Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:3]=1[O:4][CH:5]([CH2:9][CH3:10])[C:6]([OH:8])=[O:7].[Si:16]([O:23][C@H:24]1[CH2:33][C@H:32](O)[C@H:31]2[C:26]([CH:27]=[CH:28][C@H:29]([CH3:52])[C@@H:30]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH2:38]2)=[CH:25]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>>[Si:16]([O:23][C@H:24]1[CH2:33][C@H:32]([O:7][C:6](=[O:8])[CH:5]([O:4][C:3]2[CH:11]=[CH:12][C:13]([CH3:15])=[CH:14][C:2]=2[CH3:1])[CH2:9][CH3:10])[C@H:31]2[C:26]([CH:27]=[CH:28][C@H:29]([CH3:52])[C@@H:30]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:46])[CH3:47])[CH2:38]2)=[CH:25]1)([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CCC(Oc1ccc(C)cc1C)C(=O)O
Product: CCC(Oc1ccc(C)cc1C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 1468.3 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 0.46 g of (2RS)-2-(2,4-dimethylphenoxy)butyric acid and 0.81 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give1.16 g of the title compound as a colorless foam.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18]C)=[N:16][CH:17]=1>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[CH:17]=[N:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc(N)cn1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(O)nc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chlorobenzoyl chloride (1.75 g, 10.0 mmol) was added carefully to a stirred solution of 5-amino-2-methoxypyridine (1.24 g, 10.0 mmol) in dichloromethane (10 mL). After stirring overnight at room temperature, the solvent is evaporated in vacuo and the residue is heated in a pre-heated kugelrohr oven at 200° C. for 5–10 minutes under house-vacuum (around 20 mbar) yielding the title compound, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])C(F)(F)F)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH:25]1[CH2:27][CH2:26]1.[OH-:28].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:16])=[O:28])=[CH:7][N:8]2[CH2:24][CH:25]2[CH2:27][CH2:26]2)=[CH:4][CH:3]=1
Reactant: BrCC1CC1
Reactant: [OH-]
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cn(CC2CC2)c2cc(Cl)ccc12
Temperature: 60 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
A mixture of 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (300 mg, 1.21 mmol), potassium carbonate (419 mg, 3.03 mmol), and (bromomethyl)-cyclopropane (0.18 mL, 1.82 mmol) in N,N-dimethylformamide (4 mL) in a sealed reaction vessel was stirred at 60° C. for 16 h. At this time, the reaction was cooled to 25° C. and partitioned between water (30 mL) and ethyl acetate (30 mL). This mixture was treated with a 1N aqueous hydrochloric acid solution (5 mL), shaken, and separated. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a yellow oil. The resulting oil was treated with a 20% aqueous sodium hydroxide solution (7 mL) and was heated at 110° C. for 2 d. At this time, the reaction was cooled to 25° C. and was partitioned between water (75 mL) and ethyl acetate (75 mL). This solution was treated with a 1N aqueous hydrochloric acid solution (30 mL), shaken, and separated. The organic layer was washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 6-chloro-1-cyclopropylmethyl-1H-indole-3-carboxylic acid (287 mg, 95%) as a pale yellow solid: mp 219-220° C.; EI-HRMS m/e calcd for C13H12ClNO2 (M+) 249.0556, found 249.0558.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH:13]=2)=[CH:4][CH:3]=1.Cl.[CH2:16]=[O:17].N>S(=O)(=O)(O)O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]([CH2:16][OH:17])[CH2:12][N:11]([CH3:14])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: C=O
Reactant: CN1CC=C(c2ccc(F)cc2)CC1
Agent: Cl
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: CN1CC=C(c2ccc(F)cc2)C(CO)C1

Procedure:
4-(4-Fluorophenyl)-1-methyl-1,2,3,6-tetrahydropyridine (50 g) was dissolved in a mixture of 21.6 ml of concentrated sulphuric acid and 50 ml of water. To the solution were added 25 ml of concentrated hydrochloric acid and 22.4 ml of 37% formaldehyde solution. The mixture was refluxed for 5 hours, cooled, and 125 ml of concentrated ammonia were added. The mixture was extracted with 50 ml of toluene. Drying of the toluene solution and distillation gave 38 g of 4-(4-fluorophenyl)-3-hydroxymethyl-1-methyl-1,2,3,6-tetrahydropyridine with b.p. 110°-120° C at 0.1 mm Hg.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:29]/[O:30][C:31]([CH3:40])([CH3:39])[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])/[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23][NH:24][CH2:25][C@H:26]([OH:28])[CH3:27])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN([C:46](N2C=NC=C2)=[O:47])C=1>C(Cl)(Cl)Cl.CCOC(C)=O.O>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:29]/[O:30][C:31]([CH3:39])([CH3:40])[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])/[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23][N:24]2[CH2:25][C@@H:26]([CH3:27])[O:28][C:46]2=[O:47])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H](O)CNC[C@H]1NC(=O)[C@H]1NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c1csc(NC(=O)OC(C)(C)C)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: C[C@@H]1CN(C[C@H]2NC(=O)[C@H]2NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c2csc(NC(=O)OC(C)(C)C)n2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 42 %

Procedure:
To a solution of tert-butyl 2-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((2R,3S)-2-((((R)-2-hydroxypropyl)amino)methyl)-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoate (185 mg, 0.316 mmol) in chloroform (3.16 mL) was added CDI (257 mg, 1.58 mmol). After stirring at rt for 20 min the solution was diluted with EtOAc/water and the layers separated. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (Acetone-DCM, 0-100%) to afford the title compound (81 mg, 42%). LCMS: Rt=0.92 min, m/z=611.2 (M+1) Method 2m_acidic.
Reaction SMILES: [NH:1]([C:5]1[CH:9]=[CH:8][N:7]([CH2:10][C:11](O)=O)[N:6]=1)[C:2]([NH2:4])=[S:3].BrC[C:16]([O:18]C(C)(C)C)=[O:17].C(OC(=O)CCBr)(C)(C)C>>[NH:1]([C:5]1[CH:9]=[CH:8][N:7]([CH2:10][CH2:11][C:16]([OH:18])=[O:17])[N:6]=1)[C:2]([NH2:4])=[S:3]
Reactant: NC(=S)Nc1ccn(CC(=O)O)n1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC(C)(C)OC(=O)CCBr
Product: NC(=S)Nc1ccn(CCC(=O)O)n1

Procedure:
This material is prepared by an analogous procedure to (3-thioureido-pyrazol-1-yl)-acetic acid (intermediate DD) by replacing tert-butyl bromoacetate in step 2 with 3-bromo-propionic acid tert-butyl ester.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[CH3:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>>[CH3:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][N:23]([CH2:2][C:3]2[S:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:22][CH2:21]1
Reactant: CSc1ccccc1N1CCNCC1
Reactant: ClCc1nc2cccnc2s1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ccccc1N1CCN(Cc2nc3cccnc3s2)CC1

Procedure:
The product from Example 38A (150 mg, 0.81 mmol), 1-[2-(methylthio)phenyl]piperazine (160 mg, 0.98 mmol), and DIEA (280 μL, 1.6 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.37 (s, 3H) 2.75 (m, 4H) 2.97 (m, 4H) 4.06 (s, 2H) 7.13 (m, 3H) 7.56 (dd, J=8.31, 4.58 Hz, 2H) 8.33 (dd, J=8.14, 1.36 Hz, 1H) 8.59 (dd, J=4.58, 1.53 Hz, 1H); (ESI) m/z 357 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(N(CC)CC)C.Cl.[N:17]1([CH2:23][CH2:24][C:25]2[N:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]3=[C:27]([C:34](Cl)=[O:35])[N:26]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:34]([C:27]2[N:26]=[C:25]([CH2:24][CH2:23][N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[N:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=23)=[O:35])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(F)c1
Reactant: O=C(Cl)c1nc(CCN2CCOCC2)n2ccccc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(F)c1)c1nc(CCN2CCOCC2)n2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.1 %

Procedure:
To a solution of 3-fluoroaniline (0.052 mL, 0.54 mmol) and triethylamine (0.16 mL, 1.14 mmol) in CH2Cl2 (10 mL) was added 3-(2-morpholin-4-yl-ethyl)-imidazo[1,5-a]pyridine-1-carbonyl chloride hydrochloride (150 mg, 0.45 mmol). The mixture was stirred at ambient temperature for 1 h then washed with sat. aq. NaHCO3 (20 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield the title compound (30 mg, 18%). 1H NMR (DMSO-d6) δ 10.02 (1H), 8.45 (1H), 8.15 (1H), 7.88 (1H), 7.70 (1H), 7.43 (1H), 7.20 (1H), 6.95 (1H), 6.85 (1H), 3.58 (4H), 3.25 (2H), 2.80 (2H), 2.44 (4H); m/z (M+H)=369.22.
Reaction SMILES: CS(Cl)(=O)=O.CS([O:10][CH2:11][C:12]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)(=O)=O.C(N(CC)CC)C>ClCCl>[OH:10][CH2:11][C:12]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)C1(COS(C)(=O)=O)CCOCC1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(CO)CCOCC1
Reaction time: 1 h

Procedure:
Intermediate 3 Ethyl 4-(Methanesulfonyloxy)methyltetrahydropyran-4-carboxylate Methanesulfonyl chloride (4.6 ml) was added to a solution of intermediate 2 (1 1.0 g) at 0° C. in dichloromethane (30 ml), followed by triethylamine (8.0 ml). The mixture was stirred for 1 h, then washed with citric acid (5% aq, 30 ml), saturated sodium bicarbonate and brine. The organic layer was separated, and then dried (MgSO4) and evaporated to give the title compound as colourless oil (15.2 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][CH2:12][CH:13]([NH2:17])[C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:20](OCC)(=O)C.[OH-].[Na+]>C1COCC1.O>[CH2:1]([O:8][C:9]([CH:11]([CH3:20])[CH2:12][CH:13]([NH2:17])[C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: NC(CCC(=O)OCc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: CC(CC(N)C(=O)O)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In THF (500 ml) was dissolved 4-[(benzyloxy)carbonyl]-aminobutyric acid (25.0 g), and to the mixture was gradually added at −5° C. methyl iodide (37.4 g). Under nitrogen atmosphere, the mixture was stirred at 0° C. for 15 minutes and then at room temperature for 24 hours. To the mixture was added ethyl acetate (300 ml) and then water (800 ml). The mixture was made pH 11 with sodium hydroxide and washed with ether (400 ml×2). The aqueous layer was made pH 2 with concentrated hydrochloric acid and extracted with ethyl acetate(1000 ml and 500 ml×3). The organic layer was washed with 1M sodium thiosulfate solution (300 ml) and dried with magnesium sulfate. The solvent was evaporated under reduced pressure to give 4-[(benzyloxy)carbonyl]-4-methyl-aminobutyric acid (26.3 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]([O-:22])=O)=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH2:4][CH2:3]1.[Li+].CN1C(=O)CCC1.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[NH2:43][C:44]1[CH:52]=[CH:51][CH:50]=[C:49]2[C:45]=1[CH:46]=[N:47][N:48]2[CH2:53][C:54]1[CH:55]=[C:56]([CH:61]=[CH:62][CH:63]=1)[C:57]([O:59][CH3:60])=[O:58]>CO>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]([NH:43][C:44]4[CH:52]=[CH:51][CH:50]=[C:49]5[C:45]=4[CH:46]=[N:47][N:48]5[CH2:53][C:54]4[CH:55]=[C:56]([CH:61]=[CH:62][CH:63]=4)[C:57]([O:59][CH3:60])=[O:58])=[O:22])=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(CCOc2ccn3c(C(=O)[O-])cnc3c2)CC1
Reactant: COC(=O)c1cccc(Cn2ncc3c(N)cccc32)c1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: [Li+]
Solvent: CO
Solvent: CN1CCCC1=O
Product: COC(=O)c1cccc(Cn2ncc3c(NC(=O)c4cnc5cc(OCCN6CCN(C)CC6)ccn45)cccc32)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of lithium 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (0.09578 g, 0.2933 mmol) and NMP (1.5 mL) were warmed to provide a homogeneous solution and then cooled to ambient temperature. 2,4,6-Trichlorobenzoyl chloride (0.04277 mL, 0.2737 mmol) was added and the mixture stirred at ambient temperature for 0.5 hours. Methyl 3-((4-amino-1H-indazol-1-yl)methyl)benzoate (0.055 g, 0.1955 mmol) was added as a NMP solution (1.5 mL) and the mixture was heated to 80° C. and stirred for 4 hours. The mixture was dissolved in MeOH and concentrated. The residue was dissolved in saturated aqueous NaHCO3 and EtOAc and the organic layer was washed with brine and dried over Na2SO4. The crude material was purified by column chromatography (15% MeOH/CH2Cl2 adding 1% 7N NH3/MeOH) to provide methyl 3-((4-(7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)benzoate as the free base. This material was dissolved in MeOH (3.0 mL) and CHCl3 (1.0 mL), and HCl (1.955 mL, 3.910 mmol, 2.0M Et2O) was added and the mixture was stirred for 2 hours and then concentrated. The resulting solid was washed with Et2O and then with hexanes, and dried under vacuum to afford 0.085 g (64%) of the title compound. MS (ES+APCI) m/z=568 (M+H-2HCl).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][C:32](=[O:34])[CH3:33])/[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:60][CH:61]1[C:91](=[O:92])[N:63]2[C:64]([C:75]([O:77][CH:78]([C:85]3[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=3)[C:79]3[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=3)=[O:76])=[C:65](/[CH:68]=[CH:69]\[CH2:70][O:71][C:72](=[O:74])[CH3:73])[CH2:66][S:67][C@H:62]12>C1COCC1.CCOC(C)=O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][C:32](=[O:34])[CH3:33])/[C:27]([NH:60][CH:61]2[C:91](=[O:92])[N:63]3[C:64]([C:75]([O:77][CH:78]([C:79]4[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=4)[C:85]4[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=4)=[O:76])=[C:65](/[CH:68]=[CH:69]\[CH2:70][O:71][C:72](=[O:74])[CH3:73])[CH2:66][S:67][C@H:62]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(=O)OC/C=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)OC/C=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)/C(=N\OC(C)=O)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a mixture of (Z)-2-(tritylaminothiazol-4-yl)-2-acetoxyiminoacetic acid (1.95 g, 4.0 mmol) and 1-hydroxybenzotriazole (600 mg, 4.0 mmol) in THF (14 ml) was added DCC (824 mg, 4.0 mmol) and the mixture was stirred for 1 hr in an ice bath. Diphenylmethyl 7-amino-3-[(Z)-3-acetoxy-1-propenyl]-3-cephem-4-carboxylate (1.30 g, 2.8 mmol) was added to the suspension and the mixture was stirred for 4 hrs at ambient temperature, filterd, and diluted with AcOEt (60 ml). The organic phase was washed with water, dried over MgSO4, and concentrated under reduced pressure. The residue was chromatographed on a column of silica gel (Wakogel C200, 80 g), which was eluted with toluene-AcOEt (6:1). Fractions which contained the product were combined and concentrated in vacuo to give 2.01 g (77%) of diphenylmethyl 7-[(Z)-2-(tritylaminothiazol-4-yl)-2-acetoxyiminoacetamido]-3-[(Z)-3-acetoxy-1-propenyl)-3-cephem-4-carboxylate.
Reaction SMILES: [CH:1]1([CH:7]([NH2:23])[CH:8]([NH:13][CH:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:15]([O:17][CH3:18])=[O:16])[C:9]([F:12])([F:11])[F:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:24]1[CH:29]=[CH:28][N:27]=[CH:26][C:25]=1[C:30](O)=[O:31].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl.C(OCC)(=O)C>[CH:1]1([CH:7]([NH:23][C:30]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][N:24]=2)=[O:31])[CH:8]([NH:13][CH:14]([C:19]([CH3:20])([CH3:22])[CH3:21])[C:15]([O:17][CH3:18])=[O:16])[C:9]([F:12])([F:11])[F:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cnccn1
Reactant: COC(=O)C(NC(C(N)C1CCCCC1)C(F)(F)F)C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: COC(=O)C(NC(C(NC(=O)c1cnccn1)C1CCCCC1)C(F)(F)F)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of the 6A1-isomer A of methyl 2-(3-cyclohexyl-1,1,1-trifluoro-3-aminopropan-2-ylamino)-3,3-dimethylbutanoate (389 mgm), pyrazinecarboxylic acid (65 mg), 1-ethyl-3-(3′-dimethylaminopropyl)-carbodimide ((331 mg), 1-hydroxy-benzotriazole (233 mg), and N-methylmorpholine (0.19 mL) in dichloromethane was stirred at room temperature for 24 hours. The reaction mixture was then diluted with ethyl acetate and washed successively with 1N hydrochloric acid, water, brine and then dried over anhydrous sodium sulfate. Evaporation to dryness under reduced pressure gave crude methyl 2-(3-cyclohexyl-1,1,1-trifluoro-3-(pyrazine-2-carboxamido)propan-2-ylamino)-3,3-dimethylbutanoate, an isomer of a compound of formula (7) designated as 7A1-isomer A.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]#[N:14])=[CH:6][CH:5]=1.Br[C:22]1[CH:23]=[N:24][CH:25]=[N:26][CH:27]=1>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:22]2[CH:23]=[N:24][CH:25]=[N:26][CH:27]=2)[C:13]#[N:14])=[CH:8][CH:9]=1
Reactant: Brc1cncnc1
Reactant: N#CC(CCc1ccc(Cl)cc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(CCc1ccc(Cl)cc1)(c1ccccc1)c1cncnc1
Reaction time: 0.75 h

Procedure:
In a 250 ml. 3 neck round bottomed flask under nitrogen was charged 1.2 g of 60% NaH (1.5 eq., 0.0293 moles), washed 2 times with 15 ml. hexanes, in 40 ml. DMF. Dropwise was added 5.0 g. of 4-(4-chlorophenyl)-2-phenylbutanenitrile (1.0 eq., 0.0195 moles) in 10 ml. of DMF and was stirred for one hour at rt. This was followed by the addition of 4.67 g. of 5-bromopyrimidine (1.5 eq., 0.0293 moles) in 10 ml. of DMF to the reaction mixture which resulted in an exotherm to 35° C. After 45 min. GLC analysis showed no unreacted nitrile. The reaction was quenched by the addition of 100 ml. Water and then extracted with 250 ml. EtOAc. The organic phase was washed with 2 times 100 ml. water, dried over MgSO4 and concentrated to give 7.3 g. of oil. 6.0 g. of crude product was purified by flash chromatography with 3:7 EtOAc/hexane to give 2.3 g. of a white solid mp. 89°-91° C. (43.1% based on chromatographic portion).
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:16]1[C:17](=[O:27])[N:18]([CH3:26])[C:19](=[O:25])[N:20]([CH3:24])[C:21]=1[CH2:22]Br)(=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:28]([S:47][CH2:48][CH2:49][NH2:50])([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CCO.C(Cl)Cl>[CH3:24][N:20]1[C:21]2=[CH:22][N:50]([CH2:49][CH2:48][S:47][C:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:16]2[C:17](=[O:27])[N:18]([CH3:26])[C:19]1=[O:25]
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Product: Cn1c(=O)c2c(-c3ccccc3)n(CCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2n(C)c1=O
Temperature: 100 °C

Procedure:
Triethylamine (0.211 ml, 1.513 mmol) was added to a solution of 5-Benzoyl-6-(bromomethyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (Intermediate C) (510 mg, 1.513 mmol) and 2-tritylsulfanyl-ethylamine (Intermediate D) (483 mg, 1.513 mmol) in EtOH (5 ml) and the mixture heated at 100° C. under microwave irradiation for 2 hours. The reaction mixture was diluted with DCM (10 mL) and was washed with water (3×10 mL). The organic phase was passed through a hydrophobic frit and the solvent was evaporated under reduced pressure. The title product was obtained as a pale yellow solid and used without further purification.
Reaction SMILES: [CH2:1]([O:3][SiH:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2].[SiH4].[CH:12]([Si:14]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])=[CH2:13]>>[CH2:1]([O:3][Si:4]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[CH2:13][CH2:12][Si:14]([O:15][CH2:16][CH3:17])([O:18][CH2:19][CH3:20])[O:21][CH2:22][CH3:23])[CH3:2].[CH2:1]([O:3][Si:4]([O:15][CH2:16][CH3:17])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: C=C[Si](OCC)(OCC)OCC
Reactant: CCO[SiH](OCC)OCC
Agent: [SiH4]
Product: CCO[Si](CC[Si](OCC)(OCC)OCC)(OCC)OCC
Product: CCO[Si](OCC)(OCC)OCC
Reaction time: 2 h
Yield: 13 %
Yield: 8 %

Procedure:
The reaction was carried out as in Comparative Example 5, except that triethoxysilane was used as the starting silane. The reaction as monitored by GPC and was complete in two hours. Vinyltriethoxysilane (79%) was the major product formed and significant amounts of 1,2-bis(triethoxysilyl)ethane (13%) and tetraethoxysilane (8%) by-products, were also formed.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH:37]1(CO)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: OCC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCC4CCCCC4)c(C)c3C)c2cc1OC
Yield: 67 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, cyclohexylmethanol (26 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (48 mg, yield 64%).