Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.CCCCCC.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1.[CH3:27][C:28]([CH3:30])=[O:29].[NH4+].[Cl-]>C1COCC1>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([C:28]([OH:29])([CH3:30])[CH3:27])[CH:21]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CC(C)(O)c1cc(Br)ccc1F
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropyl amine (57.3 ml, 402 mmol) in THF (500 ml) was added under argon a 1.6 M solution of nBuLi in hexane (260 ml, 416 mmol) below −50° C. After stirring for 30 min at −75° C., 4-bromo-1-fluoro benzene (31.1 ml, 277 mmol) was added while keeping the temperature below −70° C. After stirring for 2 h at −75° C., acetone (41.2 ml, 554 mmol) was added below −65° C. and the reaction mixture was stirred for 1 h at −75° C., warmed up to −50° C. and poured onto 10% aqueous NH4Cl solution. The mixture was extracted with TBME, organic phases were washed with aqueous KHSO4 solution, saturated NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated. The crude product was crystallized from hexane to provide the title compound as white crystals: TLC (hexane-EtOAc 3:1): Rf=0.45; HPLC RtH5=1.045 min; 1H NMR (360 MHz, CDCl3): δ 7.74 (dd, 1H), 7.36 (m, 1H), 6.93 (dd, 1H), 2.04 (d, 1H), 1.63 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Li]C.[Li]CCCC.CN(CCN(C)C)C.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([CH:41]=[O:42])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>C1COCC1>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([CH:41]([OH:42])[C:2]2[CH:7]=[CH:6][C:5]([S:8](=[O:10])(=[O:9])[NH:11][CH3:12])=[CH:4][CH:3]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CNS(=O)(=O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CN(C)CCN(C)C
Agent: [Li]C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(C(O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 40.4 %

Procedure:
To a solution of 4-bromo-N-methyl-benzenesulfonamide (Marvel; Smith, J. Am. Chem. Soc., 45, 1923, 2697) (1.00 g, 4.00 mmol) in THF (35 mL) at −78° C. was added MeLi (4.00 mmol) and the solution was stirred at −78° C. for 15 minutes. n-BuLi (1.95M in hexanes, 2.05 mL, 4.00 mmol) was then added. After the solution was stirred at −78° C. for 45 minutes, TMEDA (1.20 mL, 8.00 mmol) was added followed by a solution of 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (4.76 g, 22.30 mmol) in THF (5 mL), and the mixture was stirred at −78° C. for 1 hour. Work-up and purification gave 4-[hydroxy-(4-methylsulfamoyl-phenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (622 mg, 41%) as a white foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:11][CH2:12][CH3:13].[Li]C(C)(C)C.[C:19](=[O:21])=[O:20]>C(OCC)C.CCCCC>[CH2:11]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:19]([OH:21])=[O:20])[CH:3]=2)[NH:7][N:6]=1)[CH2:12][CH3:13]
Reactant: O=C=O
Reactant: CCCc1n[nH]c2ccc(Br)cc12
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: CCCc1n[nH]c2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.8 %

Procedure:
To 5-bromo-3-propyl-1H-indazole (1.00 g, 4.18 mmol) in diethyl ether (60 mL), 1.3 M t-BuLi (10.9 mL, 14.2 mmol) in pentane was added slowly at −78° C. under N2 atm. After 1 hour, CO2 gas was passed through the reaction mixture at −78° C. for 1 hour and allowed to slowly warm to room temperature. The reaction mixture was quenched with saturated NH4Cl solution and the ether layer was separated. The aqueous layer was acidified with 2 N HCl and extracted with ethyl acetate to afford the title compound (350 mg, 40.8%) as an off white solid. 1H NMR (DMSO-d6): δ 11.8-13.0 (br, 1H), 8.4 (s, 1H), 7.9 (d, 1H), 7.5 (d, 1H), 3.0 (q, 2H), 1.8 (q, 2H), 0.9 (t, 3H). mp: 296-299° C.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[C:12](O)([CH3:15])([CH3:14])[CH3:13].[O-]S([O-])(=O)=O.[Mg+2].S(=O)(=O)(O)O>ClCCl>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:8])=[CH:5][CH:4]=1
Reactant: CC(C)(C)O
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Reaction time: 336 h
Yield: 39.5 %

Procedure:
This compound was prepared from 4-(bromomethyl)benzoic acid (2.15 g; 10.0 mmol), t-butyl alcohol (4.8 mL; 50 mmol), anhydrous MgSO4 (4.8 g; 40 mmol), and concentrated sulphuric acid in dichloromethane (40 mL) as described in Example 6a. After 14 days, the mixture was worked up as described in Example 6a. 1.07 g (39%) product was obtained (white solid). The product was used in 7b without further purification.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[CH:13]1([NH2:16])[CH2:15][CH2:14]1.O>CN1C(=O)CCC1>[CH:13]1([NH:16][C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([S:11][CH3:12])[N:3]=2)[CH2:15][CH2:14]1
Reactant: CSc1nc(Cl)n2nccc2n1
Reactant: NC1CC1
Solvent: CN1CCCC1=O
Solvent: O
Product: CSc1nc(NC2CC2)n2nccc2n1
Yield: 78.8 %

Procedure:
4-Chloro-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine (1.0 eq, 6.26 g, 31.19 mmol) was suspended in anhydrous NMP (50 ml). Cyclopropylamine (1.5 eq, 3.2 ml, 46.26 mmol) was added through syringe dropwise. Internal temperature rose to 47° C. The mixture was stirred without any external cooling for one hour. An additional amount of cypropylamine (1 ml) was added and the mixture stirred for another 1.5 hours. The mixture was slowly poured into water (500 ml) under stirring. The resulting solid was filtered, washed with water and dried in a vacuum oven to give N-cyclopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-amine as a tan solid (5.44 g, 79% yield). LCMS (ES):>95% pure, m/z 222 [M+H]+.
Reaction SMILES: [Ce:1].[C:2](=[O:5])([O-:4])[O-:3]>>[C:2](=[O:3])([O-:5])[O-:4].[Ce+3:1].[C:2](=[O:3])([O-:5])[O-:4].[C:2](=[O:3])([O-:5])[O-:4].[Ce+3:1]
Reactant: [Ce]
Agent: O=C([O-])[O-]
Product: [Ce+3]

Procedure:
According to the present invention, the cerium precursor solution is mixed with the carbonate precursor solution and cerium carbonate powder is obtained from the mixture via precipitation.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[C:13]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[C:14]([CH2:17]Br)[CH2:15][S:16][C@H:11]12)=[O:8].CN(C)P(N(C)C)(N(C)C)=O.[OH:48][CH2:49][CH2:50][CH2:51][C:52]([O-:54])=[O:53].[Na+]>C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[CH:13]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[C:14]([CH2:17][O:54][C:52](=[O:53])[CH2:51][CH2:50][CH2:49][OH:48])=[CH:15][S:16][C@H:11]12)=[O:8]
Reactant: O=C([O-])CCCO
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CBr)CS[C@H]12
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(COC(=O)CCCO)=CS[C@H]12
Reaction time: 1.5 h

Procedure:
To a solution of 2.24 g. (3.8 mmol) of benzhydryl 7-(2-thienylacetamido)-3-bromomethyl-3-cephem-4-carboxylate in 20 ml. of hexamethylphosphoramide (HMPA) at 0° C. under nitrogen was added a suspension of 0.530 g. (4.2 mmol) of sodium 4-hydroxybutanoate in 25 ml. of HMPA. After stirring 1.5 hours, ethyl acetate was added, and the resulting solution was washed with water (5X) and brine and dried over anhydrous MgSO4. Evaporation in vacuo to dryness provided 2.12 g. of product which was combined with that of an identical reaction ran on a 1 mmol scale. The combined products were chromatographed on a silica gel column using a cyclohexane:ethyl acetate (1:2) eluant to provide 293 mg. of a mixture of the title product and the corresponding 3-cephem compound. For the title product: nmr (CDCl3) δ1.7-2.6 ##STR26## 3.55 (m, 2, CH2OH), 3.83 (s, 2, side chain CH2), 4.63 (bs, 1, --CH2OH), 5.0 (s, 1, C4 --H), 5.23 (d, 1, J = 4 Hz, C6 --H), 5.58 (dd, 1, J = 4 and 8 Hz, C7 --H), 6.42 (bs, 1, C2 --H), 6.95 (s, 1, ester CH), and 7.36 (m, 13, thienyl + ArH).
Reaction SMILES: [N+]([C:4]([CH3:17])=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:8][CH:7]=1)([O-])=O.C[OH:19].O.Cl>[Fe].C(Cl)Cl>[N:12]1([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][C:4](=[O:19])[CH3:17])=[CH:7][CH:8]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: CC(=Cc1ccc(-n2ccnc2)cc1)[N+](=O)[O-]
Reactant: CO
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(=O)Cc1ccc(-n2ccnc2)cc1
Temperature: 25 °C

Procedure:
A 5.0 liter 3-neck flask fitted with a condenser, addition funnel, and mechanical stirrer is charged with a mixture of 218.4 g (0.954 mole) of 1-[4-(2-nitro-1-propenyl)phenyl-1H-imidazole, 449 g (8.04 mole) of iron powder (325 mesh), 6.4 g of FeCl3 6H2O, 350 ml of methanol and 760 ml of water. The mixture is heated to reflux with stirring and 450 ml of concentrated hydrochloric acid is added dropwise over a period of 2.5 hours. Refluxing is continued for two to three hours. The reaction mixture is cooled to room temperature, 1.9 liter of CH2Cl2 was added, and the mixture stirred rapidly for one hour. This is filtered, the inorganic solid is washed three times with 500 ml portions of CH2Cl2, and the layers separated. The CH2Cl2 layer is dried over MgSO4, then filtered through a bed of silica gel (600 g, 70-230 mesh), which is washed with 5 liters of CH2Cl2 and then with 13 liters of 10% methanol in methylene chloride. Evaporation of the solvent gave 126.7 g of a brown oil which crystallized on standing. The product is purified via the sodium bisulfate addition product to give a product having a mp of 71.5°-72.5° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH-].[K+].C1OCCOCCOCCOCCOCCOC1.[C:30]([C:37]1[NH:38]C=CN=1)([C:32]1NC=C[N:36]=1)=O.C(O)(=O)C1C=CC=CC=1.C(NCC1C=CC=CC=1)C1C=CC2OCOC=2C=1>O1CCCC1>[N:38]1([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH:37]=[CH:30][CH:32]=[N:36]1
Reactant: N#Cc1ccccc1F
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C(O)c1ccccc1
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccccc1-n1cccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 20 mmol of 2-fluorobezonitrile and 40 mmol of pyrrazole is mixed together in dimethylformaide with 1 equivalent of potassium hydroxide and a catalytic amount of 18-crown-6. The mixture is stirred at room temperature overnight, quenched with water and ethyl acetate and extracted with ethyl acetate. The organic extract is washed repeatedly with 1 N NaOH solution. The organic layer is then diluted with ether and washed with 1N HCl solution, dried and concentrated. 1H NMR (CDCl3) 6.55 (t, J=2 Hz, 1H), 7.42 (M, 1H), 7.65–7.82 m, 4H), 8.15 (d, J=1 Hz, 1H). 2-Pyrazol-1-yl-benzoic acid. Compound 178. A solution of compound 177 in conc HCl is refluxed overnight, cooled and concentrated. The product is precipitated by addition of 1 N NaOH until pH of 5–6, filtered and dried. 1H (CDCl3) 6.52 (t, J=3 Hz, 1H), 7.40 (d, J=8 Hz, 1H), 7.50 (t, J=8 Hz, 1H) 7.62 (t, J=8 hz, 1H), 7.81 (m, 2H), 8.12 (d, J=8 Hz, 1H). N-Benzo[1,3]dioxol-5-ylmethyl-N-benzyl-2-pyrazol-1-yl-benzamide, Compound 179. 1.1 equiv of carbonyl diimidazole is added to a solution of benzoic acid 178 (200 mg) in tetrahydrofuran (5 mL); the reaction is stirred at room temperature for 3 h. After this time N-piperonyl-N-benzylamine (0.25 g) is added in one portion. After 30 min, the reaction is filtered, diluted with ether and washed with water. The organic layer is dried (Na2SO4) and purified over column chromatography to provide the desired product (390 mg). The proton NMR displays a typically doubled pattern. 1H (CDCl3) 3.83 and 4.32 (two doublets, J=16 Hz, 1H), 3.91 (two doublets, J=8 Hz, 1H), 4.18 two doublets (J=6 Hz, 1H), 5.0 and 5.1 (two doublets, J=14 Hz, 1H), 5.93 and 5.98 (s and doublet, J=2 Hz, 2H, OCH2O), 6.35–6.40 (m, 2H), 6.51 (d, J=4 Hz, 0.5H), 6.4 (m, 1.5H), 7.0–7.88 m, 15H). LC-MS 412.3
Reaction SMILES: [ClH:1].[C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3]>C(O)C.[Pd]>[ClH:1].[C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][CH:6]=1)(=[NH:3])[NH2:4]
Reactant: CCOC(=O)C=CC=Cc1ccc(C(=N)N)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CCCCc1ccc(C(=N)N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.7 %

Procedure:
A mixture of ethyl 5-(4-amidinophenyl)-2,4-pentadienoate hydrochloride (20.00 g) and 10% Pd-C (5.00 g) in ethanol (500 ml) was stirred under H2 gas at room temperature for 3 hours. After filtration, the filtrate was evaporated in vacuo. The resulting precipitate was washed with diethyl ether to give ethyl 5-(4-amidinophenyl)pentanoate hydrochloride (19.42 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([NH:16][C:17]([C:19]1[C:20]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:18])[CH:10]=2)=[O:5])C.O.[OH-].[Li+].O1CCCC1.Cl>O.CO>[F:34][C:31]([F:32])([F:33])[C:28]1[CH:27]=[CH:26][C:25]([C:20]2[C:19]([C:17]([NH:16][C:11]3[CH:10]=[C:9]4[C:14]([CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]4)=[CH:13][CH:12]=3)=[O:18])=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 93.3 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid ethyl ester (10.28 g, 22.1 mmol) and lithium hydroxide monohydrate (1.86 g, 44.3 mmol) were added to 125 ml of a solution consisting of a 3:1:1 volume ratio of tetrahydrofuran, methanol, and water. After stirring for 3.5 h at ambient temperature, the mixture was concentrated under vacuum to yield an aqueous emulsion of a yellow oil. More water (100 ml) was added and with efficient stirring, the aqueous mixture was made acidic (pH 2) with a 1 N aqueous hydrochloric acid solution. Collection of the resulting solid by vacuum filtration, maintaining the flow of air overnight to dry the solid, and drying under vacuum afforded 9.0 g of the title compound as a yellow powder.
Reaction SMILES: [Si](CO[C:20]1([CH2:23][O:24][C:25]2[C:30]([O:31][CH3:32])=[C:29]([O:33][CH3:34])[CH:28]=[CH:27][C:26]=2[C:35]2[CH:43]=[CH:42][CH:41]=[C:40]3[C:36]=2[CH2:37][CH2:38][C:39]3=[O:44])[CH2:22][CH2:21]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:66]1CCC[CH2:67]1>>[OH:66][CH2:67][C:20]1([CH2:23][O:24][C:25]2[C:30]([O:31][CH3:32])=[C:29]([O:33][CH3:34])[CH:28]=[CH:27][C:26]=2[C:35]2[CH:43]=[CH:42][CH:41]=[C:40]3[C:36]=2[CH2:37][CH2:38][C:39]3=[O:44])[CH2:22][CH2:21]1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(OC[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC2)c1OC
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CO)CC2)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirring solution of 4-(2-((1-((tert-butyldiphenylsilyl)methoxy)cyclopropyl)methoxy)-3,4-dimethoxyphenyl)-2,3-dihydro-1H-inden-1-one (5 g, 6.25 mmol) in tetrahydrofuran, was added tetrabutylammonium fluoride trihydrate (33 mL, 33 mmol) and the resultant reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with water and extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification was done by column chromatography (silica gel, 0-40% ethyl acetate in pet ether) to afford the title compound as a yellow solid.
Reaction SMILES: [Li]CCCC.[NH:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.N#N.Cl[Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16]>C1COCC1.O>[CH:15]([Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[N:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1)([CH3:17])[CH3:16]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: c1cc[nH]c1
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1cccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 110.1 %

Procedure:
A solution n-BuLi in THF (2.5 M, 19.6 mL, 49 mmol) was added to a stirred solution of pyrrole (3 g, 44.7 mmol) in anhydrous THF (20 mL) at −78° C. in an N2 atmosphere. Then the mixture was warmed to room temperature and stirred at this temperature for 10 min. The mixture was cooled again to −78° C., and chlorotriisopropylsilane (10.5 g, 44.7 mmol) was added dropwisely with stirring. Then the mixture was warmed to room temperature and stirred for additional 30 min., diluted with water (200 mL), extracted with ether (200 mL). The organic layer was washed with water (2×100 mL) and brine (100 mL), dried over Na2SO4, concentrated to give crude 1-(triisopropylsilyl)-1H-pyrrole (11 g, 100%) as a oil. LCMS: 224 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 0.98 (m, 18H), 1.40 (m 3H), 6.20 (m, 2H), 6.80 (m, 2H).
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH:25]=[CH2:26])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H][H]>O1CCCC1>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH2:26][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:23])=[CH:27][CH:28]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=COC(=O)c1ccc(NCCCCCCCCCCCCCCCC)cc1
Reactant: [H][H]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCCC(=O)OCC)cc1

Procedure:
A solution of 4 g. (8.7 m moles) 2-ethoxycarbonyl)vinyl 4-(hexadecylamino)benzoate and 400 mg. 10% Pd(C) in 100 ml. tetrahydrofuran is hydrogenated at 50 psi until hydrogen uptake stops. The catalyst is filtered, the solution is evaporated, and the residue is crystallized from acetonitrile to yield 2-(ethoxycarbonyl)ethyl 4-(hexadecylamino)benzoate.
Reaction SMILES: O[CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(=O)C.[NH4+:24].C(O)(=O)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[NH2:24][CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1C(=CO)C(c2ccccc2)Oc2ccccc21
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: NC=C1C(=O)c2ccccc2OC1c1ccccc1

Procedure:
A solution containing 30.3 g 3-hydroxymethylidene-flavanone, 18.5 g ammonium acetate, and 6 ml glacial acetic acid in 300 ml toluene is refluxed for one hour. After cooling the solution is neutralized with a saturated sodium bicarbonate aqueous solution. The precipitate is filtered off, then dissolved in methylene chloride, washed with water, dried and evaporated. Pure 3-aminomethylidene-flavanone is obtained as pale yellow crystals; m.p. 149°-152° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.Br[C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][C:16]=1[F:17])[NH2:13]>>[F:17][C:16]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=1[C:3]1[CH:4]=[CH:5][O:1][CH:2]=1
Reactant: OB(O)c1ccoc1
Reactant: Nc1ccc(F)c(Br)c1
Product: Nc1ccc(F)c(-c2ccoc2)c1
Yield: 65 %

Procedure:
Using the same method as in Example 19-(ii), 3-furanboronic acid was reacted with the 3-bromo 4-fluoro-aniline to give 4-fluoro-3-(furan-3-yl)aniline (yield: 65%).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.CCCCCC.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](OC)=[O:27])=[CH:22][CH:21]=1>C1COCC1.C(O)(=O)C.O>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:27])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(C)cc1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: COP(=O)(CC(=O)c1ccc(C)cc1)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
To a stirred solution of dimethyl methylphosphonate (10.23 g, 82.5 mmol) in 100 ml of anhydrous THF at -78° C. was added dropwise a solution of n-butyl lithium in hexane (1.58N, 52 ml, 82.5 mmol) under argon atmosphere, and the mixture was stirred for 30 minutes. Subsequently, methyl p-methylphenylcarboxylate (5.0 g, 33 mmol, commercially available product) in 10 ml of anhydrous THF was added dropwise and the mixture was stirred for 30 minutes. This reaction mixture was allowed to warm to 0° C., diluted with 5 ml of acetic acid and 10 ml of water and concentrated. 30 ml of water was added to the residue, and the mixture was extracted with ethyl acetate (50 ml×2). The combined ethyl acetate layers were washed with water (30 ml×1) and brine (30 ml×1), dried over anhydrous sodium sulfate, and concentrated. The residue was distilled under reduced pressure to give a colorless transparent oil of dimethyl 2-p-methylphenyl-2-oxo-ethylphosphonate (7.2 g, 29.8 mmol, yield 90.2%, b.p. 150°-153° C./0.27 mmHg), which was assigned the structure by the following data:
Reaction SMILES: [N:1]([CH:4]([CH:27]1[O:31][C:30](=[O:32])[CH:29]([CH:33]([CH3:35])[CH3:34])[CH2:28]1)[CH2:5][CH:6]([CH:10]([C:12]1[CH:13]=[C:14]([Cl:26])[C:15]2[N:16]([C:18]([CH2:21][CH2:22][CH2:23][O:24][CH3:25])=[N:19][CH:20]=2)[CH:17]=1)[OH:11])[CH:7]([CH3:9])[CH3:8])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCN(C(C)C)C(C)C.[C:64](OC([O-])=O)([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65]>O1CCCC1.COC(C)(C)C.O>[Cl:26][C:14]1[C:15]2[N:16]([C:18]([CH2:21][CH2:22][CH2:23][O:24][CH3:25])=[N:19][CH:20]=2)[CH:17]=[C:12]([CH:10]([OH:11])[CH:6]([CH:7]([CH3:9])[CH3:8])[CH2:5][CH:4]([NH:1][C:64](=[O:65])[O:66][C:67]([CH3:70])([CH3:69])[CH3:68])[CH:27]2[CH2:28][CH:29]([CH:33]([CH3:35])[CH3:34])[C:30](=[O:32])[O:31]2)[CH:13]=1
Reactant: COCCCc1ncc2c(Cl)cc(C(O)C(CC(N=[N+]=[N-])C3CC(C(C)C)C(=O)O3)C(C)C)cn12
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCCCc1ncc2c(Cl)cc(C(O)C(CC(NC(=O)OC(C)(C)C)C3CC(C(C)C)C(=O)O3)C(C)C)cn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2.72 mmol of 5-(1-azido-3-{[8-chloro-3-(3-methoxypropyl)imidazo[1,5-a]pyridin-6-yl]hydroxymethyl}-4-methylpentyl)-3-isopropyldihydrofuran-2-one in 15 ml of tetrahydrofuran is mixed with 3.264 mmol of triphenylphosphine and 0.064 ml of water. The reaction solution is stirred at room temperature for 16 hours. Water (0.40 ml) is added, and the reaction mixture is then heated to reflux for 8 hours. The reaction mixture is cooled to room temperature, diluted with tert-butyl methyl ether (100 Ml) and washed with brine (50 ml), dried with sodium sulphate and evaporated. The residue is dissolved in 20 ml of tetrahydrofuran, mixed with 4.08 mmol of Hünig's base and 3.264 mmol of tert-butyl dicarbonate and left to stand at room temperature for 12 hours. The reaction solution is diluted with tert-butyl methyl ether (50 ml) and washed with 0.1M HCl and brine, dried with sodium sulphate and evaporated. The title compound is identified by means of the Rf from the residue by flash chromatography (SiO2 60 F).
Reaction SMILES: [O:1]1[C:5]2[C:6]([C:10](OC)=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[O:1]1[C:5]2[C:6]([CH2:10][OH:11])=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: COC(=O)c1cccc2ccoc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cccc2ccoc12
Yield: 90.7 %

Procedure:
A solution of methyl benzofuran-7-carboxylate (5.34 g, 30 mmol) was added to a suspension of LAH (2.31 g, 61 mmol) in THF and then heated to reflux for 30 min. The reaction was quenched with ethyl acetate and water. The mixture was made acidic with 12 N HCl until all the precipitate dissolved. The ethyl acetate layer was separated, washed with water, dried with brine, and concentrated in vacuo to give a yellow oil (4.03 g, 91%).