Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:12]([C:14]1[N:19]=[CH:18][C:17]([S:20](Cl)(=O)=[O:21])=[CH:16][CH:15]=1)#[N:13]>CN(C1C=CN=CC=1)C>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][S:20]([C:17]2[CH:18]=[N:19][C:14]([C:12]#[N:13])=[CH:15][CH:16]=2)=[O:21])[CH:7]=[CH:8][CH:9]=1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cn1
Reactant: Nc1cccc2cccnc12
Agent: CN(C)c1ccncc1
Product: N#Cc1ccc(S(=O)Nc2cccc3cccnc23)cn1
Yield: 26.9 %

Procedure:
In a similar fashion using route 18 general procedure 27, 8-aminoquinoline (200 mg, 1.39 mmol), 6-cyanopyridine-3-sulfonyl chloride 19 (337 mg, 1.66 mmol) and DMAP (cat.) gave the title compound (110 mg, 25%) after purification by column chromatography with n-hexane/EtOAc (4:1) as the eluent.
Reaction SMILES: [OH:1][CH2:2][CH:3]=[C:4]([C:6]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[C:8]([CH:15]([CH3:17])[CH3:16])[C:7]=1[OH:18])[CH3:5].I[CH2:20][CH2:21][CH3:22].[F-].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH:15]([C:8]1[C:7]([O:18][CH2:20][CH2:21][CH3:22])=[C:6]([C:4]([CH3:5])=[CH:3][CH2:2][OH:1])[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=1)([CH3:17])[CH3:16]
Reactant: CC(=CCO)c1cc(C(C)C)cc(C(C)C)c1O
Reactant: CCCI
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOc1c(C(C)=CCO)cc(C(C)C)cc1C(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.2 %

Procedure:
To a solution of 2-(3-hydroxy-1-methyl-propenyl)-4,6-diisopropyl-phenol (Intermediate 12, 1.82 g, 7.3 mmol) and 1-iodopropane (0.79 mL, 8.1 mmol) in DMF (20 mL) at room temperature was added CsF (3.9 g, 25.6 mmol). The reaction was stirred at room temperature for 1.5 h, diluted with EtOAc, washed successively with H2O, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (10% EtOAc-hexanes) to yield the title compound as an off-white solid (2.06 g, 97%).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[OH:11])([CH3:4])([CH3:3])[CH3:2].[H][H].[CH2:14]1[O:17][CH:15]1[CH3:16].Cl>O1CCCC1>[C:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[OH:11])([CH3:4])([CH3:2])[CH3:3].[C:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[O:11][CH2:14][CH:15]([OH:17])[CH3:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CO1
Reactant: [H][H]
Agent: CC(C)(C)C1CCCCC1O
Agent: Cl
Solvent: C1CCOC1
Product: CC(O)COC1CCCCC1C(C)(C)C
Temperature: 60 °C

Procedure:
To a 300 ml round bottom flask provided with a Dimroth condenser and a dropping funnel, 7.5 g (0.194 mol) of sodium hydride (62 weight % mineral oil dispersion type) and 30 ml of tetrahydrofuran were added and heated at 60° C. under a nitrogen gas flow. Then, to this solution a mixture of 30.0 g (0.192 mol) of 2-tert-butylcyclohexanol (cis:trans=8:2) and 30 ml of tetrahydrofuran was added dropwise in approximately 30 minutes, and the mixed solution was stirred under reflux for 24 hours until the generation of hydrogen gas had stopped. The reacted mixed solution was cooled to 40° C., and after dropwise adding 11.1 g (0.192 mol) of propyleneoxide to the mixed solution, the solution was further stirred under reflux for 48 hours. The mixed solution was neutralized by 3N hydrochloric acid, and the organic layer was separated from the water layer. Distillation was then conducted and 9.9 g of 2-tert-butylcyclohexanol and 24.2 g of 1-(2-tert-butylcyclohexyloxy)-2-propanol (cis:trans=8:2) (bp. 112° to 113° C./5 mm Hg) were obtained in a 59% yield. Further, the cis-trans isomers of 1-(2-tert-butylcyclohexyloxy)-2-propanol were separated from each other by column chromatography using a developing solvent composed of Kieselgel 60 (trademark) of Merck Corporation and hexane:ethyl acetate =95:5.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH2:15]([O:17][C:18](=[O:42])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]Br)[C:24]=1[CH2:39][CH2:40][CH3:41])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:15]([O:17][C:18](=[O:42])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][O:11][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:24]=1[CH2:39][CH2:40][CH3:41])[CH3:16]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1OCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCCCCOc2c(C(C)=O)ccc(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Yield: 82.7 %

Procedure:
A mixture of 0.96 g (0.005 mole) of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.26 g (0.005 mole) of 4-[4-acetyl-3-[(5-bromopentyl)oxy]-2-propylphenoxy]butanoic acid ethyl ester and 1.36 g (0.010 mole) of anhydrous potassium carbonate in 40 ml of anhydrous acetone and 20 ml of anhydrous dimethylformamide was stirred at reflux for 17 hours. The solvents were removed in vacuo and the residue was purified by HPLC using 25% ethyl acetate-hexane to yield 2.36 g (84% yield) of 4-[4-acetyl-3-[[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyl]oxy]-2-propylphenoxy]butanoic acid ethyl ester as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:29])[CH2:9][C:10]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(C(OCC)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12].[OH-].[Na+].C(O)C>CC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([C:30]2[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:29])[CH2:9][CH:10]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(CCc1ccccc1)(CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1C)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)=O
Product: CCOC(=O)C(CCc1ccccc1)CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1C
Temperature: 50 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
Step 5 A mixture of diethyl 2-[2-(3-methyl-4′-nitro-1,1′-biphenyl-4-yl)-2-oxoethyl]-2-(2-phenylethyl)malonate (4.87 g, 9.41 mmol), 1 N aqueous sodium hydroxide (10.4 mL, 10.40 mmol), ethanol (10 mL), and acetone (10 mL) was stirred at 50° C. overnight. The mixture was concentrated and the residue was dissolved in dimethoxyethane (20 mL), and stirred at 80° C. overnight. The mixture was concentrated, and the residue was dissolved in ethyl acetate (30 mL). The solution was washed with water (2×5 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The material obtained was purified by flash chromatography (10:90 ethyl acetate/hexane) to give ethyl 4-(3-methyl-4′-nitro-1,1′-biphenyl-4-yl)-4-oxo-2-(2-phenylethyl)butanoate as a light yellow oil (3.53 g, 99% yield). LC-MS ret. time 4.18 min, m/z 446.0 (MH+); 1H NMR (CDCl3) δ: 1.33 (t, 3H), 1.83-2.17 (m, 2H), 2.58 (s, 3H), 2.67-2.78 (m, 2H), 3.00 (dd, 1H), 3.14 (m, 1H), 3.49 (dd, 1H), 4.09 (q, 2H), 7.14-7.36 (m, 5H), 7.47-7.55 (m, 2H), 7.72-7.83 (m, 3H), 8.33 (d, 2H).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:46])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=5[OH:33])[CH:23]=[CH:24][CH:25]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:34])[C:12]=2[C@H:35]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH3:47][C@@H:48](O)[CH2:49][CH:50]=[CH2:51].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOC(C)=O>[CH2:1]([O:4][C:5]1([CH3:46])[CH2:6][CH2:7][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=5[O:33][C@H:50]([CH2:49][CH:48]=[CH2:47])[CH3:51])[CH:23]=[CH:24][CH:25]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:34])[C:12]=2[C@H:35]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:9][CH2:10]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(-c4cccc(-c5ccc(F)cc5O)c4)nn23)CC1
Reactant: C=CC[C@@H](C)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(-c4cccc(-c5ccc(F)cc5O[C@@H](C)CC=C)c4)nn23)CC1
Reaction time: 18 h
Yield: 96.5 %

Procedure:
To a solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(4′-fluoro-2′-hydroxy-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.27 g, 0.43 mmol, 1 equiv), (R)-pent-4-en-2-ol (0.132 mL, 1.28 mmol, 3 equiv), and PPh3 (0.23 g, 0.86 mmol, 2 equiv) in THF (2.1 mL) was added DIAD (0.166 mL, 0.86 mmol, 2 equiv). After stirring 18 h, diluted with EtOAc and washed with water. The EtOAc layer was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (0-100% EtOAc in hexane) to provide the product as a colorless glass (0.29 g, 97%). LCMS (M+1)=699.45.
Reaction SMILES: [S:1]1[C:5]([CH2:6][O:7][C:8]([NH:10][C@@H:11]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:12][NH:13][CH2:14][C@@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]2[S:32][CH:31]=[N:30][CH:29]=2)=[O:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:9])=[CH:4][N:3]=[CH:2]1.[CH3:40][CH:41]([CH3:44])[CH:42]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[CH3:40][CH:41]([CH3:44])[CH2:42][N:13]([CH2:14][C@@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]1[S:32][CH:31]=[N:30][CH:29]=1)=[O:25])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:12][C@@H:11]([NH:10][C:8]([O:7][CH2:6][C:5]1[S:1][CH:2]=[N:3][CH:4]=1)=[O:9])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)C=O
Reactant: O=C(N[C@H](CNC[C@H](Cc1ccccc1)NC(=O)OCc1cncs1)Cc1ccccc1)OCc1cncs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)CN(C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1)C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Reaction time: 0.25 h
Yield: 77.9 %

Procedure:
The product from Example 35 (180 mg, 0.32 mmol) in 1,2-dichloroethane (2.0 mL) was treated with 2-methylpropanal (36 μl, 0.38 mmol) at ambient temperature. After stirring for 15 minutes, the mixture was treated with acetic acid (22 μl, 0.38 mmol) and sodium triacetoxyborohydride (108 mg, 0.51 mmol) at ambient temperature. After stirring for 2 hours, the mixture was treated with aqueous 10% sodium bicarbonate (2.0 mL) and extracted with ethyl acetate (3×5 mL). The ethyl acetate extracts were combined, washed with brine (5 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel eluting with (chloroform:methanol, 99:1) to provide the title compound (155 mg, 78%). 1H NMR (CDCl3) δ 8.73 (s, 2H), 7.75 (s, 2H), 7.31-7.11 (m, 10H), 5.33 (br s, 2H), 5.18 (q, 4H), 3.96 (br s, 2H), 2.83 (m, 2H), 2.71 (dd, 2H), 2.42 (t, 2H), 2.21 (dd, 2H), 2.05-1.83 (m, 2H), 1.46 (m, 1H), 0.72 (dd, 6H); MS (ESI+) m/z 622 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].C(OC([NH:13][C@@H:14]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([OH:38])[CH:32]=1)[C:15]([O:17][CH2:18][C@H:19]([O:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23])[CH3:20])=[O:16])=O)(C)(C)C.C(OC)(C)(C)C>O1CCOCC1>[S:2]([OH:5])(=[O:4])(=[O:3])[CH3:1].[NH2:13][C@@H:14]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([OH:38])[CH:32]=1)[C:15]([O:17][CH2:18][C@H:19]([O:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23])[CH3:20])=[O:16]
Reactant: C[C@H](COC(=O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C)OC(=O)c1ccccc1
Agent: CS(=O)(=O)O
Solvent: COC(C)(C)C
Solvent: C1COCCO1
Product: C[C@H](COC(=O)[C@@H](N)Cc1ccc(O)c(O)c1)OC(=O)c1ccccc1
Temperature: 25 °C
Yield: 54.4 %

Procedure:
Methanesulfonic acid (3.9 mL, 60.1 mmol) was slowly added to a solution of (2R)-2-phenylcarbonyloxypropyl (2S)-2-(tert-butoxycarbonyl)amino-3-(3,4-dihydroxyphenyl)propanoate 1c (11.0 g, 22.1 mmol) in 1,4-dioxane (30 mL) while stirred at room temperature. The mixture was stirred for 2 h. The solution was slowly added to methyl tert-butyl ether (MTBE) (600 mL) with vigorous stirring. The resulting suspension was filtered. The filter cake was washed three times with methyl tert-butyl ether and air dried to afford 5.48 g (54% yield) of anhydrous mesylate salt 1 as an off-white solid.
Reaction SMILES: [S:1]([O-:4])([O-:3])=[O:2].[Na+].[Na+].Br[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1>O.O1CCOCC1>[CH2:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][CH:9]([CH2:8][S:1]([OH:4])(=[O:3])=[O:2])[CH2:10]1)=[O:16])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=S([O-])[O-]
Reactant: O=C(OCc1ccccc1)N1CCCC(CBr)C1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1CCCC(CS(=O)(=O)O)C1

Procedure:
Sodium sulphite (12.6 g) in water (25 ml) was added to a stirred solution of benzyl 3-(bromomethyl)-1-piperidinecarboxylate (7.8 g) [Preparation 60] in dioxan (25 ml). The reaction mixture was stirred at reflux for 18 hrs, after which time the solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The aqueous solution was separated and acidified with 2N aqueous hydrochloric acid. The product was then extracted with ethyl acetate, dried over magnesium sulphate and the solvent removed under reduced pressure to afford 1-[(benzyloxy)carbonyl]-3-piperidylmethanesulfonic acid as a hygroscopic solid (4.5 g).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7])=O.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>C(Cl)Cl>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:1][C:3]2[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=2)[C:6]#[N:7])[CH2:14][CH2:13]1
Reactant: CN1CCNCC1
Reactant: N#Cc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1CCN(Cc2cccc(C#N)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
A mixture of 3-formyl-benzonitrile (1.5 g, 11.45 mmol), N-methyl piperazine (1.49 g, 14.9 mmol) and NaBH(OAc)3 (3.63 g, 17.18 mmol) in DCM (75 ml) and CH3COOH (0.851 ml, 14.9 mmol) was stirred overnight at room temperature, then diluted with DCM and washed with 1 M Na2CO3. The organic phase was dried over Na2SO4 and evaporated in vacuo. The crude mixture was purified by column chromatography (eluent: DCM/MeOH/NH4OH 97:3:0.5) to give 1.7 g of 3-(4-methyl-piperazin-1-ylmethyl)-benzonitrile.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]([CH2:10]O)[CH:8]=[CH:9][C:2]1=2.C(N(CC)CC)C.CS([Cl:23])(=O)=O>ClCCl>[O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]([CH2:10][Cl:23])[CH:8]=[CH:9][C:2]1=2
Reactant: OCc1ccc2c(c1)CCO2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: ClCc1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a solution of (2,3-dihydrobenzo[b]furan-5-yl)methanol (1.5 g, 10 mmol) in dichloromethane (10 mL) were added under ice-cooling triethylamine (1.67 mL, 12 mmol) and methanesulfonyl chloride (0.85 mL, 10 mmol) and the mixture was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure and the obtained residue was dissolved in ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give an almost pure title compound (1.6 g, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=1.Br[CH2:17][C@@H:18]([N:20]1[C:24]([CH3:25])=[CH:23][CH:22]=[C:21]1[CH3:26])[CH3:19]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:17][C@@H:18]([N:20]2[C:24]([CH3:25])=[CH:23][CH:22]=[C:21]2[CH3:26])[CH3:19])[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=1
Reactant: Cc1cc(C)nc(-n2c(C)ccc2C)c1
Reactant: Cc1ccc(C)n1[C@@H](C)CBr
Product: Cc1cc(CC[C@H](C)n2c(C)ccc2C)nc(-n2c(C)ccc2C)c1

Procedure:
By analogy to Example 71, Step A, the anion of 4,6-dimethyl-2-(2,5-dimethylpyrrol-1-yl)pyridine was alkylated with (S)-1-(2-bromo-1-methylethyl)-2,5-dimethylpyrrole to give (S)-4-methyl-2-(2,5-dimethylpyrrol-1-yl)-6-(3-(2,5-dimethylpyrrol-1-yl)-3-methylpropyl)pyridine.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:17][C:16]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[CH:21]3)=[N:15][N:14]=1.[C:27](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:27][N:23]1[C:24]2[C:20](=[CH:19][C:18]([C:16]3[O:17][C:13]([C:3]4[C:4]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)=[N:5][O:6][C:2]=4[CH3:1])=[N:14][N:15]=3)=[CH:26][CH:25]=2)[CH:21]=[CH:22]1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc3[nH]ccc3c2)o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc3c(ccn3C)c2)o1
Temperature: 25 °C
Reaction time: 72 h
Yield: 86.7 %

Procedure:
To a solution of 5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1H-indole (150 mg, 0.44 mmol) in DMF (2 mL) was added potassium carbonate (121 mg, 0.88 mmol) and iodomethane (0.04 ml, 0.66 mmol) and the reaction mixture was stirred for 3 d in a closed round bottomed flask at ambient temperature. The mixture was extracted with water (20 ml) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with aqueous sodium carbonate (half saturated, 20 mL) and brine (20 mL). Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20) afforded the title compound (136 mg, 87%) as a white solid. MS: m/e=357.2 [M+H]+.
Reaction SMILES: [NH3:1].C(Cl)Cl.[O:5]1[CH2:8][CH:7]([O:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18](Cl)(=[O:20])=[O:19])=[O:11])[CH2:6]1>O>[O:5]1[CH2:8][CH:7]([O:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18]([NH2:1])(=[O:20])=[O:19])=[O:11])[CH2:6]1
Reactant: O=C(OC1COC1)c1ccccc1S(=O)(=O)Cl
Reactant: N
Solvent: ClCCl
Solvent: O
Product: NS(=O)(=O)c1ccccc1C(=O)OC1COC1

Procedure:
##STR18## 2.5 g of ammonia are passed into a methylene chloride solution of 2-(oxetan-3-oxycarbonyl)phenylsulfonyl chloride (Example H6) at a temperature of 0° to 5° C. in the course of 45 minutes. By adding water to the reaction mixture, washing the organic phase with water, drying and evaporating it and crystallising the residue from a methylene chloride/diethyl ether mixture, 6.7 g of 2-(oxetan-3-oxycarbonyl)phenylsulfonamide of melting point 169° to 170° C. are obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[N-:9]=[N+:10]=[N-:11].[Na+]>CN(C=O)C.O>[N:9]([CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1)=[N+:10]=[N-:11]
Reactant: Cc1cc(CCl)no1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(CN=[N+]=[N-])no1
Yield: 73.7 %

Procedure:
3-Chloromethyl-5-methylisoxazole (500 mg, 3.8 mmol) and sodium azide (494 mg, 7.6 mmol) were heated in DMF (10 ml) at 60° C. for 6 hours. The reaction mixture was diluted with water then extracted with EtOAc. The organic extracts were dried (MgSO4) and the volatiles removed by evaporation to give the title compound (387 mg, 73%) as an oil. NMR (DMSO): 2.40 (s, 3H), 4.48 (s, 2H), 6.28 (s, 1H).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.C(=O)(O)[O-].[Na+].[SH:24][C:25]1[CH:26]=[CH:27][C:28]2[N:29]([N:31]=[N:32][N:33]=2)[N:30]=1.Cl>O.CC(C)=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([N:31]=[N:32][N:33]=4)[N:30]=3)[CH2:15][S:14][C@H:9]12
Reactant: Sc1ccc2nnnn2n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3ccc4nnnn4n3)CS[C@H]12
Temperature: 50 °C
Reaction time: 0.12 h
Yield: 65.5 %

Procedure:
2.72 g of 7-aminocephalosporanic acid was suspended in 16 ml of water and 8 ml of acetone, and a suspension of 2.1 g of sodium bicarbonate in 16 ml of water was dropwise added thereto over a period of 7 minutes time. The inside temperature of a reactor was then increased to 50° C., and a suspension of 2.3 g of 6-mercaptotetrazolo[4,5-b]pyridazine in 35 ml of acetone was added dropwise thereto over a period of time of 10 minutes. The resulting mixture was refluxed for 6 hours at a stable inside temperature of reactor of 61° C. followed by allowing the refluxed mixture to stand. The pH of the solution was 8 and thereafter, the mixture was adjusted to a pH of 3.6 with 6 N hydrochloric acid under ice cooling, in which the pH was measured by means of a pH meter and then stirred for 1 hour. The precipitated crystals were filtered and dried over phosphorus pentoxide under reduced pressure to obtain 2.39 g of the titled compound having a melting point (decomposition) of 202° to 205° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1I>>[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Brc1ccccc1I
Reactant: Sc1ccc(Cl)cc1
Product: Clc1ccc(Sc2ccccc2Br)cc1

Procedure:
Prepared from 4-chloro-benzenethiol and 1-bromo-2-iodo-benzene.
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1.[C:15]([C:19]1[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[NH:21][N:20]=1)([CH3:18])([CH3:17])[CH3:16].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([N:21]2[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:23][C:19]([C:15]([CH3:16])([CH3:18])[CH3:17])=[N:20]2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1cc(C(C)(C)C)n[nH]1
Reactant: OB(O)c1ccc(-c2nnco2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(C(C)(C)C)nn1-c1ccc(-c2nnco2)cc1
Yield: 80.8 %

Procedure:
A mixture of 4-(1,3,4-oxadiazol-2-yl)phenylboronic acid (303 mg, 1.60 mmol) and powdered 4A molecular sieves (300 mg) in CH2Cl2 (6 mL) was heated to reflux for 2 h. Ethyl 3-tert-butyl-1H-pyrazole-5-carboxylate (310 mg, 1.6 mmol), pyridine (0.13 mL, 1.6 mmol) and copper (II) acetate (290 mg, 1.6 mmol) were added and the reaction mixture was refluxed for 24 h. The reaction was filtered and the solid was washed with EtOAc (40 mL) and MeOH (40 mL). The combined filtrate and washings were concentrated in vacuo and partitioned between EtOAc (40 mL) and water (20 mL). The organics were washed with water (20 mL), satd aq NaHCO3 (20 mL), water (20 mL), and brine (20 mL), dried (Na2SO4) and concentrated in vacuo. The oily residue was chromatographed to provide ethyl 1-(4-(1,3,4-oxadiazol-2-yl)phenyl)-3-tert-butyl-1H-pyrazole-5-carboxylate (440 mg, > 100% yield) as a visocus oil contaminated with the starting ester. The mixture was used without further purification.