Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:21]1[N:22]=[C:23]([NH2:39])[C:24]2[N:25]=[CH:26][N:27]([C:37]=2[N:38]=1)[C@@H:28]1[O:36][C@H:33]([CH2:34][OH:35])[C@@H:31]([OH:32])[C@H:29]1[OH:30]>>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][C:10]([N:7]2[CH2:8][CH2:9][CH:4]([CH2:1][C:2]#[C:3][C:21]3[N:22]=[C:23]([NH2:39])[C:24]4[N:25]=[CH:26][N:27]([C:37]=4[N:38]=3)[C@@H:28]3[O:36][C@H:33]([CH2:34][OH:35])[C@@H:31]([OH:32])[C@H:29]3[OH:30])[CH2:5][CH2:6]2)=[O:11])=[CH:18][CH:17]=1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C#CCC1CCN(C(=O)Oc2ccc(Cl)cc2)CC1
Product: Nc1nc(C#CCC2CCN(C(=O)Oc3ccc(Cl)cc3)CC2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
Batch: AB-10-015. 4-chlorophenyl 4-(prop-2-ynyl)piperidine-1-carboxylate, batch JR28-107 (0.624 g, 2.247 mmol) was added to a solution of 2-iodoadenosine (0.656 g, 1.669 mmol) according to general procedure 2. Yield: 0.445 g, 49%. 1H NMR (CD3OD) δ 8.30 (s, 1H), 7.37-7.07 (2×m, 4H), 5.93 (d, 1H), 4.71 (m, 2H), 4.31-4.17 (2×m, 3H), 3.91-3.75 (2×d, 2H), 3.07-2.93 (2×bt, 4H), 2.48 (d, 5H), 1.97-1.40 (2×m, 5H). m/z MH+=543.09. HPLC rt=7.3 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[C:17]1([C:23]#[CH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([C:9]#[N:10])=[C:6]([C:24]#[C:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:7]=1
Reactant: C#Cc1ccccc1
Reactant: N#Cc1c(Cl)nc(N)nc1-c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: N#Cc1c(C#Cc2ccccc2)nc(N)nc1-c1ccccc1
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
Following the method of Thorand and Krause (J. Org Chem. 1998, 63, 8551), to a stirred solution of 500 mg (2.17 mmol) 2-amino-4-chloro-6-phenyl-pyrimidine-5-carbonitrile in 8.5 ml dry degassed THF under argon at room temperature were added 300 mg (0.43 mmol) bis(triphenylphosphine)palladium(II) chloride, 14 mg (0.05 mmol) triphenylphosphine, 0.36 ml (3.28 mmol) phenylacetylene and 0.45 ml (3.23 mmol) triethylamine. Stirring was continued for 30 minutes then 4.0 mg (0.02 mmol) copper(I) iodide was added and the reaction mixture stirred for an additional 16 hours at room temperature. The reaction mixture was then concentrated in vacuo. Chromatography (1/2 ethyl acetate/hexane) afforded 350 mg (55%) 2-amino-4-phenyl-6-phenylethynyl-pyrimidine-5-carbonitrile as a light yellow crystalline solid. EI-MS m/e (%): 296 (M+, 100), 270 (80).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[N:8]([Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[C:7](=[O:16])[C@H:6]1[NH2:17])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[C:1]([O:4][C@@H:5]1[N:8]([Si:9]([C:12]([CH3:13])([CH3:15])[CH3:14])([CH3:10])[CH3:11])[C:7](=[O:16])[C@H:6]1[NH:17][C:32](=[O:33])[CH2:31][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@H](N)C(=O)N1[Si](C)(C)C(C)(C)C
Reactant: O=C(Cl)Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H]1[C@H](NC(=O)Cc2ccccc2)C(=O)N1[Si](C)(C)C(C)(C)C
Yield: 90.6 %

Procedure:
To a solution of 0.387 g of (3S,4S)-4-acetoxy-3-amino-1-t-butyldimethylsilyl-2-oxoazetidine in 20 ml of THF is added 0.24 of triethylamine under ice-cooling, and then, a solution of 0.32 g of phenylacetyl chloride in THF is added dropwise. The mixture is stirred under ice-cooling for one hour, the insolubles are filtered off, and the filtrate is concentrated under reduced pressure. Purifying the residue on a silica gel column (ethyl acetate:n-hexane=1:2) yields 0.511 g of (3S,4S)-4-acetoxy-1-t-butyldimethylsilyl-3-phenylacetamido-2-oxoazetidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([CH3:13])=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([S:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:29])=[O:28])[C:11]([CH3:13])=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2)[nH]c1C
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccc(F)cc2)n(S(=O)(=O)c2ccccc2)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.5 %

Procedure:
Ethyl 5-(4-fluorophenyl)-2-methyl-1H-pyrrole-3-carboxylate (4.95 g) was dissolved in absolute tetrahydrofuran (50 mL), and sodium hydride (60% in oil, 1.20 g) was added under ice-cooling. The mixture was stirred at room temperature for 15 min, and benzenesulfonyl chloride (5.30 g) was added dropwise. The reaction mixture was stirred at room temperature for 18 hr, ice water was added and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:2) to give the title compound as a solid (yield 2.75 g, 35%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([NH:13][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[C:15]([F:18])([F:17])[F:16])=[O:12])=[CH:5][C:4]=1[C:29]([F:32])([F:31])[F:30])#[N:2].[Cl-].[OH:34][NH3+:35].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[OH:34][N:35]=[C:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([NH:13][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=2)[C:15]([F:16])([F:17])[F:18])=[O:12])=[CH:5][C:4]=1[C:29]([F:30])([F:32])[F:31])[NH2:2]
Reactant: [NH3+]O
Reactant: N#Cc1ccc(/C=C/C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=NO)c1ccc(/C=C/C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc1C(F)(F)F

Procedure:
1.17 g (2.51 mmol) of (2E)-3-[4-cyano-3-(trifluoromethyl)phenyl]-N-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}acrylamide from Example Ia-46 were initially charged in a mixture of 11.7 ml of ethanol and 2.9 ml of water and admixed with 209.6 mg (3.01 mmol) of hydroxylammonium chloride and 399.5 mg (3.77 mmol) of sodium carbonate. The reaction mixture was heated under reflux for 18 hours and then admixed with water. After extracting repeatedly with ethyl acetate, the combined organic phases were dried over magnesium sulphate, the solvent was distilled off under reduced pressure and the residue was chromatographed using silica gel with cyclohexane/ethyl acetate as the eluent (gradient from 0% ethyl acetate to 100% ethyl acetate).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].[CH3:16][O:17][C:18](=[O:47])[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:24]=[CH:23][C:22]=1[O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]OS(C)(=O)=O>>[CH3:16][O:17][C:18](=[O:47])[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:24]=[CH:23][C:22]=1[O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][O:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15]
Reactant: COC(=O)CCCCOc1ccc(OCCCCCOS(C)(=O)=O)c(CCC(=O)OC)c1
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Product: CCCc1c(OCCCCCOc2ccc(OCCCCC(=O)OC)cc2CCC(=O)OC)ccc2c1OCCC2=O
Yield: 61 %

Procedure:
Using the procedure of example 11 and starting with 0.28 g (1.4 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one and 0.66 g (1.4 mmol) of 2-[[5-[(methylsulfonyl)oxy]pentyl]oxy]-5-(5-methoxy-5-oxopentyloxy)benzenepropanoic acid methyl ester (from example 57), 5-(5-methoxy-5-oxopentyloxy)-2-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid methyl ester was obtained in 61% yield (0.5 g) as colorless solid. This diester (0.85 mmol) was saponified with 3 mL of 3N aqueous lithium hydroxide in 20 mL of tetrahydrofuran, at room temperature, for 24 hr. Work-up as in example 4 gave a crystalline acid which was flash-chromatographed on silica gel, eluting with 95:5:1 chloroform-methanol-acetic acid. There was obtained 0.44 g (93%) of pure 5-(4-carboxybutoxy)-2-[5-[(3,4-dihydro-4-oxo-8 propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid. Recrystallization from ethyl acetate gave 0.35 g (74%) of a colorless solid, mp 138°-139° C.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:18]2[C@@H:9]([CH2:10][C@H:11]([CH3:21])[C:12]3[C@:17]2([CH3:19])[CH:16]=[CH:15][C:14](=[O:20])[CH:13]=3)[C@H:8]2[C@@:4]([CH3:27])([C@@:5]([OH:26])([C:22](=[O:25])[CH2:23][OH:24])[CH2:6][CH2:7]2)[CH2:3]1.[H][H]>CCOC(C)=O.C(O)C>[OH:1][C@@H:2]1[C@H:18]2[C@@H:9]([CH2:10][C@H:11]([CH3:21])[C:12]3[C@:17]2([CH3:19])[CH2:16][CH2:15][C:14](=[O:20])[CH:13]=3)[C@H:8]2[C@@:4]([CH3:27])([C@@:5]([OH:26])([C:22](=[O:25])[CH2:23][OH:24])[CH2:6][CH2:7]2)[CH2:3]1
Reactant: C[C@H]1C[C@@H]2[C@H]([C@@H](O)C[C@@]3(C)[C@H]2CC[C@]3(O)C(=O)CO)[C@@]2(C)C=CC(=O)C=C12
Reactant: [H][H]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[C@H]1C[C@@H]2[C@H]([C@@H](O)C[C@@]3(C)[C@H]2CC[C@]3(O)C(=O)CO)[C@@]2(C)CCC(=O)C=C12
Yield: 94.2 %

Procedure:
In a 250 mL round-bottomed flask was suspended (6S,8S,9S,10R,11S,13S,14S,17R)-11,17-dihydroxy-17-(2-hydroxyacetyl)-6,10,13-trimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one (6α-Methylprednisolon, 4.3 g, 11.48 mmol) in EtOAc (80 mL) and the reaction mixture was diluted with ethanol (20.0 mL). Tris(triphenylphosphine)rhodium(I)chloride (Wilkinson's catalyst, 1 g, 1.08 mmol) was added together with a magnetic stirrer bar and the flask was vigorously stirred in a hydrogen atmosphere (1 atm) at room temperature for 1 week. The reaction mixture was filtered through a glass filter funnel and the filtrate was concentrated in vacuo to yield 4.07 g of the desired compound as a light brown solid which was used in the next step without any further purification. APCI-MS m/z: 377 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[S:15][CH:14]3[C:16](=[O:19])[N:17]([CH3:18])[CH:11]([C:12](=[O:21])[N:13]3[CH3:20])[S:10]2)=[CH:5][CH:4]=1.C([Li])CCC.CCCCCC.[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Na+].[Cl-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[S:15][CH:14]3[C:16](=[O:19])[N:17]([CH3:18])[C:11]([CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:12](=[O:21])[N:13]3[CH3:20])[S:10]2)=[CH:5][CH:4]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(C2SC3C(=O)N(C)C(S2)C(=O)N3C)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C2SC3C(=O)N(C)C(Cc4ccccc4)(S2)C(=O)N3C)cc1
Temperature: -78 °C
Reaction time: 0.13 h
Yield: 40.2 %

Procedure:
Thioacetal 5 (194 mg, 0.6 mmol, 1 eq.) was dissolved in anhydrous THF (25 mL) and the solution was cooled to −78° C. To the stirred solution 1.54 M n-butyllithium in hexane (545 μL, 0.84 mmol, 1.4 eq.) was added dropwise over a period of 1 min. After 30 second benzyl bromide (356 μL, 513 mg, 3 mmol, 5 eq) was added to the stirred mixture over a period of 30 sec. After the mixture was stirred for 8 min at −78° C. the resulting red, cloudy solution was allowed to warm to room temperature and was stirred. It took about 30 min. The TLC shows one major product and a little (˜5%) of starting material. Saturated NaCl solution was added into the reaction mixture and the solution was extracted with dichloromethane. The organic solution was washed with water twice, dried under MgSO4 and concentrated under vacuum. The oily residue was treated with hexane. One part of the material got solid and the hexane solution was removed. The yellow solid was washed again with hexane and dried under vacuum. The solid crude material was dissolved in dichloromethane (2 mL), methanol (4 mL) and hexane (about 20 mL) was added. The white precipitate was filtered off to give the pure product 100 mg of 26 (40.8%). 1H NMR (CDCl3, TMS, ppm) δ: 7.36 (d, J=8.7 Hz, 2H), 724 (m, 51), 6.88 (d, J=8.7 Hz, 2H), 5.19 (s, 1H), 5.10 (s, 1H), 4.15 (d, J=16.6 Hz, 1H), 3.82 (s, 3H), 3.25 (d, J=16.5 Hz, 1H), 3.15 (s, 3H), 3.11 (5, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]([CH3:25])[CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:26]([O:28][CH3:29])=[O:27])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:36][CH2:37]I>CN(C)C=O.O>[CH2:36]([N:22]1[CH2:23][CH2:24][CH:19]([N:18]([CH3:25])[C:17]2[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:26]([O:28][CH3:29])=[O:27])[CH:14]=3)[NH:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:20][CH2:21]1)[CH3:37]
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N(C)C3CCNCC3)nc2c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCC(N(C)C2=C(c3ccc(F)cc3)Nc3ccc(C(=O)OC)cc3N2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-[methyl(piperidin-4-yl)amino]quinoxaline-6-carboxylate (100 mg, 0.25 mmol) in N,N-dimethylformamide (30 mL) was added potassium carbonate (157.6 mg, 1.14 mmol) and CH3CH2I (71.32 mg, 0.46 mmol), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then diluted with water (200 mL) and extracted with dichloromethane (4×50 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (1% methanol in dichloromethane) to afford methyl 3-[(1-ethylpiperidin-4-yl)(methyl)amino]-2-(4-fluorophenyl)-1,4-dihydroquinoxaline-6-carboxylate as light yellow oil (53 mg, 46%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:12]([OH:16])[CH2:13][C:14]#[CH:15]>C(N(CC)CC)C.ClCCl>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([C:15]#[C:14][CH2:13][CH2:12][OH:16])[CH:3]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: C#CCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCCC#Cc1cnc2ccccc2c1
Yield: 136.9 %

Procedure:
A solution of 3-bromoquinoline (13.57 mL, 0.10 mol) and 3-butyn-1 ol (9.0 mL, 0.12 mol) in 40 mL of triethylamine and 75 mL of dichloromethane is degassed by bubbling dry nitrogen through it for 15 minutes, and 0.7 g (0.00I mol) of bis(triphenyl-phosphine)palladium dichloride and 0.013 g of cuprous iodide are added. The flask is flushed with nitrogen and the mixture heated to reflux for 5 hours. The cooled mixture is diluted with dichloromethane and washed with water, dried (sodium sulfate), and concentrated to give 27 g of a gold oil. The oil was triturated with diethyl ether to give 18.2 g of the title compound as a tan solid; mp 95.7°-96.7° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:27][CH:28]2[CH2:30][CH2:29]2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[O:37])=[CH:34][CH:33]=1.C[Si](Cl)(C)C>C(O)CCC>[CH:28]1([NH:27][C:4]2[C:5]3[C:10]([C:11]4[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=4)=[CH:9][NH:8][C:6]=3[N:7]=[C:2]([NH:31][C:32]3[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[O:37])=[CH:34][CH:33]=3)[N:3]=2)[CH2:29][CH2:30]1
Reactant: NC(=O)c1ccc(N)cc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccncc3)c3c(NC4CC4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: NC(=O)c1ccc(Nc2nc(NC3CC3)c3c(-c4ccncc4)c[nH]c3n2)cc1
Temperature: 135 °C
Reaction time: 48 h
Yield: 7.6 %

Procedure:
A mixture of 2-chloro-N-cyclopropyl-5-(pyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (135 mg, 0.307 mmol), 4-aminobenzamide (100 mg, 0.735 mmol) and trimethylsilyl chloride (0.200 mL, 1.58 mmol) in nBuOH (3 mL) was stirred at 135° C. for 48 h. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound (9 mg). MS 386.2 (M+H); UV 201.8, 309.8 nm.
Reaction SMILES: Cl.[NH2:2][C@:3]([CH3:24])([CH2:6][CH2:7][C:8]1[O:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:11][CH:12]=1)[CH2:4][OH:5].O.C(=O)([O-])O.[K+].Cl[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33]>C(OCC)(=O)C>[CH2:35]([O:34][C:32]([NH:2][C@:3]([CH3:24])([CH2:6][CH2:7][C:8]1[O:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][O:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)=[CH:11][CH:12]=1)[CH2:4][OH:5])=[O:33])[CH:36]=[CH2:37]
Reactant: C[C@](N)(CO)CCc1ccc(C#CCCOC2CCCCC2)o1
Reactant: C=CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N[C@@](C)(CO)CCc1ccc(C#CCCOC2CCCCC2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
To a suspension of (2R)-2-amino-2-methyl-4-[5-(4-cyclohexyloxybut-1-ynyl)furan-2-yl]butan-1-ol (0.5305 g, 1.66 mmol) obtained in Example 20 in a mixed solvent of ethyl acetate (16 ml) and water (16 ml) were added potassium hydrogencarbonate (0.1995 g, 1.99 mmol) first and then allyl chloroformate (0.21 ml, 1.98 mmol) with stirring, and the resulting mixture was stirred at room temperature for 30 minutes. After stirring, the reaction mixture was diluted with ethyl acetate and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo to afford the title compound (0.6202 g, yield: 93%)
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:26][O:27][CH3:28])[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([O-:23])=[O:22])=[C:15]([CH2:18][O:19][CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].FC(F)(F)C([O-])=O.[C:37]([O:43][CH2:44]I)(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39].C(OCC)(=O)C>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:26][O:27][CH3:28])[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([O:23][CH2:44][O:43][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[O:22])=[C:15]([CH2:18][O:19][CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: COCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Reactant: CC(C)(C)C(=O)OCI
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COCC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Yield: 90.4 %

Procedure:
To a solution of 45 mg of sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylate (prepared from the corresponding trifluoroacetate) in 1 ml of dimethylacetamide were added, at -15° C., 27 mg of iodomethyl pivalate and the mixture was allowed to react for 15 minutes. At the end of this time, 20 ml of ethyl acetate were added to the reaction mixture, and the mixture was washed, in turn, with water, an aqueous solution of potassium bisulphate and an aqueous solution of sodium bicarbonate. The organic phase was separated and concentrated by evaporation under reduced pressure, and the residue was subjected to column chromatography through silica gel eluted with a 3:1 by volume mixture of ethyl acetate and hexane, to give 49 mg of the title compound, whose properties were identical with those of the compound obtained in Example 1.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH:17]([NH:19][C:20]([N:22]3[CH2:27][CH2:26][CH:25]([N:28]4[CH2:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[NH:30][C:29]4=[O:38])[CH2:24][CH2:23]3)=[O:21])[C:16](=[O:39])[N:15]([CH3:40])[CH2:14][C:13]=2[CH:41]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH:17]([NH:19][C:20]([N:22]3[CH2:27][CH2:26][CH:25]([N:28]4[CH2:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[NH:30][C:29]4=[O:38])[CH2:24][CH2:23]3)=[O:21])[C:16](=[O:39])[N:15]([CH3:40])[CH2:14][C:13]=2[CH:41]=1
Reactant: [H][H]
Reactant: CN1Cc2cc(OCc3ccccc3)ccc2CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Agent: [Pd]
Solvent: CO
Product: CN1Cc2cc(O)ccc2CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Reaction time: 12 h

Procedure:
To a stirred solution of 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid (8-benzyloxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-amide (187 mg, 0.34 mmol) in methanol (30 mL) followed by 10% palladium on carbon (30 mg) under nitrogen. The reaction mixture was brought to 1 atmosphere of hydrogen and stirred for 12 h. The catalyst was filtered and the solvent was evaporated to give 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid (8-hydroxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-amide in quantitative yield. MS (ESI) 464 (M+H); Rf=1.34.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH:21]([C:24]1[CH:28]=[C:27]([NH2:29])[NH:26][N:25]=1)([CH3:23])[CH3:22]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:29][C:27]2[NH:26][N:25]=[C:24]([CH:21]([CH3:23])[CH3:22])[CH:28]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CC(C)c1cc(N)[nH]n1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CC(C)c1cc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)[nH]n1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 3-isopropyl-1H-pyrazol-5-amine (12.5 mg, 0.1 mmol). The title compound was obtained as a solid (7.1 mg, 16% yield). MS m/z: 458.00, 460.00 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:33])[C@@H:4]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:5]([O:7][Si:8]([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:6].O.[OH-].[Li+].Cl>O1CCCC1.O>[C:29]([O:28][C:26]([NH:25][C@@H:4]([C@H:5]([O:7][Si:8]([C:21]([CH3:22])([CH3:24])[CH3:23])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:6])[C:3]([OH:33])=[O:2])=[O:27])([CH3:30])([CH3:31])[CH3:32]
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 8 h
Yield: 98.7 %

Procedure:
(2S,3R)-2-tert-Butoxycarbonylamino-3-(tert-butyl-diphenyl-silanyloxy)-butyric acid methyl ester (3.56 g, 7.55 mmol) was taken up in a mixture of tetrahydrofuran (10 mL) and water (3 mL) and cooled using an ice bath. Lithium hydroxide monohydrate (1.27 g, 30.2 mmol) was then added and the reaction was left to stir overnight. The solution was acidified using hydrochloric acid (2 M) until the solution was pH 2. The solution was then extracted with ethyl acetate. The organics were dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (3.41 g, 98%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 1.02-1.11 (m, 21H), 4.26-4.35 (m, 1H), 4.41-4.51 (m, 1H), 5.34 (d, J=9.0 Hz, 1H), 7.35-7.49 (m, 6H), 7.63-7.77 (m, 4H). LCMS (m/z) 458.1 [M+H], Tr=3.68 min.