. After 16 h, the reaction was found to be complete. Preparative HPLC chromatography provided, after evaporation of solvent, the desired product as a white solid. 1H NMR (300 MHz, CD3OD+CDCl3) δ, ppm: 9.04 (s, 1H), 8.45 (dd, 1H), 7.80-7.65 (m, 1H), 7.15-7.08 (m, 1H), 4.42-4.30 (m, 1H), 3.84-3.77 (m, 1H), 2.70-2.60 (m, 2H), 2.25-2.11 (m, 2H), 1.97-1.83 (m, 2H), 1.62-1.40 (m, 2H); MS (EI) m/z 385.3 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:15])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])=[C:5]([CH3:16])[O:4][N:3]=1.C(O[CH:20]=[C:21]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])C.C(O)C>C(Cl)Cl>[CH2:25]([O:24][C:22](=[O:23])[C:21](=[CH:20][NH:15][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:16])[CH:8]=1)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:26]
Reactant: COc1ccc(N)cc1-c1c(C)noc1C
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccc(OC)c(-c2c(C)noc2C)c1)C(=O)OCC
Temperature: 130 °C
Yield: 86 %

Procedure:
[3-(3,5-Dimethyl-4-isoxazolyl)-4-(methyloxy)phenyl]amine (for a preparation see Intermediate 2) (39 g, 179 mmol) was dissolved in diethyl [(ethyloxy)methylidene]propanedioate (38.6 g, 179 mmol) and heated to 130° C., giving a steady effervescence as ethanol boiled off. The solution was heated for 1 h, then cooled to room temperature and evaporated in vacuo to give a brown oil. The product was dissolved in DCM (100 ml) and loaded onto a 750 g silica column, then eluted with 0-100% EtOAc/cyclohexane to give diethyl({[3-(3,5-dimethyl-4-isoxazolyl)-4-(methyloxy)phenyl]amino}methylidene)propanedioate (59.5 g, 153 mmol, 86% yield) as pale yellow crystalline solid. LCMS (formate) Rt 1.15 min, MH+ 389.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][C@H:12]2[N:11]([C:19](=[O:22])[CH2:20]Cl)[C:10]2[CH:23]=[CH:24][CH:25]=[CH:26][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([NH:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])O.[Na+]>ClCCCl>[CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][C@H:12]2[N:11]([C:19](=[O:22])[CH2:20][N:34]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:10]2[CH:23]=[CH:24][CH:25]=[CH:26][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1[C@H]2CCC[C@H]2N(C(=O)CCl)c2ccccc2N1Cc1ccccc1
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C1[C@H]2CCC[C@H]2N(C(=O)CN(Cc2ccccc2)Cc2ccccc2)c2ccccc2N1Cc1ccccc1
Yield: 28 %

Procedure:
A solution of (3aR*,10aS*)-9-benzyl-4-(chloroacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]-cyclopenta[e][1,4]diazepin-10(1H)-one (1.0 g, 2.7 mmol) and dibenzylamine (5.36 g, 27.1 mmol) in 1,2-dichloroethane (30 mL) was refluxed for 17 hours, to which was added a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with dichloromethane. The extract solution was washed with water and dried, followed by distilling off the solvent. The residue was purified by silica-gel column chromatography (ethyl acetate-hexane 1:1) to give 0.40 g (yield 28%) as an oily product.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]([NH:26][C:27](=[O:29])[CH3:28])[S:8][C@@H:9]2[C@:16]([NH:22][CH:23]=[O:24])([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:15](=[O:25])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=[O:3])[NH2:2].[Na+:30].C(OO)(=[O:33])C>>[C:1]([O:4][CH2:5][C:6]1[CH:7]([NH:26][C:27](=[O:29])[CH3:28])[S:8](=[O:33])[C@@H:9]2[C@:16]([NH:22][CH:23]=[O:24])([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:15](=[O:25])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=[O:3])[NH2:2].[Na+:30]
Reactant: CC(=O)OO
Reactant: CC(=O)NC1S[C@H]2N(C(=O)[C@@]2(NC=O)c2cccs2)C(C(=O)[O-])=C1COC(N)=O
Agent: [Na+]
Product: CC(=O)NC1C(COC(N)=O)=C(C(=O)[O-])N2C(=O)[C@@](NC=O)(c3cccs3)[C@H]2S1=O

Procedure:
Oxidation of sodium 3-carbamoyloxymethyl-7α-formamido-7β-thien-2-yl-acetamido-ceph-3-em-4-carboxylate with peracetic acid in analogous manner to that described in Example 6(d) gives the title compound as a mixture of R- and and S-sulphoxide isomers.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>C1COCC1>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc(C)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C=O)cn1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 81.6 %

Procedure:
A solution of methyl 6-methylnicotinate (0.5 g, 3.3 mmol) in THF (16 mL) at 0° C. was treated dropwise with lithium aluminum hydride in THF (6.6 mL, 1 M), stirred at 0° C. for 1.5 hours, treated with ethyl acetate (3 mL), and stirred at 25° C. The reaction was partitioned between ethyl acetate and saturated NaHCO3, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated. A solution of the residue (0.395 g) in dichloromethane (16 mL) was treated with MnO2 (2 g), stirred at 25° C. for 68 hours, and filtered through celite® to give the title compound (0.326 g, 80% yield), which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[CH:7]=[N:8][C:4]=2[C:3]=1[NH2:18].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30]>ClCCl>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:18][C:3]2[C:4]3[N:8]=[CH:7][N:6]([CH2:9][C:10]4[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=4)[C:5]=3[CH:16]=[CH:17][C:2]=2[CH3:1])=[O:28])=[CH:22][C:21]=1[C:29]([F:30])([F:31])[F:32]
Reactant: Cc1ccc2c(ncn2Cc2ccncc2)c1N
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClCCl
Product: Cc1ccc2c(ncn2Cc2ccncc2)c1NC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 4 h

Procedure:
Compound 2d (100 mg, 0.42 mmol) is weighed into a round bottom flask and dissolved in dichloromethane (3 mL). 1-Chloro-4-isocyanato-2-trifluoromethyl-benzene (93 mg, 0.42 mmol) is added as a solid and the homogeneous mixture is stirred for 4 h. The precipitate is collected via filtration and are washed with ether and collected to yield compound 2g as a white amorphous solid.