Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:5]1([CH2:11][CH3:12])[O:9][CH:8](C)[CH2:7][O:6]1)(=O)C.[C:13](=O)([O-])[O-:14].[K+].[K+].O1CCCC1>O>[CH2:11]([C:5]1([CH2:13][OH:14])[O:6][CH2:7][CH2:8][O:9]1)[CH3:12]
Reactant: O=C([O-])[O-]
Reactant: CCC1(OC(C)=O)OCC(C)O1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCC1(CO)OCCO1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 71.5 %

Procedure:
A mixture of methyl(2-ethyl-1,3-dioxolan-2-yl) acetate (1.39 g, 7.94 mmol), potassium carbonate (2.19 g, 15.9 mmol), tetrahydrofuran (20 ml) and water (10 ml) was stirred at room temperature for 6 hours and 50 minutes. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, which was subjected to NH silica gel pad filtration. The filtrate was concentrated under reduced pressure to obtain the title compound (0.75 g, 71.5%) as colorless oil.
Reaction SMILES: [CH3:1][Si:2]([CH3:53])([CH3:52])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:35][CH:34]3[N:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:31]([CH2:32][CH2:33]3)[CH2:30]2)[CH:9]=1.[Br:54]N1C(=O)CCC1=O>CC#N.ClCCl>[CH3:51][Si:48]([CH3:50])([CH3:49])[CH2:47][CH2:46][O:45][CH2:44][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:52])[CH3:53])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:30][CH:31]3[N:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:34]([CH2:33][CH2:32]3)[CH2:35]2)[C:9]=1[Br:54]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n1)C2
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C2CCC1CC(c1nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c1Br)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
To a mixture of tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.7 g, 2.3 mmol) in CH3CN (10 mL) and dichloromethane (10 mL) was added N-bromosuccinimide (0.45 g, 2.5 mmol) portionwise and the resulting mixture was stirred at room temperature for 0.5 h, at which time LC/MS confirmed full conversion of starting material to product. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel. Elution with EtOAc/Hexanes (0-50%) gave tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.7 g, 93%).
Reaction SMILES: C(N(CC)CC)C.C1(=O)NC(=O)CC1.Cl[C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17].[F:22][C:23]([F:34])([F:33])[C@H:24]([CH3:32])[C@@H:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[NH2:26]>C(OCC)(=O)C.C1COCC1>[CH2:19]([O:18][C:16]([NH:26][C@H:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C@H:24]([C:23]([F:34])([F:33])[F:22])[CH3:32])=[O:17])[CH:20]=[CH2:21]
Reactant: CCOC(=O)[C@@H](N)[C@@H](C)C(F)(F)F
Reactant: C=CCOC(=O)Cl
Agent: O=C1CCC(=O)N1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N[C@H](C(=O)OCC)[C@@H](C)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
9.7 ml (69.3 mmol) of triethylamine were added dropwise to a solution of 6.38 g (55.4 mmol) of succinimide in 90 ml of abs. THF. The resulting suspension was cooled to 0° C., and a solution of 6.68 g (55.4 mmol) of allyl chloroformate in 10 ml of abs. THF was added dropwise. The mixture was stirred at 0° C. for 1 h, and three portions of in total 9.2 g (about 46 mmol) of ethyl (3R)-4,4,4-trifluorovalinate (diastereomer mixture, crude product) were added. The reaction mixture was warmed to RT overnight, then diluted with ethyl acetate, washed with sat. sodium bicarbonate solution and sat. sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1→4:1). This gave 6.50 g of the target product (about 50% of theory, diastereomer ratio about 2:1).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH:3]([OH:22])[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1.[S:25](Cl)([CH3:28])(=[O:27])=[O:26].C(N(CC)CC)C.C1COCC1>O>[F:24][C:2]([F:1])([F:23])[CH:3]([O:22][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:4][O:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[CH2:10][CH2:11]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccccc1)N1CCC(OCC(O)C(F)(F)F)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OC(COC1CCN(C(=O)OCc2ccccc2)CC1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of benzyl 4-(3,3,3-trifluoro-2-hydroxypropoxy)piperidine-1-carboxylate (983 mg), mesyl chloride (0.438 mL), triethylamine (0.789 mL) and THF (10 mL) was stirred at 0° C. for 1 hr, and then at room temperature overnight. Water was added thereto, and the obtained mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.12 g).
Reaction SMILES: C(N(CC)C(C)C)(C)C.N1([C:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH:20]=2)CCCC1.[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1.[O:34]1CCOCC1>O>[CH:28]1([C:31]([CH:20]2[C:15](=[O:34])[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:19]2)=[O:32])[CH2:30][CH2:29]1
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)N1CC=C(N2CCCC2)CC1
Reactant: C1COCCO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(=O)C(C(=O)C2CC2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N,N-Diisopropylethylamine (4.14 mL, 23.8 mmol) was added to a solution of tert-butyl 4-pyrrolidin-1-yl-3,6-dihydropyridine-1(2H)-carboxylate (5.00 g, 19.8 mmol) in 1,4-dioxane (10 mL). The reaction mixture was cooled in an ice bath and treated drop-wise with a solution of cyclopropanecarbonyl chloride (2.18 mL, 23.8 mmol) in 1,4-dioxane (3 mL). The mixture was allowed to stir at room temperature for 16 hours; water (10 mL) was added, and the solution was heated at reflux for 30 minutes. After cooling, the reaction was diluted with additional water (10 mL), and extracted with diethyl ether. The combined organic layers were washed sequentially with water, with 5% aqueous citric acid solution and with saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification using silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) provided the product as a yellow oil. Yield: 4.23 g, 15.8 mmol, 80%. 1H NMR (400 MHz, CDCl3) δ 4.39 (br s, 2H), 3.59 (br dd, J=5.9, 5.9 Hz, 2H), 2.43 (br dd, J=5.7, 5.9 Hz, 2H), 1.74-1.85 (br m, 1H), 1.50 (s, 9H), 1.17-1.22 (m, 2H), 0.96-1.02 (m, 2H).
Reaction SMILES: [O:1]=[S:2]1(=[O:35])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:34])[N:14]([N:23]=[C:24]3[CH2:29][CH2:28][CH2:27][CH:26]([C:30]([F:33])([F:32])[F:31])[CH2:25]3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:35]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:34])[N:14]([NH:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH:26]([C:30]([F:33])([F:31])[F:32])[CH2:25]3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1
Reactant: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1N=C1CCCC(C(F)(F)F)C1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1NC1CCCC(C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 248A (0.103 g, 0.20 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.015 mL, 0.42 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.15 mL, 0.30 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of approximately 2-4, diluted with water, and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with dichloromethane to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.21 (m, 4 H) 1.76 (m, 2 H) 2.31 (m, 1 H) 3.11 (m, 2 H) 3.97 (m, 1 H) 5.81 (d, J=19.85 Hz, 1 H) 7.05 (m, 1 H) 7.28 (m, 2 H) 7.53 (m, 2 H) 7.66 (d, J=8.09 Hz, 1 H) 7.75 (d, J=7.72 Hz, 1 H) 8.06 (dd, J=8.09, 1.47 Hz, 1 H). MS (ESI−) m/z 505 (M−H)−.
Reaction SMILES: [OH:1][CH:2]([CH3:15])[CH2:3][C:4]([CH:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH:8]=[C:7]1[CH3:14])=[O:5].CCN(CC)CC.CN(C1C=CC=CN=1)C.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl>C(Cl)Cl>[C:32]([O:1][CH:2]([CH3:15])[CH2:3][C:4](=[O:5])[CH:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH:8]=[C:7]1[CH3:14])(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC1=CCCC(C)(C)C1C(=O)CC(C)O
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1=CCCC(C)(C)C1C(=O)CC(C)OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 65 h
Yield: 77.2 %

Procedure:
To a solution of 3-hydroxy-1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-1-butanone (4.00 g, 92% pure, 17.5 mmol), NEt3 (3.2 ml, 22.85 mmol) and dimethylamino pyridine (DMAP) (400 mg) in CH2Cl2 (100 ml) was added benzoylchloride (2.43 ml, 20.94 mmol). The reaction medium was stirred for 65 h at room temperature. Then, the mixture was acidified with 5% aqueous HCl and extracted twice with ether and washed with water, saturated aqueous NaHCO3 and then with saturated aqueous NaCl. Finally, the organic phases were dried over Na2SO4, concentrated at 50-60°/0.03 mbar) and purified by flash-chromatography over SiO2 (cyclohexane/AcOEt=97:3). 4.25 g of product were thus obtained (yield: 73%).
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:70][CH:71]([CH3:75])[C@H:72]([NH2:74])[CH3:73]>CN(C=O)C>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:74][C@H:72]([CH3:73])[CH:71]([CH3:75])[CH3:70])=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CC(C)[C@@H](C)N
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)N[C@H](C)C(C)C)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31 mg, 0.06 mmol) in DMF (0.5 mL) were added HBTU (27 mg, 0.072 mmol), triethylamine (16.9 uL, 0.12 mmol) and (2R)-3-methyl-2-butanamine (10.5 uL, 0.09 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (14 mg, 40%). LC-MS m/z 591 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH:15]([CH3:18])[CH2:16]I)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>>[O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH:15]([CH3:18])[CH2:16][N:24]2[CH2:25][CH2:26][CH2:27][CH:22]([CH2:21][O:20][CH3:19])[CH2:23]2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCc1cccnc1
Reactant: CC(CI)Cc1cccc(Oc2ccccc2)c1
Product: COCC1CCCN(CC(C)Cc2cccc(Oc3ccccc3)c2)C1
Temperature: 25 °C
Yield: 19.9 %

Procedure:
3-(m-Phenoxyphenyl)-2-methylpropyl iodide (1.0 g) was added to 3-methoxymethylpyridine (1.75 g) at room temperature, and the resultant mixture was stirred at 120° C. for 4 hours, cooled to room temperature and washed with diethyl ether three times. The resultant mixture was admixed with methanol (20 ml) and then with acetic acid (2 ml). To the resulting mixture, 5% palladium-carbon (0.5 g) was added at room temperature under nitrogen stream, and then hydrogenation was carried out under nitrogen stream. After absorption of hydrogen was completed, the catalyst was removed by filtration, and the filtrate was combined with 15% aqueous sodium hydroxide solution (50 ml) and extracted with diethyl ether. The ether layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give N-[3-(m-phenoxyphenyl)-2-methylpropyl]-3-methoxymethylpiperidine (0.2 g).
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[C:15](Cl)(=[O:24])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClC(Cl)C>[C:18]1([CH2:17][CH2:16][C:15]([NH:14][C:2]2[CH:3]=[CH:4][C:5]3[O:6][C:7]4[CH2:13][CH2:12][CH2:11][CH2:10][C:8]=4[C:9]=3[CH:1]=2)=[O:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: NC1CCc2oc3ccccc3c2C1
Solvent: CC(Cl)Cl
Product: O=C(CCc1ccccc1)Nc1ccc2oc3c(c2c1)CCCC3
Yield: 50.9 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.15 g, 0.80 mmol), hydrocinnamoyl chloride (0.12 mL, 0.80 mmol), and poly(vinylpyridine) (0.5 g) in dichloroethane (8 mL) provided 3-phenyl-N-(6,7,8,9-tetrahydrodibenzo[b,d]furan-2-yl)propanamide (0.13 g) after flash column chromatography (elution with 35% ethyl acetate-hexanes). MS (ESI) m/z 320.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH3:13][C@H:14]1[S:20][C@H:19]([C:21]([OH:23])=O)[CH2:18][C:17]2[CH:24]=[C:25]3[O:30][CH2:29][O:28][C:26]3=[CH:27][C:16]=2[C:15]1=[O:31].[NH2:32][C:33]1[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][CH:34]=1.ON1C2C=CC=CC=2N=N1>ClCCl.CN(C)C=O.O>[CH2:43]([O:42][P:38]([CH2:37][C:36]1[CH:35]=[CH:34][C:33]([NH:32][C:21]([C@@H:19]2[CH2:18][C:17]3[CH:24]=[C:25]4[O:30][CH2:29][O:28][C:26]4=[CH:27][C:16]=3[C:15](=[O:31])[C@@H:14]([CH3:13])[S:20]2)=[O:23])=[CH:47][CH:46]=1)([O:39][CH2:40][CH3:41])=[O:45])[CH3:44]
Reactant: C[C@H]1S[C@H](C(=O)O)Cc2cc3c(cc2C1=O)OCO3
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CCOP(=O)(Cc1ccc(NC(=O)[C@@H]2Cc3cc4c(cc3C(=O)[C@@H](C)S2)OCO4)cc1)OCC
Temperature: 0 °C
Reaction time: 15 h
Yield: 40.9 %

Procedure:
A solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.69 g) in dichloromethane (12 ml) was added to a solution of (2S,4R)-(+)-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxylic acid (0.84 g) and diethyl 4-aminobenzylphosphonate (0.73 g) in N,N-dimethylformamide (DMF) (12 ml) at 0° C., followed by the addition of 1-hydroxybenzotriazole (HOBt) (0.51 g). This mixture was stirred at 0° C. for 1 hour and at room temperature for 15 hours, after which it was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), after which the solvent was distilled off; the residual crystals were collected by filtration, followed by recrystallization from ethyl acetate-hexane and successively from methanol-hexane to yield (2S, 4R)-(+)-N-[4-(diethoxyphosphorylmethyl)phenyl]-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxamide (0.62 g, 41%). Colorless prisms. Melting point 183-184° C. Optical rotation [α]D (23° C.) +190.5° (c=0.50, CHCl3).
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.C(=O)([O-])O.[Na+].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>O1CCCC1>[OH:8][C:3]1[CH:4]=[CH:5][C:6]([NH:7][C:15](=[O:16])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:1][CH:2]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(O)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.8 %

Procedure:
To a suspension of p-aminophenol (7.0 g, 63.9 mmol) in tetrahydrofuran (105 mL) was added saturated aqueous sodium hydrogen carbonate (70 mL), and benzyl chloroformate (12.0 g, 70.3 mmol) was added dropwise at 0° C. After stirring at room temperature for 16 hr, the reaction mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with saturated brine (100 mL) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was washed with hexane/ethyl acetate (=4/1) and collected by filtration to give the title compound (8.2 g, 53%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[CH:5][C:4]([C:8]([NH:10][C@@:11]2([C:16]([OH:18])=O)[CH2:15][CH2:14][O:13][CH2:12]2)=[O:9])=[CH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:41][C:42]1[CH:49]=[C:48]([NH:50][C:51]2[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][C:52]=2[C:59]([F:62])([F:61])[F:60])[CH:47]=[CH:46][C:43]=1[CH2:44][NH2:45]>O1CCCC1.CN(C=O)C.C(N(CC)CC)C>[F:41][C:42]1[CH:49]=[C:48]([NH:50][C:51]2[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][C:52]=2[C:59]([F:60])([F:61])[F:62])[CH:47]=[CH:46][C:43]=1[CH2:44][NH:45][C:16]([C@:11]1([NH:10][C:8]([C:4]2[CH:5]=[N:6][NH:7][C:2](=[O:1])[CH:3]=2)=[O:9])[CH2:15][CH2:14][O:13][CH2:12]1)=[O:18]
Reactant: O=C(N[C@@]1(C(=O)O)CCOC1)c1cn[nH]c(=O)c1
Reactant: COc1ccc(Nc2ccc(CN)c(F)c2)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(Nc2ccc(CNC(=O)[C@]3(NC(=O)c4cn[nH]c(=O)c4)CCOC3)c(F)c2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19 %

Procedure:
(S)-3-[(6-oxo-1,6-dihydro-pyridazine-4-carbonyl)-amino]-tetrahydrofuran-3-carboxylic acid (0.55 mmol) was dissolved in a mixture of 30 mL tetrahydrofuran, 4 mL DMF and 0.15 mL triethylamine, then TBTU (0.19 g, 0.58 mmol) was added and the mixture was stirred for 30 minutes at ambient temperature. Then 2-fluoro-4-(4-methoxy-2-trifluoromethyl-phenylamino)-benzylamine (0.17 g, 0.55 mMol, from 1b) was added and the mixture was stirred for a further two hours. As there was still some unreacted amine present, another 10 mg of the acid and 20 mg TBTU were added and the mixture was stirred further overnight. Then the solvents were evaporated off and the residue was chromatographed on silica gel (eluant: dichloromethane/methanol/ammonia: 95/5/0.5). In this way the product was obtained in a yield of 19% of theory.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)N(S(C2C=CC=CC=2)(=O)=O)C=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH3:34][S:35]SC.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO.O>[CH2:1]([N:8]1[C:18]2[C:19](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:11]=[C:9]1[S:35][CH3:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSSC
Reactant: O=C(NCc1ccccc1)c1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CSc1cc2ccccc2n1Cc1ccccc1
Temperature: -20 °C
Yield: 100.5 %

Procedure:
A solution of the above N-benzyl-1-(phenylsulfonyl)indole -3-carboxamide [XXIV: R8 =CH2Ph] (4.2 g, 11 mmol) in dry THF (200 mL) was treated at -78° C. with a solution of 2.5M n-BuLi in hexanes (9.1 mL, 23 mmol), and the stirred mixture was allowed to warm to -20° C. for 15 minutes, before being recooled to -78° C., when it was treated with methyldisulfide (2.5 mL, 28 mmol). The mixture was allowed to warm to 20° C., then quenched with water (25 mL). Volatiles were removed under reduced pressure, and the residue was extracted with EtOAc. Workup of the organic layer gave a crude product. This was dissolved in MeOH (300 mL), mixed with a solution of K2CO3 (6.9 g, 50 mmol) in water (125 mL), and heated under gentle reflux under N2 for 2 hours to ensure complete hydrolysis of the phenylsulfonyl group (J. Org. Chem. 1985;50:5451-5457). MeOH was removed under reduced pressure, and the residue was diluted with water and extracted with CH2Cl2. Chromatography of the resulting oil on Al2O3 (eluting with CH2Cl2) gave N-benzyl-2-(methylthio)indole -3-carboxalnide [XXV: R8 =CH2Ph] (2.8 g, 88% yield) as an oil.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:53]/[O:54][C@H:55]([C:57]([O:59][CH:60]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[O:58])[CH3:56])/[C:27]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37]Cl)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([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)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:73][C:74]1[S:75][C:76]2[C:77]([N:82]=1)=[N:78][CH:79]=[CH:80][CH:81]=2.SC1SC2C=CN=CC=2N=1>>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:53]/[O:54][C@H:55]([C:57]([O:59][CH:60]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[O:58])[CH3:56])/[C:27]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37][S:73][C:74]4[S:75][C:76]5[C:77]([N:82]=4)=[N:78][CH:79]=[CH:80][CH:81]=5)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([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)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(NC(=O)/C(=N\O[C@@H](C)C(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Reactant: Sc1nc2ncccc2s1
Agent: Sc1nc2cnccc2s1
Product: COc1ccc(COC(=O)C2=C(CSc3nc4ncccc4s3)CS[C@@H]3C(NC(=O)/C(=N\O[C@@H](C)C(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Yield: 62.4 %

Procedure:
Using 305 mg of p-methoxybenzyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-{(S)-1-diphenylmethoxycarbonylethoxyimino}acetamido]-3-chloromethyl-3-cephem-4-carboxylate and 60 mg of 2-mercaptothiazolo[4,5-b]pyridine in place of p-methoxybenzyl 7-{(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido}-3-chloromethyl-3-cephem-4-carboxylate and 2-mercaptothiazolo[4,5-c]pyridine, respectively, the reaction and purification were carried out in the same manner as in Example 1(a) to obtain 215 mg of the title compound in a yield of 62%.