Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:24]=[CH:23][C:11]([C:12]([C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16](O)=[O:17])=[O:13])=[CH:10][CH:9]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[Br:7][C:8]1[CH:24]=[CH:23][C:11]([C:12]([C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[CH:16]=[O:17])=[O:13])=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Br)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: O=Cc1ccccc1C(=O)c1ccc(Br)cc1
Reaction time: 2 h

Procedure:
To a stirred solution of 8.2 g. of lithium aluminum hydride in 180 ml. of tetrahydrofuran was added 40 g. of 2-(4-bromobenzoyl)-benzoic acid in the course of 30 minutes. The mixture, after being kept at 25° for 2 hours, was cooled and 40 ml. of a saturated sodium sulfate solution was added slowly. The mixture was filtered and the filtrate concentrated. The resulting oily residue was dissolved in 32 ml. of acetic acid and 96 ml. of xylene. This solution was added to a mixture of 17.1 g. of selenium dioxide in 60 ml. of acetic acid and 120 ml. of xylene and refluxed for 17 hours. During this time about 22 ml. of an aqueous phase had collected in a Dean Stark receiver. The solution was filtered, washed with sodium hydroxide and concentrated. Addition of petroleum ether gave white prisms melting at 103°-109°. Recrystallization from a mixture of ether and petroleum ether raised the melting point to 110°- 113°. Ultraviolet inflexion (2-propanol) at 225 μ (ε = 17,500) and maximum at 261 μ (ε = 22,200); infrared absorption (CHCl3) at 1675 cm-1 and 1705 cm-1.
Reaction SMILES: C([Li])(CC)C.[N:6]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1.CN(C)CCN(C)C.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>C(OCC)C.O>[N:6]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:8][CH2:7]1
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2ccccc21
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1cccc2c1N(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Yield: 37.6 %

Procedure:
A 1.3 M solution of sec-butyl lithium in cyclohexanes (1642 mL, 2.13 mol) was added dropwise to a solution of 1,1-dimethylethyl 2,3-dihydro-1H-indole-1-carboxylate (300 g, 1.37 mol) and N,N,N′,N′ tetramethyl-1,2-ethanediamine (248 mL, 1.64 mol) in dry diethyl ether (2.5 L) at −78° C. The reaction mixture was stirred for 2 hours at this temperature and ethyl chloroformate (143.9 mL, 1.50 mol) was added dropwise to the mixture at −78° C. After the addition, the reaction was allowed to warm to room temperature overnight. Water (1 L) was added carefully to the mixture and the organic layer was separated and dried (Na2SO4). The solution was concentrated and the residue was purified by silica-gel column chromatography (PE:EA=10:1), giving 150 g (38%) of the title compound.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:18]([OH:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[C:11]([CH2:12][CH2:13]1)=[CH:10][C:9](O)=[C:8]([O:21][CH3:22])[CH:7]=3)[CH2:4][CH2:3]2.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].C1(=O)CCCCC1>C(=O)(O)[O-].[Na+]>[CH3:22][O:21][C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][CH2:13][C@@H:14]3[C@@H:5]([C:6]=2[CH:7]=1)[CH2:4][CH2:3][C@@:2]1([CH3:1])[C@H:15]3[CH2:16][CH2:17][C:18]1=[O:19]
Reactant: COc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Agent: CC(C)[O-]
Agent: O=C([O-])O
Agent: [Al+3]
Solvent: O=C1CCCCC1
Product: COc1ccc2c(c1)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2
Temperature: 25 °C
Yield: 77.6 %

Procedure:
2-Methoxyestradiol (Scheme 1, Compound 1) (10 g, 33.1 mmol) was placed in a 1 L round bottom flask that was equipped with a 25 mL Dean-Stark trap and a reflux condenser. The entire apparatus had been flame dried under an argon atmosphere. Toluene (400 mL) was added to dissolve the starting material. Aluminum isopropoxide (34.6 g, 169 mmol) and cyclohexanone (135 mL, 1.3 mol) were added and the entire reaction mixture was heated at reflux (145°-150° C.) for 20 h. Saturated aqueous sodium bicarbonate solution (200 mL) was added after the reaction mixture was allowed to cool to room temperature. The organic material was extracted with dichloromethane (3×300 mL). The aqueous emulsion was acidified with 3 N HCl (˜20 mL) until the emulsion separated and the aqueous layer was extracted with ethyl acetate (2×75 mL). The combined organic extracts were dried over magnesium sulfate and condensed using a rotary evaporator. The cyclohexanone and cyclohexanol were removed by vacuum distillation. When the distillation pot was cool enough, hexane was added and 2-methoxyestrone (Scheme 1, Compound 4) precipitated out of solution. 7.72 g (25.7 mmol, 78%) of product was obtained. 1H NMR (300 MHz, CDCl3) δ 6.81 (s, 1H), 6.68 (s, 1H), 5.46 (s, 1H), 3.88 (s, 3H), 2.89-2.76 (m,2H), 2.61-1.24 (m, 13H), 0.94 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[N+:18]([C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19].CCN(CC)CC.C(OC(C)(C)C)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:4]1[CH2:8][C@H:7]([O:9][S:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=2)(=[O:28])=[O:29])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])=[O:17]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Agent: CC(C)(C)OC=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2cccc([N+](=O)[O-])c2)CN1C(=O)OC(C)(C)C
Temperature: 2.5 °C
Reaction time: 18 h

Procedure:
N-Boc-cis-4-hydroxy proline methyl ester (1.0 eq, 6.0 g) were dissolved in MeCl2 (60.0 ml) and 3-nitrobenzenesulfonyl chloride (1.06 eq; 5.747 g) was added. This clear colorless solution was cooled to 0-5° C. and the Et3N (3.0 eq., 10.19 ml) was carefully added. After 0.5 h a yellowish thin suspension was formed, which was stirred for 18 h at ambient temperature. The mixture turned then into a light brown suspension. LC-MS-analysis revealed that the reaction was complete. The reaction mixture was diluted with additional MeCl2 (100 ml) and extracted in succession with aq. 0.5 N HCl, 10% Na2CO3. The combined org. layers were washed with brine, dried over Na2SO4, filtered and evaporated to dryness to yield a light brown viscous oil (10.8 g; 102%). MS (ESI): m/z=331.2 [M+H-Boc]+
Reaction SMILES: C([N:8]1[CH:13]=[CH:12][C:11]2=[C:14]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[N:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:16]=[C:10]2[C:9]1=O)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:35]>>[Cl:35][C:9]1[C:10]2=[N:16][N:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[C:14]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[C:11]2[CH:12]=[CH:13][N:8]=1
Reactant: O=c1c2nn(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)c2ccn1Cc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc(-c2c3ccnc(Cl)c3nn2-c2ccc(Cl)cc2Cl)cc1
Yield: 58 %

Procedure:
A stirred suspension of 6-benzyl-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2,6-dihydropyrazolo[3,4-c]pyridin-7-one (I-1A-1b; 153 mg, 0.32 mmol) in POCl3 (3.5 ml) was heated to reflux for 48 hr. After the reaction was cooled and concentrated, in vacuo, an ethyl acetate solution of the residue was washed with saturated aqueous NaHCO3 and then brine. The solution was dried (Na2SO4), concentrated, in vacuo, and then purified on a Biotage™ Flash 12M column using 0-15-30% ethyl acetate in hexanes to afford I-1A-1c as an off-white solid (75 mg, 58%): +ESI MS (M+1) 408.0; 1H NMR (400 MHz, CD2Cl2) δ 8.01 (d, J=5.8 Hz, 1H), 7.57-7.53 (m, 3H), 7.47 (dd, J=8.7, 2.1 Hz, 1H), 7.41 (d, J=8.7 Hz, 2H), 7.27 (d, J=8.7 Hz, 2H).
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:17])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:16].CCN(CC)CC.[CH2:25]([CH:29]1[CH2:35][CH:34]2[NH:36][CH:31]([CH2:32][CH2:33]2)[CH2:30]1)[CH2:26][CH2:27][CH3:28]>C(Cl)Cl.CC(O)C>[CH2:25]([CH:29]1[CH2:30][CH:31]2[N:36]([CH2:2][C@@H:3]([CH3:17])[CH2:4][N:5]3[C:10]4[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=4[O:8][CH2:7][C:6]3=[O:16])[CH:34]([CH2:33][CH2:32]2)[CH2:35]1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCC1CC2CCC(C1)N2
Reactant: Cc1ccc2c(c1)N(C[C@H](C)CI)C(=O)CO2
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)COc2ccc(C)cc21
Yield: 62.6 %

Procedure:
Crude (S)-4-(3-iodo-2-methylpropyl)-6-methyl-4H-benzo[1,4]oxazin-3-one (0.19 g, 0.54 mmol), Et3N (0.5 mL) and 3-butyl-8-azabicyclo[3.2.1]octane (0.10 g, 0.61 mmol) were reacted according to GP17. Flash CC (SiO2; CH2Cl2/i-PrOH 92:8) gave the title compound (0.13 g, 62%). 1H NMR (CD3OD) δ 7.05 (s, 1H), 6.86 (d, J=8.4 Hz, 1H), 6.81 (dm, J=8.4 Hz, 1H), 4.52 (ABq J=14.8, 24.8 Hz, 2H), 4.05 (dd, J=5.6, 14.0 Hz, 1H), 3.94 (dd, J=8.8, 14.0 Hz, 1H), 3.05-3.16 (m, 2H), 2.35-2.14 (m, 2H), 2.31 (s, 3H), 2.05-1.78 (m, 3H), 1.63-1.40 (m, 5H), 1.36-1.12 (m, 5H), 0.99 (d, J=6.4 Hz, 3H), 0.90 (t, J=6.8 Hz, 3H); 13C NMR (CD3OD) δ 167.4, 144.9, 133.7, 129.2, 125.6, 117.7, 117.3, 68.5, 63.2 (br), 62.5(br), 56.0(Br), 43.3, 37.8 (br), 31.3, 30.5, 30.0, 28.3, 26.7, 26.4, 23.7, 21.0, 16.8, 14.2.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1>CCO.[Pd]>[NH2:9][C:5]1[CH:4]=[N:3][C:2]([F:1])=[C:7]([CH3:8])[CH:6]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1F
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)cnc1F
Reaction time: 16 h
Yield: 78 %

Procedure:
2-Fluoro-3-methyl-5-nitropyridine (from Step 32b above) was combined with 100 mg of 5% Pd/C in EtOH (100 mL), and the mixture was stirred under an atmosphere of hydrogen for 16 hours. The mixture was filtered and concentrated. The crude product was chromatographed (silica gel; CHCl3/MeOH, 99:1 to 94:6) to yield 5.2 g (78%) of the title compound: 1H NMR (DMSO-d6, 300 MHz) δ7.26 (t, J=2.7 Hz, 1H), 6.95 (dd, J=8.1 Hz, 1H), 5.11 (br, s, 2H), 2.10 (s, 3H); MS (CI/NH3) m/z: 127 (M+H)+, 144 (M+NH4)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][CH:30]([C:33]([O:35]CC)=[O:34])[CH2:29][CH2:28]1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1(C)C=CC=CC=1>[CH3:18][N:16]1[C:15](=[O:19])[CH:14]=[CH:13][C:12]([C:10](=[O:11])[CH2:9][C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([N:27]3[CH2:28][CH2:29][CH:30]([C:33]([OH:35])=[O:34])[CH2:31][CH2:32]3)=[CH:7][CH:6]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])=[CH:17]1
Reactant: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Reactant: CCOC(=O)C1CCNCC1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)c1)c1ccc(N2CCC(C(=O)O)CC2)cc1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-5-(3-(4-bromophenyl)-3-o-tolylpropanoyl)-1-methylpyridin-2(1H)-one (example 223, step 3; 500 mg, 1.22 mmol) in toluene (7 mL) was added ethyl piperidine-4-carboxylate (293 mg, 1.83 mmol), sodium tert-butoxide (234 mg, 2.44 mmol), tris(di-benzylideneacetone)dipalladium(0) (22.3 mg, 24.4 μmol) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (23.7 mg, 48.7 μmol) and the reaction mixture was stirred for 1 h at 85° C. The reaction mixture was evaporated and the residue chromatographed to afford the title compound (101 mg, 18%; light yellow foam, MS (ESI−): m/z=: 457.4 [M−H]−) and (R)-methyl 1-(4-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxo-1-o-tolylpropyl)phenyl)piperidine-4-carboxylate (174 mg, 30%; light yellow foam, MS (ESI+): m/z=: 487.4 [M+H]+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2N)=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].[I-:20].[K+]>O.II>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[I:20])=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: Cc1ccc(-c2ccccc2N)cc1
Agent: Cl
Agent: II
Agent: O=N[O-]
Solvent: O
Product: Cc1ccc(-c2ccccc2I)cc1
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 58.2 %

Procedure:
A suspension of 10.0 g (54.6 mmol) of 4-methyl-2'-amino-1,1'-biphenyl in 135 mL of water containing 15 mL of concentrated hydrochloric acid was cooled at -5° C. and treated dropwise with a solution of 3.94 g (57.1 mmol) of sodium nitrite in 9.24 mL of water while maintaining the temperature below 0° C. After the addition was complete, the reaction mixture was stirred an additional 10 minutes. The reaction mixture was slowly poured into a vigorously stirred solution of 29.6 g (178 mmol) of potassium iodide and 643 mg (2.5 mmol) of iodine dissolved in 80 mL of water. When the addition was complete, the reaction mixture was slowly warmed to 35° C. and stirred for an additional 25 minutes. The reaction mixture was cooled, and extracted with ethyl ether. The combined extracts were washed with aqueous 10% sodium thiosulfate (3×). aqueous saturated sodium bicarbonate (1×), and water (1×). The extracts were dried over magnesium sulfate, filtered and evaporated under vacuum to yield 14 g of crude product. The product was purified by chromatography over silica gel, eluting with hexanes to yield 9.34 g (31.8 mmol, 58%) of the product. FAB-MS: calculated for C13H11I 294; found 295 (M+1). 1H NMR (200 MHz, CDCl3): 2.42 (s, 3H): 7.14 (dt, 1H), 7.32 (m, 5H), 7.95 (dd, 1H).
Reaction SMILES: [CH3:1][Si:2]([CH:5]=[N+]=[N-])([CH3:4])[CH3:3].C(OCC)C.[O:13]1[CH2:18][CH2:17][CH2:16][O:15][CH:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[CH:33]=[C:32]([C:34]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH2:35])[CH:31]=[CH:30][C:28]=3[N:29]=2)=[C:21]([F:42])[CH:20]=1>O1CCOCC1>[O:15]1[CH2:16][CH2:17][CH2:18][O:13][CH:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[CH:33]=[C:32]([C:34]4([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[CH2:35][CH:5]4[Si:2]([CH3:1])([CH3:3])[CH3:4])[CH:31]=[CH:30][C:28]=3[N:29]=2)=[C:21]([F:42])[CH:20]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C=C(c1ccccc1)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2c1
Solvent: CCOCC
Solvent: C1COCCO1
Product: C[Si](C)(C)C1CC1(c1ccccc1)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2c1
Temperature: 150 °C

Procedure:
In a reactor bottle (trimethylsilyl)diazomethane, 2.0 M in diethyl ether (2.4 mL, 4.8 mmol) was added to a mixture of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-6-(1-phenylvinyl)-benzo[d]thiazole (0.650 g, 1.6 mmol), in anhydrous dioxane 15.00 mL. The reaction mixture was heated to 150° C. for 18 h. At which time the crude reaction mixture was concentrate in vacuo and purified by silica gel chromatography to afford as a mixture of isomers 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-6-(1-phenyl-2 (trimethylsilyl)cyclopropyl)benzo[d]thiazole. MS (ESI) m/z: Calculated: 503.2; Observed: 504.0 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1/[CH:9]=[CH:10]/[CH2:11][N:12]1[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH2:20][N:21]2[C:26]3[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:25]=3[O:24][CH2:23][C:22]2=[O:33])[C@H:14]([C:34]([O:36]C)=[O:35])[CH2:13]1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1/[CH:9]=[CH:10]/[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][CH2:20][N:21]2[C:26]3[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:25]=3[O:24][CH2:23][C:22]2=[O:33])[CH:14]([C:34]([OH:36])=[O:35])[CH2:13]1
Reactant: COC(=O)[C@@H]1CN(C/C=C/c2cc(F)ccc2F)CC[C@@H]1CCCN1C(=O)COc2ccc(OC)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(c1)N(CCCC1CCN(C/C=C/c3cc(F)ccc3F)CC1C(=O)O)C(=O)CO2
Temperature: 30 °C
Yield: 20.6 %

Procedure:
A solution of methyl Cis(±)-1-[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]-4-[3-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylate (Example 123) (105 mg, 0.204 mmol) in methanol (1 mL) was treated with a solution of sodium hydroxide (1N, 1 mL) the reaction was warmed to 30° C. for 18 hours. The temperature was increased to 60° C. for 6 hours. The solvents were evaporated, the reaction was diluted with ethyl acetate and water. The pH was adjusted to 7 with 1N HCl. The layers were separated. The aqueous phase was extracted with ethyl acetate (2×20mL). The organic layers were combined dried over magnesium sulfate and concentrated at reduced pressure. The residue was taken up and dichloromethane and precipitated with ether in a dry ice/acetone bath. The solvent was decanted. The solid was dried under high vacuum to obtain 21 mg (20%) of an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:27])=[C:6]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[OH:20])[N:10]([CH2:21][C:22](OCC)=[O:23])[N:9]=2)[CH:7]=1.[NH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:27])=[C:6]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[OH:20])[N:10]([CH2:21][C:22]([NH:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:23])[N:9]=2)[CH:7]=1
Reactant: CCOC(=O)Cn1nc(-c2cc(Cl)ccc2O)nc1-c1cc(Cl)ccc1O
Reactant: NCCN1CCOCC1
Solvent: CCO
Product: O=C(Cn1nc(-c2cc(Cl)ccc2O)nc1-c1cc(Cl)ccc1O)NCCN1CCOCC1

Procedure:
4 g of ethyl [3,5-bis(5-chloro-2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate (Example 40) and 2.6 g of 4-(2-aminoethyl)morpholine are boiled under reflux for 18 h in 50 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from isopropanol. After drying, 2-[3,5-bis(5-chloro-2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-N-(2-morpholin-4-yl-ethyl)acetamide remains as colorless crystals of m.p. 224-226° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@@H:12]2[C@H:17]([NH:18][C:19]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=3)=O)[CH2:16][CH2:15][S:14](=[O:32])(=[O:31])[CH2:13]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C([O-])([O-])=O.[K+].[K+].O=P(Cl)(Cl)Cl>C(#N)C>[CH2:1]([O:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]2[C:19]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=3)=[N:18][C@@H:17]3[CH2:16][CH2:15][S:14](=[O:32])(=[O:31])[CH2:13][C@@H:12]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1cc([C@H]2CS(=O)(=O)CC[C@H]2NC(=O)c2ccc(C(=O)OC)cc2)ccc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)OC)cc1)=N[C@@H]1CCS(=O)(=O)C[C@H]21
Temperature: 85 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of methyl 4-{[(3R,4R)-3-(3-ethoxy-4-methoxyphenyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl]carbamoyl}benzoate (22.8 g; compound C4) and K2CO3 (6.82 g) in absolute ACN (200 ml) is added POCl3 (13.6 ml) at 0° C. (ice bath). The suspension is allowed to come to RT within 1 h and is subsequently refluxed at 85° C. for 6 h. Afterwards the mixture is stirred for 12 h at RT under nitrogen atmosphere. The mixture is quenched with water (500 ml) and adjusted to pH7 by addition of 0.4 M NaOH. The ACN is destilled of and to the remaining suspension DCM (500 ml) is added. The pH value is adjusted to 8.1 by addition of aqueous sodium hydroxide solution (0.4 M) and saturated aqueous solution of sodium bicarbonate and the mixture is stirred at RT for 12 h. The organic layer is separated and the aqueous layer is extracted with DCM (300 ml). The combined organic layers are dried over sodium sulfate, filtered and evaporated in vacuo to dryness. The resulting residue is purified by flash column chromatography [silica gel, eluent system: n-hexane/EtOAc/triethylamine 11/8/1 (v/v/v)] to obtain a crude solid. The residue is treated with DIP (400 ml) and stirred at reflux temperature for 3 h. The suspension is cooled to 0° C. with an ice bath and filtered off. The filter cake is washed with DIP and dried in vacuo at 70° C. to obtain the title compound as a solid.
Reaction SMILES: C([C:4]1[N:5]=[C:6](F)[N:7]([C:9]([C:22]2[CH:27]=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:8]=1)C=C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:41]([O:44][CH2:45][C:46]1[CH2:47][S:48][C@@H:49]2[CH:56]([NH2:57])[C:55](=[O:58])[N:50]2[C:51]=1[C:52]([OH:54])=[O:53])(=[O:43])[CH3:42]>CN(C=O)C>[C:41]([O:44][CH2:45][C:46]1[CH2:47][S:48][C@@H:49]2[CH:56]([NH:57][C:6]3[N:7]([CH2:9][CH:22]=[CH2:27])[CH:8]=[CH:4][N:5]=3)[C:55](=[O:58])[N:50]2[C:51]=1[C:52]([OH:54])=[O:53])(=[O:43])[CH3:42]
Reactant: C=CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1ccnc1NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 11.4 %

Procedure:
A mixture of 4-allyl-2-fluoro-1-triphenylmethyl imidazole (1.21 g.) and toluene-p-sulphonic acid monohydrate (0.635 g.) in DMF (8.5 ml.) was stirred at ambient temperature for 1 minute then at 80°. 3-Acetoxymethyl-7-aminoceph-3-em-4-carboxylic acid (0.904 g.) was added and the mixture was heated at 80° for 2.5 hours. The solution was evaporated to dryness in vacuo and water and EtOAc added to the residue. The aqueous layer was separated, evaporated to dryness, the residue redissolved in water and purified by preparative HPLC on Whatman "Partisil 10" using water/MeOH/HOAc 70:30:1 v/v/v as eluant to give 3-acetoxymethyl-7-(3-allylimidazol-2-yl)aminoceph-3-em-4-carboxylic acid (0.142 g.) having the following n.m.r. in d6DMSO+CD3COOD: 2.0 (s, 3H); 3.15 (d, 2H); 3.23 (d, 1H); 3.54 (d, 1H); 4.7 (d, 1H); 4.97 (d, 1H); 4.9- 5.2 (m, 3H); 5.48 (d, 1H); 5.8 (m, 1H); 6.3 (s, 1H).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)=[O:4].[NH2:27][CH2:28][C:29]([OH:31])=[O:30]>>[C:25]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:4])[N:6]=1)#[N:26]
Reactant: COC(=O)c1nc(C#N)c2c(Oc3cccc(OC)c3)cccc2c1O
Reactant: NCC(=O)O
Product: COc1cccc(Oc2cccc3c(O)c(C(=O)NCC(=O)O)nc(C#N)c23)c1

Procedure:
The title compound was synthesized from 1-cyano-4-hydroxy-8-(3-methoxy-phenoxy)-isoquinoline-3-carboxylic acid methyl ester and glycine in analogy to example 1b; MS-(−)-ion: M−1=392.4.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:14]([NH:16][C@@H:17]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH:18]([OH:25])[C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])=[O:15])[CH3:13])=O)C1C=CC=CC=1.[ClH:30]>CO.[Pd]>[ClH:30].[NH2:11][C@H:12]([C:14]([NH:16][C@@H:17]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH:18]([OH:25])[C:19]([O:21][CH:22]([CH3:23])[CH3:24])=[O:20])=[O:15])[CH3:13]
Reactant: CC(C)C[C@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(O)C(=O)OC(C)C
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@H](C)N)C(O)C(=O)OC(C)C

Procedure:
To a solution of 56 mg of the isopropyl hexanoate compound in 3ml of methanol were added 0.2 ml of a 2N-hydrochloric acid and 20 mg of a 10% of palladium charcoal, and the mixture was hydrogenated under a hydrogen atmosphere. After filtration of the catalyst, the filtrate was evaporated under reduced pressure to obtain 42 mg of isopropyl (2RS, 3S)-3-(L-alanyl)amino-2-hydroxy-5-methylhexanoate hydrochloride as a colorless viscous oil.