Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH3:28])[C:7]2[C:16]3[CH:15]=[C:14]([O:17][CH2:18][CH2:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:26])[C:8]=2[N:27]=1)[CH2:2][CH2:3][CH3:4].[CH:29]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH2:1]([C:5]1[N:6]([CH3:28])[C:7]2[C:16]3[CH:15]=[C:14]([O:17][CH2:18][CH2:19][CH:20]4[CH2:21][CH2:22][N:23]([C:34]([CH:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)=[O:35])[CH2:24][CH2:25]4)[CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:26])[C:8]=2[N:27]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)C1CCCC1
Reactant: CCCCc1nc2c(N)nc3ccc(OCCC4CCNCC4)cc3c2n1C
Product: CCCCc1nc2c(N)nc3ccc(OCCC4CCN(C(=O)C5CCCC5)CC4)cc3c2n1C

Procedure:
A modification of the method described in Example 15 was used to treat 2-butyl-1-methyl-8-(2-piperidin-4-ylethoxy)-1H-imidazo[4,5-c]quinolin-4-amine with cyclopentanecarbonyl chloride. The crude product was purified by column chromatography on silica gel to provide 2-butyl-8-{2-[1-(cyclopentylcarbonyl)piperidin-4-yl]ethoxy}-1-methyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 147.2-150.1° C.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]1[CH2:11][O:10][CH2:9][CH2:8]1.OC1C=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH3:23])[C:18](=[O:24])[CH2:17][CH2:16]2.C(I)C>>[CH2:11]([O:10][C:9]1[CH:8]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH3:23])[C:18](=[O:24])[CH2:17][CH2:16]2)[CH3:7]
Reactant: CN1C(=O)CCc2cc(O)ccc21
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCI
Product: CCOc1ccc2c(c1)CCC(=O)N2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.8 %

Procedure:
1.0M potassium t-butoxide/THF (5.65 ml, 5.65 mmol) was added to 6-Hydroxy-1-methyl-3,4-dihydro-1H-quinolin-2-one (200 mg, 1.13 mmol) followed by the addition of ethyl iodide (452 μl, 5.65 mmol). The reaction mixture was stirred at room temperature for 2 hours and heated to 45° C. for an overnight. The salts were filtered off, rinsed with ethyl acetate and the combined filtrate was concentrated down to a residue. This was chromatographed using 1:1 ethylacetate/hexane to yield the title compound as a white solid (76 mg, 33% yield). 1H NMR (400 MHz, CDCl3) δ 1.36 (3H, t, J=6.9 Hz), 2.58 (2H, m), 2.82 (2H, m), 3.29 (3H, s), 3.96 (2H, q, J=7.0 Hz), 6.71 (2H, m), 6.84 (1H, d, J=8.7 Hz). m/z (APCI+) 206 (M+1). HPLC (aqueous 200 Mm ammonium acetate buffer/acetonitrile gradient, 3.0 ml/min, Hewlett Packard ODS Hypersil 5 μM, 125×4 mm column), 4.453 min.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH2:9][Si:10]([O:15]C)([O:13]C)[O:11]C)(=[O:5])[C:2]([CH3:4])=[CH2:3].Cl[Si:18]([CH3:21])([CH3:20])[CH3:19]>>[C:1]([O:6][CH2:7][CH2:8][CH2:9][Si:10]([O:15][Si:18]([CH3:21])([CH3:20])[CH3:19])([O:13][Si:18]([CH3:21])([CH3:20])[CH3:19])[O:11][Si:18]([CH3:21])([CH3:20])[CH3:19])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C[Si](C)(C)Cl
Reactant: C=C(C)C(=O)OCCC[Si](OC)(OC)OC
Product: C=C(C)C(=O)OCCC[Si](O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](C)(C)C

Procedure:
γ-Methacryloxypropyl-tris (trimethylsiloxy)silane (TRIS) was prepared by hydrolysis of 0.1 mole of γ-methacryloxypropyl-trimethoxysilane (MEMO) and 0.35 mole of chlorotrimethylsilane and subsequent distillation following the same procedure as in Example (a).
Reaction SMILES: C(O[Si](OCC)(OCC)CCC[O:8][C:9]1[CH:22]=[CH:21][C:12]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[C:11]([OH:23])[CH:10]=1)C>C(O)C.O>[OH:23][C:11]1[CH:10]=[C:9]([OH:8])[CH:22]=[CH:21][C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14]
Reactant: CCO[Si](CCCOc1ccc(C(=O)c2ccccc2)c(O)c1)(OCC)OCC
Solvent: CCO
Solvent: O
Product: O=C(c1ccccc1)c1ccc(O)cc1O

Procedure:
A mixture of 12.495 grams of recrystallized 4-allyloxy-2-hydroxybenzophenone (AHBP), 8.215 grams of triethoxysilane and 0.20 grams of the platinum substituted silica gel of Example 1 was heated at 90° C. It was found that the AHBP melted around 55° C. The reaction mixture became yellow and homogeneous. The temperature of the reaction mixture then quickly rose to 130° C. and then dropped to 90° C. After heating the mixture of an additional hour at about 90° C., the mixture was allowed to cool to 23° C., diluted with 50 ml of hexane and then filtered. The platinum substituted silica gel was recovered as a free-flowing tan powder. The filtrate was concentrated on a rotary evaporator and 20 grams of a yellow oil, a quantitative yield of product was recovered. Based on method of preparation and reverse phase TLC, 4/1;ethanol/water, the product was 4-(3'-triethoxysilylpropoxy)-2-hydroxybenzophenone (SHBP). A trace amownt of 2,4-dihydroxybenzophenone was also obtained. The 1H NMR spectrum of the SHBP was found to be identical to a spectrum of SHBP prepared from AHBP and triethoxysilane using a platinum catalyst shown by Karstedt, U.S. Pat. No. 3,775,452.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH:29]([CH3:31])[CH3:30])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)(Cl)=O.[Cl-].[CH2:37]([NH:41][CH3:42])[CH:38]([CH3:40])[CH3:39]>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]([CH:29]([CH3:30])[CH3:31])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][N:41]([CH2:37][CH:38]([CH3:40])[CH3:39])[CH3:42])=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: CNCC(C)C
Reactant: CC(C)N(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(C)CN(C)Cc1cnnn1-c1cccc(C2=Nc3cc(N(C)C(C)C)c(Cl)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isopropyl-methyl-amino)-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 96) (220 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with N-isobutylmethylamine in DMF according to the method described in Example 45. Obtained as a light yellow solid (190 mg, 75%).
Reaction SMILES: B#B.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][C:14](O)=[O:15])=[CH:7][CH:6]=1>O1CCCC1>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[CH:7][CH:6]=1
Reactant: COc1ccc(CCCC(=O)O)cc1
Agent: B#B
Solvent: C1CCOC1
Product: COc1ccc(CCCCO)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A flask containing 250 ml. 1 M diborane in tetrahydrofuran is thoroughly cooled in an ice-water bath. To the stirred solution is slowly added 38.8 g. of 4-(4-methoxyphenyl)butyric cid in 100 ml. tetrahydrofuran. After addition is completed the reaction is stirred for 16 hours at room temperature, then poured slowly into 1 l. stirred ice-water. The aqueous solution is extracted three times with 300 ml. portions of ether. The combined organic extracts are washed with water and brine, dried, and evaporated to a nearly colorless oil of 4-(4-methylphenyl)-1-butanol.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[CH:8]=[N:7][CH:6]=[CH:5][C:4]=2[C:3]=1[NH2:12].[F:13][C:14]([F:26])([F:25])[C:15]1[CH:24]=[CH:23][C:18]([CH2:19][N:20]=[C:21]=[O:22])=[CH:17][CH:16]=1>>[F:1][C:2]1[C:3]([NH:12][C:21]([NH:20][CH2:19][C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:26])[F:25])=[CH:24][CH:23]=2)=[O:22])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Reactant: Nc1c(F)ccc2cnccc12
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1c(F)ccc2cnccc12

Procedure:
Prepared from 6-fluoroisoquinolin-5-amine (Description 89) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES+) 364 (M+H)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][CH:8]=1.[C:17](Cl)(=[O:19])[CH3:18].Cl>C(Cl)Cl>[CH3:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:8]=1[C:17](=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: COc1ccc(OC)c(OC)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(OC)c(C(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 50 %

Procedure:
To methylene chloride, 47.5 g of aluminum chloride were added, followed by the addition of 30 g of 2,4,5-trimethoxybenzene and then 13 ml of acetyl chloride under ice cooling. The resulting mixture was stirred at room temperature for 6 hours. After the completion of the reaction, 1N hydrochloric acid was added to the reaction mixture under ice cooling. The resulting mixture was then extracted with methylene chloride. The extract so obtained was washed successively with 1N hydrochloric acid, a 1N aqueous solution of sodium hydrochloride and saturated saline and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The crude product so obtained was washed with ethanol, whereby 18.6 g of 2',4',5'-trimethoxyacetophenone were obtained (yield: 50%).
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([CH:17]([CH3:19])[CH3:18])=[CH:11][C:12]=2[CH:14]([OH:16])[CH3:15])[C:7]([CH3:21])([CH3:20])[CH2:6][CH2:5]1)[CH2:2][CH3:3].C[N+]1([O-])CCOCC1>>[CH:17]([C:10]1[CH:9]=[C:8]2[C:13](=[C:12]([C:14](=[O:16])[CH3:15])[CH:11]=1)[N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][C:7]2([CH3:21])[CH3:20])([CH3:18])[CH3:19]
Reactant: CCCN1CCC(C)(C)c2cc(C(C)C)cc(C(C)O)c21
Agent: C[N+]1([O-])CCOCC1
Product: CCCN1CCC(C)(C)c2cc(C(C)C)cc(C(C)=O)c21

Procedure:
Following General Procedure D, 1-(1-n-propyl-6-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-8-yl)-ethan-1-ol (Intermediate 11, 4.54 g, 18.1 mmol) and 4-methylmorpholine N-oxide (4.23 g, 36.2 mmol) were reacted to give the title compound as a yellow oil.
Reaction SMILES: O[C:2]1([CH3:18])[N:6]([C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])[C@@H:5]([C:13]([O:15]CC)=[O:14])[CH2:4][CH2:3]1>FC(F)(F)C(O)=O>[CH2:10]([O:9][C:7]([N:6]1[CH:2]([CH3:18])[CH2:3][CH2:4][C@@H:5]1[C:13]([OH:15])=[O:14])=[O:8])[CH:11]=[CH2:12]
Reactant: C=CCOC(=O)N1[C@@H](C(=O)OCC)CCC1(C)O
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)N1C(C)CC[C@@H]1C(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(R)-1-allyl 2-ethyl 5-hydroxy-5-methylpyrrolidine-1,2-dicarboxylate (3.0 g, 12 mmol) was dissolved in trifluoroacetic acid (20 mL) and cooled to 0° C. before borane-pyridine complex (2.9 mL, 23 mmol) was added. The reaction mixture was heated to 90° C. for 3 h before it was concentrated in vacuo and NaOH −5 N (30 mL) was added. The mixture was stirred for 2 h at 60° C., then cooled, washed with ethyl acetate (30 mL), acidified to ˜pH 5 with conc HCl, extracted with dichloromethane, separated, dried over sodium sulfate, and concentrated in vacuo to give the title compound. MS (ES+): 214 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:36])[C@@H:4]([NH:14][C:15]([C:17]1[S:21][C:20]([NH:22][C:23](=[O:34])[CH2:24][C:25]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:26]=2[CH:27]=[N:28][NH:29]3)=[N:19][C:18]=1[CH3:35])=[O:16])[CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].O.[OH-].[Li+].C1COCC1.Cl>O>[NH:29]1[C:30]2[C:26](=[C:25]([CH2:24][C:23]([NH:22][C:20]3[S:21][C:17]([C:15]([NH:14][C@@H:4]([CH2:5][NH:6][C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])[C:3]([OH:36])=[O:2])=[O:16])=[C:18]([CH3:35])[N:19]=3)=[O:34])[CH:33]=[CH:32][CH:31]=2)[CH:27]=[N:28]1
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1sc(NC(=O)Cc2cccc3[nH]ncc23)nc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(NC(=O)Cc2cccc3[nH]ncc23)sc1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)O
Temperature: 25 °C
Yield: 63.4 %

Procedure:
A mixture of the (S)-2-{[2-(2-1H-Indazol-4-yl-acetylamino)-4-methyl-thiazole-5-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acid methyl ester (34 mg, 0.0646 mmol), lithium hydroxide monohydrate (32 mg, 0.763 mmol), THF (2 mL) and water (1 mL) was stirred at 25° C. for 1½ h. Aqueous 2N HCl was added and the reaction mixture was stirred for 2 hrs and then concentrated under reduced pressure. The resulting crude product was purified by HPLC to give (S)-2-{[2-(2-1H-Indazol-4-yl-acetylamino)-4-methyl-thiazole-5-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acid (21 mg, 63.5%) as a white solid. MS m/e 513.5 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Br[CH:20]1[C:25](=O)[CH:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22][CH2:21]1>C(O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH:24]2[C:23]3[N:18]=[C:16]([NH:15][C:5]4[CH:6]=[CH:7][C:8]([N:9]5[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]5)=[C:3]([O:2][CH3:1])[CH:4]=4)[S:17][C:22]=3[CH2:21][CH2:20][CH2:25]2)=[CH:28][CH:29]=1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: O=C1C(Br)CCCC1c1ccc(Cl)cc1
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCCC3c2ccc(Cl)cc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 18.7 %

Procedure:
A suspension of [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (50 mg, 0.19 mmol) and of crude 6-bromo-2-(4-chloro-phenyl)-cyclohexanone (74 mg, 0.26 mmol) in ethanol (2 mL) was heated to reflux under an atmosphere of nitrogen for 2 days. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane/methanol (19:1 v/v) as eluent to yield the title compound (16 mg, 19%) as a brown gum. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.37 (s, 1H), 7.79 (s, 1H), 7.68 (d, 1H), 7.66 (s, 2H), 7.50 (d, 1H), 7.26 (d, 1H), 7.17 (d, 1H), 7.03 (s, 1H), 3.80 (m, 1H), 3.80 (s, 3H), 2.87 (m, 2H), 2.18 (m, 2H), 2.14 (s, 3H), 1.90 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[CH2:5][O:6][Si:7]([C:20]([CH3:23])([CH3:22])[CH3:21])([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.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([O-:37])=[O:36])=[CH:31][CH:30]=1.[Na+]>C(O)CC>[C:20]([Si:7]([O:6][CH2:5][C:4]1[CH:24]=[CH:25][CH:26]=[CH:27][C:3]=1[CH2:2][S:35]([C:32]1[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=1)(=[O:37])=[O:36])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:21])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](OCc1ccccc1CBr)(c1ccccc1)c1ccccc1
Reactant: O=S([O-])c1ccc(Cl)cc1
Agent: [Na+]
Solvent: CCCO
Product: CC(C)(C)[Si](OCc1ccccc1CS(=O)(=O)c1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Temperature: 90 °C
Reaction time: 14 h

Procedure:
In propanol (20 ml) was dissolved (2-bromo methylbenzyloxy)-t-butyldiphenylsilane (3.10 g, 7.05 mmol), followed by the addition of sodium 4-chlorobenzenesulfinate (1.80 g, 9.06 mmol). At 90° C., the resulting mixture was stirred for 14 hours. After the reaction mixture was allowed to cool down, the residue obtained by concentrating the reaction mixture under reduced pressure was added with ethyl acetate. The resulting mixture was washed with water, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, whereby the title compound (3.90 g, quant.) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].[ClH:12]>[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.ClC(C(F)(F)F)=C>[Cl:12][CH:3]([C:2]([F:11])([F:10])[F:1])[CH2:4][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: Cl
Agent: C=C(Cl)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: N#CC(C#N)(CCC(F)(F)F)CC(Cl)C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1.6 g of 2-(3,3,3-trifluoropropyl)malononitrile was dissolved in 20 ml of a solution (1 mol/L) of tetrabutylammonium fluoride in tetrahydrofuran, 5 ml of 2-chloro-3,3,3-trifluoropropene was added thereto at 0° C., and the mixture was stirred at room temperature for 3 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.22 g of 2-(2-chloro-3,3,3-trifluoropropyl)-2-(3,3,3-trifluoropropyl)malononitrile (hereinafter, referred to as the present compound (58)).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[C:17]([C:24]([F:27])([F:26])[F:25])[CH:18]=[CH:19][CH:20]=2)[N:15]=1.[CH:28](OCC)=[O:29]>C1COCC1>[Cl:13][C:14]1[C:23]([CH:28]=[O:29])=[CH:22][C:21]2[C:16](=[C:17]([C:24]([F:26])([F:25])[F:27])[CH:18]=[CH:19][CH:20]=2)[N:15]=1
Reactant: FC(F)(F)c1cccc2ccc(Cl)nc12
Reactant: CCOC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1cc2cccc(C(F)(F)F)c2nc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a cold solution of butyllithium (0.498 g, 1.7 mmol) in 2 mL dry THF at −20C. was added diisopropyl amine (0.192 g, 1.9 mmol) drop wise and reaction mixture was allowed to stir at 0° C. for 1 h. then reaction mixture was again cooled to −78° C. and a solution of 2-chloro-8-trifluoromethyl-quinoline (0.4 g, 1.70 mmol) in 4 mL dry THF was added drop wise continued stirring for 5-10 min then added ethyl formate (0.12 g, 1.7 mmol) drop wise, continued stirring for 0.5 h. n-Butyllithium was quenched with ammonium chloride solution and extracted with ether (3×10 mL). The combined organic layers were washed with brine solution, dried over sodium sulfate, concentrated under vacuum to get the crude compound. The crude residue was purified over silica gel (100-200 mesh) using 10% ethyl acetate: petroleum ether to afford the desired compound (0.15 g, 34%).
Reaction SMILES: [CH:1]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][O:25]C3CCCCO3)=[CH:18][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[OH:25][CH2:24][CH2:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH:9]([O:8][C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:33][CH:32]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCOC2CCCCO2)cc1)Oc1ccc(C(C)C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)C(Cc1ccc(OCCO)cc1)Oc1ccc(C(C)C)cc1
Yield: 96.4 %

Procedure:
In a similar manner to that described in Reference example 3(f), a reaction was carried out using ethyl 2-(4-isopropylphenoxy)-3-[4-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl]propionate (20.6 g), which is the product of Reference example 5(e), and p-toluenesulfonic acid monohydrate (7.85 g) and the reaction mixture was treated to afford the desired compound (16.2 g) as a syrup.
Reaction SMILES: [NH2:1][C@@H:2]1[C:13](=[O:14])[N:4]2[C:5]([C:10]([OH:12])=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12.S(=O)(=O)(O)O.[CH3:20][C:21](=[CH2:23])[CH3:22].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O1CCOCC1>[NH2:1][C@@H:2]1[C:13](=[O:14])[N:4]2[C:5]([C:10]([O:12][C:21]([CH3:23])([CH3:22])[CH3:20])=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12
Reactant: C=C(C)C
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: 0 °C

Procedure:
A mixture of 7β-amino-3-methylceph-3-em-4-carboxylic acid (16.09 g., 75.2 m.moles), dioxan (100 ml.), sulphuric acid (10 ml.) and isobutylene (90 ml.) was shaken in a pressure bottle until a clear solution resulted (21/2 hours). The solution was cooled and poured into a mixture of aqueous sodium bicarbonate (600 ml.), ice (100 g.), and ethyl acetate (150 ml.). The aqueous layer was twice more extracted with ethyl acetate and the extracts were washed with brine and dried. Evaporation left a gum which was triturated with petrol (b.p. 40° - 60°) to give off-white crystals (11.17 g., 55%). A sample was recrystallised from ether to give the pure ester, m.p. 126°, [α]D + 107° (EtOH), λmax. 271 nm. (E1cm.1% 239) (Found: C, 53.1; H, 6.5; N, 10.1; S, 11.5 C12H18N2O3S requires: C, 53.3; H, 6.7; N, 10.35; S, 11.85%).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30]([O:34][C:35]([N:37]1[CH2:42][C@@H:41]2[CH2:43][C@H:38]1[CH2:39][NH:40]2)=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35]([N:37]1[CH2:42][C@@H:41]2[CH2:43][C@H:38]1[CH2:39][N:40]2[C:20]([C:19]1[CH:18]=[N:17][C:16]([NH:15][C:12]2[N:13]=[CH:14][C:9]3[CH:8]=[C:7]([C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[N:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[C:10]=3[N:11]=2)=[CH:24][CH:23]=1)=[O:22])=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4C[C@@H]5C[C@H]4CN5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCC1

Procedure:
Following general amide formation method 1, 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid (0.150 g, 0.380 mmol) was combined with (S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (100 mg, 0.504 mmol, 1.3 eq), which gave 5-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-(S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester and used directly in the next step. MS m/z 575.7 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][NH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][C:3]=1[CH2:15][N:16]1[C:20](=[O:21])[C:19]([CH3:23])([CH3:22])[CH2:18][O:17]1.S([O-])([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1.[Ag]=O>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]=[N:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][C:3]=1[CH2:15][N:16]1[C:20](=[O:21])[C:19]([CH3:22])([CH3:23])[CH2:18][O:17]1
Reactant: CCOC(=O)NNc1ccc(CN2OCC(C)(C)C2=O)c(Cl)c1
Agent: O=[Ag]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: CCOC(=O)N=Nc1ccc(CN2OCC(C)(C)C2=O)c(Cl)c1
Reaction time: 1 h
Yield: 81.8 %

Procedure:
A stirred mixture of 2-[[2-chloro-4-(ethoxycarbonylhydrazo)phenyl]methyl]-4,4-dimethyl-3-isoxazolidinone (1.24 g, 0.0036 mole) and magnesium sulfate (0.5 g, 0.004 mole) in toluene was cooled in a water bath. Silver oxide (0.6 g) was added and the mixture was stirred for one hour. Additional silver oxide (0.6 g) was added, and the mixture was stirred an additional one hour. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting first with 1:4 ethyl acetate:heptane and then 1:1 ethyl acetate:heptane. Appropriate fractions were combined and concentrated under reduced pressure to yield 1.0 g of 2-[[2-chloro-4-(ethoxycarbonylazo)phenyl]methyl]-4,4-dimethyl-3-isoxazolidinone as a red oil. The NMR spectrum was consistent with the proposed structure.