Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.N1C=CC=CC=1.[N+:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[C:28]=1[CH2:36][CH2:37][O:38][C:39](Cl)=[O:40])([O-:26])=[O:25].CC(O)C.N#N>C(Cl)Cl>[N+:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[C:28]=1[CH2:36][CH2:37][O:38][C:39]([O:7][CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2][C@@H:3]1[OH:4])=[O:40])([O-:26])=[O:25]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: O=C(Cl)OCCc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: N#N
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC(C)O
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](COC(=O)OCCc3c([N+](=O)[O-])cccc3[N+](=O)[O-])O2)c(=O)[nH]c1=O
Temperature: -50 °C
Reaction time: 1 h
Yield: 43.1 %

Procedure:
Thymidine (1 g, 4.13 mmol) was co-evaporated with pyridine (3×10 ml, pro analysi quality, additionally dried over molecular sieve 4 Å), dissolved in pyridine (15 ml, see above) and cooled down to -50° C. A solution of 2-(2,6-dinitrophenyl)ethoxycarbonyl chloride (1.7 g, 6.19 mmol) in CH2Cl2 (15 ml, dist. over CaH2) was added dropwise thereto for 1 h. After a further 3.5 h stirring in conditions of i-PrOH/N2 cooling (-50° to -20° C.), the mixture was diluted with CH2Cl2 (50 ml) and washed with H2O (50 ml). The aqueous phases were post-extracted with CH2Cl2 (2×50 ml). The combined organic phases were dried over Na2SO4, filtered, concentrated under reduced pressure and co-evaporated using toluene (3×50 ml). The crude product (2.66 g) was treated with CH2Cl2 /MeOH 2:1 (60 ml) at boiling temperature. The white precipitate obtained was filtered by suction and recrystallized from MeOH (25 ml). 5'-O-(2-(2,6-dinitrophenyl)ethoxycarbonyl)thymidine (855 mg, 43%) was obtained as a colorless solid. The combined filtrates were concentrated under reduced pressure to a dry state and purified by column chromatography (1.4 g crude product, 56 g SiO2 17×3 cm, CH2Cl2 /MeOH 100:5 1240 ml, 100:7 105 ml, 100:10 330 ml). 5'-O-(2-(2,6-dinitrophenyl)ethoxcarbonyl)thymidine (691 mg, 34.8%) was obtained as a colorless solid. The yield of 5'-O-(2-(2,6-dinitrophenyl)ethoxycarbonyl)thymidine totalled 1.55 g (78%)
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[S:18][C:19]([CH3:25])=[C:20]([C:22]([OH:24])=[O:23])[N:21]=4)=[C:13]([NH:26][CH:27]([CH3:29])[CH3:28])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.CN.CN(C(ON1N=N[C:42]2C=CC=N[C:41]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[S:18][C:19]([CH3:25])=[C:20]([C:22]([O:24][CH2:41][CH3:42])=[O:23])[N:21]=4)=[C:13]([NH:26][CH:27]([CH3:29])[CH3:28])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Cc1sc(-c2cnc(Nc3ccc4ncsc4c3)cc2NC(C)C)nc1C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1nc(-c2cnc(Nc3ccc4ncsc4c3)cc2NC(C)C)sc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methylthiazole-4-carboxylic acid (25b) was dissolved in DMF (10 mL), to it methanamine (1 equiv.) was added followed by the addition of HATU (1.5 equiv.) and DIPEA (4 equiv.) and stirred for 3 h at room temperature. The reaction mixture was concentrated to remove DMF under reduced pressure. The crude material obtained was purified by flash column chromatography using silica gel and MeOH: CHCl3 as eluent. The material obtained was triturated with diethyl ether and hexane to afford ethyl 2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methylthiazole-4-carboxylate. 1H NMR: 400 MHz, DMSO-d6: δ 1.32 (d, J=6.40 Hz, 6H), 2.73 (s, 3H), 2.81 (d, J=4.40 Hz, 3H), 3.64-3.69 (m, 1H), 6.13 (s, 1H), 7.58 (dd, J=2.00, 8.80 Hz, 1H), 7.95 (d, J=8.80 Hz, 1H), 8.13 (d, J=4.80 Hz, 1H), 8.20 (d, J=7.20 Hz, 1H), 8.37 (s, 1H), 8.71 (d, J=2.00 Hz, 1H), 9.15 (s, 1H), 9.33 (s, 1H). LC/MS: ZORBAX SB C18, 4.6×50 mm, 5 μm; Solvent A=10% MeOH: 90% H2O: 0.1% TFA; Solvent B=90% MeOH: 10% H2O: 0.1% TFA; gradient 0-100% B over 2 min (3 min run time); retention time: 1.606 min; LCMS (ES-API), m/z 439.0 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 6.323 min; Purity: 96.3%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:16]>CO.O1CCOCC1.O>[ClH:16].[CH3:15][O:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: COC1CCNCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-methoxypiperidine-1-carboxylic acid tert-butyl ester (Preparation 67, 1.58 g, 7.34 mmol) in methanol (20 mL) was added hydrochloric acid in 1,4-dioxane (4M, 10 mL) and the mixture stirred for 3 h at rt. Concentration in vacuo gave an oil which was redissolved in water (100 mL). The aqueous layer was washed with ethyl acetate (2×30 mL) and concentrated to give the title compound as colourless solid. δH (D2O): 1.80, 2.14 (4H, 2m), 3.13 (2H, m), 3.38 (2H, m), 3.40 (3H, s), 3.68 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].Cl>N1C=CC=CC=1.N1CCCCC1>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:12][C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C(O)CC(=O)O
Reactant: N#Cc1ccc(C=O)cc1
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: N#Cc1ccc(C=CC(=O)O)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
0.2mol of p-cyanobenzaldehyde and 0.3mol of malonic acid were dissolved in 80ml of pyridine at room temperature, and 30 drops of piperidine were added thereto. The mixture was heated and stirred for 4 hours at about 100° C. After the reaction, the solution was poured slowly into dilute hydrochloric acid (250ml hydrochloric acid/250g water). Then, the resulting white precipitate was separated by filtering and washed with dilute hydrochloric acid and water, and was recrystallized by use of glacial acetic acid to obtain p-cyanocinnamic acid. 0.3mol of thionyl chloride was added to 0.1mol of the p-cyanocinnamic acid and the mixture was heated and stirred at about 80° C for 3 hours. An excess thionyl chloride was then removed under reduced pressure to obtain p-cyanocinnamic acid chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[CH3:13][O:14][CH2:15]OC.B(F)(F)F.CCOCC.CCCCCC>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:13][O:14][CH3:15])[C:6](=[O:11])[C:5]2=[O:12]
Reactant: COCOC
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Agent: FB(F)F
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COCN1C(=O)C(=O)c2cc(Br)ccc21
Temperature: 40 °C
Yield: 49.8 %

Procedure:
To a 500 mL round-bottomed flask, was added 5-bromoisatin (5.00 g, 22.1 mmol), formaldehyde dimethyl acetal (111 mL, 22.1 mmol), and boron trifluoride diethyl etherate (16.7 mL, 133 mmol). The resulting mixture was heated at 40° C. TLC (1:1 hexane:EtOAc) showed starting material was consumed. The mixture was then diluted with EtOAc (100 mL) and washed with brine/water (60 mL), brine (60 mL) and brine/bicarbonate (60 mL). The organic layer was dried over sodium sulfate and evaporated to provide an orange solid. The solid was taken up in EtOAc (50 mL) with heating, and hexane (10 mL) was added until the mixture became cloudy. A black precipitate formed immediately that should have been removed. The mixture was heated to reflux and allowed to stand at room temperature and then at −20° C. Orange red crystals were filtered washing with hexane and manually separated from the black precipitate to provide the title compound (2.97 g, 49.7% yield) as a red crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.29 (s, 3H), 5.08 (s, 2H), 7.19 (d, J=8.22 Hz, 1H), 7.77 (s, 1H), 7.85 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([O:7][C@@H:8]2[O:25][C@H:24]([CH2:26][O:27]C(=O)C)[C@@H:19]([O:20]C(=O)C)[C@H:14]([O:15]C(=O)C)[C@H:9]2[O:10]C(=O)C)[C:3]=1[CH2:31][C:32]1[S:33][CH:34]=[CH:35][C:36]=1C.[CH3:38][O-].[Na+].[CH2:41](O)[CH3:42]>>[C@@H:8]1([O:7][C:4]2[C:3]([CH2:31][C:32]3[CH:42]=[CH:41][C:34]([S:33][CH3:38])=[CH:35][CH:36]=3)=[C:2]([CH3:1])[NH:6][N:5]=2)[O:25][C@H:24]([CH2:26][OH:27])[C@@H:19]([OH:20])[C@H:14]([OH:15])[C@H:9]1[OH:10]
Reactant: CCO
Reactant: C[O-]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C)c2Cc2sccc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Na+]
Product: CSc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-methyl-4-[(methylthiophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.42 g) in ethanol (5 mL) was added sodium methoxide (28% methanol solution, 0.042 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=5/1) to give 3-(β-D-glucopyranosyloxy)-5-methyl-4-[(4-methylthiophenyl)methyl]-1H-pyrazole (0.23 g).
Reaction SMILES: I(C1C=CC=CC=1C(O)=O)(=O)=O.[NH2:13][C:14]([NH:16][C:17]1[NH:18][C:19]2[C:24]([C:25]=1[C:26]([NH2:28])=[O:27])=[CH:23][CH:22]=[C:21]([CH2:29][OH:30])[CH:20]=2)=[O:15].O>CS(C)=O>[NH2:13][C:14]([NH:16][C:17]1[NH:18][C:19]2[C:24]([C:25]=1[C:26]([NH2:28])=[O:27])=[CH:23][CH:22]=[C:21]([CH:29]=[O:30])[CH:20]=2)=[O:15]
Reactant: NC(=O)Nc1[nH]c2cc(CO)ccc2c1C(N)=O
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)Nc1[nH]c2cc(C=O)ccc2c1C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
2-Iodoxybenzoic acid (1.8 g, 6.4 mmol) was added to a solution of 2-aminocarbonylamino-6-hydroxymethylindole-3-carboxamide (Compound 16-1, 1.4 g, 5.8 mmol) in dimethyl sulfoxide (100 mL), and the mixture was stirred at room temperature for 30 minutes. Water (100 mL) was added to the reaction mixture under ice-cooling, and the precipitated solid was separated by filtration. The resultant solid was washed with 0.25 N sodium hydroxide aqueous solution-(5 mL) and water (5 mL) and dried under reduced pressure to give the title compound (1.1 g) as a brown solid (yield 74%).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:10]=1[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[S:26](Cl)(=[O:28])=[O:27]>N1C=CC=CC=1>[CH2:1]([S:8][C:9]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:10]=1[NH:11][S:26]([C:18]1[O:17][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=1)(=[O:27])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cc(Cl)ccc1SCc1ccccc1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)ccc1SCc1ccccc1)c1cc2ccccc2o1
Yield: 26.6 %

Procedure:
Following General Procedure B, the title compound (235 mg) was prepared from 2-(benzylthio)-5-chloroaniline(509 mg, 2.052 mmol) and benzofuran-2-sulfonyl chloride (443 mg, 2.052 mmol) in pyridine (5 ml).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1.[CH3:28][N:29]([CH3:44])[C:30]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:31]=1[CH:32]=[CH:33][CH:34]=[C:35]2[S:40](Cl)(=[O:42])=[O:41].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][S:40]([C:35]3[C:36]4[C:31](=[C:30]([N:29]([CH3:44])[CH3:28])[CH:39]=[CH:38][CH:37]=4)[CH:32]=[CH:33][CH:34]=3)(=[O:42])=[O:41])=[CH:13][CH:14]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(Nc2ccnc3nc(C)ccc23)c1
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Sc2ccc(OS(=O)(=O)c3cccc4c(N(C)C)cccc34)cc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 19 (167 mg, 0.94 mmol) was reacted with 5-Dimethylamino-naphthalene-1-sulfonyl chloride (245 mg, 0.94 mmol) in 10 mL of CH2Cl2 with N,N-diisopropylethylamine (0.530 mL, 410 mmol) for 22 h. Washed with water and dried over Na2SO4, filtered and concentrated under vacuum giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (35 mg, 40%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.75 (s, 3 H) 2.86 (s, 6 H) 6.65 (d, J=6.99 Hz, 1 H) 6.76 (d, J=9.19 Hz, 2 H) 6.87 (d, 2 H) 7.16 (d, J=8.82 Hz, 1 H) 7.34 (d, J=7.72 Hz, 1 H) 7.53-7.62 (m, 2 H) 7.69-7.79 (m, 3 H) 7.97 (d, J=7.35 Hz, 1 H) 8.22 (d, J=8.82 Hz, 1 H) 8.50 (d, J=6.99 Hz, 1 H) 8.60 (d, J=8.46 Hz, 1 H) 8.82 (d, J=8.82 Hz, 1 H); MS 1 H) 8.50 (d, J=6.99 Hz, 1 H) 8.60 (d, J=8.46 Hz, 1 H) 8.82 (d, J=8.82 Hz, 1 H); MS (DCI NH3+) m/z 611 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:20][C:21]([C:23]2[C:24](=[O:36])[N:25]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:26]([CH3:29])[C:27]=2[CH3:28])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.CS(O[CH2:42][C:43]1([O:46][C:47](=[O:49])[CH3:48])[CH2:45][CH2:44]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[C:47]([O:46][C:43]1([CH2:42][O:19][C:15]2[CH:14]=[C:13]3[C:18]([C:9]([O:8][C:7]4[CH:6]=[CH:5][C:4]([NH:20][C:21]([C:23]5[C:24](=[O:36])[N:25]([C:30]6[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=6)[N:26]([CH3:29])[C:27]=5[CH3:28])=[O:22])=[CH:3][C:2]=4[F:1])=[CH:10][CH:11]=[N:12]3)=[CH:17][CH:16]=2)[CH2:45][CH2:44]1)(=[O:49])[CH3:48]
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(O)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Reactant: CC(=O)OC1(COS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(=O)OC1(COc2ccc3c(Oc4ccc(NC(=O)c5c(C)n(C)n(-c6ccccc6)c5=O)cc4F)ccnc3c2)CC1
Temperature: 40 °C
Reaction time: 24 h
Yield: 26 %

Procedure:
To a mixture of compound N-(3-fluoro-4-(7-hydroxyquinolin-4-yloxy)phenyl)-1,5-di-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (342 mg, 0.708 mmol) and (1-acetoxycyclopropyl)methyl methanesulfonate (1.77 mmol) in 5 mL of DMA was added Cs2CO3 (2.8 g, 8.85 mmol). After stirring at 40° C. for 1 day, the reaction mixture was concentrated in vacuo and the residue was chromatographed on a silica gel column (50:1 (v/v) CH2Cl2/CH3OH) to give the title compound as a white solid (110 mg, 26%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](I)[C:5]([NH2:9])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:17][C:18]([CH3:22])([CH3:21])[C:19]#[CH:20].N#N>C1(C)C=CC=CC=1.O.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>[Cl:1][C:2]1[N:7]=[C:6]([C:20]#[C:19][C:18]([CH3:22])([CH3:21])[CH3:17])[C:5]([NH2:9])=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)C
Reactant: Nc1ccc(Cl)nc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: N#N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)C#Cc1nc(Cl)ccc1N
Temperature: 70 °C
Yield: 87.9 %

Procedure:
To a solution of 6-chloro-2-iodo-pyridin-3-ylamine (16.0 g, 62.7 mmol) in toluene (160 mL) and water (80 mL) were added Et3N (12.7 g, 125 mmol), Pd(PPh3)2Cl2 (2.2 g, 3.1 mmol), CuI (238 mg, 1.3 mmol) and 3,3-dimethyl-but-1-yne (7.7 g, 94 mmol) successively under N2 atmosphere. The reaction mixture was heated at 70° C. for 3 hours and was allowed to cool to room temperature. The resulting mixture was extracted with ethyl acetate (150 mL×3). The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum to give 6-chloro-2-(3,3-dimethyl-but-1-ynyl)-pyridin-3-ylamine (11.5 g, 88%), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>>[C:17]1([NH:16][S:12]([C:3]2[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[Cl:1])(=[O:14])=[O:13])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Nc2ccccc2)c1Cl
Yield: 4.7 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (540 mg, 1.85 mmol), aniline (173 mg, 1.85 mmol) and triethylamine (0.61 mL, 5.55 mmol) were reacted to form the desired product (1 30 mg, 20%). 1NMR (MeOD-d4): δ7.65 (d, 1H), 7.58 (d, 1H), 7.40 (t, 2H), 7.15 (m, 3H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][C:26]([C:25]([F:24])([F:35])[F:36])=[CH:27][CH:28]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 4-trifluoromethylbenzoyl chloride (14 mg) and N,N-diisopropylethylamine (22 l) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[N:5]=[CH:4][NH:3]1.[Br:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Br.C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C>CN(C=O)C>[Br:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][N:3]1[C:2](=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[N:5]=[CH:4]1
Reactant: BrCc1cccc(Br)c1
Reactant: CCOC(=O)c1ccc2nc[nH]c(=O)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCOC(=O)c1ccc2ncn(Cc3cccc(Br)c3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
Into a round-bottom flask was added ethyl 4-oxo-3,4-dihydroquinazoline-6-carboxylate (0.14 g, 0.63 mmol), 3-bromobenzyl bromide (0.24 g, 0.95 mmol), cesium carbonate (0.25 g, 0.76 mmol), acetonitrile (12 mL) and DMF (3 mL). The reaction mixture was stirred at rt for 16 h. The mixture was then concentrated and to the residue was added EtOAc and water. After separation, the aqueous phase was extracted with EtOAc (2×). The combined organic phases were then washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. Flash column chromatography (25% to 50% EtOAc/hexanes) afforded ethyl 3-(3-bromobenzyl)-4-oxo-3,4-dihydroquinazoline-6-carboxylate (0.17 g, 68%) as a white solid. LC-MS: (FA) ES+ 388; 1H NMR (CDCl3, 300 MHz) δ 9.00 (d, J=1.70 Hz, 1H), 8.39 (dd, J=8.5, 1.9 Hz, 1H), 8.26 (s, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.52 (s, 1H), 7.46 (d, J=7.7 Hz, 1H), 7.26 (m, 2H), 5.17 (s, 2H), 4.42 (q, J=7.2 Hz, 2H), 1.42 (t, J=7.0 Hz, 3H).
Reaction SMILES: CN(C)CCN(C)C.C([Li])(CC)C.[CH:14]([C:17]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:18]=1[C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:20])([CH3:16])[CH3:15].[S:32](=[O:34])=[O:33].[NH3:35].Cl>CCOCC.O1CCCC1.O>[NH2:35][S:32]([C:26]1[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=[C:17]([CH:14]([CH3:16])[CH3:15])[C:18]=1[C:19]([N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])=[O:20])(=[O:34])=[O:33]
Reactant: O=S=O
Reactant: N
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1C(C)C
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)C(=O)c1c(C(C)C)cc(OC)cc1S(N)(=O)=O
Temperature: -70 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of N,N,N',N'-tetramethylethylenediamine (300 mL) in anhydrous ether (4 L) was added s-butyllithium (1.3M, 4 L) and the mixture was cooled in -70° C. under nitrogen. A solution of 2-isopropyl-4-methoxy-N,N-diethylbenzamide (454.2 g) in anhydrous ether (300 mL) was added dropwise over 30 minutes. The temperature was maintained at or below -60° C. during the addition. After the addition the mixture was stirred at -70° C. for one hour, allowed to warm to -50° C. for 30 minutes, then cooled back to -70° C. By cannulation tube a solution of sulfur dioxide (200 g) in anhydrous ether (200 mL) precooled to -40° C. was added under positive nitrogen pressure over a 20-minute period. The temperature of the reaction mixture during the addition was maintained below -40° C. A white powdery precipitate of aryllithium sulphinate separated out almost immediately. After the addition the cooling bath was removed and the mixture was stirred at ambient temperature for two hours, then cooled to -5° C. With continued stirring sulfuryl chloride (190 mL) was added dropwise over a 15-minute period while maintaining the temperature below 10° C. After further stirring for 30 minutes at 0°-5° C. a white precipitate was filtered off and washed with anhydrous ether (2 L). Removal of the solvent at atmospheric pressure gave a dark oil, which was dissolved in tetrahydrofuran (1.4 L). The solution was cooled to -10° C. and concentrated aqueous ammonia (28%, 540 mL) was added in portions over 15 minutes. The temperature was kept at 15° C. or below throughout the addition. After stirring for 15 minutes at ambient temperature the tetrahydrofuran and excess ammonia were removed under vacuum to give a dark oil, which was diluted with water (6.0 L) and acidified with hydrochloric acid (3N) to pH 1. The resulting light yellow solid was collected by filtration, washed with water (800 mL), dried at 60° C. under vacuum for 18 hours and recrystallized from ethyl acetate-hexane (800 mL-3 L) to give 2-aminosulfonyl-6-isopropyl-4-methoxy-N,N-diethylbenzamide (429 g, 72% yield, m.r. 122°-125° C.).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:26])[CH:12]([NH:13][C:14](=[O:25])[C:15]([C:17]3[N:18]=[C:19]([NH:22]C=O)[S:20][CH:21]=3)=[O:16])[C@H:4]2[S:3]1.P(Cl)(Cl)([Cl:29])=O.C(OCC)C>CO>[ClH:29].[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:26])[CH:12]([NH:13][C:14](=[O:25])[C:15]([C:17]3[N:18]=[C:19]([NH2:22])[S:20][CH:21]=3)=[O:16])[C@H:4]2[S:3]1
Reactant: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)C(=O)c3csc(NC=O)n3)[C@H]2S1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)C(=O)c3csc(=NC=O)[nH]3)[C@H]2S1
Solvent: CCOCC
Solvent: CO
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)C(=O)c3csc(N)n3)[C@H]2S1
Product: Cl
Reaction time: 0.5 h

Procedure:
To a suspension of 2-methyl-7-[2-(2-formylaminothiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 2-methyl-7-[2-(2-formylimino-2,3-dihydrothiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, (3.0 g.) in methanol (60 ml.) was added dropwise phosphorus oxychloride (2.55 L g.) under ice-cooling and stirring, and the mixture was stirred for 3.5 hours at the same temperature and then for 30 minutes at room temperature. After the reaction, the reaction mixture was poured into diethyl ether (400 ml.). The precipitates were collected by filtration, washed with diethyl ether and then dried to give 2-methyl-7-[2-(2-aminothiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid hydrochloride, which can be represented as 2-methyl-7-[2-(2-imino-2,3-dihydrothiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid hydrochloride (2.2 g.), mp >270° C.