Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>CN(C=O)C.C1COCC1>[Cl:21][C:6]1([C:5]2[CH:17]=[CH:18][C:2]([F:1])=[CH:3][CH:4]=2)[C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=[O:12])[O:11]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1OC(Cl)(c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
THF (25 mL) was added to 2-(4-fluorobenzoyl)benzoic acid (5 g, 20.4 mmol) followed by thionyl chloride (2.97 mL, 40.9 mmol) and a catalytic amount of DMF (3 drops). The system was stirred under nitrogen for 4 h at room temperature. Removal of the solvent gave 3-chloro-3-(4-fluorophenyl)-3H-isobenzofuran-1-one as a colourless oil (5.35 g, 20.4 mmol, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:22])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1.S1(=O)(=O)CCCC1.C([N:32]([C:38]([O-])=[O:39])[N:33]=[CH:34]N(C)C)C>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:22]2[CH:34]=[N:33][NH:32][C:38]2=[O:39])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1
Reactant: CCN(N=CN(C)C)C(=O)[O-]
Reactant: COc1ccc(N2CCN(c3ccc(N)cc3Br)CC2)cc1
Solvent: O=S1(=O)CCCC1
Solvent: CCO
Product: COc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cc3Br)CC2)cc1
Temperature: 25 °C

Procedure:
To a stirred mixture of 54.3 parts of 3-bromo-4-[4-(4-methoxyphenyl)-1-piperazinyl]-benzenamine and 189 parts of tetrahydrothiophene 1,1-dioxide was added portionwise, during a 30 minutes-period, 28.6 parts of ethyl[(dimethylamino)methylene]hydrazinecarboxylate at 160° C. Upon completion, stirring and heating were continued at 170° C. till all ethanol was distilled off. After cooling to room temperature, 120 parts of 4-methyl-2-pentanone were added to dissolve the sticky residue. The whole was heated till a solution was obtained. After cooling, the supernatant phase was decanted and the residue was stirred in 2,2'-oxybispropane. The product was filtered off and dried, yielding 44.6 parts of 4-[3-bromo-4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (int. 34).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH2:9].N1C=CC=CC=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1.Cl>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH3:16])[CH:19]=1)(=[O:26])=[O:25]
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1ccc(F)cc1F
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc(S(=O)(=O)Nc2ccc(F)cc2F)c1
Reaction time: 12 h

Procedure:
To 2,4-difluoro-phenylamine(42, 0.44 mL, 4.4 mmol) in methylene chloride (10.0 mL), under an atmosphere of nitrogen, were added pyridine (1.00 mL, 12.4 mmol) and 3-methoxy-benzenesulfonyl chloride (1.00 g, 4.84 mmol). After 12 hours, the reaction was poured into cold 1 M HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give light yellow solid (91, 0.90 g, 69%). MS (ESI) [M+H+]+=300.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH:6]=[CH:7][C:8](O)=[O:9].S(Cl)([Cl:16])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH:6]=[CH:7][C:8]([Cl:16])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: COc1cccc(C=CC(=O)O)c1
Product: COc1cccc(C=CC(=O)Cl)c1

Procedure:
A solution of 3-methoxycinnamic acid (75.0 g, 0.42 mol) in thionyl chloride (250 mL) was heated at reflux for 1 h. The majority of the the thionyl chloride was then distilled off and the resulting residue was treated with dichloromethane and residual thionyl chloride was removed by codistillation to give 3-methoxycinnamic acid chloride of sufficient purity to be used without further purification. Pyridine (186 mL, 2.3 mol) and N,O-dimethylhydroxylamine hydrochloride (45.17 g, 0.46 mol) were added to a 0° C. solution of 3-methoxycinnamic acid chloride(0.42 mol) in dry dichloromethane (500 mL). The solution was stirred for 18 h at room temperature, diluted with dichloromethane (200 mL), and washed sequentially with 1N HCl, saturated sodium bicarbonate, and brine. It was then dried over MgSO4 and concentrated in vacuo to give the title compound as a dark oil (88.43 g, 95%): 1H NMR (300 MHz, CDCl3) δ 3.25 (s, 3H), 3.68 (s, 3H), 3.84 (s, 3H), 6.82-6.86 (m, 1H), 7.00 (d, J=16.1 Hz, 1H), 7.10 (br s, 1H), 7.15-7.20 (m, 1H), 7.32 (t, J=6.6 Hz, 1H), 7.72 (d, J=16.0 Hz, 1H).
Reaction SMILES: [F:1][CH2:2][CH:3](O)[CH2:4][F:5].N1C=CC=CC=1.C(#N)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH3:37][O:38][C:39]1[C:49]([N+:50]([O-:52])=[O:51])=[CH:48][C:42]2[CH2:43][CH2:44][NH:45][CH2:46][CH2:47][C:41]=2[CH:40]=1>>[F:1][CH2:2][CH:3]([N:45]1[CH2:46][CH2:47][C:41]2[CH:40]=[C:39]([O:38][CH3:37])[C:49]([N+:50]([O-:52])=[O:51])=[CH:48][C:42]=2[CH2:43][CH2:44]1)[CH2:4][F:5]
Reactant: OC(CF)CF
Reactant: COc1cc2c(cc1[N+](=O)[O-])CCNCC2
Agent: O=C([O-])[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [K+]
Solvent: CC#N
Solvent: c1ccncc1
Product: COc1cc2c(cc1[N+](=O)[O-])CCN(C(CF)CF)CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
A mixture of 1,3-difluoro-propan-2-ol (0.697 mL, 9.00 mmol) and pyridine (0.910 mL, 11.2 mmol) in acetonitrile (42.3 mL, 810 mmol) was cooled at 0° C. and trifluoromethanesulfonic anhydride (1.59 mL, 9.45 mmol) was added dropwise. The mixture was stirred for 30 minutes and then potassium carbonate (1.24 g, 9.00 mmol) and 7-methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.00 g, 4.50 mmol) were added. The reaction was heated at 50° C. overnight and then cooled to room temperature and concentrated under reduced pressure. The residue was taken up in DCM (75 mL) and washed with water (75 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-100% EtOAc/hex as the eluting solvent to obtain 3-(2-fluoro-1-fluoromethyl-ethyl)-7-methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow amorphous solid (679 mg, 50%). LCMS (m/e) 301 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.67 (s, 1H), 6.83 (s, 1H), 4.75-4.65 (m, 2H), 4.63-4.54 (m, 2H), 3.96 (s, 3H), 3.29-3.11 (m, 1H), 2.99-2.93 (m, 2H), 2.93-2.82 (m, 6H).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]([O-:11])=[O:10].Cl>CO>[NH2:3][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]([OH:11])=[O:10]
Reactant: Nc1ccsc1C(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccsc1C(=O)O
Temperature: 60 °C
Yield: 81.6 %

Procedure:
Add 5 N NaOH (50 ml) to a solution of metlhyl 3-aminothiophene-2-carboxylate (7.86, 50.0 mmole) in methanol (250 ml). Heat the reaction mixture at 60° C. overnight. Adjust the pH to about 6 to 7 by adding 1 N HCl. Extract with ethyl acetate (5×200 ml). Combine the organic layers, dry over Na2SO4. Filter and concentrate to provide 3-amino-thiophene-2-carboxylic acid (5.84 g, 82%) as a white powder, which was used immediately for the next step. MS (ES+): 144 (M+H); (ES−): 142 (M−H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[N:10]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:8]2)#[N:2].[H][H]>CO.[Ni]>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[N:10]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:8]2
Reactant: [H][H]
Reactant: N#Cc1cccc2ccn(CC(=O)O)c12
Agent: [Ni]
Solvent: CO
Product: NCc1cccc2ccn(CC(=O)O)c12
Reaction time: 6 h
Yield: 96 %

Procedure:
Raney Ni (7.0 g) was added to a solution of 2-(7-cyano-1H-indol-1-yl)acetic acid (700 mg, 3.5 mmol) in MeOH (15 ml), and the mixture was hydrogenated for 6 h at RT and 60 psi hydrogen in a Parr apparatus. The reaction mixture was filtered over celite and the filtrate was concentrated under vacuum. The crude product so obtained was used directly in the following stage without being purified further. Yield: 96% (692 mg, 3.36 mmol)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][NH2:9])=[CH:5][CH:4]=1.[CH:12]1(I)[CH2:16][CH2:15][CH2:14][CH2:13]1>CC#N.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][NH:9][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CCN)cc1
Reactant: IC1CCCC1
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccc(CCNC2CCCC2)cc1
Temperature: 25 °C
Yield: 194.7 %

Procedure:
4-Methoxyphenethyl amine (0.8 mL, 6 mmol), and cyclopentyl iodide (0.22 mL, 2 mmol) in CH3CN (5 mL) were irradiated for 10 min in a microwave at 110° C. After cooling to room temperature the mixture was diluted with CH2Cl2 and washed with NaHCO3 solution. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo. The crude product was purified by silica gel chromatography using hexane as eluent and the product N-(4-methoxyphenethyl)cyclopentanamine (0.854 g, 65%) was obtained as a colorless liquid which solidified upon standing. 1H NMR (400 MHz, CDCl3): δ 8.49 (s, 1H), 7.10 (d, 2H, J=8.6 Hz), 6.78 (d, 2H, J=8.6 Hz), 3.74 (s, 3H), 3.69-3.65 (m, 1H), 3.08-3.07 (m, 4H), 1.84-1.83 (m, 2H), 1.82-1.81 (m, 2H), 1.66-1.56 (m, 4H). LC-MS (ESI) Calcd for: C14H21NO [M+H]+: 220.16. Found: 220.00.
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[C:30]([NH2:35])[N:29]=[C:28]2[C:36]([N:38]1[CH2:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39]1)=[O:37])=[O:14])=O)(C)(C)C>O1CCOCC1.ClCCl>[ClH:1].[ClH:1].[NH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[C:30]([NH2:35])[N:29]=[C:28]2[C:36]([N:38]1[CH2:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39]1)=[O:37])=[O:14]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCCCC(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
250 μl of 4N HCl in dioxane are added to 300 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]-4,5-difluorobenzyl 4-tert-butoxycarbonylaminobutyrate in 5 ml of dichloromethane with ice-cooling. The mixture is subsequently stirred at 25° C. for a further 1 h, the precipitate is filtered off with suction and washed with 2 ml of dichloromethane.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:37])[N:7]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:8]([C@H:12]([NH:15][CH2:16][CH2:17][CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:13][CH3:14])=[N:9]2)=[CH:4][CH:3]=1.[CH:38](=O)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[NH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@@H:12]([C:8]1[N:7]([NH:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:6](=[O:37])[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1)[CH2:13][CH3:14]
Reactant: CC[C@@H](NCCCN1C(=O)c2ccccc2C1=O)c1nc2cc(Cl)ccc2c(=O)n1Nc1ccccc1
Reactant: O=Cc1ccccc1
Product: CC[C@H](c1nc2cc(Cl)ccc2c(=O)n1Nc1ccccc1)N(CCCN)Cc1ccccc1

Procedure:
This compound was synthesized as described in general procedure C except 2-{3-[(R)-1-(7-chloro-4-oxo-3-phenylamino-3,4-dihydro-quinazolin-2-yl)-propylamino]-propyl}-isoindole-1,3-dione was used instead of (R)-2-(3-(1-(7-chloro-4-oxo-3-(phenylamino)-3,4-dihydroquinazolin-2-yl)but-3-ynylamino)propyl)isoindoline-1,3-dione and benzaldehyde was used instead of 4-methyl benzaldehyde. Yield (16%). LCMS: m/e 477.04 [M+H].
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].C1OCCOCCOCCOCCOC1.Br[CH2:57]/[CH:58]=[CH:59]\[C:60]([CH3:70])([O:62][Si:63]([CH2:68][CH3:69])([CH2:66][CH3:67])[CH2:64][CH3:65])[CH3:61]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:57]/[CH:58]=[CH:59]\[C:60]([CH3:70])([O:62][Si:63]([CH2:66][CH3:67])([CH2:68][CH3:69])[CH2:64][CH3:65])[CH3:61])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC[Si](CC)(CC)OC(C)(C)/C=C\CBr
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)/C=C\CO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 97.8 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol), 15-crown-5 (10 μl) and (Z)-l-bromo-4-methyl-4-triethylsilyloxy-2-pentene (125 mg, 0.428 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=30:1, developed once) to give the title compound as a colorless oil (80.7 mg, 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1>C1COCC1>[Br:39][C:40]1[CH:46]=[CH:45][C:43]([NH:44][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:3]=2[O:2][CH3:1])=[CH:42][CH:41]=1
Reactant: Nc1ccc(Br)cc1
Reactant: COc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])cc1C(=O)Nc1ccc(Br)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 2-methoxy-5-nitro-benzoic acid (2.00 g, 10.1 mmol), HATU (3.86 g, 10.1 mmol), TEA (4.23 mL) and 100 mL THF was stirred for 30 min. Then 4-bromoaniline (1.75 g, 10.1 mmol) was added and the mixture was stirred for 3 days and concentrated. The crude material was dissolved in EtOAc and the organic phase was washed with satd. aq. NaHCO3. The precipitate was collected and again dissolved in EtOAc and washed with water and satd. NaHCO3. The organic phase was dried with Na2SO4, filtered and concentrated to furnish the subtitle compound. Yield: 930 mg (26%). MS [M+H]+=351 (Br-isotope pattern); TLC: Rf=0.94 (silica gel, DCM:EtOH 9:1).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:27][S:28]([C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1)(=[O:30])=[O:29]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:35][C:34]3[CH:33]=[CH:32][C:31]([S:28]([CH3:27])(=[O:30])=[O:29])=[CH:38][CH:37]=3)[C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: O=C1Nc2cnc(Cl)nc2N2CCOCC12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(CN2C(=O)C3COCCN3c3nc(Cl)ncc32)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (PREPARATION x1, 1.5 g, 6.23 mmol) was dissolved in DMF (25 mL) to give an orange solution. The mixture was cooled to 0° C. and lithium bis(trimethylsilyl)amide (1.04 g, 6.23 mmol), followed by 4-methylsulfonylbenzyl bromide (1.71 g, 6.86 mmol), were added. The reaction mixture was stirred at 0° C. for 1 hour and was subsequently diluted with ethyl acetate and washed with brine (100 mL) to give a suspension. An orange precipitate was collected on a fitted glass funnel and was washed with water (3×20 mL) and dried over night in a stream of nitrogen. The crude solid was triturated with hot ethyl acetate (2×) to give the title compound which was used without further purification (1.78 g, 69.8%). ESI-MS m/z [M+H]+ calc'd for C17H17ClN4O4S, 409.07. found 409.3.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:16](OS(C2C=CC(C)=CC=2)(=O)=O)[C@@H:15]([CH2:28][OH:29])[O:14][C@H:11]([O:12][CH3:13])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CS(C)=O.CCOCC>[CH2:1]([O:8][C@@H:9]1[CH2:16][C@@H:15]([CH2:28][OH:29])[O:14][C@H:11]([O:12][CH3:13])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@H]1C[C@H](OCc2ccccc2)[C@H](OS(=O)(=O)c2ccc(C)cc2)[C@@H](CO)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CO[C@@H]1C[C@H](OCc2ccccc2)C[C@@H](CO)O1
Temperature: 80 °C
Yield: 81.3 %

Procedure:
Methyl 3-O-benzyl-4-O-tosyl-2-deoxy-α-D-ribohexopyranoside (6.55 g, 15.50 mmoles) is dissolved in dry DMSO (50 ml). Sodium borohydride (2.35 g; 62.01 mmoles) is added and the reaction is stirred under nitrogen in a bath maintained at 80° C. for four days. The reaction is cooled to room temperature and diluted with ether and extracted with water. The aqueous extract is then extracted four times with ether. The combined ether extracts are dried (MgSO4), filtered, and the solvent evaporated in vacuo to give crude product. This crude product is purified by flash chromatography on a 60 mm×150 mm column eluting with 15% (by volume) acetone in methylene chloride. A small portion (0.9 g) containing an impurity is rechromatographed on a 30 mm×130 mm column with the same eluant to give a combined total of 3.18 g of methyl 3-O-benzyl-2,4-dideoxy-α-D-erythro-hexopyranoside as a gum, [α]D25 +58.56 (c, 0.7, CHCl3)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Br[CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: CC(Br)c1ccccc1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1C(C)c1ccccc1

Procedure:
The title compound, MS: m/e=322.1 (M+H+), was prepared in accordance with the general method of example 1 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and (1-bromoethyl)benzene.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]([O:12]C)=[O:11])[CH:7]=[N:8][CH:9]=1)(=[O:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([C:4]1[CH:5]=[C:6]([C:10]([OH:12])=[O:11])[CH:7]=[N:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1cncc(C(C)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)c1cncc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 5-acetylpyridine-3-carboxylate (0.15 g, 0.84 mmol) in methanol (2.10 mL) was added aqueous 1N sodium hydroxide solution (2.51 mL, 2.51 mmol). The resulting mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure to give a residue that was acidified with aqueous 1 N hydrogen chloride solution and extracted with ethyl acetate. The organic extracts were combined, dried over magnesium sulfate, filtered and concentrated to provide the title compound: 1H NMR (500 MHz, CDCl3) δ 9.43 (d, J=1.4 Hz, 1 H), 9.36 (s, 1 H), 8.84 (s, 1 H), 2.70 (s, 3 H).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:7]2[CH2:20][CH2:21][N:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:6]12)=[O:4].C[O-].[Na+]>CO>[C:26]([O:25][C:23]([N:22]1[CH:6]2[CH:7]([N:8]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:9][CH:5]2[C:3]([OH:4])=[O:2])[CH2:20][CH2:21]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: COC(=O)C1CN(C(=O)OCc2ccccc2)C2CCN(C(=O)OC(C)(C)C)C12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2C1C(C(=O)O)CN2C(=O)OCc1ccccc1
Reaction time: 16 h
Yield: 101.7 %

Procedure:
A solution of 25 (1.4 g, 3.5 mmol) in MeOH (20 mL) was added to a solution of NaOMe (0.34 g, 6.3 mmol) in MeOH at ambient temperature. The reaction mixture was stirred for 16 h and then concentrated. The residue was diluted with EtOAc, washed successively with 1M HCl, brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 13 as an orange-colored foam (1.39 g) that was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:11](Br)[C:12]#[CH:13].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O>[CH2:13]([O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[C:12]#[CH:11]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C#CCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
4-Nitrophenol (1.00 g, 7.19 mmol), propargyl bromide (80 wt % in toluene; 0.788 mL, 7.09 mmol), and K2CO3 (1.08 g, 7.84 mmol) were stirred in acetone (16.0 mL) at 60° C. for 18 h. The reaction mixture was cooled to room temperature and diluted with water (200 mL). 4-(prop-2-ynyloxy)nitrobenzene was isolated as a white solid by suction filtration (1.12 g). 1H NMR (CDCl3): δ 8.22 (d, J=9.0 Hz, 2H), 7.05 (d, J=9.0 Hz, 2H), 4.80 (d, J=2.4 Hz, 2H), 2.59 (t, J=2.4 Hz, 1H).
Reaction SMILES: [Cl:1][C@@:2]1([CH3:32])[C@H:7]([C:8]([OH:10])=[O:9])[N:6]2[C:11](=[O:31])[C@@H:12]([NH:13][C:14](=[O:30])[CH:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)NC(OC(C)(C)C)=O)[C@H:5]2[S:4][CH2:3]1.[C:33]1([C:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[N+]=[N-])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[Cl:1][C@@:2]1([CH3:32])[C@H:7]([C:8]([O:10][CH:39]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:9])[N:6]2[C:11](=[O:31])[C@@H:12]([NH:13][C:14](=[O:30])[CH2:15][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:5]2[S:4][CH2:3]1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC(C(=O)N[C@@H]1C(=O)N2[C@@H]1SC[C@@](C)(Cl)[C@@H]2C(=O)O)c1ccccc1
Solvent: ClCCl
Product: C[C@@]1(Cl)CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Yield: 96 %

Procedure:
To a solution of 3β-chloro-3α-methyl-7β-(α-tert. -butoxycarbonylaminophenylacetamido)cepham-4α-carboxylic acid (0.9 g) in methylene chloride (20 ml), is added a solution of diphenyldiazomethane in methylene chloride until the red color or the reaction solution does not disappear. The reaction mixture is evaporated to remove the solvent, leaving a residue of benzhydryl 3β-chloro-3α-methyl-7β-phenylacetamidocepham-4α-carboxylate (1.17 g). Yield: 96%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:16][N:17]1[C:21]([CH3:22])=[CH:20][C:19]([NH2:23])=[N:18]1>>[CH3:16][N:17]1[C:21]([CH3:22])=[CH:20][C:19]([NH:23][C:2]2[CH:3]=[CH:4][C:5]([N:10]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]3)=[C:6]([CH:9]=2)[C:7]#[N:8])=[N:18]1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Reactant: Cc1cc(N)nn1C
Product: Cc1cn(-c2ccc(Nc3cc(C)n(C)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1,5-dimethyl-1H-pyrazol-3-ylamine. The title compound was obtained as a yellowish solid (Yield=36%). MS ISP (m/e): 293.2 (100) [(M+H)+].