Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C:22]([N:24]2[CH2:29][CH2:28][CH:27]([C:30]([O:32]C)=[O:31])[CH2:26][CH2:25]2)=[O:23])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.Cl>CO>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C:22]([N:24]2[CH2:29][CH2:28][CH:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]2)=[O:23])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1CCN(C(=O)c2ccc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C(=O)N4CCC(C(=O)O)CC4)ccc3c2)CC1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 1-(6-(trans-4-tert-butylcyclohexyloxy)-2-naphthoyl)piperidine-4-carboxylate (150 mg, 0.33 mmol) in MeOH (5 mL) was added NaOH (68 mg, 1.7 mmol, 5.0 eq) and H2O (0.5 mL). The reaction mixture was stirred at 85° C. for 2 h. After the reaction was cooled to 0° C., the pH of the solution was adjusted to 6 with 3 N HCl. The mixture was filtered and the yellow solid was the desired product 1-(6-(trans-4-tert-butylcyclohexyloxy)-2-naphthoyl)piperidine-4-carboxylic acid (90 mg, yield: 70%). ESI-MS (M+1)+: 438.3. 1HNMR (400 MHz, CD3OD) δ: 7.83˜7.81 (m, 3H), 7.41 (d, 1H), 7.28 (s, 1H), 7.16 (d, 1H), 4.44˜4.37 (m, 1H), 3.30 (br, 2H), 2.65˜2.60 (m, 1H), 2.29˜2.27 (m, 2H), 1.93˜1.90 (m, 4H), 1.44˜1.41 (m, 3H), 1.32˜1.31 (m, 2H), 1.28˜1.25 (m, 3H), 1.15˜1.12 (m, 1H), 0.92 (s, 9H). HPLC: 98.45%
Reaction SMILES: S(OOS([O-])(=O)=O)([O-])(=O)=[O:2].[K+].[K+].[CH2:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[OH-].[K+]>[CH2:13]=[CH:14][C:15]1[CH:20]=[CH:19][C:18]([OH:2])=[CH:17][CH:16]=1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: C=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Product: C=Cc1ccc(O)cc1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
50.5 g of 19.66 percent poly(4-vinylpyridine) methanol solution from Ex. 2 (˜10.0 g of polymer) was placed in a 500 ml single neck flask and stripped of solvent on a rotary evaporator. To the dried polymer was then added 110 g of RO water and 10.0 g of con. hydrochloric acid. The mixture was stirred until a uniform pale yellow aqueous solution was obtained. This solution was then charged into a 500 ml three-necked round bottom flask equipped with a mechanical paddle stirrer, a nitrogen inlet, a pot thermometer, heating mantle and condenser. 0.43 g of potassium persulfate was then added followed by 30.0 g (˜0.288 moles) of styrene. The biphasic stirred mixture was then rapidly heated to 65° C. under nitrogen. After only 2 hrs., the latex solids were determined to be 27 percent (theory 27.1 percent) or ˜100 percent conversion. A small portion of the final latex was coagulated in dilute potassium hydroxide solution for analysis. NMR indicated a composition of 24.8 percent poly(4-VP) and 75.2 percent polystyrene (theory 25 percent poly(4-VP) and 75 percent PS). Latex particle size was 150 nm.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]([CH3:16])[CH:14]=[O:15])[CH:10]=[CH:11][CH:12]=2)=[C:4]([CH3:19])[CH:3]=1.CC[O:22]C(CCl)=O>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]([CH3:16])[C:14]([OH:22])=[O:15])[CH:10]=[CH:11][CH:12]=2)=[C:4]([CH3:19])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1Oc1cccc(C(C)C=O)c1
Reactant: CCOC(=O)CCl
Product: Cc1cc(Cl)ccc1Oc1cccc(C(C)C(=O)O)c1

Procedure:
2-[m-(p-chloro-o-methyl-phenoxy)phenyl]propionaldehyde, which has been synthesized in accordance with Example 1 from 3-(p-chloro-o-methyl-phenoxyphenyl)acetophenone having the melting point of 148° - 156° C./0.5 mmHg and ethyl ester of chloroacetic acid, is subjected to oxidative treatment in the manner of Example 1 to obtain the contemplated product.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH:19]2[C@H:24]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@@H:23]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@H:22]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C@@H:21]([CH2:49][O:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[O:20]2)=[CH:5][C:6]=1[CH2:7][O:8][Si](C(C)C)(C(C)C)C(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:1][C:2]1[S:3][C:4]([CH:19]2[C@H:24]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@@H:23]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@H:22]([O:41][CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[C@@H:21]([CH2:49][O:50][CH2:51][C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)[O:20]2)=[CH:5][C:6]=1[CH2:7][OH:8]
Reactant: CC(C)[Si](OCc1cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)sc1Cl)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCc1cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)sc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of compound 34 (8.22 g) in THF (50 mL) was added TBAF (1M in THF, 20 mL, 19.9 mmol) dropwise at 0° C. The mixture was stirred at room temperature for 2 hours. The mixture was extracted with EtOAc/H2O (100 mL/250 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (Biotage) to provide the title compound 35 (5.2 g, 89% (3-steps)).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[O:3]1.[C:17]1([N:23]=[C:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[C:17]1([NH:23][C:24]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)=[CH:14][N:13]=2)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(NC(=O)Nc3ccccc3)nc2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ambient solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.350 g, 1.59 mmol) in tetrahydrofuran (4 mL) was added phenyl isocyanate (0.174 mL, 1.59 mmol). The solution was stirred at room temperature for 1 h and was then concentrated under reduced pressure. The solid was washed with diethyl ether (2 mL) and air-dried to give the title compound. MS (ESI) m/z 221 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:21][C:19]([F:20])([F:22])[C:18]1[C:13]([N:10]2[CH2:11][CH2:12][C@@H:8]([NH2:7])[CH2:9]2)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ncccc2C(F)(F)F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CCN(c2ncccc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of D1 (11.5 g, 0.04 mol) in DCM (80 ml) was cooled (ice-bath) and TFA (excess, 50ml) was added. Reaction was warmed to ambient temperature, stirred for 3 h and partitioned between ethyl acetate and aqueous sodium hydroxide. The organic phase was separated, dried (MgSO4) and filtered. Removal of solvent under reduced pressure afforded the crude product as a yellow oil. Bulb to bulb distillation under reduced pressure initially afforded the product as a oil which crystallised on standing.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.Cl.[NH2:15][C@@H:16]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[C:17]([N:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1)=[O:18]>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][C@H:16]([NH:15][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:13])[C:17]([N:19]2[CH2:20][CH2:21][CH:22]([OH:25])[CH2:23][CH2:24]2)=[O:18])=[CH:28][CH:29]=1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Reactant: N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1)c1cc2cc(Cl)ncc2[nH]1

Procedure:
Route A: To a solution of 2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl)propionic acid (EXAMPLE 228, 1.4 g, 3.87 mmol) in DMF (35 mL) was added HATU (1.77 g, 4.64 mmol) and the reaction stirred for 10 min. 4-Hydroxypiperidine (0.43 g, 4.26 mmol) was added, followed by DIPEA (0.8 mL, 4.64 mmol) and the reaction stirred at rt for 16 h. Solvent was removed in vacuo and the crude material partitioned between ethyl acetate (50 mL) and water (50 mL). The organics were washed with sodium bicarbonate (2×30 mL) and brine (2×30 mL), dried (MgSO4) and the solvent removed in vacuo. Purification by column chromatography (SiO2, 96:4 dichloromethane/methanol) gave the title compound. m/z (ES+)=445.15 [M+H]+; RT=3.24 min. Route B: The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and 2-(S)-amino-3-(4-fluorophenyl)-1-(4-hydroxypiperidin-1-yl)propan-1-one hydrochloride (Preparation 20). The product was purified by chromatography on silica gel eluting with methanol/dichloromethane (1:19) to give the title compound as a pale yellow solid. δH (CD3OD): 1.08-1.19 (0.5H, m), 1.29-1.51 (1.5H, m), 1.54-1.62 (0.5H, m), 1.73-1.84 (1.5H, m), 3.06-3.36 (4H, m), 3.67-3.95 (2.5H, m), 4.03-4.10 (0.5H, m), 5.32 (1H, t), 6.97-7.04 (2H, m), 7.14 (1H, s), 7.26-7.33 (2H, m), 7.66 (1H, s), 8.55 (1H, s); m/z (ES+)=445 [M+H]+; RT=3.27 min.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[CH3:15])=O.COC1C=CC(/C=[C:31]2/[C:32]([NH:34][C:35]([S:37]/2)=[NH:36])=[O:33])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:36][C:35]1[S:37]/[C:31](=[CH:1]\[C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]3[CH3:15])/[C:32](=[O:33])[N:34]=1
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Reactant: Cc1c(C#N)cnc2ccc(C=O)cc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1c(C#N)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12

Procedure:
Similar procedure as described in example 28c was used, starting from 6-formyl-4-methyl-quinoline-3-carbonitrile (example 73c), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-methyl-quinoline-3-carbonitrile. LC-MS m/e 295 (MH+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C1COCC1>[CH3:16][S:17]([O:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:19])=[O:18]
Reactant: OCCc1cccs1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCc1cccs1

Procedure:
The 2-(2-thienyl)ethanol (Aldrich, 0.16 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19])([O:3][CH2:4][CH3:5])=[O:2].[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[C:20]([O:19][C:14]1[CH2:15][CH2:16][CH2:17][CH2:18][C:13]=1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CCCCCCCC1CCCCC1=O
Product: CCOC(=O)CCCCCCCC1=C(OC(C)=O)CCCC1

Procedure:
Treatment of 2-(7-carbethoxyheptyl)cyclohexan-1-one (Example 16) with acetic anhydride by the procedure of Example 24 is productive of the subject compound.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:15])=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[C:16]([C:18]1[CH:30]=[CH:29][C:21]([CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:20][CH:19]=1)#[N:17]>>[CH3:15][C:3]1[C:2]([N:26]2[CH2:27][CH2:28][N:23]([CH2:22][C:21]3[CH:29]=[CH:30][C:18]([C:16]#[N:17])=[CH:19][CH:20]=3)[CH2:24][CH2:25]2)=[N:7][N:6]2[C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=[C:5]2[CH:4]=1
Reactant: N#Cc1ccc(CN2CCNCC2)cc1
Reactant: Cc1cc2nnc(C(F)(F)F)n2nc1Cl
Product: Cc1cc2nnc(C(F)(F)F)n2nc1N1CCN(Cc2ccc(C#N)cc2)CC1
Yield: 74.7 %

Procedure:
The method of Example 12 was repeated using a mixture of 6-chloro-7-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (0.078 g, 0.33 mmol) and 1-(4-cyanobenzyl)-piperazine (0.199 g, 0.99 mmol) to give 4-((4-(7-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperazin-1-yl)methyl)benzonitrile (0.099 g, 75%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[S:8](N)([NH2:11])(=[O:10])=[O:9]>>[O:1]=[C:2]1[NH:3][CH2:4][CH2:5][N:6]([S:8]([NH2:11])(=[O:10])=[O:9])[CH2:7]1
Reactant: NS(N)(=O)=O
Reactant: O=C1CNCCN1
Product: NS(=O)(=O)N1CCNC(=O)C1

Procedure:
The subtitle compound was prepared according to the procedure outlined in Example 62 step i) using 2-oxopiperazine (0.5 g) and sulfamide (0.45 g) to give a beige solid. Yield: 0.83 g.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:31][NH:30][C:29](=[O:32])[C:4]=2[C:5]([C:23]2[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=2)=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15]C(=O)OC(C)(C)C.Cl>CC(O)=O>[NH2:15][C@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]1[NH:8][C:7]1[N:6]=[C:5]([C:23]2[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=2)[C:4]2[C:29](=[O:32])[NH:30][CH2:31][C:3]=2[C:2]=1[Cl:1]
Reactant: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(Cl)c3c2C(=O)NC3)cn1
Agent: Cl
Solvent: CC(=O)O
Product: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3N)c(Cl)c3c2C(=O)NC3)cn1
Yield: 63 %

Procedure:
A solution of tert-butyl (1S,2R)-2-(7-chloro-4-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (10.00 mg, 0.022 mmol) in HCl (0.5 mL, 16.46 mmol) and HOAc (1 mL) was stirred at RT for 30 min. The reaction mixture was concentrated and the resulting residue was washed with IPE to give the HCl salt of the title compound (5 mg, 63.9%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.48-1.97 (m, 8 H), 3.72-3.78 (m, 1 H), 3.96 (br s, 3 H), 4.35 (d, J=4.88 Hz, 2 H), 4.57 (br s, 1 H), 6.29 (d, J=6.83 Hz, 1 H), 7.93 (br s, 2 H), 8.40-8.45 (m, 1 H), 8.49 (s, 1 H), 8.98 (s, 1 H). [M+H] calc'd for C17H21ClN6O, 361; found, 361.
Reaction SMILES: [SH:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][O:12][CH3:13])[N:10]=[C:6]2[N:5]=[C:4]([CH3:14])[CH:3]=1.CC(O[CH2:19][C:20]1[CH2:29][S:28][C@@H:23]2[C@H:24]([NH2:27])[C:25](=[O:26])[N:22]2[C:21]=1[C:30]([OH:32])=[O:31])=O.O.N>C(#N)C>[NH2:27][CH:24]1[C:25](=[O:26])[N:22]2[C:21]([C:30]([OH:32])=[O:31])=[C:20]([CH2:19][S:1][C:2]3[N:7]4[N:8]=[C:9]([CH2:11][O:12][CH3:13])[N:10]=[C:6]4[N:5]=[C:4]([CH3:14])[CH:3]=3)[CH2:29][S:28][C@H:23]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: COCc1nc2nc(C)cc(S)n2n1
Agent: N
Solvent: CC#N
Solvent: O
Product: COCc1nc2nc(C)cc(SCC3=C(C(=O)O)N4C(=O)C(N)[C@H]4SC3)n2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.7 %

Procedure:
In 600 ml of acetonitrile were suspended 30.1 g of 7-mer- capto-2-methoxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidine and 38.9 g of 7-aminocephalosporanic acid and 68.7 ml of boron trifluoride - ethyl ether complex was added thereto, and the mixture was stirred at room temperature for 6 hours. One liter of water was added to the reaction mixture and the mixture was adjusted to pH 2 with addition of a conc. aqueous ammonia. The precipitated crystals were collected by filtration, washed with water and with acetone, and then dried to obtain 30 g of the title compound.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]=[C:32]=[S:33])[CH:26]=1>O1CCCC1>[C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:32](=[S:33])[NH:31][C:27]4[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=4)[CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: S=C=Nc1cccnc1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: S=C(Nc1cccnc1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.9 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (246 mg, 1.00 mmol) and triethylamine (0.139 ml, 1.00 mmol) in tetrahydrofuran (6 ml) was added 3-pyridylisothiocyanate (0.167 ml, 1.50 mmol), the mixture was stirred at room temperature for 3 hours and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of tetrahydrofuran and ethyl acetate to obtain the desired product (233 mg, 61.0%) as a solid.
Reaction SMILES: [CH2:1]([C:13]1[S:17][C:16]([C:18]2[CH:22]=[CH:21][S:20][CH:19]=2)=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Br:23]N1C(=O)CCC1=O>CN(C=O)C>[Br:23][C:19]1[S:20][CH:21]=[CH:22][C:18]=1[C:16]1[S:17][C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:14][CH:15]=1
Reactant: CCCCCCCCCCCCc1ccc(-c2ccsc2)s1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCc1ccc(-c2ccsc2Br)s1
Temperature: 0 °C
Yield: 97 %

Procedure:
5′-Dodecyl-3,2′-bithiophene (34.5 g, 103 mmol, 1 eq) prepared above was placed in a three-necked flask equipped with a dropping funnel and a reflux tube. The atmosphere in the flask was replaced by Ar, 500 ml of dehydrated DMF was added thereto, and the mixture was stirred. The reaction solution was cooled to 0° C., and N-bromosuccinimide (19.2 g, 108 mmol, 1.05 eq) dissolved in 100 ml of dehydrated DMF in a separate vessel was added dropwise to the reaction solution. After the completion of the dropwise addition, the mixture was stirred for one hr, was brought to room temperature, and was stirred for 6 hr. The solvent was removed by evaporation, and the residue was extracted with diethyl ether, followed by washing with water until pH=7. The extract was dehydrated over Na2SO4, the solvent was removed by evaporation, and the residue was purified by chromatography on silica gel to give an objective substance 2-bromo-5′-dodecyl-3,2′-bithiophene as a light yellow liquid (which solidified a few hours after that) (about 41.5 g, yield about 97%). An NMR spectrum of the compound thus obtained was measured at room temperature with an NMR spectrometer (model JNM-LA400W, manufactured by Japan Electric Optical Laboratory). 1H-NMR (d6-DMSO, TMS/ppm): 0.86 (t, 3H, J=6.83 Hz), 1.26 (m, 18H), 1.66 (m, 2H), 2.80 (t, 2H, J=7.32 Hz), 6.83 (d, 1H, J=2.93 Hz), 7.22 (d, 1H, J=5.34 Hz), 7.32 (d, 1H, J=3.90 Hz), 7.59 (d, 1H, J=5.37 Hz).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:13][C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>ClCCl>[C:1]([NH:5][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([Br:13])[CH:15]=1)(=[O:22])=[O:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: CC(C)(C)N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1cccc(Br)c1
Reaction time: 1 h
Yield: 1248 %

Procedure:
tert-Butylamine (3.14 g, 3.0 mmol, 1.1 eq) and triethylamine (5.94 g, 58.6 mmol, 1.5 eq.) were dissolved in dichloromethane (20 mL) and stirred at room temperature while 3-bromobenzenesulfonyl chloride (10.0 g, 39.1 mmol) was added slowly. The mixture was stirred for 1 hour and then concentrated by evaporation under reduced pressure. The residue was taken up in 5% citric acid and ethyl acetate. The organic layer is washed repeatedly with brine and water, dried over anhydrous magnesium sulfate and concentrated to give N-tert-butyl-3-bromobenzenesulfonamide (10.94 g) as a white powder.
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][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[N:21]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[C:22]=[O:23]>CN(C=O)C>[CH:24]1([NH:21][C:22]([N:18]2[CH2:19][CH2:20][CH:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:23])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Reactant: O=C=NC1CCCCC1
Solvent: CN(C)C=O
Product: COc1cc2ncnc(C3CCN(C(=O)NC4CCCCC4)CC3)c2cc1OC
Yield: 50.2 %

Procedure:
A solution of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (30 mg, 0.110 mmol), as prepared in Example 1d, in DMF (1 mL) was treated with isocyanato-cyclohexane (20.6 mg, 0.165 mmol) at RT overnight. The reaction was then partitioned between EtOAc (10 mL) and H2O (10 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. Purification by prep tlc (1:9 MeOH/DCM) afforded the title compound as a light yellow solid (22 mg, 50%). 1H NMR (300 MHz, CDCl3) δ 9.08 (s, 1H), 7.38 (s, 1H), 7.26 (s, 1H), 4.35 (d, 1H), 4.14 (d, 1H), 4.07 (s, 6H), 3.68 (m, 1H), 3.53 (m, 1H), 3.03 (m, 2H), 2.12-1.90 (m, 4H), 1.70-1.55 (m, 5H), 1.40-1.09 (m, 5H); LC/MS (ESI): calcd mass 398.2, found 399.3 [M+1]+.
Reaction SMILES: Br[CH2:2][C:3](=[O:14])[CH2:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6].[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1>C(Cl)Cl>[N:15]1([CH2:2][C:3](=[O:14])[CH2:4][S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:7])=[O:6])[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: c1c[nH]cn1
Reactant: O=C(CBr)CS(=O)(=O)c1ccccc1
Solvent: ClCCl
Product: O=C(Cn1ccnc1)CS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 50 g (0.180 mole) finely ground 1-bromo-3-phenylsulfonylpropan-2-one (the product of Example 10) in 125 ml methylene chloride cooled to about 0°-5° C., 36.8 g (0.54 mole) imidazole in 300 ml methylene chloride were added dropwise. The reaction mixture was maintained at 0°-5° C. for one hour, allowed to warm to room temperature and was stirred overnight. The methylene chloride was removed in vacuo at room temperature. The resulting oil was partitioned with 200 ml water and 200 ml ethyl acetate. The aqueous phase was extracted with ethyl acetate (four times 125 ml). The combined ethyl acetate extracts were treated with decolorizing charcoal, dried, filtered and concentrated. The precipitate which formed was triturated with methanol-isopropyl alcohol yielding 17.9 g of the above-identified product, as an off-white solid, melting point 137°-140° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[CH:17]1([CH2:22][C:23](O)=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH:17]1([CH2:22][C:23]([N:12]2[CH2:11][CH2:10][N:9]([C:4]3[C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=[CH:6][N:5]=3)[CH2:14][CH2:13]2)=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: O=C(O)CC1CCCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(CC1CCCC1)N1CCN(c2ncccc2C(F)(F)F)CC1
Yield: 43 %

Procedure:
Coupling of 1-(3-(trifluoromethyl)pyridin-2-yl)piperazine (271 mg, 1.17 mmol) with 2-cyclopentylacetic acid (100 mg, 0.78 mmol) was carried out according to a similar procedure described for example 19A using N,N-dimethylformamide (1 mL) as solvent and benzotriazole-1 yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (700 mg, 1.56 mmol) as coupling agent. 1-(cyclopentylacetyl)-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine was obtained in 43% yield (114 mg) as colorless oil.