Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C:14]([C:15](=O)[CH2:16]Cl)=[CH:13][CH2:12][N:11]1[C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:25](=[S:28])([S-:27])[NH2:26].[NH4+]>CO.C(N)(=S)C1C=CN=CC=1>[Si:1]([O:8][CH2:9][C@@H:10]1[C:14]([C:15]2[N:26]=[C:25]([SH:28])[S:27][CH:16]=2)=[CH:13][CH2:12][N:11]1[C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: NC(=S)[S-]
Reactant: C=CCOC(=O)N1CC=C(C(=O)CCl)[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: NC(=S)c1ccncc1
Agent: [NH4+]
Solvent: CO
Product: C=CCOC(=O)N1CC=C(c2csc(S)n2)[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 38.8 %

Procedure:
To a solution of allyl (2S)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-(chloroacetyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (163 mg, 0.44 mmol) in methanol (2 ml) were added at 0–5° C. thioisonicotinamide (2 mg) and ammonium dithiocarbamate (72 mg, 0.65 mmol). The reaction mixture was raised to room temperature and stirred for 40 minutes. The mixture was stirred at 65–70° C. for 30 minutes and then at 75–85° C. for 1 hour. The solvent was removed in vacuo. To the solution was added ethyl acetate and the solution was separated with a separating funnel. The aqueous layer was extracted with ethyl acetate. The organic layer was washed twice with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was recrystallized from ethyl acetate/hexane to give allyl (2S)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-(2-mercapto-1,3-thiazol-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (70.5 mg, 39%).
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([F:9])=[CH:4][N:3]=1.[Br:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13]Br>>[Br:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][N:7]1[C:6](=[O:8])[C:5]([F:9])=[CH:4][N:3]=[C:2]1[Cl:1]
Reactant: BrCc1ccccc1Br
Reactant: O=c1[nH]c(Cl)ncc1F
Product: O=c1c(F)cnc(Cl)n1Cc1ccccc1Br
Yield: 11 %

Procedure:
The title compound was prepared in 11% yield from 2-chloro-5-fluoro-3H-pyrimidin-4-one and 2-bromobenzyl bromide according to the procedure for Example 1B. 1H NMR (400 MHz, CDCl3): δ 7.82 (d, 1H, J=1.2 Hz), 7.62 (dd, 1H, J=7.6, 1.2 Hz), 7.17-7.30 (m, 2H), 6.78 (d, 1H, J=7.6 Hz), 5.52 (s, 2H). MS (ES) [m+H] calc'd for C11H7N2OFClBr, 317, 319; found 317, 319.
Reaction SMILES: [CH2:1]([C:3](=[CH2:6])[CH:4]=[O:5])[CH3:2].[SH:7][C:8]1[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11]>C1COCC1.CCOCC>[C:10]([C:9]1[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=1[S:7][CH2:6][CH:3]([CH2:1][CH3:2])[CH:4]=[O:5])(=[O:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=C(C=O)CC
Reactant: O=C(c1ccccc1)c1ccccc1S
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(C=O)CSc1ccccc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 63.6 %

Procedure:
To an ice bath cooled solution of 9.76 g (0.116 mole) of 2-ethylacrolein in 40 mL of dry THF was added 24.6 g (0.116 mole) of 2-mercaptobenzophenone in 40 mL of THF followed by 13 g (0.128 mole) of triethylanine. The reaction mixture was stirred at room temperature for 3 days, diluted with ether, and was washed successively with dilute HCl, brine, and 1 M potassium carbonate. The ether layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by HPLC (10% EtOAc-hexane) to give 22 g (64%) of 11 in the second fraction. An attempt to further purifiy this material by kugelronr distillation at 0.5 torr (160-190° C.) gave a fraction (12.2 g) which contained starting material indicating a reversed reaction during distillation. This material was dissolved in ether (100 mL) and was washed with 50 mL of 1 M potassium carbonate three times to give 6.0 g of a syrup which was purified by HPLC (10% EtOAc-hexane) to give 5.6 g of pure 11.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH2:11][C:10]([C:16]3[CH:21]=[C:20]([Cl:22])[C:19]([Cl:23])=[C:18]([Cl:24])[CH:17]=3)([C:12]([F:15])([F:14])[F:13])[O:9][N:8]=2)[O:4][C:3]=1[CH2:25][OH:26]>ClCCl.O=[Mn]=O>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH2:11][C:10]([C:16]3[CH:17]=[C:18]([Cl:24])[C:19]([Cl:23])=[C:20]([Cl:22])[CH:21]=3)([C:12]([F:15])([F:14])[F:13])[O:9][N:8]=2)[O:4][C:3]=1[CH:25]=[O:26]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)oc1CO
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)oc1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.8 %

Procedure:
MnO2 (1.75 g) is added portion wise to a solution of {3-methyl-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-furan-2-yl}-methanol (1.72 g) in dichloromethane (40 ml). After 16 hours at room temperature, additional MnO2 (4.37 g) is added portion wise and the reaction mixture is stirred at room temperature for a further 3 hours. The reaction mixture is filtered through a plug of Celite and the filtration cake is washed with dichloromethane. The filtrate is concentrated in vacuo to yield 3-methyl-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-furan-2-carbaldehyde (1.28 g) as a light yellow foam. The crude product obtained is used without further purification. MS (HPLC/MS): 426 (MH+). Retention time: 2.21 min.
Reaction SMILES: [OH:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]=[C:3]1[C:12]([F:15])([F:14])[F:13].[CH3:16][S:17](Cl)(=[O:19])=[O:18].Cl>N1C=CC=CC=1>[CH3:16][S:17]([O:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]=[C:3]1[C:12]([F:15])([F:14])[F:13])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: On1c(C(F)(F)F)nc2ncc(Cl)cc21
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)On1c(C(F)(F)F)nc2ncc(Cl)cc21
Temperature: 5 °C

Procedure:
1-Hydroxy-6-chloro-2-(trifluoromethyl)-1H-imidazo-(4,5-b)pyridine (5 grams) in 15 milliliters of pyridine was cooled to 5° C. with stirring and methylsulfonyl chloride (5 milliliters) was added in 1-milliliter portions, maintaining the temperature at about 5° C. After the addition was completed, the reaction mixture was stirred for two hours at 5°-10° C., then poured into 30 grams of ice and 20 milliliters of concentrated hydrochloric acid. The desired 1-(methylsulfonyloxy)-6-chloro-2-(trifluoromethyl)- 1H-imidazo(4,5-b)pyridine product precipitated and was separated by filtration and washed with water. The washed product was taken up in diethyl ether with a trace of acetone, dried over magnesium sulfate and the solvent evaporated under vacuum. The product so obtained melted at 136.7° C.
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.[CH3:12][N:13]([C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=1)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17]>>[CH3:12][N:13]([C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:23][CH:22]=1)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18]
Reactant: Brc1cnc2ccccc2c1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CN(C(=O)OC(C)(C)C)c1ccc(-c2cnc3ccccc3c2)cc1

Procedure:
3-Bromoquinoline (42 mg, 0.2 mmol) and tert-butyl methyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (66 mg, 0.2 mmol) were reacted using General Procedure (A) to afford tert-butyl methyl(4-(quinolin-3-yl)phenyl)carbamate a clear wax (44 mg, 66%). 1H NMR (400 MHz, CDCl3): δ 9.18 (d, J=2.4 Hz, 1H), 8.31 (d, J=2.0 Hz, 1H), 8.15 (m, 1H), 7.89 (m, 1H), 7.73 (m, 1H), 7.68 (m, 2H), 7.59 (m, 1H), 7.42 (m, 2H), 3.3 (s, 3H), 1.50 (s, 9H); MS (ESI): 335 (M+H+). tert-Butyl methyl(4-(quinolin-3-yl)phenyl)carbamate (44 mg, 0.13 mmol) was then treated with TFA by using the general procedure P. The crude product was purified by HPLC to afford T477 as an orange-colored wax (13 mg, 29%). 1H NMR (400 MHz, CDCl3): δ 9.46 (d, J=2.0 Hz, 1H), 8.79 (d, J=1.6 Hz, 1H), 8.47 (d, J=8.4 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 7.95 (m, 1H), 7.83 (m, 1H), 7.62 (m, 2H), 6.82 (m, 2H), 2.94 (s, 3H); MS (ESI): 235 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:6](=[O:20])[C:5]2=O.Cl.[NH2:23][NH:24][C:25]([NH2:27])=[O:26]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:6](=[O:20])/[C:5]/2=[N:23]/[NH:24][C:25]([NH2:27])=[O:26]
Reactant: NNC(N)=O
Reactant: CC(C)N(CCN1C(=O)C(=O)c2cc(Cl)ccc21)C(C)C
Agent: Cl
Product: CC(C)N(CCN1C(=O)/C(=N/NC(N)=O)c2cc(Cl)ccc21)C(C)C
Yield: 49.4 %

Procedure:
By using 5-chloro-1-(2-diisopropylaminoethyl)isatin and semicarbazide hydrochloride, a method analogous to that described in Example 4 was carried out to obtain (E)-5-chloro-1-(2-diisopropylaminoethyl)isatin 3-semicarbazone having a melting point of 154°-155° C. (yield: 49.4%, recrystallizing solvent: chloroform-hexane).
Reaction SMILES: C(O)(=O)C.O.[C:6]([CH2:8][N:9]1[C:14]2[CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=[CH:18][C:13]=2[O:12][CH2:11][C:10]1=[O:22])#[N:7]>[Fe].C(O)C>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][CH2:11][C:10](=[O:22])[N:9]([CH2:8][C:6]#[N:7])[C:14]=2[CH:15]=1
Reactant: N#CCN1C(=O)COc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: N#CCN1C(=O)COc2ccc(N)cc21
Temperature: 80 °C
Yield: 74.4 %

Procedure:
A mixture of ethanol (15 ml), acetic acid (1 g), water (25 ml) and iron (3 g) is stirred at 80° C., and 4-cyanomethyl-6-nitro-2H-1,4-benzoxazin-3(4H)-one (2.33 g) is added portionwise thereto. The whole is stirred at 80° C. until gas evolution ceases. The reaction mixture is mixed with active carbon (1 g) and ethanol (20 ml), refluxed for 15 minutes, and filtered. The filtrate is poured into chilled water. The deposited crystals are collected by filtration, and dried to obtain 6-amino-4-cyanomethyl-2H-1,4-benzoxazin-3(4H)-one (1.51 g).
Reaction SMILES: [CH2:1]([NH:7][C:8](=[O:14])[CH:9]=[CH:10][C:11]([OH:13])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([O-])(=O)C.[Na+]>C(OC(=O)C)(=O)C>[CH2:1]([N:7]1[C:8](=[O:14])[CH:9]=[CH:10][C:11]1=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCNC(=O)C=CC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCCCCCN1C(=O)C=CC1=O
Temperature: 110 °C

Procedure:
4-(Hexylamino)-4-oxo-2-butenoic acid (Preparation 54, 75.8 g, 0.38 mol) was partially dissolved in acetic anhydride (1.5 l) and sodium acetate (125.6 g, 0.19 mol) was added in one portion. The reaction mixture was gradually heated to 110° C. for 4 h. Acetic anhydride was removed in vacuo and the title compound was obtained by vacuum distillation of the crude residue to give a colourless oil (49.8 g, 72%) which partially crystallised upon standing.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]2[C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH2:3]1.Cl.[CH3:23][C:24]1([NH2:30])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]2[C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=[C:11]([NH:30][C:24]3([CH3:23])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:10]=2)[CH2:3]1
Reactant: CC1(N)CCOCC1
Reactant: CS(=O)(=O)c1ncc(C(N)=O)c(N[C@@H]2CCC[C@H](O)C2)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC1(Nc2ncc(C(N)=O)c(N[C@@H]3CCC[C@H](O)C3)n2)CCOCC1
Temperature: 180 °C
Yield: 10.7 %

Procedure:
4-((1R,3S)-3-Hydroxycyclohexylamino)-2-(methylsulfonyl)pyrimidine-5-carboxamide (0.740 g, 2.354 mmol; synthesis described herein), 4-methyltetrahydro-2H-pyran-4-amine hydrochloride (0.892 g, 5.88 mmol), DIEA (1.645 mL, 9.42 mmol) and NMP (20 mL) were combined and heated for 1 h at 180° C. in a microwave. The solvent was concentrated under reduced pressure and the residue was purified by column chromatography (0-10% methanol in DCM) to afford 4-((1R,3S)-3-hydroxycyclohexylamino)-2-(4-methyltetrahydro-2H-pyran-4-ylamino)pyrimidine-5-carboxamide (88 mg, 0.252 mmol, 10.70% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.96 (br. s., 1H), 8.35 (s, 1H), 6.76 (br. s., 1H), 4.65 (d, J=4.69 Hz, 1H), 3.56 (dd, J=3.32, 6.83 Hz, 4H), 3.40-3.47 (m, 1H), 2.20-2.29 (m, 2H), 2.10 (d, J=10.93 Hz, 1H), 1.76-1.89 (m, 2H), 1.66-1.73 (m, 1H), 1.50-1.59 (m, 2H), 1.39 (s, 3H), 1.16-1.26 (m, 1H), 1.03-1.12 (m, 3H). MS (ESI) m/z 350.4 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@@H:15]([NH:28][C:29]([C@@H:31]2[CH2:36][CH2:35][CH2:34][N:33]([C:37](=[O:53])[CH2:38][CH2:39][CH:40]3[CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42][CH2:41]3)[CH2:32]2)=[O:30])[CH:16]([C:24]([O:26]C)=[O:25])[C:17]([O:19][C:20](C)(C)C)=[O:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@@H:15]([NH:28][C:29]([C@@H:31]2[CH2:36][CH2:35][CH2:34][N:33]([C:37](=[O:53])[CH2:38][CH2:39][CH:40]3[CH2:41][CH2:42][NH:43][CH2:44][CH2:45]3)[CH2:32]2)=[O:30])[CH:16]([C:17]([O:19][CH3:20])=[O:18])[C:24]([OH:26])=[O:25])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(C(=O)OC(C)(C)C)[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cccc(OCc2ccccc2)c1
Solvent: O=CO
Product: COC(=O)C(C(=O)O)[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCNCC2)C1)c1cccc(OCc2ccccc2)c1
Reaction time: 120 h
Yield: 116215.8 %

Procedure:
Tert-butyl methyl 2-[(S)-[3-(benzyloxy)phenyl]({[(3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidin-3-yl]carbonyl}amino)methyl]propanedioate (700 mg, 0.95 mmol) was solved in formic acid (5.4 mL) and stored for 5 days at room temperature. The mixture was concentrated under reduced pressure to yield 640 g of raw (3S)-3-[3-(benzyloxy)phenyl]-2-(methoxycarbonyl)-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid. The methyl ester in THF (65 mL) and triethylamine (2.5 mL, 18 mmol) was heated to 60° C. for 4 hours. After concentration under reduced pressure the residue was purified by preparative HPLC to yield 147 mg of methyl (3S)-3-[3-(benzyloxy)phenyl]-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoate.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>N1C=CC=CC=1>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(NS(=O)(=O)c2ccccc2)ccc1F
Temperature: 10 °C
Reaction time: 0.33 h

Procedure:
4-fluoro-3-nitro-aniline (7.8 g, 50 mmol) is taken up in 50 mL pyridine and cooled to 10° C. The benzenesulphonic acid chloride (7.0 mL, about 55 mmol) is added dropwise with stirring within about 20 min at 10-20° C. The mixture is stirred for about 0.5 h at ambient temperature and poured onto ice water. After acidifying with conc. hydrochloric acid the mixture is extracted with 150 mL ethyl acetate, washed with water, dried and concentrated by evaporation. The residue is dissolved in diethylether, diluted with petroleum ether and cooled. The crystals formed are filtered off, washed with diethylether/petroleum ether and dried.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:29]([C:30]([CH3:33])([CH3:32])[CH3:31])[N:28]=[C:27]([CH:34]=O)[CH:26]=2)=[CH:21][CH:20]=1>>[C:30]([N:29]1[C:25]([C:22]2[CH:21]=[CH:20][C:19]([Cl:18])=[CH:24][CH:23]=2)=[CH:26][C:27]([CH2:34][NH:17][CH2:16][CH2:15][N:12]2[CH2:13][CH2:14][N:9]([C:3]3[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])[CH2:10][CH2:11]2)=[N:28]1)([CH3:33])([CH3:32])[CH3:31]
Reactant: Cc1ccc(N2CCN(CCN)CC2)c(C)c1
Reactant: CC(C)(C)n1nc(C=O)cc1-c1ccc(Cl)cc1
Product: Cc1ccc(N2CCN(CCNCc3cc(-c4ccc(Cl)cc4)n(C(C)(C)C)n3)CC2)c(C)c1
Yield: 60.3 %

Procedure:
Compound 33 was prepared using the same method as that of Example 1 except that 4-(2,4-dimethylphenyl)piperazin-1-ylethylamine and 5-(4-chlorophenyl)-1-t-butyl pyrazole-3-carbaldehyde were used.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11]([C:13]2([CH2:18][CH:19]([CH2:23][O:24][CH2:25][CH2:26][O:27]C)[C:20]([OH:22])=[O:21])[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH2:6][CH2:5]1)([OH:3])=[O:2].C[Si](I)(C)C>ClCCl>[C:1]([C@@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11]([C:13]2([CH2:18][CH:19]([CH2:23][O:24][CH2:25][CH2:26][OH:27])[C:20]([OH:22])=[O:21])[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH2:6][CH2:5]1)([OH:3])=[O:2]
Reactant: COCCOCC(CC1(C(=O)N[C@H]2CC[C@@H](C(=O)O)CC2)CCCC1)C(=O)O
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: O=C(O)C(COCCO)CC1(C(=O)N[C@H]2CC[C@@H](C(=O)O)CC2)CCCC1
Reaction time: 6 h
Yield: 28.5 %

Procedure:
3-{1-[(cis-4-Carboxy-cyclohexyl)carbamoyl]-cyclopentyl}-2-[2-(methoxy)ethoxymethyl]propanoic acid (0.80 g, 2 mmole) was dissolved in dry dichloromethane (15 ml) and treated with trimethylsilyl iodide (1.4 ml, 10 mmole) at 0° C. under nitrogen. After 6 hours at 0° C., the reaction was poured into ice-cold dilute sodium hydrogen carbonate and washed with dichloromethane. The aqueous phase was acidified with concentrated hydrochloric acid and extracted with ethyl acetate (3×50 ml). The first extract contained starting material, the second and third extracts were combined, washed with dilute sodium thiosulphate, dried (Na2SO4) and evaporated to give an orange oil. The residue was azeotroped with dichloromethane and washed with dichloromethane to give the title compound as a glassy foam (0.22 g, 29%). Found: C,57.24; H,8.07; N,3.42. C19H31NO7. 0.1 CH2Cl2 0.25 H2O requires C,57.58; H,8.02; N,3.52%.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=[CH:11][C:4]=12)[NH2:2].[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH:29]([CH:32]=O)[CH:30]=O.C1(C)C=CC=CC=1>>[CH3:17][Si:16]([CH3:19])([CH3:18])[CH2:15][CH2:14][O:13][CH2:12][N:9]1[C:5]2=[N:6][CH:7]=[CH:8][C:3]([N:1]3[CH:30]=[C:29]([C:21]4[O:20][C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]=4)[CH:32]=[N:2]3)=[C:4]2[CH:11]=[CH:10]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(NN)ccnc21
Reactant: O=CC(C=O)c1nc2ccccc2o1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1ccc2c(-n3cc(-c4nc5ccccc5o4)cn3)ccnc21
Temperature: 70 °C
Yield: 69.5 %

Procedure:
To 4-hydrazino-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (0.083 g, 0.00030 mol) 3782-117-1 and 1,3-benzoxazol-2-ylmalonaldehyde (0.056 g, 0.00030 mol) in toluene (1.5 mL, 0.014 mol) was added molecular sieves. The mixture was heated in a sealed tube at 70° C. (an oil bath) with stilling for 2 h. The solvent was removed in vacuo and the crude product was purified by FCC on silica using ethyl acetate:hexanes 3:7 to give 2-[1-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]-1,3-benzoxazole (0.090 gm) as an oil, LC/MS (M+H)+: 432.
Reaction SMILES: [CH:1]1[C:17]2=[C:18]3[C:8]([C:9]([C:11]4[C:16]2=[CH:15][CH:14]=[CH:13][CH:12]=4)=[O:10])=[CH:7][CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.O.[Cl:20]([O-])(=O)=O.[K+].Cl>C(O)(=O)C>[Cl:20][C:3]1[CH:2]=[CH:1][C:17]2[C:16]3[C:11]([C:9](=[O:10])[C:8]4[C:18]=2[C:4]=1[CH:5]=[CH:6][CH:7]=4)=[CH:12][CH:13]=[CH:14][CH:15]=3
Reactant: O=C1c2ccccc2-c2cccc3cccc1c23
Reactant: [O-][Cl+2]([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2ccccc2-c2ccc(Cl)c3cccc1c23
Reaction time: 2 h

Procedure:
A 10g amount of benzanthrone was dissolved in a solvent mixture of 100g acetic acid and 100 g of water. 6 g of potassium chlorate was added to the solution and the mixture was heated and stirred at 90°-95° C for 2 hours. 12 g of conc. hydrochloric acid was added dropwise to the mixture during 1 hour and 20 minutes. After the addition, the mixture was stirred for 1 hour to complete the reaction. The reaction mixture was cooled, filtered, washed with water and dried. The product was recrystallized from chlorobenzene to obtain 3-chlorobenzanthrone having a melting point of 179°-190° C (orange needle crystals).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11].[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:19][C:18]1[N:17]=[CH:16][C:15]2[C:20]([C:23]3[CH2:24][CH2:25][N:26]([C:36]([NH:35][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:37])[CH2:27][CH:28]=3)=[CH:21][O:22][C:14]=2[C:13]=1[O:12][C@@H:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: O=C=Nc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCN(C(=O)Nc4ccccc4)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 7-[(R)-1-(2,6-Dichloro-3-fluorophenyl)-ethoxy]-3-(1,2,3,6-tetrahydropyridin-4-yl)-furo[3,2-c]pyridin-6-ylamine (10.0 mg, 0.0237 mmol), phenyl isocyanate (0.00519 g, 0.0436 mmol), DIPEA (0.033 mL, 0.19 mmol) in DMF (1 mL) was stirred at rt for 15 min. Purification by HPLC afforded the title compound as a colorless solid. 1H NMR (CD3OD, 400 MHz): δ=1.90 (d, J=6.8 Hz, 3H), 2.58 (br. s., 2H), 3.77 (t, J=5.7 Hz, 2H), 4.25 (d, J=2.5 Hz, 2H), 6.32 (br. s., 1H), 6.52 (d, J=6.8 Hz, 1H), 7.04 (t, J=7.3 Hz, 1H), 7.17-7.32 (m, 3H), 7.34-7.46 (m, 3H) 7.69 (s, 1H), 8.23 (s, 1H). MS (ES+): m/z 541.03/543.05 (100/68) [MH+]. HPLC: tR=3.39 min (ZQ3, polar—5 min).
Reaction SMILES: C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[NH2:13][C@@H:14]1[C:31](=[O:32])[N:16]2[C:17]([C:28]([OH:30])=[O:29])=[C:18]([S:21][C:22]3[N:26]([CH3:27])[N:25]=[N:24][N:23]=3)[CH2:19][S:20][C@H:15]12.[N:33]1([CH2:38][C:39](Cl)=[O:40])[CH:37]=[N:36][N:35]=[N:34]1>C(Cl)Cl>[N:33]1([CH2:38][C:39]([NH:13][C@@H:14]2[C:31](=[O:32])[N:16]3[C:17]([C:28]([OH:30])=[O:29])=[C:18]([S:21][C:22]4[N:26]([CH3:27])[N:25]=[N:24][N:23]=4)[CH2:19][S:20][C@H:15]23)=[O:40])[CH:37]=[N:36][N:35]=[N:34]1
Reactant: Cn1nnnc1SC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(Cl)Cn1cnnn1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: ClCCl
Product: Cn1nnnc1SC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cn3cnnn3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
0.306 ml (1.27 mmols) of bis-trimethylsilylacetamide is added to a suspension of 200 mg (0.63 mmol) of 7β-amino-3-(1-methyl-5-tetrazolylthio)-3-cephem-4-carboxylic acid in 3.2 ml of methylene chloride and the mixture is stirred under nitrogen at room temperature for 40 minutes. The solution is cooled to 0° C., 224 mg (1.52 mmols) of tetrazol-1-ylacetyl chloride are added and the mixture is stirred for 11/2 hours at 0° C. and extracted with aqueous sodium bicarbonate solution. The pH of the aqueous phase is adjusted to 1.5 and this phase is extracted with ethyl acetate. The organic phase is dried over sodium sulphate and evaporated in a rotary evaporator and gives 7β-[2-(tetrazol-1-yl)-acetylamino]-3-(1-methyl-5-tetrazolylthio)-3-cephem-4-carboxylic acid; thin layer chromatogram (silica gel; butanol/acetic acid/water, 75:7.5:21), Rf value 0.17; IR spectrum (nujol); characteristic bands at 3400, 1780, 1720 and 1690 cm-1.