Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH:11]1([OH:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.Cl[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][N:20]=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH:11]1([O:17][C:19]2[N:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: OC1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc(OC2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
Add sodium bis(trimethylsilyl)amide (3.9 mL, 7.93 mmol, 2M solution in THF) to a solution of cyclohexanol (824 μL, 7.93 mmol) in THF (10 mL). Stir for 30 min at room temperature and then add a solution of 6-chloro-nicotinonitrile (1 g, 7.2 mmol) in anhydrous THF (5 mL). Stir at room temperature overnight and then quench the reaction by addition of saturated aqueous NaHCO3 (100 mL) and extract the aqueous phase with DCM (3×100 mL). Wash the combined organic extracts with brine (100 mL), dry over MgSO4 and concentrate in vacuo to obtain the desired intermediate as a yellow solid (1.04 g, 71%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:33])[N:10]([C@@H:13]2[C@@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH2:16][N:15]([C:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[O:26])[CH2:14]2)[CH2:11][CH3:12])=[CH:4][CH:3]=1.Cl[C:35]1[N:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][N:36]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:33])[N:10]([C@@H:13]2[C@@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH2:16][N:15]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:35]4[N:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][N:36]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:14]2)[CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: N#Cc1cnc(Cl)nc1
Reactant: CCN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCNCC2)C[C@@H]1c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCN(c3ncc(C#N)cn3)CC2)C[C@@H]1c1ccc(Cl)cc1
Temperature: 65 °C
Reaction time: 22 h

Procedure:
A mixture of 94.7 mg (0.2 mmol)[(3R,4S)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester, 83.7 mg (0.3 mmol) 2-chloropyrimidine-5-carbonitrile and 129 mg (1 mmol) DIPEA in 2.5 mL DMF was shaken a for 22 h at 65° C. The mixture was subjected to preparative HPLC purification on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fraction were evaporated to access 58 mg (51%) of the title compound as off-white solid. MS m/e: 577.3 [M+H]+.
Reaction SMILES: C([N:9]1[CH2:14][CH2:13][C:12]2([CH2:19][C:18](=[O:20])[C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[S:15]2)[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.[ClH:25]>C(O)C>[ClH:25].[NH:9]1[CH2:14][CH2:13][C:12]2([CH2:19][C:18](=[O:20])[C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[S:15]2)[CH2:11][CH2:10]1
Reactant: O=C1CC2(CCN(C(=O)c3ccccc3)CC2)Sc2ccccc21
Agent: Cl
Solvent: CCO
Product: O=C1CC2(CCNCC2)Sc2ccccc21
Reaction time: 18 h
Yield: 92 %

Procedure:
A solution of product from Step C (3.2 g, 0.0095 mol) in ethanol (50 ml) and 6N HCl (50 ml) was heated at reflux. After 18 hours, the reaction was concentrated to dryness and the residue crystallized from ethanol to yield 2.9 g (92%) of product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[C:7]2B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]([O:39][CH3:40])[CH:34]=1.O>C1COCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[C:7]2[CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]([O:39][CH3:40])[CH:34]=1
Reactant: COc1cc(CCl)ccn1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c2cccc(F)c2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1cc(Cc2ccnc(OC)c2)c2cccc(F)c2n1
Temperature: 100 °C

Procedure:
To a mixture of methyl 8-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-2-carboxylate (S1) (130 mg, 0.393 mmol), Cs2CO3 (384 mg, 1.178 mmol), PdCl2(dppf)-CH2Cl2 adduct (32.1 mg, 0.039 mmol) in a microwave tube were added a solution of 4-(chloromethyl)-2-methoxypyridine (124 mg, 0.785 mmol) in THF (3 mL) followed by adding water (0.3 mL). The mixture was heated at 100° C. for 1 h. The reaction was cooled and diluted with EtOAc. The bottom H2O layer was removed. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by reverse-phase HPLC (C-18 column, gradient 5-90% MeCN in H2O with both containing 0.05% TFA) to give methyl 8-fluoro-4-[(2-methoxypyridin-4-yl)methyl]quinoline-2-carboxylate (V4). ES-MS [M+1]+: 327.2.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:11][C:12](=O)[C:13]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[N:16][C:14]=2[N:15]=1)[CH3:2].P(Cl)(Cl)([Cl:27])=O.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:27][C:12]1[C:13]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[N:16][C:14]=2[N:15]=[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][CH2:1][CH3:2])[N:11]=1
Reactant: CCSc1ccccc1-c1nc2ncc(C(F)(F)F)cc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCSc1ccccc1-c1nc(Cl)c2cc(C(F)(F)F)cnc2n1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 970 mg of 2-(2-ethylsulfanylphenyl)-6-trifluoromethyl-3H-pyrido[2,3-d]pyrimidin-4-one, 0.39 ml of phosphorus oxychloride, 428 mg of N,N-diisopropylethylamine and 20 ml of toluene was stirred at 100° C. for 5 hours. A saturated aqueous sodium bicarbonate solution was added to the cooled reaction mixture, and the mixture was extracted with t-butyl methyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 996 mg of 4-chloro-2-(2-ethylsulfanylphenyl)-6-trifluoromethylpyrido[2,3-d]pyrimidine (Compound of Present Invention 22).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][C:12]#[N:13])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[NH2:14][C:15]1[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=1>C(O)(=O)C>[Br:1][C:2]1[CH:10]=[C:6]2[C:5]([CH:11]=[C:12]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:13]=[C:7]2[OH:8])=[CH:4][CH:3]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: N#CCc1ccc(Br)cc1C(=O)O
Solvent: CC(=O)O
Product: Cc1cc(Nc2cc3ccc(Br)cc3c(O)n2)n[nH]1

Procedure:
Similar procedure as described in example 9B was used, starting from 5-Bromo-2-cyanomethyl-benzoic acid, 3-amino-5-methylpyrazol and acetic acid to give 7-Bromo-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-ol. LC-MS: m/e 319 (MH+).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.[CH2:33]([N:36]=[C:37]=[O:38])[CH:34]=[CH2:35]>>[CH2:33]([NH:36][C:37]([NH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:31])([F:32])[F:30])[CH:23]=2)=[O:20])=[CH:16][CH:17]=1)=[O:38])[CH:34]=[CH2:35]
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: C=CCN=C=O
Agent: Cl
Product: C=CCNC(=O)Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride and allyl isocyanate by using the same techniques as in Example 119.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[NH:12][C:13]([C:16]([C:18]3[C:19](Cl)=[N:20][CH:21]=[CH:22][CH:23]=3)=O)=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.O.[NH2:26][NH2:27]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[NH:12][C:13]([C:16]3[C:18]4[C:19](=[N:20][CH:21]=[CH:22][CH:23]=4)[NH:27][N:26]=3)=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1cccc(F)c1)c1ccc(C(=O)c2cccnc2Cl)[nH]1
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=C(Nc1cccc(F)c1)c1ccc(-c2n[nH]c3ncccc23)[nH]1
Temperature: 80 °C
Yield: 45 %

Procedure:
A mixture of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-2-carboxylic acid (3-fluoro-phenyl)-amide (477 mg, 1.4 mmol) and hydrazine hydrate (2 mL) in ethanol (30 mL) was heated at 80° C. for 24 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 200 mg (45%) of the titled compound.
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:22](=O)[CH2:23]Br)[CH:19]=[CH:20][CH:21]=1>CC(C)=O>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:22]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=3[CH3:8])[S:13][CH:23]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Reactant: COc1cccc(C(=O)CBr)c1
Solvent: CC(C)=O
Product: COC(=S)c1cc(-c2nc(-c3cccc(OC)c3)cs2)c(C)s1
Yield: 64.5 %

Procedure:
Methyl 4-[4-(3-methoxyphenyl)(1,3-thiazol-2-yl)-5-methylthiothiophene-2-carboxylate: 32 mg (0.133 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 2 mL of reagent grade acetone. 3′-Methoxy-2-bromo acetophenone (0.155 mmol; 36 mg; Aldrich Chemical Co.) was added and the solution was allowed to reflux for 2.5 h. The solution was allowed to cool and a solid was filtered and washed with methanol and dried in vacuo. The solid was purified on 1 mm silica plate eluting with 25% ethyl acetate/hexane to afford 31 mg (63% yield) of methyl 4-[4-(3-methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]([NH:17]S(C(C)(C)C)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl.O1CCOCC1>CO>[NH2:17][CH:11]([C:4]1[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(NS(=O)C(C)(C)C)c1c(OC)cccc1OC
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCOC(=O)C(N)c1c(OC)cccc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) solution of ethyl 2-(2,6-dimethoxyphenyl)-2-(1,1-dimethylethylsulfinamido)-acetate (4.215 g; 12.27 mmol) in anh. MeOH (120 ml) was treated dropwise with a solution of 4 M HCl in dioxane (6.30 ml; 25.20 mmol). The resulting heterogeneous mixture was further stirred at 0° C., under nitrogen, for 10 min., and then at rt for 1 h. Concentration to dryness under reduced pressure afforded the chlorhydrate salt of ethyl 2-amino-2-(2,6-dimethoxyphenyl)acetate as a yellow oil. LC-MS (conditions D): tR=0.66 min.; [M+H]+: 240.40 g/mol.
Reaction SMILES: C([NH:4][C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:14]([CH3:16])[CH3:15])C=C.[OH-].[Na+].[C:19]1(C)[CH:24]=CC=C[CH:20]=1>[Cl-].[Cl-].[Zn+2]>[CH2:24]([C:8]1[CH:7]=[C:6]([CH:14]([CH3:15])[CH3:16])[C:5]([NH2:4])=[C:10]([CH:11]([CH3:12])[CH3:13])[CH:9]=1)[CH:19]=[CH2:20]
Reactant: C=CCNc1c(C(C)C)cccc1C(C)C
Reactant: Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Product: C=CCc1cc(C(C)C)c(N)c(C(C)C)c1
Yield: 70.9 %

Procedure:
N-allyl-2,6-diisopropyl aniline (18.33 g, 0.084 mol) and ZnCl2 (13.6 g, 0.1 mol) were added to a 100 ml toluene solution. This solution was refluxed for 5 hr and then poured into a NaOH aqueous solution. Extraction with Et2O (3×50 ml) and distillation (79.93 Pa, 98° C.) yielded 13.0 g (70.9%) of 4-allyl-2,6-diisopropyl aniline. Nd30=1.5340, 1H-NMR (ppm,CDCl3): δ=6.85(s, 2H, Ph-Hm),5.98(m, 1H, CH═C),5.09(d, 1H, C═C—Htrans),5.03(d, 1H, C═C—Hcis),3.6(br, 2H, NH2), 3.30(d, 2H, CH2—C═C), 2.92(m, 2H, CH(Me)2), 1.26(d, 12H, C(CH3)2)
Reaction SMILES: S([O:5][CH2:6][CH2:7][N:8]1[C:12]([NH2:13])=[C:11]([NH2:14])[CH:10]=[N:9]1)(O)(=O)=O.[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][C@H:25]([OH:29])[C:26](O)=[O:27])=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>O>[NH2:13][C:12]1[N:8]([CH2:7][CH2:6][OH:5])[N:9]=[CH:10][C:11]=1[NH:14][C:26](=[O:27])[C@@H:25]([OH:29])[CH2:24][CH2:23][NH:22][C:20](=[O:21])[O:19][C:15]([CH3:16])([CH3:17])[CH3:18]
Reactant: Nc1cnn(CCOS(=O)(=O)O)c1N
Reactant: CC(C)(C)OC(=O)NCC[C@H](O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)NCC[C@H](O)C(=O)Nc1cnn(CCO)c1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4,5-diamino-1H-pyrazol-1-yl)ethanol sulfate (2 g) and (2S)-4-[(tert-butoxycarbonyl)amino]-2-hydroxybutanoic acid (1.92 g) in water (8 ml) were added triethylamine (2.32 ml) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.76 g), and the mixture was stirred at room temperature for 3 hours. The whole mixture was extracted with ethyl acetate-tetrahydrofuran (1:1) and the solvent was evaporated under reduced pressure to give a crude product of tert-butyl ((3S)-4-{[5-amino-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}-3-hydroxy-4-oxobutyl)carbamate. The obtained crude product was used for Preparation 38 without further purification.
Reaction SMILES: [SiH:1]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Si:32]([CH:63]=[CH2:64])([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>>[Si:1]([CH2:64][CH2:63][Si:32]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: C=C[Si](CCCCCCCCCC)(CCCCCCCCCC)CCCCCCCCCC
Reactant: CCCCCCCCCC[SiH](CCCCCCCCCC)CCCCCCCCCC
Product: CCCCCCCCCC[Si](CCCCCCCCCC)(CCCCCCCCCC)CC[Si](CCCCCCCCCC)(CCCCCCCCCC)CCCCCCCCCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 93.9 %

Procedure:
The reaction was carried out in a similar manner as described in Example I. A mixture of (n-C10H21)3SiH (25.0 g, 55.3 mmole), (n-C10H21)3SiCH═CH2 (26.4 g, 55.3 mmole) and Pt(acetylacetonate)2 (22 mg, 5.53×10−2 mmole) was placed in the flask. The reaction mixture was stirred at room temperature for two days and then at ˜40° C. for another two days. The product was purified by column chromatography as described in Example I. After removal of the solvent, a crude product was obtained. The crude product was distilled to remove the low boiling components at <230° C./5×10−5 mmHg and yielded the desired product (n-C10H21)3SiCH2CH2Si(n-C10H21)3 (48.4 g, colorless liquid, 94 percent yield). The infrared spectrum and mass spectra data were consistent with the expected structure. In the analysis for C62H130Si2, the amount calculated was: C, 79.91; H, 14.06; Si, 6.03 percent, while the amount found was: C, 80.12; H, 14.15; Si, 5.92 percent.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[NH:7][C:5](=[O:6])[N:4]([C@@H:10]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([N:17]=[N+:18]=[N-:19])[CH2:11]2)[CH:3]=1.[C:20]1(=[O:26])[O:25][C:23](=[O:24])[CH2:22][CH2:21]1>>[CH3:1][C:2]1[C:8](=[O:9])[NH:7][C:5](=[O:6])[N:4]([C@@H:10]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([N:17]=[N+:18]=[N-:19])[CH2:11]2)[CH:3]=1.[C:20]([OH:25])(=[O:26])[CH2:21][CH2:22][C:23]([OH:6])=[O:24]
Reactant: O=C1CCC(=O)O1
Agent: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Product: O=C(O)CCC(=O)O

Procedure:
AZT was reacted with succinic anhydride to form AZT-succinic acid. This was reacted by the DCC/HOSu method with a mixture of Gly-Tris-Mono, Di and Tripalmitate (GTPn) which was prepared by catalytic hydrogenation of Z-GTPn. Column chromatography on silica gel and preparative HPLC were used to isolate the final compounds:
Reaction SMILES: C[O-].[Na+].Cl.[C:5]([NH2:8])(=[NH:7])[CH3:6].[Cl:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([NH:16]N)=[O:15])=[CH:12][CH:11]=1>C(O)C>[NH:7]=[C:5]([NH:8][NH:16][C:14](=[O:15])[C:13]1[CH:18]=[CH:19][C:10]([Cl:9])=[CH:11][CH:12]=1)[CH3:6]
Reactant: NNC(=O)c1ccc(Cl)cc1
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=N)NNC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.09 g (20 mmol) sodium methoxide in 20 mL ethanol are added to a solution of 1.91 g (20 mmol) acetamidine hydrochloride in 30 mL ethanol. The mixture is stirred for 30 minutes at ambient temperature and then filtered. The filtrate is combined with 2.3 g (13.5 mmol) 4-chlorobenzoic acid hydrazide, stirred overnight at ambient temperature, cooled with an ice bath and then filtered. The precipitate is washed with cold ethanol and dried. Yellow solid. Yield: 1.45 g (51%); mass spectroscopy [M+H]+=212/214.
Reaction SMILES: [CH:1]([O:3][C@H:4]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)=[CH:25][CH:24]=1)[C@@H:5]([CH:19]=[O:20])[CH2:6][CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])=[O:2].P([O-])(O)(O)=[O:38].[Na+].OO.Cl([O-])=O.[Na+]>C(#N)C.O>[O:18]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16](=[O:17])[N:8]1[CH2:7][CH2:6][C@@H:5]([C@H:4]([O:3][CH:1]=[O:2])[CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)=[CH:27][CH:28]=1)[C:19]([OH:38])=[O:20]
Reactant: O=P([O-])(O)O
Reactant: COc1ccc(-c2ccc(CC[C@@H](OC=O)[C@@H](C=O)CCN3C(=O)c4ccccc4C3=O)cc2)cn1
Agent: OO
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Solvent: O
Product: COc1ccc(-c2ccc(CC[C@@H](OC=O)[C@H](CCN3C(=O)c4ccccc4C3=O)C(=O)O)cc2)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 221.1 %

Procedure:
The compound obtained in step h (0.54 g) was taken in acetonitrile (6 mL) and water (1 mL). To this solution, sodium dihydrogen phosphate (0.054 g) was added. The reaction mixture was cooled to 0° C. and hydrogen peroxide (1 mL) and sodium chlorite (0.208 g) were added. After stirring the reaction mixture for an additional 1 hour, the solvents were evaporated on a rotary evaporator; the residue was taken into water and extracted with ethyl acetate. The organic layer was washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to get the title compound (0.5 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([CH3:19])[CH:13]=1)[NH:8][CH:7]=[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:5]2=[O:25].C(=O)([O-])[O-].[K+].[K+].[CH2:32](I)[CH3:33]>CN(C)C=O>[CH2:32]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[C:11]([C:12]3[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([CH3:19])[CH:13]=3)[CH:10]=2)[C:5](=[O:25])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:7]1)[CH3:33]
Reactant: CCOC(=O)c1c[nH]c2cc(-c3cc(C)nc(C)c3)c(F)cc2c1=O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2cc(-c3cc(C)nc(C)c3)c(F)cc2c1=O
Reaction time: 0.33 h

Procedure:
A mixture containing 34 g of ethyl 6-fluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarboxylate, finely divided anhydrous potassium carbonate and 250 ml of dimethylformamide was heated with stirring on a steam bath for 20 minutes and then 9 ml of ethyl iodide was added over a 20 minute period. The reaction mixture was heated on a steam bath with stirring for 2 and 1/2 hours and then concentrated to dryness on a rotary evaporator. The residue was shaken well with 300 ml of water and 500 ml of chloroform. The layers were separated and the aqueous layer was extracted with another 200 ml portion of chloroform. The combined chloroform extracts were concentrated in vacuo to remove the chloroform. The remaining solid was dissolved in 150 ml of hot isopropyl alcohol, the hot solution treated with decolorizing charcoal and filtered. The filtrate was concentrated on a rotary evaporator to a volume of about 50 ml which was diluted with ether until turbid. The mixture was allowed to cool and the separated crystalline solid was collected, washed with ether and dried at 80°-85° C. to yield 18.5 g of ethyl 1-ethyl-6-fluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarboxylate, m.p. 221°-224° C. Further concentration of the mother liquor yielded another 3.4 g (60%) of product, m.p. 220°-223° C. A larger run (0.3 mole scale) gave the above compound, m.p. 222°-225° C., in 80% yield.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH2:39]O)=[CH:31]1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:39][C:32]3[C:33]4[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]([CH3:29])[CH:31]=3)[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cc(CO)c2ccccc21
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Cn1cc(COc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c2ccccc21

Procedure:
The title compound was prepared from 3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenol and (1-methyl-1H-indol-3-yl)-methanol according to the procedure of Example 69. MS (ES) m/z 523.1.
Reaction SMILES: O(P(O[C:18]1[CH2:19][C@@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[SH:42][C@@H:43]1[CH2:47][N:46]([C:48]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=2)=[O:49])[C@@H:45]([CH:61]2[CH2:65][NH:64][C:63](=[O:66])[CH2:62]2)[CH2:44]1>>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[C:18]([S:42][C@@H:43]3[CH2:47][N:46]([C:48]([O:50][CH2:51][C:52]4[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=4)=[O:49])[C@@H:45]([CH:61]4[CH2:65][NH:64][C:63](=[O:66])[CH2:62]4)[CH2:44]3)[CH2:19][C@H:20]12)[CH3:39]
Reactant: O=C1CC([C@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CN1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)C[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@H](C4CNC(=O)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)C[C@H]12
Yield: 33.2 %

Procedure:
The same procedure as in Example 1-1 was carried out by using p-nitrobenzyl (5R,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (300 mg, 0.55 mmol) and (2R,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-4-yl)pyrrolidine (200 mg, 0.55 mmol, compound of Reference Example 2) to obtain p-nitrobenzyl (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[(2R,4S)-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-4-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (127 mg, yield: 35%).