Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[K+].[CH3:3][C:4]1[CH2:8][C:7]([CH3:9])=[C:6]([CH3:10])[C:5]=1[CH3:11].Cl[Si:13]([C:36]1[CH:41]=[C:40]([CH3:42])[CH:39]=[C:38]([Si:43]([CH3:46])([CH3:45])[CH3:44])[CH:37]=1)([C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:26]=1)[C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=1.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C1(C)C=CC=CC=1>[CH3:42][C:40]1[CH:39]=[C:38]([Si:43]([CH3:46])([CH3:45])[CH3:44])[CH:37]=[C:36]([Si:13]([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=2)([C:25]2[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([Si:32]([CH3:33])([CH3:34])[CH3:35])[CH:26]=2)[C:8]2[CH:7]([CH3:9])[C:6]([CH3:10])=[C:5]([CH3:11])[C:4]=2[CH3:3])[CH:41]=1
Reactant: CC1=C(C)C(C)=C(C)C1
Reactant: Cc1cc([Si](C)(C)C)cc([Si](Cl)(c2cc(C)cc([Si](C)(C)C)c2)c2cc(C)cc([Si](C)(C)C)c2)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1=C(C)C(C)C([Si](c2cc(C)cc([Si](C)(C)C)c2)(c2cc(C)cc([Si](C)(C)C)c2)c2cc(C)cc([Si](C)(C)C)c2)=C1C
Temperature: 50 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
Under a nitrogen atmosphere, potassium hydride (0.88 g, 21.82 mmol in terms of potassium hydride) dispersed in mineral oil was washed with hexane. Tetrahydrofuran (38 mL) was added and this mixture was warmed to 50° C. A solution of 1,2,3,4-tetramethylcyclopenta-1,3-diene (2.00 g, 16.37 mmol) dissolved in tetrahydrofuran (8 mL) was added dropwise and stirred at 50° C. for one hour. To this solution, a solution of chlorotris(5-methyl-3-trimethylsilyl-phenyl)silane (7.81 g, 14.11 mmol) dissolved in tetrahydrofuran (38 mL) was added dropwise and stirred at 65° C. for 3 hours. The resultant mixture was added dropwise at 0° C. to a solution of a 10% sodium hydrogen carbonate (38 mL) and a 10% sodium carbonate (38 mL). Toluene (38 mL) was added to separate an organic phase, and the organic phase was dried over sodium sulfate and then filtrated. The solvent was removed under reduced pressure. Purification was performed by silica gel column chromatography to obtain 1-tris(5-methyl-3-trimethylsilyl-phenyl)silyl-2,3,4,5-tetramethylcyclopentadiene (5.40 g, yield 59.9%).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[S:7][C:8]([C:11](=O)[CH2:12][CH2:13][CH2:14][Cl:15])=[CH:9][CH:10]=1)(=[O:3])[CH3:2].O>C([SiH](CC)CC)C.FC(F)(F)C(O)=O>[C:1]([NH:4][CH2:5][C:6]1[S:7][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][Cl:15])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1ccc(C(=O)CCCCl)s1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(=O)NCc1ccc(CCCCCl)s1
Temperature: 25 °C
Reaction time: 10 h
Yield: 70.5 %

Procedure:
A mixture of 2-acetylaminomethyl-5-(4-chlorobutyryl)thiophene (15 g) in triethylsilane (21.6 ml) and trifluoroacetic acid (70 ml) was stirred at room temperature for 10 hours. The reaction mixture was poured into water, extracted with ethyl acetate, and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 10 g of 2-acetylaminomethyl-5-(4-chlorobutyl)thiophene.
Reaction SMILES: [OH-:1].[K+].[CH3:3][C:4]([N:23]1[CH2:27][CH2:26][C@H:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:24]1)([CH3:22])[CH2:5][CH2:6][C:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:8]#[N:9]>CC(O)(CC)CC>[CH3:22][C:4]([N:23]1[CH2:27][CH2:26][C@H:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:24]1)([CH3:3])[CH2:5][CH2:6][C:7]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:8]([NH2:9])=[O:1]
Reactant: CC(C)(CCC(C#N)(c1ccccc1)c1ccccc1)N1CC[C@H](Oc2ccccc2)C1
Reactant: [OH-]
Agent: CCC(C)(O)CC
Agent: [K+]
Product: CC(C)(CCC(C(N)=O)(c1ccccc1)c1ccccc1)N1CC[C@H](Oc2ccccc2)C1
Temperature: 25 °C
Yield: 82 %

Procedure:
Potassium hydroxide (5.10 g, 91.98 mmol) was added to a solution of the product of example 1 (1.95 g, 4.60 mmol) in 3-methyl-3-pentanol (40 mL) and the mixture was heated under reflux for 24 hours. The reaction mixture was then cooled to room temperature, concentrated in vacuo and the residue was partitioned between ethyl acetate (70 mL) and water (40 mL). The aqueous layer was separated, extracted with ethyl acetate (50 mL) and the combined organic solution was dried over sodium sulfate and concentrated in vacuo. The residue was then re-crystallised from hexane/ethyl acetate and dried under vacuum for 18 hours to afford the title compound as a white solid in 82% yield, 1.66 g.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[O:24]1[C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=[N:25]1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:29]([C:28]5[O:24][N:25]=[CH:26][CH:27]=5)=[O:30])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: O=C(Cl)c1ccno1
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4ccno4)nc3cc21

Procedure:
Isoxazole-5-carboxylic acid[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and isoxazole-5-carbonyl chloride (78 μl, 0.87 mmol). The title compound was obtained as light brown powder (76 mg, 23%).
Reaction SMILES: CS([O:5][CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C@H:8]1[C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=1)(=O)=O.[Cl:28][C:29]1[CH:30]=[CH:31][C:32](O)=[N:33][CH:34]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C(OCC)(=O)C>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([N:9]2[C@@H:8]([C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=3)[C@H:7]([CH2:6][O:5][C:32]3[CH:31]=[CH:30][C:29]([Cl:28])=[CH:34][N:33]=3)[O:11][C:10]2=[O:12])=[CH:14][CH:15]=1
Reactant: Oc1ccc(Cl)cn1
Reactant: CS(=O)(=O)OC[C@@H]1OC(=O)N(c2ccc(Cl)cc2)[C@H]1c1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1O[C@@H](COc2ccc(Cl)cn2)[C@H](c2cc(F)cc(F)c2)N1c1ccc(Cl)cc1
Temperature: 35 °C
Reaction time: 2 h
Yield: 4.7 %

Procedure:
The ((4S,5R)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl methanesulfonate (49 mg, 0.117 mmol), 5-chloropyridin-2-ol (45 mg, 0.35 mmol), and K2CO3 (48 mg, 0.35 mmol) are dissolved in DMF (1.0 mL) and stirred at 35° C. for 2 h, as judged complete by LC-MS. The reaction is diluted with water and ethyl acetate. The organic is washed with brine, dried over MgSO4, filtered and concentrated. Separation of the N- and O-alkylated products by preparative HPLC (C-18, 10-80% ACN/water (0.05% TFA)) gave 2.5 mg of the desired product. 1H NMR (acetone-d6, 400 MHz) δ 8.15 (d, 1H, J=2.7 Hz), 7.76 (dd, 1H, J=8.8, 2.7 Hz), 7.54-7.57 (m 2H), 7.32-7.36 (m, 2H), 7.22-7.28 (m, 2H), 7.02 (tt, 1H, J=9.1, 2.3 Hz), 6.86 (d, 1H, J=8.8 Hz), 5.77 (d, 1H, J=5.6 Hz), 4.85 (ddd, 1H, J=5.2, 4.0, 4.0 Hz), 4.72-4.79 (m, 2H). HPLC-MS calculated C21H14Cl2F2N2O3 (M+H+): 451.0, found: 451.0.
Reaction SMILES: C1(C(C2CCCCCCCCC2)=C(C2CCCCCCCCC2)C([O-])=O)CCCCCCCCC1.C(O)(=O)C(C)=C.[C:42]([O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52]OC(CCC)=O)(=[O:46])[C:43]([CH3:45])=[CH2:44]>>[C:42]([O:47][CH2:48][CH2:49][O:50][CH2:51][CH3:52])(=[O:46])[C:43]([CH3:45])=[CH2:44]
Reactant: C=C(C)C(=O)OCCOCCOC(=O)CCC
Agent: C=C(C)C(=O)O
Agent: O=C([O-])C(=C(C1CCCCCCCCC1)C1CCCCCCCCC1)C1CCCCCCCCC1
Product: C=C(C)C(=O)OCCOCC

Procedure:
In the same way as the embodiment 1, synthesis of terpolymer was performed using 3.4 grams (0.0166 mols) of tricyclodecanylacrylate, 0.7 grams (0.0083 mols) of methacrylic acid, and 4 grams (0.0166 mols) of propylcarbonyloxyethoxyethyl methacrylate, which is a compound having been obtained in the synthesis example 10, in place of ethoxyethyl methacrylate. As a result, there was obtained 4.86 grams of poly (tricyclodecylacrylate-propylcarbonyloxyethoxyethyl methacrylate-methacrylic acid). The yield was 60%.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]2[NH:6][C:7]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[N+:20]([O-])([OH:22])=[O:21].[N+]([O-])(O)=O.C(O)(=O)C>C(O)(=O)C.O>[OH:1][C:2]1[CH:19]=[CH:18][C:5]2[NH:6][C:7]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[C:3]=1[N+:20]([O-:22])=[O:21]
Reactant: CCOC(=O)CC1=NS(=O)(=O)c2cc(O)ccc2N1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)CC1=NS(=O)(=O)c2c(ccc(O)c2[N+](=O)[O-])N1
Reaction time: 19 h
Yield: 41 %

Procedure:
A suspension of the product of Example 352C (100 mg, 0.352 mmol) in glacial acetic acid (3 mL) was treated at room temperature with a solution of concentrated nitric acid in glacial acetic acid (1.43 M, 0.305 mL, 0.436 mmol) and stirred at this temperature for 19 hours. Added additional 1.43 M nitric acid/acetic acid (0.020 mL, 0.029 mmol) and let stir for 1.5 hours. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 8% methanol/dichloromethane to give the title compound as a light yellow solid (47 mg, 41%). MS (ESI−) m/z 328 (M−H)−. 1H NMR (300 MHz, PYRIDINE-d5) δ 0.98 (t, J=7.17 Hz, 3 H) 3.86 (s, 2 H) 4.01 (q, J=7.23 Hz, 2 H) 7.11 (d, J=8.82 Hz, 1 H) 7.22 (d, J=8.82 Hz, 1 H).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:26]([CH3:34])([CH2:27][CH2:28][C:29]=32)[C@@H:18]([C@H:19]([CH3:25])[CH2:20][CH2:21][C:22](O)=O)[CH2:17][CH:16]=4)[C:10]1([CH3:36])[CH3:35])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Si:1]([O:8][C@H:9]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:26]([CH3:34])([CH2:27][CH2:28][C:29]=32)[C@@H:18]([C@H:19]([CH3:25])[CH2:20][CH2:21][CH2:22][NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:17][CH:16]=4)[C:10]1([CH3:35])[CH3:36])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Reactant: Nc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](CCCNc1ccccc1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3

Procedure:
3β-tert-Butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24 oic acid (0.15 g) is reacted with aniline following the procedure outlined in example 10 and reduced with lithium aluminum hydride (0.15 g) in THF at room temperature. Aqueous work-up and crystallization from methanol gives 3β-tert-butyldimethylsilyloxy-4,4-dimethyl-24-phenylamino-5α-chola-8,14-dien (106 mg). 1H-NMR (CDCl3, 300 MHz): δ=7.17 (2H, t); 6.69 (1H, t); 6.6 (2H, d); 5.35 (1H, s); 3.6 (1H, s); 3.2 (1H, m); 3.09 (2H, m); 0.9 (9H, s); 0.04 (6H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][C@H:8]1[CH2:20][CH3:21].C(OC([NH:30][C:31]1[S:35][C:34]([C:36]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=2[F:43])=[N:33][C:32]=1[C:44](O)=[O:45])=O)(C)(C)C>>[NH2:30][C:31]1[S:35][C:34]([C:36]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=2[F:43])=[N:33][C:32]=1[C:44]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][C@H:8]1[CH2:20][CH3:21])=[O:45]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1c(N)cnn1C
Product: CC[C@@H]1CNCCN1c1c(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)cnn1C
Yield: 21 %

Procedure:
Following the procedure for Example 112, reacting (R)-tert-butyl 4-(4-amino-1-methyl-1H-pyrazol-5-yl)-3-ethylpiperazine-1-carboxylate and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 gave 114 as a white solid (30 mg, 21% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 7.91 (s, 1H), 7.36-7.27 (m, 1H), 7.02 (t, J=8.9 Hz, 2H), 6.24 (s, 2H), 3.76 (s, 3H), 3.25-3.15 (m, 2H), 3.11-2.90 (m, 4H), 2.58 (t, J=5.5 Hz, 1H), 1.41-1.31 (m, 1H), 1.28-1.14 (m, 1H), 0.79 (t, J=7.5 Hz, 3H). Alkyl NH not observed. LCMS (ES+) m/z 448 (M+1).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Sn](C)(C)C)=[CH:17][CH:16]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:36][C@H:35]([CH2:37][N:38]3[CH:42]=[CH:41][N:40]=[N:39]3)[O:34][C:33]2=[O:43])=[CH:28][CH:27]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>O1CCOCC1>[Si:1]([O:8][CH2:9][CH:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:26]3[CH:27]=[CH:28][C:29]([N:32]4[CH2:36][C@H:35]([CH2:37][N:38]5[CH:42]=[CH:41][N:40]=[N:39]5)[O:34][C:33]4=[O:43])=[CH:30][CH:31]=3)=[CH:17][CH:16]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(I)cc1
Reactant: CC(C)(C)[Si](C)(C)OCC1CC(c2ccc([Sn](C)(C)C)cc2)=NO1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)OCC1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3)cc2)=NO1
Temperature: 90 °C
Yield: 40.9 %

Procedure:
5-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-3-[4-(trimethylstannyl)phenyl]-4,5-dihydroisoxazole (0.5 g, 1.1 mmol), (5R)-3-(4-iodophenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (0.49 g, 1.32 mmol), and tri-2-furylphosphine (0.051 g, 0.22 mmol) were dissolved in 1,4-dioxane (6 ml) and degassed three times. Tris (dibenzylideneacetone)palladium (0) (0.1 g, 0.11 mmol) was added and the solution was degassed three times. The solution was stirred and heated to 90° C. for 18 hours. The mixture was concentrated in vacuo and then purified by silica flash chromatography with 5-10% methanol in dichloromethane as eluent giving 0.24 g desired product.
Reaction SMILES: Cl.[Cl-].N[C@@H:4]1[C:21](=[O:22])[N:6]2[C:7]([C:18]([OH:20])=[O:19])=[C:8]([CH2:11][N+:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:9][S:10][C@H:5]12.C1(ON=C(C2N=C(NC=O)SC=2)C(O)=O)CC1.C(OCC)(=O)C>C[Si](C)(C)NC(=O)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.O1CCCC1>[N+:12]1([CH2:11][C:8]2[CH2:9][S:10][C@@H:5]3[CH2:4][C:21](=[O:22])[N:6]3[C:7]=2[C:18]([O-:20])=[O:19])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(C[n+]3ccccc3)CS[C@H]12
Agent: CC(=O)N[Si](C)(C)C
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C([O-])C1=C(C[n+]2ccccc2)CS[C@@H]2CC(=O)N12
Reaction time: 0.67 h
Yield: 75.9 %

Procedure:
1-[(7β-Amino-4-carboxy-3-cephem-3-yl)methyl]pyridinium chloride hydrochloride (960 mg) was dissolved in a solution of N-trimethylsilylacetamide (1.5 g) and bis(trimethylsilyl)acetamide (2.8 ml) in tetrahydrofuran (10 ml). To this solution was added the activated acid solution, which was prepared from 2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (500 mg) according to a similar manner to that described in Example 1, at -20° C. The mixture was stirred at -20° C. to -10° C. for 40 minutes. The mixture was poured into ethyl acetate (250 ml). The precipitate was collected and suspended in methanol (20 ml). To the suspension was added concentrated hydrochloric acid (0.62 ml) and the mixture was warmed at 30° to 35° C. for 2 hours. The mixture was poured into ice-water (50 ml), adjusted to pH 2.5 with saturated aqueous solution of sodium bicarbonate, and washed with ethyl acetate. The aqueous solution was subjected to column chromatography on a non-ionic adsorption resin "Diaion HP-20" (30 ml). After the column was washed with water (300 ml), 1% isopropyl alcohol (60 ml), and 3% isopropyl alcohol (60 ml) successively, the elution was carried out with 5% isopropyl alcohol (250 ml) and 10% isopropyl alcohol (150 ml) successively. The fractions containing the object compound were collected, combined, concentrated in vacuo to about 100 ml and lyophilized to give 7β-2-(2-aminothiazol-4-yl)-2-(cyclopropyloxyimino)acetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer) (553 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:15])=[C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:21]1[N:25]2[CH:26]=[CH:27][C:28]([C:30]([F:33])([F:32])[F:31])=[N:29][C:24]2=[N:23][CH:22]=1)CCC>>[F:15][C:5]1[CH:4]=[CH:3][C:2]([C:21]2[N:25]3[CH:26]=[CH:27][C:28]([C:30]([F:31])([F:32])[F:33])=[N:29][C:24]3=[N:23][CH:22]=2)=[CH:7][C:6]=1[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: Cc1ccnc(-c2cc(Br)ccc2F)c1
Product: Cc1ccnc(-c2cc(-c3cnc4nc(C(F)(F)F)ccn34)ccc2F)c1

Procedure:
2-(5-Bromo-2-fluorophenyl)-4-methylpyridine was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine by the method of Example 32. Purification by chromatography on silica gel eluting with dichloromethane containing 1% methanol, then crystallisation from ethyl acetate/isohexane, gave 3-[4-fluoro-3-(4-methylpyridin-2-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as a yellow powder: δH (400 MHz, CDCl3) 8.87 (1H, d, J 7), 8.58 (1H, d, J 5), 8.24 (1H, dd, J 7 and 2), 8.12 (1H, s), 7.71 (1H, s), 7.53-7.58 (1H, m), 7.38 (1H, dd, J 11 and 8), 7.26 (1H, d, J 7), 7.16 (1H, d, J 5), 2.46 (3H, s); m/z (ES+) 373 (M++H).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16]C[CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1SC2C[O:31]CCC=2C=1C(OCC)=O.C1(S(Cl)(=O)=O)C=CC=CC=1>>[C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16][O:31][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Reactant: CCOC(=O)c1c(N)sc2c1CCOC2
Agent: O=S(=O)(Cl)c1ccccc1
Product: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCOC2

Procedure:
Prepared by proceeding in a similar manner to Intermediate 1, starting from ethyl 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylate (Intermediate 7) and benzenesulphonyl chloride
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[C:13]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]3[C:11]2=[O:20])=[C:6]([OH:21])[CH:5]=1)([O-])=O.C1(=O)NC(=O)C2=CC=CC=C12>CN(C)C=O.[Ni]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:11](=[O:20])[C:12]3=[CH:19][CH:18]=[CH:17][CH:16]=[C:13]3[C:14]2=[O:15])=[C:6]([OH:21])[CH:5]=1
Reactant: O=C1c2ccccc2C(=O)N1c1ccc([N+](=O)[O-])cc1O
Agent: [Ni]
Agent: O=C1NC(=O)c2ccccc21
Solvent: CN(C)C=O
Product: Nc1ccc(N2C(=O)c3ccccc3C2=O)c(O)c1

Procedure:
40 g of Raney-Nickel (washed neutral) were added to 284 g (1 mol) of N-(4-nitro-2-hydroxyphenyl)-phthalimide in 1.75 liters of dimethyl formamide (DMF) and the phthalimide was hydrogenated under a pressure of 15-20 bar at 60° C. The filtrate was precipitated in 3.5 liters of water, suction filtered, washed and dried. Yield: 230 g=90% of theoretical yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[F:8].Cl[C:13]1[C:14]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=3)[CH2:21][CH2:20]2)=[N:15][CH:16]=[CH:17][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[C:14]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)[CH2:21][CH2:20]3)=[N:15][CH:16]=[CH:17][N:18]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: Cn1cc(CN2CCN(c3nccnc3Cl)CC2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cn1cc(CN2CCN(c3nccnc3-c3ccc(F)c(Cl)c3)CC2)cn1
Temperature: 110 °C
Yield: 57.8 %

Procedure:
Add 3-chloro-4-fluorobenzeneboronic acid (71 mg, 0.41 mmol) to a mixture of 3′-chloro-4-(1-methyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (104 mg, 0.34 mmol), potassium carbonate (113 mg, 0.82 mmol) and tetrakis(triphenyl-phosphine)palladium(0) (0.002 g, 0.002 mmol) in N,N-dimethylacetamide (2 mL) and water (1 mL). Purge with nitrogen and heat overnight at 110° C. Cool to room temperature, add water (10 mL), extract with DCM (3×20 mL), combine and purify using high pH reverse phase HPLC to give title compound (76 mg, 57.7%). MS (ES): m/z=387 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][N:8]([C:11]2[C:20]([CH:21]=[O:22])=[CH:19][C:18]3[C:13](=[CH:14][C:15]([F:23])=[CH:16][CH:17]=3)[N:12]=2)[CH2:9][CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].[Cl-].[NH4+].O>C(O)C>[CH:1]1([CH2:7][N:8]([C:11]2[C:20]([CH2:21][OH:22])=[CH:19][C:18]3[C:13](=[CH:14][C:15]([F:23])=[CH:16][CH:17]=3)[N:12]=2)[CH2:9][CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC1CCCCC1)c1nc2cc(F)ccc2cc1C=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCN(CC1CCCCC1)c1nc2cc(F)ccc2cc1CO
Reaction time: 2 h

Procedure:
To a mixture of 2-[N-(cyclohexylmethyl)-N-ethylamino]-7-fluoroquinoline-3-carbaldehyde (230 mg, 0.73 mmol) in ethanol (2 mL) is added sodium borohydride (30 mg, 0.79 mmol) and the mixture is stirred for 2 hours. After addition of sat. ammonium chloride and water, the mixture is extracted with ethyl acetate. The combined organic layer is washed with brine, dried over magnesium sulfate, filtered and concentrated to give [N-(cyclopentylmethyl)-N-ethylamino]quinolin-3-yl}methanol, which is used without further purification.
Reaction SMILES: [Mg].[CH2:2]([N:9]1[C:13]([C:14](=[O:16])[CH3:15])=[CH:12][N:11]=[CH:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.O1[CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH2:2]([N:9]1[C:13]([C:14]([OH:16])([CH2:19][CH2:20][C:21]2[CH:22]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:15])=[CH:12][N:11]=[CH:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C1CCOC1
Reactant: CC(=O)c1cncn1Cc1ccccc1
Agent: Cl
Agent: [Mg]
Product: CC(O)(CCc1ccccc1)c1cncn1Cc1ccccc1
Temperature: 25 °C

Procedure:
1.0 g of magnesium turnings are covered with 5 ml of dry tetrahydrofuran. To the mixture is added 7.8 g of (2-bromoethyl)benzehe in 30 ml of dry tetrahydrofuran at such a rate that a smooth reaction is maintained. The mixture is then heated under reflux for one hour. After being cooled to room temperature, 3.0 g of 1-(3-benzyl-3H-imidazol-4-yl)-ethanone in 20 ml of tetrahyrofuran is added dropwise to the Grignard reagent and the reaction mixture is refluxed for one hour. The cooled reaction mixture is poured into a cold dilute hydrochloric acid solution. Work-up of the mixture gives the crude product, which is recrystallized from ethyl acetate. The yield is 3.3 g.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([OH:9])[C:5]([Cl:8])=[CH:6][CH:7]=1.[H-].[Na+].[F:13][CH:14]([F:21])[CH2:15]OS(C)(=O)=O>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH2:15][CH:14]([F:21])[F:13])[C:3]=1[F:10]
Reactant: Oc1c(Cl)ccc(Br)c1F
Reactant: CS(=O)(=O)OCC(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1c(Br)ccc(Cl)c1OCC(F)F
Temperature: 70 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
A solution of 3-bromo-6-chloro-2-fluorophenol (15.4 g, 0.068 mol) in DMF (25 mL) was slowly added to a suspension of sodium hydride (60% dispersion in mineral oil) (4.0 g, 0.10 mol) in DMF (100 mL) and the mixture was stirred 1 hour. A solution of methanesulfonic acid 2,2 difluoroethyl ester (17.5 g, 0.109 mol) in DMF (10 mL) was slowly added. The resulting solution was heated to 70° C. for 18 hours. The solution was diluted with water (200 mL) and extracted with ethyl ether. The combined organic phases were dried (sodium sulfate) and concentrated. The residual oil was purified by chromatography (in hexanes) to give 1-bromo-4-chloro-3-(2,2-difluoroethoxy)-2-fluorobenzene (9.0 g, 0.031 mol): 1H NMR (CDCl3): δ 7.3 (m, 1H), 7.10 (dd, 1H), 6.15 (dt, 1H), 4.35 (m, 2H).